User login
Atezolizumab bests chemo in NSCLC patients with high PD-L1 expression
NATIONAL HARBOR, MD – interim results of a phase 3 trial suggest.
When compared with platinum-based chemotherapy, atezolizumab significantly improved OS in patients who had PD-L1 expression of 50% or greater on tumor cells (TC) or 10% or greater on tumor-infiltrating immune cells (IC).
Patients with lower levels of PD-L1 expression had a numerical, but not statistically significant, benefit in OS with atezolizumab.
Giuseppe Giaccone, MD, PhD, of Georgetown University, Washington, presented these results, from the IMpower110 trial, as a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer.
The trial enrolled treatment-naive, PD-L1–selected patients with stage IV NSCLC. Patients with EGFR-positive or ALK-positive NSCLC were excluded.
The overall population consisted of 554 patients with PD-L1 expression of at least 1% on TC or IC (TC1/2/3 or IC1/2/3). There were 328 patients with PD-L1 expression of at least 5% on TC or IC (TC2/3 or IC2/3) and 205 patients with PD-L1 expression of at least 50% on TC or 10% on IC (TC3 or IC3).
All patients were randomized to receive atezolizumab or platinum-based chemotherapy. Atezolizumab was given at 1,200 mg every 3 weeks until disease progression or loss of clinical benefit. In the chemotherapy arm, patients with nonsquamous NSCLC received cisplatin or carboplatin plus pemetrexed, and patients with squamous NSCLC received cisplatin or carboplatin plus gemcitabine. Chemotherapy was given for 4-6 cycles, after which patients received pemetrexed (nonsquamous) or best supportive care (squamous) until progression.
Baseline characteristics were similar between the treatment arms and across the PD-L1 subgroups.
Overall survival
OS was evaluated hierarchically, starting with the TC3 or IC3 population. This group had a significant improvement in OS with atezolizumab. At a median follow-up of 15.7 months, the median OS was 13.1 months with chemotherapy and 20.2 months with atezolizumab (hazard ratio, 0.59; P = .0106).
The TC2/3 or IC2/3 population had a numerical, but not significant, improvement in OS with atezolizumab. At a median follow-up of 15.2 months, the median OS was 14.9 months with chemotherapy and 18.2 months with atezolizumab (HR, 0.72; P = .0416).
“The prespecified alpha boundary was not crossed in this analysis,” Dr. Giaccone said. “Therefore, it cannot be considered statistically significant, although, numerically, there is clearly an advantage with atezolizumab versus chemotherapy.”
There was no significant improvement in OS in the overall population (TC1/2/3 or IC1/2/3). At a median follow-up of 13.4 months, the median OS was 14.1 months in the chemotherapy arm and 17.5 months in the atezolizumab arm (HR, 0.83; P = .1481).
Dr. Giaccone noted that 29.6% of patients in the atezolizumab arm and 49.5% of those in the chemotherapy arm received at least one subsequent cancer therapy. The proportion of patients that received second-line cancer therapies was similar across the PD-L1 subgroups.
Progression-free survival
Progression-free survival (PFS) was significantly better with atezolizumab, regardless of PD-L1 expression.
In the TC3/IC3 population, the median PFS was 5.0 months with chemotherapy and 8.1 months with atezolizumab (HR, 0.63; P = .0070). In the TC2/3 or IC2/3 group, the median PFS was 5.5 months with chemotherapy and 7.2 months with atezolizumab (HR, 0.67; P = .0030). In the overall population, the median PFS was 5.5 months with chemotherapy and 5.7 months with atezolizumab (HR, 0.77; P = .0104).
Safety
“The safety profile of atezolizumab was consistent with prior observations,” Dr. Giaccone said.
The incidence of treatment-related adverse events (AEs) was 90.2% in the atezolizumab arm and 94.7% in the chemotherapy arm. Rates of grade 3/4 related AEs were 12.9% and 44.1%, respectively. There was one grade 5 AE in the chemotherapy arm and none in the atezolizumab arm.
AEs that were more frequent with atezolizumab included increased aspartate aminotransferase, pruritus, and hypothyroidism.
This trial is sponsored by Hoffmann-La Roche, and Dr. Giaccone disclosed grants and nonfinancial support from the company.
SOURCE: Giaccone G et al. SITC 2019, Abstract O81.
NATIONAL HARBOR, MD – interim results of a phase 3 trial suggest.
When compared with platinum-based chemotherapy, atezolizumab significantly improved OS in patients who had PD-L1 expression of 50% or greater on tumor cells (TC) or 10% or greater on tumor-infiltrating immune cells (IC).
Patients with lower levels of PD-L1 expression had a numerical, but not statistically significant, benefit in OS with atezolizumab.
Giuseppe Giaccone, MD, PhD, of Georgetown University, Washington, presented these results, from the IMpower110 trial, as a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer.
The trial enrolled treatment-naive, PD-L1–selected patients with stage IV NSCLC. Patients with EGFR-positive or ALK-positive NSCLC were excluded.
The overall population consisted of 554 patients with PD-L1 expression of at least 1% on TC or IC (TC1/2/3 or IC1/2/3). There were 328 patients with PD-L1 expression of at least 5% on TC or IC (TC2/3 or IC2/3) and 205 patients with PD-L1 expression of at least 50% on TC or 10% on IC (TC3 or IC3).
All patients were randomized to receive atezolizumab or platinum-based chemotherapy. Atezolizumab was given at 1,200 mg every 3 weeks until disease progression or loss of clinical benefit. In the chemotherapy arm, patients with nonsquamous NSCLC received cisplatin or carboplatin plus pemetrexed, and patients with squamous NSCLC received cisplatin or carboplatin plus gemcitabine. Chemotherapy was given for 4-6 cycles, after which patients received pemetrexed (nonsquamous) or best supportive care (squamous) until progression.
Baseline characteristics were similar between the treatment arms and across the PD-L1 subgroups.
Overall survival
OS was evaluated hierarchically, starting with the TC3 or IC3 population. This group had a significant improvement in OS with atezolizumab. At a median follow-up of 15.7 months, the median OS was 13.1 months with chemotherapy and 20.2 months with atezolizumab (hazard ratio, 0.59; P = .0106).
The TC2/3 or IC2/3 population had a numerical, but not significant, improvement in OS with atezolizumab. At a median follow-up of 15.2 months, the median OS was 14.9 months with chemotherapy and 18.2 months with atezolizumab (HR, 0.72; P = .0416).
“The prespecified alpha boundary was not crossed in this analysis,” Dr. Giaccone said. “Therefore, it cannot be considered statistically significant, although, numerically, there is clearly an advantage with atezolizumab versus chemotherapy.”
There was no significant improvement in OS in the overall population (TC1/2/3 or IC1/2/3). At a median follow-up of 13.4 months, the median OS was 14.1 months in the chemotherapy arm and 17.5 months in the atezolizumab arm (HR, 0.83; P = .1481).
Dr. Giaccone noted that 29.6% of patients in the atezolizumab arm and 49.5% of those in the chemotherapy arm received at least one subsequent cancer therapy. The proportion of patients that received second-line cancer therapies was similar across the PD-L1 subgroups.
Progression-free survival
Progression-free survival (PFS) was significantly better with atezolizumab, regardless of PD-L1 expression.
In the TC3/IC3 population, the median PFS was 5.0 months with chemotherapy and 8.1 months with atezolizumab (HR, 0.63; P = .0070). In the TC2/3 or IC2/3 group, the median PFS was 5.5 months with chemotherapy and 7.2 months with atezolizumab (HR, 0.67; P = .0030). In the overall population, the median PFS was 5.5 months with chemotherapy and 5.7 months with atezolizumab (HR, 0.77; P = .0104).
Safety
“The safety profile of atezolizumab was consistent with prior observations,” Dr. Giaccone said.
The incidence of treatment-related adverse events (AEs) was 90.2% in the atezolizumab arm and 94.7% in the chemotherapy arm. Rates of grade 3/4 related AEs were 12.9% and 44.1%, respectively. There was one grade 5 AE in the chemotherapy arm and none in the atezolizumab arm.
AEs that were more frequent with atezolizumab included increased aspartate aminotransferase, pruritus, and hypothyroidism.
This trial is sponsored by Hoffmann-La Roche, and Dr. Giaccone disclosed grants and nonfinancial support from the company.
SOURCE: Giaccone G et al. SITC 2019, Abstract O81.
NATIONAL HARBOR, MD – interim results of a phase 3 trial suggest.
When compared with platinum-based chemotherapy, atezolizumab significantly improved OS in patients who had PD-L1 expression of 50% or greater on tumor cells (TC) or 10% or greater on tumor-infiltrating immune cells (IC).
Patients with lower levels of PD-L1 expression had a numerical, but not statistically significant, benefit in OS with atezolizumab.
Giuseppe Giaccone, MD, PhD, of Georgetown University, Washington, presented these results, from the IMpower110 trial, as a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer.
The trial enrolled treatment-naive, PD-L1–selected patients with stage IV NSCLC. Patients with EGFR-positive or ALK-positive NSCLC were excluded.
The overall population consisted of 554 patients with PD-L1 expression of at least 1% on TC or IC (TC1/2/3 or IC1/2/3). There were 328 patients with PD-L1 expression of at least 5% on TC or IC (TC2/3 or IC2/3) and 205 patients with PD-L1 expression of at least 50% on TC or 10% on IC (TC3 or IC3).
All patients were randomized to receive atezolizumab or platinum-based chemotherapy. Atezolizumab was given at 1,200 mg every 3 weeks until disease progression or loss of clinical benefit. In the chemotherapy arm, patients with nonsquamous NSCLC received cisplatin or carboplatin plus pemetrexed, and patients with squamous NSCLC received cisplatin or carboplatin plus gemcitabine. Chemotherapy was given for 4-6 cycles, after which patients received pemetrexed (nonsquamous) or best supportive care (squamous) until progression.
Baseline characteristics were similar between the treatment arms and across the PD-L1 subgroups.
Overall survival
OS was evaluated hierarchically, starting with the TC3 or IC3 population. This group had a significant improvement in OS with atezolizumab. At a median follow-up of 15.7 months, the median OS was 13.1 months with chemotherapy and 20.2 months with atezolizumab (hazard ratio, 0.59; P = .0106).
The TC2/3 or IC2/3 population had a numerical, but not significant, improvement in OS with atezolizumab. At a median follow-up of 15.2 months, the median OS was 14.9 months with chemotherapy and 18.2 months with atezolizumab (HR, 0.72; P = .0416).
“The prespecified alpha boundary was not crossed in this analysis,” Dr. Giaccone said. “Therefore, it cannot be considered statistically significant, although, numerically, there is clearly an advantage with atezolizumab versus chemotherapy.”
There was no significant improvement in OS in the overall population (TC1/2/3 or IC1/2/3). At a median follow-up of 13.4 months, the median OS was 14.1 months in the chemotherapy arm and 17.5 months in the atezolizumab arm (HR, 0.83; P = .1481).
Dr. Giaccone noted that 29.6% of patients in the atezolizumab arm and 49.5% of those in the chemotherapy arm received at least one subsequent cancer therapy. The proportion of patients that received second-line cancer therapies was similar across the PD-L1 subgroups.
Progression-free survival
Progression-free survival (PFS) was significantly better with atezolizumab, regardless of PD-L1 expression.
In the TC3/IC3 population, the median PFS was 5.0 months with chemotherapy and 8.1 months with atezolizumab (HR, 0.63; P = .0070). In the TC2/3 or IC2/3 group, the median PFS was 5.5 months with chemotherapy and 7.2 months with atezolizumab (HR, 0.67; P = .0030). In the overall population, the median PFS was 5.5 months with chemotherapy and 5.7 months with atezolizumab (HR, 0.77; P = .0104).
Safety
“The safety profile of atezolizumab was consistent with prior observations,” Dr. Giaccone said.
The incidence of treatment-related adverse events (AEs) was 90.2% in the atezolizumab arm and 94.7% in the chemotherapy arm. Rates of grade 3/4 related AEs were 12.9% and 44.1%, respectively. There was one grade 5 AE in the chemotherapy arm and none in the atezolizumab arm.
AEs that were more frequent with atezolizumab included increased aspartate aminotransferase, pruritus, and hypothyroidism.
This trial is sponsored by Hoffmann-La Roche, and Dr. Giaccone disclosed grants and nonfinancial support from the company.
SOURCE: Giaccone G et al. SITC 2019, Abstract O81.
REPORTING FROM SITC 2019
Levothyroxine dose for checkpoint inhibitor toxicity may be too high
CHICAGO – both for patients with preexisting and de novo hypothyroidism.
The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.
Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.
Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.
The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.
The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.
However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.
To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.
The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.
At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.
For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.
The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.
For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).
Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.
For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.
However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.
Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.
The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.
Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.
Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.
CHICAGO – both for patients with preexisting and de novo hypothyroidism.
The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.
Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.
Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.
The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.
The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.
However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.
To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.
The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.
At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.
For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.
The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.
For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).
Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.
For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.
However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.
Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.
The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.
Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.
Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.
CHICAGO – both for patients with preexisting and de novo hypothyroidism.
The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.
Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.
Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.
The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.
The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.
However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.
To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.
The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.
At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.
For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.
The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.
For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).
Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.
For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.
However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.
Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.
The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.
Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.
Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.
REPORTING FROM ATA 2019
Behind the scenes of a radical new cancer cure
An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just “come in and talk to one of the doctors,” she remembers the voice saying.
Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzer’s cancer had grown, and fast — first during one type of chemotherapy, then through a second. Out of standard options, Birzer’s local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy — or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzer’s death was all but certain. She signed the consent form.
Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer “alumni” smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: “I need you to tell me whether she’s alive or dead.”
Birzer wasn’t dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldn’t be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).
Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzer’s own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.
This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer — the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should — and shouldn’t — change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.
CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasn’t a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isn’t even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasn’t a question of whether my hospital would be involved, but how we could stay ahead. We weren’t alone.
Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.
The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDA’s concerns. Of the 10 or so patients I’ve treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.
Johnson and Birzer, who I didn’t treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing “I don’t know.” Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.
Cancer, by definition, means something has gone very wrong within — a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. That’s how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer), radiation (using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. It’s rare to have that one magic bullet.
Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesn’t belong either. But since cancer cells come from normal ones, they’ve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune system’s upper hand. As I once watched a fellow oncologist describe it to a patient: “I’m not treating you. You are treating you.”
What if we could go one step further? What if we could genetically engineer a patient’s own immune cells to spot and fight cancer, as a sort of “best hits” of genetic therapy and immunotherapy?
Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a person’s T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first — giving the technology its name — is a CAR, which sits on the T-cell’s surface and binds to a protein on the tumor cell’s surface, like a lock and key. The second serves as the T-cell’s caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number — a typical “dose” ranges from hundreds of thousands to hundreds of millions — they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.
Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical company’s headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.
I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.
“That’s it?” my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.
Once the cells are in, they can’t turn off. That this may cause collateral damage was evident from the start. In 2009 — working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland — oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undark’s interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission — but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.
With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.
The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia — B-cell acute lymphoblastic leukemia — that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.
In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses “remarkable” and “potentially paradigm changing.” When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. “A remarkable thing happened” was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.
That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. “Look,” she nudged me. “Do you see all these ‘non-member’ badges?” I turned. Members were doctors like us who treated blood cancers. I couldn’t imagine who else would want to be here. “Who are they?” I asked. “Investors,” she said. It felt obvious the moment she said it.
For patients, the dreaded “c” word is cancer. For oncologists, it’s cure. When patients ask, I’ve noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain it’s gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so I’ve learned, finding inspiration in slow, incremental change.
This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.
The dreaded word was being tossed around — could this be the cure we’ve always wanted?
When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.
It was May 2018 when I rotated through my hospital’s unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients’ immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldn’t maintain my patients’ blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.
We now have a name for this effect — cytokine release syndrome — that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.
Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.
Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patient’s immune system would be the opposite of what you’d want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didn’t know. Whenever a CAR-T patient spiked a fever, I struggled with the question — is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.
The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer spoke gibberish or had violent seizures. Some couldn’t interact at all, unable to follow simple commands like “squeeze my fingers.” How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.
Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.
In turn, I relied heavily on a laminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors’ workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.
I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a café and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldn’t have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? “They were calling us,” she said.
Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. “These become standard languages that apply to all studies,” she said, listing benchmarks like a patient’s age, kidney function, and platelet count. “But we have no idea whether criteria for chemotherapy would apply to cellular therapy.”
Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease — without strict trial criteria, anyone is fair game.
When I was making rounds at my hospital, I never wandered too far from these patients’ rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?
CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzer’s first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didn’t know, but the lead doctor’s instinct was that it was a good sign.
Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.
Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. “She started saying things that were crazy,” Johnson explained.
One of Birzer's sentences was “guinea pigs eat greens like hay and pizza.” Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: “They don’t eat pizza.” And Birzer replied, “They do eat pizza, but only gluten-free.”
Johnson remembers being struck by the certainty in her partner’s delirium. Not only was Birzer confused, she was confident she was not. “She was doubling down on everything,” Johnson described. “She was absolutely sure she was right.”
Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating — and fast. Her speech became more and more garbled. Soon she couldn’t name simple objects and didn’t know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasn’t bleeding into her brain.
Fortunately, she wasn’t. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzer’s nurse was about to step out of the room when she noticed Birzer’s arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.
Birzer’s saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Children’s Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. “Where are the papers?” she remembered thinking. “There was nothing.”
Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.
What does this mean? Gust interprets it as a patient’s symptoms having more to do with cytokines than the CAR-T cells. “Cytokine release syndrome is the number one risk factor” for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. “In the beginning we didn’t manage as aggressively. We were worried about impairing the function of the CAR-T,” she added. “Now we give steroids right away.”
But the steroids don’t always work. Several doses of steroids didn’t prevent Birzer from seizing. The morning after Johnson’s alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partner’s bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.
Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldn’t find the words despite the nurses and Johnson’s encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.
She took cues from the adults around her on whether her actions were appropriate. The best example of this was her “I love you” phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: “I love you!” And the person emptying the trash: “I love you!” Months later, she was having lunch with a friend who asked, “Do you remember when you told me you loved me?” Birzer said, “Well, I stand by that one.”
When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didn’t exist. She couldn’t hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. “Then peas would fly in my face,” Johnson said.
Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.
As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients I’ve treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldn’t speak for a week – she would look around her ICU room and move her mouth as though trying her hardest — and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often can’t predict how a patient will do. Our instincts can be just plain wrong.
I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors — higher burdens of cancer, baseline cognitive problems before therapy — “the individual patient tells you nothing,” she confirmed.
So we wait.
Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?
So, who gets CAR-T? That leads to the tougher question — who doesn’t? That depends on the type of cancer and whether their insurance can pay.
CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just weren’t happening in solid tumors.
Cancer is one word, but it’s not one disease. “It’s easier to prove why something works when it works than show why it doesn’t work when it doesn’t work,” said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasn’t worked in solid cancers involves what Gill believes are two main barriers. First, it’s a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, they’re faced with a hostile environment and will likely die before they can work.
At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells don’t. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.
Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years’ worth of data and the outlook isn’t as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?
The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and we’re finding that’s exactly what’s happening. Through blood testing, we see that many patients who relapse lose the target.
Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. It’s an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint what’s after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.
Then there’s the other dreaded “c” word: Cost. Novartis’ Kymriah runs up to $475,000 while Kite Pharma’s Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.
They are daunting numbers. Some limitations on health care we accept — maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.
Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didn’t work after one month, the company said it wouldn’t send a bill.
Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. It’s not “a major issue,” he told me over the phone. “Look, of course — [with] health care in this country, if you don’t have insurance, then you’re screwed. That is no different when it comes to CAR-T as it is for anything else,” he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise — months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. “Any discussion of cost is completely irresponsible without weighing the other side of the equation,” Gill said.
How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry it’s a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.
This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T — besides the efficacy — is its ease. It’s a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and you’re done.
Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. “It wasn’t an issue,” said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didn’t pay a cent.
One year after Birzer’s infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But she’s mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: “My jokes about cancer didn’t kill.”
People handed a devastating diagnosis don’t spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.
Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.
I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages don’t say anything about an individual experience, they’re also all patients have to go on. When someone on the same treatment dies, it’s shattering for everyone. Was one person the exception, or a harbinger another’s fate? Who is the outlier?
I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, it’s only 40 percent. What’s the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: “I think CAR-T cells are like chemotherapy in the 1950s. They’re not better than chemotherapy — they’re just different.” For an adversary as tough as cancer, we’ll take any tool we can get.
There remain many questions. Can we use CAR-T earlier in a cancer’s course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.
For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldn’t return to normal. She didn’t even pause. “If you’re not dead,” she said, “you’re winning.”
Ilana Yurkiewicz, M.D., is a physician at Stanford University and a medical journalist. She is a former Scientific American Blog Network columnist and AAAS Mass Media Fellow. Her writing has also appeared in Aeon Magazine, Health Affairs, and STAT News, and has been featured in "The Best American Science and Nature Writing."
This article was originally published on Undark. Read the original article.
An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just “come in and talk to one of the doctors,” she remembers the voice saying.
Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzer’s cancer had grown, and fast — first during one type of chemotherapy, then through a second. Out of standard options, Birzer’s local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy — or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzer’s death was all but certain. She signed the consent form.
Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer “alumni” smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: “I need you to tell me whether she’s alive or dead.”
Birzer wasn’t dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldn’t be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).
Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzer’s own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.
This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer — the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should — and shouldn’t — change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.
CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasn’t a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isn’t even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasn’t a question of whether my hospital would be involved, but how we could stay ahead. We weren’t alone.
Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.
The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDA’s concerns. Of the 10 or so patients I’ve treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.
Johnson and Birzer, who I didn’t treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing “I don’t know.” Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.
Cancer, by definition, means something has gone very wrong within — a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. That’s how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer), radiation (using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. It’s rare to have that one magic bullet.
Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesn’t belong either. But since cancer cells come from normal ones, they’ve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune system’s upper hand. As I once watched a fellow oncologist describe it to a patient: “I’m not treating you. You are treating you.”
What if we could go one step further? What if we could genetically engineer a patient’s own immune cells to spot and fight cancer, as a sort of “best hits” of genetic therapy and immunotherapy?
Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a person’s T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first — giving the technology its name — is a CAR, which sits on the T-cell’s surface and binds to a protein on the tumor cell’s surface, like a lock and key. The second serves as the T-cell’s caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number — a typical “dose” ranges from hundreds of thousands to hundreds of millions — they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.
Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical company’s headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.
I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.
“That’s it?” my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.
Once the cells are in, they can’t turn off. That this may cause collateral damage was evident from the start. In 2009 — working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland — oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undark’s interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission — but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.
With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.
The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia — B-cell acute lymphoblastic leukemia — that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.
In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses “remarkable” and “potentially paradigm changing.” When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. “A remarkable thing happened” was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.
That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. “Look,” she nudged me. “Do you see all these ‘non-member’ badges?” I turned. Members were doctors like us who treated blood cancers. I couldn’t imagine who else would want to be here. “Who are they?” I asked. “Investors,” she said. It felt obvious the moment she said it.
For patients, the dreaded “c” word is cancer. For oncologists, it’s cure. When patients ask, I’ve noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain it’s gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so I’ve learned, finding inspiration in slow, incremental change.
This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.
The dreaded word was being tossed around — could this be the cure we’ve always wanted?
When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.
It was May 2018 when I rotated through my hospital’s unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients’ immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldn’t maintain my patients’ blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.
We now have a name for this effect — cytokine release syndrome — that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.
Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.
Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patient’s immune system would be the opposite of what you’d want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didn’t know. Whenever a CAR-T patient spiked a fever, I struggled with the question — is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.
The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer spoke gibberish or had violent seizures. Some couldn’t interact at all, unable to follow simple commands like “squeeze my fingers.” How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.
Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.
In turn, I relied heavily on a laminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors’ workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.
I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a café and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldn’t have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? “They were calling us,” she said.
Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. “These become standard languages that apply to all studies,” she said, listing benchmarks like a patient’s age, kidney function, and platelet count. “But we have no idea whether criteria for chemotherapy would apply to cellular therapy.”
Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease — without strict trial criteria, anyone is fair game.
When I was making rounds at my hospital, I never wandered too far from these patients’ rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?
CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzer’s first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didn’t know, but the lead doctor’s instinct was that it was a good sign.
Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.
Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. “She started saying things that were crazy,” Johnson explained.
One of Birzer's sentences was “guinea pigs eat greens like hay and pizza.” Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: “They don’t eat pizza.” And Birzer replied, “They do eat pizza, but only gluten-free.”
Johnson remembers being struck by the certainty in her partner’s delirium. Not only was Birzer confused, she was confident she was not. “She was doubling down on everything,” Johnson described. “She was absolutely sure she was right.”
Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating — and fast. Her speech became more and more garbled. Soon she couldn’t name simple objects and didn’t know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasn’t bleeding into her brain.
Fortunately, she wasn’t. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzer’s nurse was about to step out of the room when she noticed Birzer’s arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.
Birzer’s saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Children’s Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. “Where are the papers?” she remembered thinking. “There was nothing.”
Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.
What does this mean? Gust interprets it as a patient’s symptoms having more to do with cytokines than the CAR-T cells. “Cytokine release syndrome is the number one risk factor” for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. “In the beginning we didn’t manage as aggressively. We were worried about impairing the function of the CAR-T,” she added. “Now we give steroids right away.”
But the steroids don’t always work. Several doses of steroids didn’t prevent Birzer from seizing. The morning after Johnson’s alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partner’s bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.
Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldn’t find the words despite the nurses and Johnson’s encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.
She took cues from the adults around her on whether her actions were appropriate. The best example of this was her “I love you” phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: “I love you!” And the person emptying the trash: “I love you!” Months later, she was having lunch with a friend who asked, “Do you remember when you told me you loved me?” Birzer said, “Well, I stand by that one.”
When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didn’t exist. She couldn’t hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. “Then peas would fly in my face,” Johnson said.
Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.
As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients I’ve treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldn’t speak for a week – she would look around her ICU room and move her mouth as though trying her hardest — and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often can’t predict how a patient will do. Our instincts can be just plain wrong.
I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors — higher burdens of cancer, baseline cognitive problems before therapy — “the individual patient tells you nothing,” she confirmed.
So we wait.
Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?
So, who gets CAR-T? That leads to the tougher question — who doesn’t? That depends on the type of cancer and whether their insurance can pay.
CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just weren’t happening in solid tumors.
Cancer is one word, but it’s not one disease. “It’s easier to prove why something works when it works than show why it doesn’t work when it doesn’t work,” said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasn’t worked in solid cancers involves what Gill believes are two main barriers. First, it’s a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, they’re faced with a hostile environment and will likely die before they can work.
At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells don’t. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.
Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years’ worth of data and the outlook isn’t as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?
The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and we’re finding that’s exactly what’s happening. Through blood testing, we see that many patients who relapse lose the target.
Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. It’s an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint what’s after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.
Then there’s the other dreaded “c” word: Cost. Novartis’ Kymriah runs up to $475,000 while Kite Pharma’s Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.
They are daunting numbers. Some limitations on health care we accept — maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.
Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didn’t work after one month, the company said it wouldn’t send a bill.
Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. It’s not “a major issue,” he told me over the phone. “Look, of course — [with] health care in this country, if you don’t have insurance, then you’re screwed. That is no different when it comes to CAR-T as it is for anything else,” he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise — months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. “Any discussion of cost is completely irresponsible without weighing the other side of the equation,” Gill said.
How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry it’s a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.
This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T — besides the efficacy — is its ease. It’s a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and you’re done.
Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. “It wasn’t an issue,” said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didn’t pay a cent.
One year after Birzer’s infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But she’s mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: “My jokes about cancer didn’t kill.”
People handed a devastating diagnosis don’t spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.
Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.
I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages don’t say anything about an individual experience, they’re also all patients have to go on. When someone on the same treatment dies, it’s shattering for everyone. Was one person the exception, or a harbinger another’s fate? Who is the outlier?
I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, it’s only 40 percent. What’s the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: “I think CAR-T cells are like chemotherapy in the 1950s. They’re not better than chemotherapy — they’re just different.” For an adversary as tough as cancer, we’ll take any tool we can get.
There remain many questions. Can we use CAR-T earlier in a cancer’s course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.
For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldn’t return to normal. She didn’t even pause. “If you’re not dead,” she said, “you’re winning.”
Ilana Yurkiewicz, M.D., is a physician at Stanford University and a medical journalist. She is a former Scientific American Blog Network columnist and AAAS Mass Media Fellow. Her writing has also appeared in Aeon Magazine, Health Affairs, and STAT News, and has been featured in "The Best American Science and Nature Writing."
This article was originally published on Undark. Read the original article.
An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just “come in and talk to one of the doctors,” she remembers the voice saying.
Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzer’s cancer had grown, and fast — first during one type of chemotherapy, then through a second. Out of standard options, Birzer’s local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy — or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzer’s death was all but certain. She signed the consent form.
Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer “alumni” smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: “I need you to tell me whether she’s alive or dead.”
Birzer wasn’t dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldn’t be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).
Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzer’s own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.
This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer — the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should — and shouldn’t — change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.
CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasn’t a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isn’t even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasn’t a question of whether my hospital would be involved, but how we could stay ahead. We weren’t alone.
Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.
The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDA’s concerns. Of the 10 or so patients I’ve treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.
Johnson and Birzer, who I didn’t treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing “I don’t know.” Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.
Cancer, by definition, means something has gone very wrong within — a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. That’s how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer), radiation (using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. It’s rare to have that one magic bullet.
Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesn’t belong either. But since cancer cells come from normal ones, they’ve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune system’s upper hand. As I once watched a fellow oncologist describe it to a patient: “I’m not treating you. You are treating you.”
What if we could go one step further? What if we could genetically engineer a patient’s own immune cells to spot and fight cancer, as a sort of “best hits” of genetic therapy and immunotherapy?
Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a person’s T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first — giving the technology its name — is a CAR, which sits on the T-cell’s surface and binds to a protein on the tumor cell’s surface, like a lock and key. The second serves as the T-cell’s caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number — a typical “dose” ranges from hundreds of thousands to hundreds of millions — they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.
Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical company’s headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.
I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.
“That’s it?” my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.
Once the cells are in, they can’t turn off. That this may cause collateral damage was evident from the start. In 2009 — working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland — oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undark’s interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission — but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.
With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.
The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia — B-cell acute lymphoblastic leukemia — that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.
In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses “remarkable” and “potentially paradigm changing.” When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. “A remarkable thing happened” was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.
That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. “Look,” she nudged me. “Do you see all these ‘non-member’ badges?” I turned. Members were doctors like us who treated blood cancers. I couldn’t imagine who else would want to be here. “Who are they?” I asked. “Investors,” she said. It felt obvious the moment she said it.
For patients, the dreaded “c” word is cancer. For oncologists, it’s cure. When patients ask, I’ve noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain it’s gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so I’ve learned, finding inspiration in slow, incremental change.
This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.
The dreaded word was being tossed around — could this be the cure we’ve always wanted?
When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.
It was May 2018 when I rotated through my hospital’s unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients’ immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldn’t maintain my patients’ blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.
We now have a name for this effect — cytokine release syndrome — that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.
Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.
Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patient’s immune system would be the opposite of what you’d want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didn’t know. Whenever a CAR-T patient spiked a fever, I struggled with the question — is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.
The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer spoke gibberish or had violent seizures. Some couldn’t interact at all, unable to follow simple commands like “squeeze my fingers.” How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.
Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.
In turn, I relied heavily on a laminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors’ workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.
I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a café and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldn’t have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? “They were calling us,” she said.
Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. “These become standard languages that apply to all studies,” she said, listing benchmarks like a patient’s age, kidney function, and platelet count. “But we have no idea whether criteria for chemotherapy would apply to cellular therapy.”
Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease — without strict trial criteria, anyone is fair game.
When I was making rounds at my hospital, I never wandered too far from these patients’ rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?
CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzer’s first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didn’t know, but the lead doctor’s instinct was that it was a good sign.
Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.
Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. “She started saying things that were crazy,” Johnson explained.
One of Birzer's sentences was “guinea pigs eat greens like hay and pizza.” Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: “They don’t eat pizza.” And Birzer replied, “They do eat pizza, but only gluten-free.”
Johnson remembers being struck by the certainty in her partner’s delirium. Not only was Birzer confused, she was confident she was not. “She was doubling down on everything,” Johnson described. “She was absolutely sure she was right.”
Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating — and fast. Her speech became more and more garbled. Soon she couldn’t name simple objects and didn’t know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasn’t bleeding into her brain.
Fortunately, she wasn’t. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzer’s nurse was about to step out of the room when she noticed Birzer’s arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.
Birzer’s saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Children’s Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. “Where are the papers?” she remembered thinking. “There was nothing.”
Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.
What does this mean? Gust interprets it as a patient’s symptoms having more to do with cytokines than the CAR-T cells. “Cytokine release syndrome is the number one risk factor” for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. “In the beginning we didn’t manage as aggressively. We were worried about impairing the function of the CAR-T,” she added. “Now we give steroids right away.”
But the steroids don’t always work. Several doses of steroids didn’t prevent Birzer from seizing. The morning after Johnson’s alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partner’s bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.
Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldn’t find the words despite the nurses and Johnson’s encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.
She took cues from the adults around her on whether her actions were appropriate. The best example of this was her “I love you” phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: “I love you!” And the person emptying the trash: “I love you!” Months later, she was having lunch with a friend who asked, “Do you remember when you told me you loved me?” Birzer said, “Well, I stand by that one.”
When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didn’t exist. She couldn’t hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. “Then peas would fly in my face,” Johnson said.
Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.
As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients I’ve treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldn’t speak for a week – she would look around her ICU room and move her mouth as though trying her hardest — and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often can’t predict how a patient will do. Our instincts can be just plain wrong.
I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors — higher burdens of cancer, baseline cognitive problems before therapy — “the individual patient tells you nothing,” she confirmed.
So we wait.
Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?
So, who gets CAR-T? That leads to the tougher question — who doesn’t? That depends on the type of cancer and whether their insurance can pay.
CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just weren’t happening in solid tumors.
Cancer is one word, but it’s not one disease. “It’s easier to prove why something works when it works than show why it doesn’t work when it doesn’t work,” said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasn’t worked in solid cancers involves what Gill believes are two main barriers. First, it’s a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, they’re faced with a hostile environment and will likely die before they can work.
At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells don’t. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.
Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years’ worth of data and the outlook isn’t as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?
The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and we’re finding that’s exactly what’s happening. Through blood testing, we see that many patients who relapse lose the target.
Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. It’s an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint what’s after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.
Then there’s the other dreaded “c” word: Cost. Novartis’ Kymriah runs up to $475,000 while Kite Pharma’s Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.
They are daunting numbers. Some limitations on health care we accept — maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.
Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didn’t work after one month, the company said it wouldn’t send a bill.
Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. It’s not “a major issue,” he told me over the phone. “Look, of course — [with] health care in this country, if you don’t have insurance, then you’re screwed. That is no different when it comes to CAR-T as it is for anything else,” he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise — months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. “Any discussion of cost is completely irresponsible without weighing the other side of the equation,” Gill said.
How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry it’s a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.
This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T — besides the efficacy — is its ease. It’s a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and you’re done.
Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. “It wasn’t an issue,” said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didn’t pay a cent.
One year after Birzer’s infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But she’s mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: “My jokes about cancer didn’t kill.”
People handed a devastating diagnosis don’t spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.
Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.
I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages don’t say anything about an individual experience, they’re also all patients have to go on. When someone on the same treatment dies, it’s shattering for everyone. Was one person the exception, or a harbinger another’s fate? Who is the outlier?
I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, it’s only 40 percent. What’s the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: “I think CAR-T cells are like chemotherapy in the 1950s. They’re not better than chemotherapy — they’re just different.” For an adversary as tough as cancer, we’ll take any tool we can get.
There remain many questions. Can we use CAR-T earlier in a cancer’s course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.
For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldn’t return to normal. She didn’t even pause. “If you’re not dead,” she said, “you’re winning.”
Ilana Yurkiewicz, M.D., is a physician at Stanford University and a medical journalist. She is a former Scientific American Blog Network columnist and AAAS Mass Media Fellow. Her writing has also appeared in Aeon Magazine, Health Affairs, and STAT News, and has been featured in "The Best American Science and Nature Writing."
This article was originally published on Undark. Read the original article.
Inflammatory arthritis induced by ICIs can persist after therapy
according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.
“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”
Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.
To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.
Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.
According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).
The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.
The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.
SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.
according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.
“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”
Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.
To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.
Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.
According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).
The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.
The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.
SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.
according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.
“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”
Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.
To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.
Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.
According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).
The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.
The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.
SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.
FROM ANNALS OF THE RHEUMATIC DISEASES
Immunotherapies under investigation in newly diagnosed B-ALL
SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.
“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”
Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Blinatumomab
Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).
The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).
Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).
The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.
In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).
Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
Inotuzumab ozogamicin
Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.
The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.
The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).
Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.
Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.
SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.
“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”
Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Blinatumomab
Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).
The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).
Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).
The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.
In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).
Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
Inotuzumab ozogamicin
Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.
The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.
The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).
Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.
Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.
SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.
“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”
Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Blinatumomab
Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).
The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).
Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).
The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.
In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).
Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
Inotuzumab ozogamicin
Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.
The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.
The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).
Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.
Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.
EXPERT ANALYSIS FROM NCCN HEMATOLOGIC MALIGNANCIES
Adding radiation to immunotherapy may extend PFS in progressive lung cancer
For patients with metastatic non–small cell lung cancer (NSCLC) who have disease progression on immunotherapy, adding stereotactic body radiotherapy (SBRT) could improve progression-free survival (PFS), according to investigators.
Patients with more CD8+ T cells in circulation, and those with higher tumor infiltrating lymphocyte (TIL) scores derived the most benefit from SBRT, lead author Allison Campbell, MD, PhD, of Yale Cancer Center in New Haven, Conn., and colleagues, reported at the annual meeting of the American Society for Radiation Oncology.
“In rare cases, adding radiation to immunotherapy has been shown to result in therapeutic synergy,” Dr. Campbell said. “When we give high-dose radiation to patients on immunotherapy, some tumors that were not targeted by the radiation can shrink, and this is called ‘the abscopal effect.’ ”
The investigators designed the phase 2 trial to determine if the abscopal effect would occur if high-dose radiation was delivered to a single site in patients who had progressed on checkpoint inhibitor therapy. Fifty-six patients were enrolled, all with at least two sites of metastatic NSCLC. Of these patients, 6 had already progressed on immunotherapy, while 50 were naive to immunotherapy and began pembrolizumab during the trial, with 16 eventually progressing; collectively, these 22 patients with disease progression were identified as candidates for SBRT. Almost all candidates (21 out of 22) completed SBRT, which was delivered in three or five high-dose fractions. Only one site was treated, while other sites were tracked over time with computed tomography (CT) to assess for the abscopal effect. In addition, blood was analyzed for circulating immune cell composition.
After a median follow-up of 15.2 months, the disease control rate was 57%, with some abscopal responses detected. Two patients (10%) achieved a partial response lasting more than 1 year, and 10 patients (48%) maintained stable disease after SBRT. Although programmed death-ligand 1 (PD-L1) positivity was associated with a trend toward increased PFS, this was not statistically significant. In contrast, TIL score was significantly correlated with PFS; patients with TIL scores of 2-3 had a median PFS of 6.7 months, compared with 2.2 months among those with TIL scores of 1 or less. Similarly, immune-related adverse events predicted outcome, with patients who experienced such events achieving longer median PFS than those who did not (6.5 vs 2.2 months). Furthermore, blood testing revealed that the best responders had more CD8+ killer T cells and fewer CD4+ regulatory T cells in peripheral blood compared with patients who responded poorly.
After Dr. Campbell’s presentation, Benjamin Movsas, MD, chair of radiation oncology at the Henry Ford Cancer Institute in Detroit, offered some expert insight. “[The findings from this study] suggest perhaps that radiation may be able to reinvigorate the immune system,” Dr. Movsas said. “Maybe we can get more mileage out of the immunotherapy with this approach. Could radiation kind of be like an immune vaccine of sorts? There’s a lot of exciting possibilities.”
Dr. Movsas also noted how biomarker findings may be able to guide treatment decisions, highlighting how T cell populations predicted outcomes. “This era of precision medicine is really helping us improve benefits,” he said. “The immune profile really matters.”
The investigators disclosed relationships with Genentech, AstraZeneca, Merck, and others.
SOURCE: Campbell et al. ASTRO 2019. Abstract 74.
For patients with metastatic non–small cell lung cancer (NSCLC) who have disease progression on immunotherapy, adding stereotactic body radiotherapy (SBRT) could improve progression-free survival (PFS), according to investigators.
Patients with more CD8+ T cells in circulation, and those with higher tumor infiltrating lymphocyte (TIL) scores derived the most benefit from SBRT, lead author Allison Campbell, MD, PhD, of Yale Cancer Center in New Haven, Conn., and colleagues, reported at the annual meeting of the American Society for Radiation Oncology.
“In rare cases, adding radiation to immunotherapy has been shown to result in therapeutic synergy,” Dr. Campbell said. “When we give high-dose radiation to patients on immunotherapy, some tumors that were not targeted by the radiation can shrink, and this is called ‘the abscopal effect.’ ”
The investigators designed the phase 2 trial to determine if the abscopal effect would occur if high-dose radiation was delivered to a single site in patients who had progressed on checkpoint inhibitor therapy. Fifty-six patients were enrolled, all with at least two sites of metastatic NSCLC. Of these patients, 6 had already progressed on immunotherapy, while 50 were naive to immunotherapy and began pembrolizumab during the trial, with 16 eventually progressing; collectively, these 22 patients with disease progression were identified as candidates for SBRT. Almost all candidates (21 out of 22) completed SBRT, which was delivered in three or five high-dose fractions. Only one site was treated, while other sites were tracked over time with computed tomography (CT) to assess for the abscopal effect. In addition, blood was analyzed for circulating immune cell composition.
After a median follow-up of 15.2 months, the disease control rate was 57%, with some abscopal responses detected. Two patients (10%) achieved a partial response lasting more than 1 year, and 10 patients (48%) maintained stable disease after SBRT. Although programmed death-ligand 1 (PD-L1) positivity was associated with a trend toward increased PFS, this was not statistically significant. In contrast, TIL score was significantly correlated with PFS; patients with TIL scores of 2-3 had a median PFS of 6.7 months, compared with 2.2 months among those with TIL scores of 1 or less. Similarly, immune-related adverse events predicted outcome, with patients who experienced such events achieving longer median PFS than those who did not (6.5 vs 2.2 months). Furthermore, blood testing revealed that the best responders had more CD8+ killer T cells and fewer CD4+ regulatory T cells in peripheral blood compared with patients who responded poorly.
After Dr. Campbell’s presentation, Benjamin Movsas, MD, chair of radiation oncology at the Henry Ford Cancer Institute in Detroit, offered some expert insight. “[The findings from this study] suggest perhaps that radiation may be able to reinvigorate the immune system,” Dr. Movsas said. “Maybe we can get more mileage out of the immunotherapy with this approach. Could radiation kind of be like an immune vaccine of sorts? There’s a lot of exciting possibilities.”
Dr. Movsas also noted how biomarker findings may be able to guide treatment decisions, highlighting how T cell populations predicted outcomes. “This era of precision medicine is really helping us improve benefits,” he said. “The immune profile really matters.”
The investigators disclosed relationships with Genentech, AstraZeneca, Merck, and others.
SOURCE: Campbell et al. ASTRO 2019. Abstract 74.
For patients with metastatic non–small cell lung cancer (NSCLC) who have disease progression on immunotherapy, adding stereotactic body radiotherapy (SBRT) could improve progression-free survival (PFS), according to investigators.
Patients with more CD8+ T cells in circulation, and those with higher tumor infiltrating lymphocyte (TIL) scores derived the most benefit from SBRT, lead author Allison Campbell, MD, PhD, of Yale Cancer Center in New Haven, Conn., and colleagues, reported at the annual meeting of the American Society for Radiation Oncology.
“In rare cases, adding radiation to immunotherapy has been shown to result in therapeutic synergy,” Dr. Campbell said. “When we give high-dose radiation to patients on immunotherapy, some tumors that were not targeted by the radiation can shrink, and this is called ‘the abscopal effect.’ ”
The investigators designed the phase 2 trial to determine if the abscopal effect would occur if high-dose radiation was delivered to a single site in patients who had progressed on checkpoint inhibitor therapy. Fifty-six patients were enrolled, all with at least two sites of metastatic NSCLC. Of these patients, 6 had already progressed on immunotherapy, while 50 were naive to immunotherapy and began pembrolizumab during the trial, with 16 eventually progressing; collectively, these 22 patients with disease progression were identified as candidates for SBRT. Almost all candidates (21 out of 22) completed SBRT, which was delivered in three or five high-dose fractions. Only one site was treated, while other sites were tracked over time with computed tomography (CT) to assess for the abscopal effect. In addition, blood was analyzed for circulating immune cell composition.
After a median follow-up of 15.2 months, the disease control rate was 57%, with some abscopal responses detected. Two patients (10%) achieved a partial response lasting more than 1 year, and 10 patients (48%) maintained stable disease after SBRT. Although programmed death-ligand 1 (PD-L1) positivity was associated with a trend toward increased PFS, this was not statistically significant. In contrast, TIL score was significantly correlated with PFS; patients with TIL scores of 2-3 had a median PFS of 6.7 months, compared with 2.2 months among those with TIL scores of 1 or less. Similarly, immune-related adverse events predicted outcome, with patients who experienced such events achieving longer median PFS than those who did not (6.5 vs 2.2 months). Furthermore, blood testing revealed that the best responders had more CD8+ killer T cells and fewer CD4+ regulatory T cells in peripheral blood compared with patients who responded poorly.
After Dr. Campbell’s presentation, Benjamin Movsas, MD, chair of radiation oncology at the Henry Ford Cancer Institute in Detroit, offered some expert insight. “[The findings from this study] suggest perhaps that radiation may be able to reinvigorate the immune system,” Dr. Movsas said. “Maybe we can get more mileage out of the immunotherapy with this approach. Could radiation kind of be like an immune vaccine of sorts? There’s a lot of exciting possibilities.”
Dr. Movsas also noted how biomarker findings may be able to guide treatment decisions, highlighting how T cell populations predicted outcomes. “This era of precision medicine is really helping us improve benefits,” he said. “The immune profile really matters.”
The investigators disclosed relationships with Genentech, AstraZeneca, Merck, and others.
SOURCE: Campbell et al. ASTRO 2019. Abstract 74.
REPORTING FROM ASTRO 2019
CAR T-cell therapy found safe, effective for HIV-associated lymphoma
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
FROM CANCER
Nivolumab falls short in ccRCC patients with brain metastases
Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.
In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.
The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.
These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.
Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.
Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).
Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.
All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.
The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.
Response
The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.
Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.
The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.
All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
Survival
The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).
The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.
The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.
Safety
The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).
Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).
The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.
This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.
Trial results have raised more questions about the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma (ccRCC) and brain metastases, according to Jarred P. Reed, MD, and colleagues.
In a phase 2 trial, half of ccRCC patients with previously untreated brain metastases had intracranial progression while receiving treatment with nivolumab. The risk of intracranial progression was higher among patients with previously untreated brain metastases than among those who had received prior focal therapy. However, global progression-free survival rates were similarly short in patients with previously treated and untreated brain metastases.
It isn’t clear why nivolumab exhibited such “disappointing activity” in this trial, Dr. Reed and colleagues wrote in an editorial, but the authors presented several possibilities.
The study’s results may be explained by “unique biologic mechanisms” associated with brain metastasis in ccRCC. The brain microenvironment may weaken the response to nivolumab, or patients with brain metastases may have tumor cells better able to evade the immune system. These patients may also have specific alterations in signaling pathways that are important for cell survival.
To gain more insight, future immunotherapy trials should include patients with brain metastases, Dr. Reed and coauthors wrote.
Jarred P. Reed, MD, and coauthors Edwin M. Posadas, MD, and Robert A. Figlin, MD, are from Cedars-Sinai Medical Center in Los Angeles. The authors disclosed relationships with Bristol-Myers Squibb, which markets nivolumab, and many other companies. These comments are adapted from their editorial (J Clin Oncol. 2019 Aug 10;37[23]:1987-9).
Trial results have raised more questions about the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma (ccRCC) and brain metastases, according to Jarred P. Reed, MD, and colleagues.
In a phase 2 trial, half of ccRCC patients with previously untreated brain metastases had intracranial progression while receiving treatment with nivolumab. The risk of intracranial progression was higher among patients with previously untreated brain metastases than among those who had received prior focal therapy. However, global progression-free survival rates were similarly short in patients with previously treated and untreated brain metastases.
It isn’t clear why nivolumab exhibited such “disappointing activity” in this trial, Dr. Reed and colleagues wrote in an editorial, but the authors presented several possibilities.
The study’s results may be explained by “unique biologic mechanisms” associated with brain metastasis in ccRCC. The brain microenvironment may weaken the response to nivolumab, or patients with brain metastases may have tumor cells better able to evade the immune system. These patients may also have specific alterations in signaling pathways that are important for cell survival.
To gain more insight, future immunotherapy trials should include patients with brain metastases, Dr. Reed and coauthors wrote.
Jarred P. Reed, MD, and coauthors Edwin M. Posadas, MD, and Robert A. Figlin, MD, are from Cedars-Sinai Medical Center in Los Angeles. The authors disclosed relationships with Bristol-Myers Squibb, which markets nivolumab, and many other companies. These comments are adapted from their editorial (J Clin Oncol. 2019 Aug 10;37[23]:1987-9).
Trial results have raised more questions about the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma (ccRCC) and brain metastases, according to Jarred P. Reed, MD, and colleagues.
In a phase 2 trial, half of ccRCC patients with previously untreated brain metastases had intracranial progression while receiving treatment with nivolumab. The risk of intracranial progression was higher among patients with previously untreated brain metastases than among those who had received prior focal therapy. However, global progression-free survival rates were similarly short in patients with previously treated and untreated brain metastases.
It isn’t clear why nivolumab exhibited such “disappointing activity” in this trial, Dr. Reed and colleagues wrote in an editorial, but the authors presented several possibilities.
The study’s results may be explained by “unique biologic mechanisms” associated with brain metastasis in ccRCC. The brain microenvironment may weaken the response to nivolumab, or patients with brain metastases may have tumor cells better able to evade the immune system. These patients may also have specific alterations in signaling pathways that are important for cell survival.
To gain more insight, future immunotherapy trials should include patients with brain metastases, Dr. Reed and coauthors wrote.
Jarred P. Reed, MD, and coauthors Edwin M. Posadas, MD, and Robert A. Figlin, MD, are from Cedars-Sinai Medical Center in Los Angeles. The authors disclosed relationships with Bristol-Myers Squibb, which markets nivolumab, and many other companies. These comments are adapted from their editorial (J Clin Oncol. 2019 Aug 10;37[23]:1987-9).
Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.
In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.
The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.
These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.
Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.
Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).
Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.
All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.
The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.
Response
The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.
Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.
The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.
All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
Survival
The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).
The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.
The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.
Safety
The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).
Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).
The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.
This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.
Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.
In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.
The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.
These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.
Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.
Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).
Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.
All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.
The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.
Response
The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.
Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.
The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.
All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
Survival
The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).
The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.
The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.
Safety
The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).
Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).
The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.
This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.
FROM JOURNAL OF CLINICAL ONCOLOGY
Pretreatment CT data may help predict immunotherapy benefit in ovarian cancer
Pretreatment CT data may help identify responders to immunotherapy in ovarian cancer, according to a new study.
Specifically, fewer sites of disease and lower intratumor heterogeneity on contrast-enhanced CT may indicate a higher likelihood of durable response to immune checkpoint inhibitors, according to results of the retrospective study, recently published in JCO Precision Oncology.
“Our results suggest that quantitative analysis of baseline contrast-enhanced CT may facilitate the delivery of precision medicine to patients with ovarian cancer by identifying patients who may benefit from immunotherapy,” wrote Yuki Himoto, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
The study leverages findings from the emerging field of radiomics, which the investigators note allows for “virtual sampling” of tumor heterogeneity within a single lesion and between lesions.
“This information may complement molecular profiling in personalizing medical decisions,” Dr. Himoto and coauthors explained.
The study cohort included 75 patients with recurrent ovarian cancer who were enrolled in ongoing, prospective trials of immunotherapy, according to the researchers. Of that group, just under one in five derived a durable clinical benefit, defined as progression-free survival lasting at least 24 weeks.
In univariable analysis, they found a number of contrast-enhanced CT variables were linked to durable clinical benefit, including fewer disease sites, lower cluster-site entropy and dissimilarity, which they wrote were an indicator of lower intertumor heterogeneity, and higher energy in the largest-volume lesion, which they described as an indicator of lower intratumor heterogeneity.
However, in multivariable analysis, the only variables that were still associated with durable clinical benefit were fewer disease sites (odds ratio, 1.64; 95% confidence interval, 1.19-2.27; P = .012) and higher energy in the largest lesion (odds ratio, 1.41; 95% CI, 1.11-1.81; P = .006), according to the report.
Those two factors combined were a composite indicator of durable clinical benefit (C-index, 0.821).
These findings could represent a step forward in the provision of immunotherapy in ovarian cancer, which exhibits poor response to immune checkpoint inhibitors, compared with some other cancer types, the investigators wrote.
More insights are needed, however, to help personalize the selection of immunotherapy in ovarian cancer, including a better understanding of cancer immune reactions and retooling of immune response criteria, they added.
“Composite multimodal multifaceted biomarkers that noninvasively capture spatiotemporal tumor heterogeneity will likely be necessary to comprehensively assess immune the tumor microenvironment and serve as clinical decision support for prognosis inference and prediction of response,” Dr. Himoto and associates wrote.
The study was supported by the National Cancer Institute, among other sources. Study authors reported disclosures related to Merck, Bristol-Myers Squibb, Genentech, Celgene, AstraZeneca, Y-mAbs Therapeutics, and others.
SOURCE: Himoto Y et al. JCO Precis Oncol. 2019 Aug 13. doi: 10.1200/PO.19.00038.
Pretreatment CT data may help identify responders to immunotherapy in ovarian cancer, according to a new study.
Specifically, fewer sites of disease and lower intratumor heterogeneity on contrast-enhanced CT may indicate a higher likelihood of durable response to immune checkpoint inhibitors, according to results of the retrospective study, recently published in JCO Precision Oncology.
“Our results suggest that quantitative analysis of baseline contrast-enhanced CT may facilitate the delivery of precision medicine to patients with ovarian cancer by identifying patients who may benefit from immunotherapy,” wrote Yuki Himoto, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
The study leverages findings from the emerging field of radiomics, which the investigators note allows for “virtual sampling” of tumor heterogeneity within a single lesion and between lesions.
“This information may complement molecular profiling in personalizing medical decisions,” Dr. Himoto and coauthors explained.
The study cohort included 75 patients with recurrent ovarian cancer who were enrolled in ongoing, prospective trials of immunotherapy, according to the researchers. Of that group, just under one in five derived a durable clinical benefit, defined as progression-free survival lasting at least 24 weeks.
In univariable analysis, they found a number of contrast-enhanced CT variables were linked to durable clinical benefit, including fewer disease sites, lower cluster-site entropy and dissimilarity, which they wrote were an indicator of lower intertumor heterogeneity, and higher energy in the largest-volume lesion, which they described as an indicator of lower intratumor heterogeneity.
However, in multivariable analysis, the only variables that were still associated with durable clinical benefit were fewer disease sites (odds ratio, 1.64; 95% confidence interval, 1.19-2.27; P = .012) and higher energy in the largest lesion (odds ratio, 1.41; 95% CI, 1.11-1.81; P = .006), according to the report.
Those two factors combined were a composite indicator of durable clinical benefit (C-index, 0.821).
These findings could represent a step forward in the provision of immunotherapy in ovarian cancer, which exhibits poor response to immune checkpoint inhibitors, compared with some other cancer types, the investigators wrote.
More insights are needed, however, to help personalize the selection of immunotherapy in ovarian cancer, including a better understanding of cancer immune reactions and retooling of immune response criteria, they added.
“Composite multimodal multifaceted biomarkers that noninvasively capture spatiotemporal tumor heterogeneity will likely be necessary to comprehensively assess immune the tumor microenvironment and serve as clinical decision support for prognosis inference and prediction of response,” Dr. Himoto and associates wrote.
The study was supported by the National Cancer Institute, among other sources. Study authors reported disclosures related to Merck, Bristol-Myers Squibb, Genentech, Celgene, AstraZeneca, Y-mAbs Therapeutics, and others.
SOURCE: Himoto Y et al. JCO Precis Oncol. 2019 Aug 13. doi: 10.1200/PO.19.00038.
Pretreatment CT data may help identify responders to immunotherapy in ovarian cancer, according to a new study.
Specifically, fewer sites of disease and lower intratumor heterogeneity on contrast-enhanced CT may indicate a higher likelihood of durable response to immune checkpoint inhibitors, according to results of the retrospective study, recently published in JCO Precision Oncology.
“Our results suggest that quantitative analysis of baseline contrast-enhanced CT may facilitate the delivery of precision medicine to patients with ovarian cancer by identifying patients who may benefit from immunotherapy,” wrote Yuki Himoto, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
The study leverages findings from the emerging field of radiomics, which the investigators note allows for “virtual sampling” of tumor heterogeneity within a single lesion and between lesions.
“This information may complement molecular profiling in personalizing medical decisions,” Dr. Himoto and coauthors explained.
The study cohort included 75 patients with recurrent ovarian cancer who were enrolled in ongoing, prospective trials of immunotherapy, according to the researchers. Of that group, just under one in five derived a durable clinical benefit, defined as progression-free survival lasting at least 24 weeks.
In univariable analysis, they found a number of contrast-enhanced CT variables were linked to durable clinical benefit, including fewer disease sites, lower cluster-site entropy and dissimilarity, which they wrote were an indicator of lower intertumor heterogeneity, and higher energy in the largest-volume lesion, which they described as an indicator of lower intratumor heterogeneity.
However, in multivariable analysis, the only variables that were still associated with durable clinical benefit were fewer disease sites (odds ratio, 1.64; 95% confidence interval, 1.19-2.27; P = .012) and higher energy in the largest lesion (odds ratio, 1.41; 95% CI, 1.11-1.81; P = .006), according to the report.
Those two factors combined were a composite indicator of durable clinical benefit (C-index, 0.821).
These findings could represent a step forward in the provision of immunotherapy in ovarian cancer, which exhibits poor response to immune checkpoint inhibitors, compared with some other cancer types, the investigators wrote.
More insights are needed, however, to help personalize the selection of immunotherapy in ovarian cancer, including a better understanding of cancer immune reactions and retooling of immune response criteria, they added.
“Composite multimodal multifaceted biomarkers that noninvasively capture spatiotemporal tumor heterogeneity will likely be necessary to comprehensively assess immune the tumor microenvironment and serve as clinical decision support for prognosis inference and prediction of response,” Dr. Himoto and associates wrote.
The study was supported by the National Cancer Institute, among other sources. Study authors reported disclosures related to Merck, Bristol-Myers Squibb, Genentech, Celgene, AstraZeneca, Y-mAbs Therapeutics, and others.
SOURCE: Himoto Y et al. JCO Precis Oncol. 2019 Aug 13. doi: 10.1200/PO.19.00038.
FROM JCO PRECISION ONCOLOGY
Lichenoid dermatitis with mycosis fungoides features linked to checkpoint inhibitor therapy
A patient treated with immune checkpoint inhibitor therapy for thyroid carcinoma presented with lichenoid dermatitis that resembled mycosis fungoides and also showed with monoclonal T-cell receptor gene rearrangement.
A case report published in the Journal of Cutaneous Pathology describes the “unusual” case and highlights another form of lichenoid dermatitis that may occur with immune checkpoint inhibitor therapy.
The patient was a 66-year-old man with BRAFV600E-mutated anaplastic thyroid carcinoma, who was enrolled in a clinical trial of the checkpoint inhibitor atezolizumab, in combination with the BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib.
Around 11 months after starting treatment, he presented to a dermatology department with a 1.5-cm x 1.2-cm crusted, erythematous plaque on his abdomen that had appeared 3 weeks earlier. He also had several follicular-based erythematous papules on his extremities and a single verrucous papule on his index finger, which the authors wrote were likely associated with the vemurafenib therapy.
The patient had previously had a squamous cell carcinoma removed but had no history of cutaneous lymphoma.
A punch biopsy of the abdominal lesion showed dense lichenoid, lymphohistiocytic infiltrate with papillary dermal fibrosis, and scattered multinucleated giant histiocytes. Immunohistochemical studies showed the lesion had an abnormal immunophenotype in which CD4+ cells were four to five times more common than CD8+ cells, and there was partial loss of CD7 expression.
The lesion was treated with 0.05% clobetasol cream and monitored without interrupting the cancer therapy. The lesion gradually reduced in size, but 4 months later, another lesion appeared on the patient’s right clavicle.
A skin biopsy revealed lichenoid lymphohistiocytic infiltrate with occasional giant cells in the superficial dermis, as well as atypical, hyperchromatic lymphocytes with clear halos. Immunohistochemical studies showed that the new lesion was similar to the earlier abdominal lesion.
T-cell receptor gene rearrangement studies on both lesions showed that the abdominal lesion had both monoclonal TCR-gamma and TCR-beta gene rearrangements. The clavicle lesion showed the same monoclonal TCR-gamma rearrangement as the abdominal lesion, but lacked the TCR-beta gene rearrangement.
The lesions continued to be treated with clobetasol cream (0.05%), and the patient remained on the anticancer treatment regimen.
Michael T. Tetzlaff, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote that up to half of all patients treated with immune checkpoint inhibitors develop some kind of cutaneous immune-related adverse event, and lichenoid dermatitis is one of the most common seen in biopsies.
“Clinical and pathological recognition of monoclonal [lichenoid dermatitis associated with immune checkpoint inhibitors] in the context of [immune checkpoint inhibitor] therapy will be important for accurate diagnosis and patient care,” they wrote.
The researchers did not report financial disclosures.
SOURCE: Tetzlaff MT et al. J Cutan Pathol. 2019 Jun 29. doi: 10.1111/cup.13536.
A patient treated with immune checkpoint inhibitor therapy for thyroid carcinoma presented with lichenoid dermatitis that resembled mycosis fungoides and also showed with monoclonal T-cell receptor gene rearrangement.
A case report published in the Journal of Cutaneous Pathology describes the “unusual” case and highlights another form of lichenoid dermatitis that may occur with immune checkpoint inhibitor therapy.
The patient was a 66-year-old man with BRAFV600E-mutated anaplastic thyroid carcinoma, who was enrolled in a clinical trial of the checkpoint inhibitor atezolizumab, in combination with the BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib.
Around 11 months after starting treatment, he presented to a dermatology department with a 1.5-cm x 1.2-cm crusted, erythematous plaque on his abdomen that had appeared 3 weeks earlier. He also had several follicular-based erythematous papules on his extremities and a single verrucous papule on his index finger, which the authors wrote were likely associated with the vemurafenib therapy.
The patient had previously had a squamous cell carcinoma removed but had no history of cutaneous lymphoma.
A punch biopsy of the abdominal lesion showed dense lichenoid, lymphohistiocytic infiltrate with papillary dermal fibrosis, and scattered multinucleated giant histiocytes. Immunohistochemical studies showed the lesion had an abnormal immunophenotype in which CD4+ cells were four to five times more common than CD8+ cells, and there was partial loss of CD7 expression.
The lesion was treated with 0.05% clobetasol cream and monitored without interrupting the cancer therapy. The lesion gradually reduced in size, but 4 months later, another lesion appeared on the patient’s right clavicle.
A skin biopsy revealed lichenoid lymphohistiocytic infiltrate with occasional giant cells in the superficial dermis, as well as atypical, hyperchromatic lymphocytes with clear halos. Immunohistochemical studies showed that the new lesion was similar to the earlier abdominal lesion.
T-cell receptor gene rearrangement studies on both lesions showed that the abdominal lesion had both monoclonal TCR-gamma and TCR-beta gene rearrangements. The clavicle lesion showed the same monoclonal TCR-gamma rearrangement as the abdominal lesion, but lacked the TCR-beta gene rearrangement.
The lesions continued to be treated with clobetasol cream (0.05%), and the patient remained on the anticancer treatment regimen.
Michael T. Tetzlaff, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote that up to half of all patients treated with immune checkpoint inhibitors develop some kind of cutaneous immune-related adverse event, and lichenoid dermatitis is one of the most common seen in biopsies.
“Clinical and pathological recognition of monoclonal [lichenoid dermatitis associated with immune checkpoint inhibitors] in the context of [immune checkpoint inhibitor] therapy will be important for accurate diagnosis and patient care,” they wrote.
The researchers did not report financial disclosures.
SOURCE: Tetzlaff MT et al. J Cutan Pathol. 2019 Jun 29. doi: 10.1111/cup.13536.
A patient treated with immune checkpoint inhibitor therapy for thyroid carcinoma presented with lichenoid dermatitis that resembled mycosis fungoides and also showed with monoclonal T-cell receptor gene rearrangement.
A case report published in the Journal of Cutaneous Pathology describes the “unusual” case and highlights another form of lichenoid dermatitis that may occur with immune checkpoint inhibitor therapy.
The patient was a 66-year-old man with BRAFV600E-mutated anaplastic thyroid carcinoma, who was enrolled in a clinical trial of the checkpoint inhibitor atezolizumab, in combination with the BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib.
Around 11 months after starting treatment, he presented to a dermatology department with a 1.5-cm x 1.2-cm crusted, erythematous plaque on his abdomen that had appeared 3 weeks earlier. He also had several follicular-based erythematous papules on his extremities and a single verrucous papule on his index finger, which the authors wrote were likely associated with the vemurafenib therapy.
The patient had previously had a squamous cell carcinoma removed but had no history of cutaneous lymphoma.
A punch biopsy of the abdominal lesion showed dense lichenoid, lymphohistiocytic infiltrate with papillary dermal fibrosis, and scattered multinucleated giant histiocytes. Immunohistochemical studies showed the lesion had an abnormal immunophenotype in which CD4+ cells were four to five times more common than CD8+ cells, and there was partial loss of CD7 expression.
The lesion was treated with 0.05% clobetasol cream and monitored without interrupting the cancer therapy. The lesion gradually reduced in size, but 4 months later, another lesion appeared on the patient’s right clavicle.
A skin biopsy revealed lichenoid lymphohistiocytic infiltrate with occasional giant cells in the superficial dermis, as well as atypical, hyperchromatic lymphocytes with clear halos. Immunohistochemical studies showed that the new lesion was similar to the earlier abdominal lesion.
T-cell receptor gene rearrangement studies on both lesions showed that the abdominal lesion had both monoclonal TCR-gamma and TCR-beta gene rearrangements. The clavicle lesion showed the same monoclonal TCR-gamma rearrangement as the abdominal lesion, but lacked the TCR-beta gene rearrangement.
The lesions continued to be treated with clobetasol cream (0.05%), and the patient remained on the anticancer treatment regimen.
Michael T. Tetzlaff, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote that up to half of all patients treated with immune checkpoint inhibitors develop some kind of cutaneous immune-related adverse event, and lichenoid dermatitis is one of the most common seen in biopsies.
“Clinical and pathological recognition of monoclonal [lichenoid dermatitis associated with immune checkpoint inhibitors] in the context of [immune checkpoint inhibitor] therapy will be important for accurate diagnosis and patient care,” they wrote.
The researchers did not report financial disclosures.
SOURCE: Tetzlaff MT et al. J Cutan Pathol. 2019 Jun 29. doi: 10.1111/cup.13536.
FROM THE JOURNAL OF CUTANEOUS PATHOLOGY
Key clinical point:
Major finding: Checkpoint inhibitor therapy can trigger lichenoid dermatitis with mycosis fungoides–like features.
Study details: A case report involving a 66-year-old man with BRAFV600E-mutated anaplastic thyroid carcinoma.
Disclosures: The researchers did not report financial disclosures.
Source: Tetzlaff MT et al. J Cutan Pathol. 2019 Jun 29. doi: 10.1111/cup.13536.