Hematologic Malignancies

Chimeric antigen receptor (CAR) T-cell therapy, described as a “living drug,” is now available for patients with relapsed/refractory multiple myeloma who have been treated with four or more prior lines of therapy.

The Food and Drug Administration said these patients represent an “unmet medical need” when it granted approval for the new product – idecabtagene vicleucel (ide-cel; Abecma), developed by bluebird bio and Bristol-Myers Squibb.

Ide-cel is the first CAR T-cell therapy to gain approval for use in multiple myeloma. It is also the first CAR T-cell therapy to target B-cell maturation antigen.

Previously approved CAR T-cell products target CD19 and have been approved for use in certain types of leukemia and lymphoma.

All the CAR T-cell therapies are customized treatments that are created specifically for each individual patient from their own blood. The patient’s own T cells are removed from the blood, are genetically modified and expanded, and are then infused back into the patient. These modified T cells then seek out and destroy blood cancer cells, and they continue to do so long term.

In some patients, this has led to eradication of disease that had previously progressed with every other treatment that had been tried – results that have been described as “absolutely remarkable” and “one-shot therapy that looks to be curative.”

However, this cell therapy comes with serious adverse effects, including neurologic toxicity and cytokine release syndrome (CRS), which can be life threatening. For this reason, all these products have a risk evaluation and mitigation strategy, and the use of CAR T-cell therapies is limited to designated centers.

In addition, these CAR T-cells products are phenomenally expensive; hospitals have reported heavy financial losses with their use, and patients have turned to crowdfunding to pay for these therapies.
 

‘Phenomenal’ results in MM

The FDA noted that approval of ide-cel for multiple myeloma is based on data from a multicenter study that involved 127 patients with relapsed/refractory disease who had received at least three prior lines of treatment.

The results from this trial were published Feb. 25 in the New England Journal of Medicine.

An expert not involved in the trial described the results as “phenomenal.”

Krina Patel, MD, an associate professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, said that “the response rate of 73% in a patient population with a median of six lines of therapy, and with one-third of those patients achieving a deep response of complete response or better, is phenomenal.

“We are very excited as a myeloma community for this study of idecabtagene vicleucel for relapsed/refractory patients,” Dr. Patel told this news organization at the time.

The lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

Both experts highlighted the poor prognosis for patients with relapsed/refractory disease. Recent decades have seen a flurry of new agents for myeloma, and there are now three main classes of agents: immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.

Nevertheless, in some patients, the disease continues to progress. For patients for whom treatments with all three classes of drugs have failed, the median progression-free survival is 3-4 months, and the median overall survival is 9 months.

In contrast, the results reported in the NEJM article showed that overall median progression-free survival was 8.8 months, but it was more than double that (20.2 months) for patients who achieved a complete or stringent complete response.

Estimated median overall survival was 19.4 months, and the overall survival was 78% at 12 months. The authors note that overall survival data are not yet mature.

The patients who were enrolled in the CAR T-cell trial had undergone many previous treatments. They had undergone a median of six prior drug therapies (range, 3-16), and most of the patients (120, 94%) had also undergone autologous hematopoietic stem cell transplant.

In addition, the majority of patients (84%) had disease that was triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% had disease that was penta-exposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% had disease that was penta-refractory.

In the NEJM article, the authors report that about a third of patients had a complete response to CAR T-cell therapy.

At a median follow-up of 13.3 months, 94 of 128 patients (73%) showed a response to therapy (P < .001); 42 (33%) showed a complete or stringent complete response; and 67 patients (52%) showed a “very good partial response or better,” they write.

In the FDA announcement of the product approval, the figures for complete response were slightly lower. “Of those studied, 28% of patients showed complete response – or disappearance of all signs of multiple myeloma – to Abecma, and 65% of this group remained in complete response to the treatment for at least 12 months,” the agency noted.

The FDA also noted that treatment with Abecma can cause severe side effects. The label carries a boxed warning regarding CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life threatening.

The most common side effects of Abecma are CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first 1-2 weeks after treatment, but some side effects may occur later.

The agency also noted that, to further evaluate the long-term safety of the drug, it is requiring the manufacturer to conduct a postmarketing observational study.

“The FDA remains committed to advancing novel treatment options for areas of unmet patient need,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

“While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual’s age and the stage of the condition at the time of diagnosis. Today’s approval provides a new treatment option for patients who have this uncommon type of cancer.”

A version of this article first appeared on Medscape.com.

Chimeric antigen receptor (CAR) T-cell therapy, described as a “living drug,” is now available for patients with relapsed/refractory multiple myeloma who have been treated with four or more prior lines of therapy.

The Food and Drug Administration said these patients represent an “unmet medical need” when it granted approval for the new product – idecabtagene vicleucel (ide-cel; Abecma), developed by bluebird bio and Bristol-Myers Squibb.

Ide-cel is the first CAR T-cell therapy to gain approval for use in multiple myeloma. It is also the first CAR T-cell therapy to target B-cell maturation antigen.

Previously approved CAR T-cell products target CD19 and have been approved for use in certain types of leukemia and lymphoma.

All the CAR T-cell therapies are customized treatments that are created specifically for each individual patient from their own blood. The patient’s own T cells are removed from the blood, are genetically modified and expanded, and are then infused back into the patient. These modified T cells then seek out and destroy blood cancer cells, and they continue to do so long term.

In some patients, this has led to eradication of disease that had previously progressed with every other treatment that had been tried – results that have been described as “absolutely remarkable” and “one-shot therapy that looks to be curative.”

However, this cell therapy comes with serious adverse effects, including neurologic toxicity and cytokine release syndrome (CRS), which can be life threatening. For this reason, all these products have a risk evaluation and mitigation strategy, and the use of CAR T-cell therapies is limited to designated centers.

In addition, these CAR T-cells products are phenomenally expensive; hospitals have reported heavy financial losses with their use, and patients have turned to crowdfunding to pay for these therapies.
 

‘Phenomenal’ results in MM

The FDA noted that approval of ide-cel for multiple myeloma is based on data from a multicenter study that involved 127 patients with relapsed/refractory disease who had received at least three prior lines of treatment.

The results from this trial were published Feb. 25 in the New England Journal of Medicine.

An expert not involved in the trial described the results as “phenomenal.”

Krina Patel, MD, an associate professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, said that “the response rate of 73% in a patient population with a median of six lines of therapy, and with one-third of those patients achieving a deep response of complete response or better, is phenomenal.

“We are very excited as a myeloma community for this study of idecabtagene vicleucel for relapsed/refractory patients,” Dr. Patel told this news organization at the time.

The lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

Both experts highlighted the poor prognosis for patients with relapsed/refractory disease. Recent decades have seen a flurry of new agents for myeloma, and there are now three main classes of agents: immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.

Nevertheless, in some patients, the disease continues to progress. For patients for whom treatments with all three classes of drugs have failed, the median progression-free survival is 3-4 months, and the median overall survival is 9 months.

In contrast, the results reported in the NEJM article showed that overall median progression-free survival was 8.8 months, but it was more than double that (20.2 months) for patients who achieved a complete or stringent complete response.

Estimated median overall survival was 19.4 months, and the overall survival was 78% at 12 months. The authors note that overall survival data are not yet mature.

The patients who were enrolled in the CAR T-cell trial had undergone many previous treatments. They had undergone a median of six prior drug therapies (range, 3-16), and most of the patients (120, 94%) had also undergone autologous hematopoietic stem cell transplant.

In addition, the majority of patients (84%) had disease that was triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% had disease that was penta-exposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% had disease that was penta-refractory.

In the NEJM article, the authors report that about a third of patients had a complete response to CAR T-cell therapy.

At a median follow-up of 13.3 months, 94 of 128 patients (73%) showed a response to therapy (P < .001); 42 (33%) showed a complete or stringent complete response; and 67 patients (52%) showed a “very good partial response or better,” they write.

In the FDA announcement of the product approval, the figures for complete response were slightly lower. “Of those studied, 28% of patients showed complete response – or disappearance of all signs of multiple myeloma – to Abecma, and 65% of this group remained in complete response to the treatment for at least 12 months,” the agency noted.

The FDA also noted that treatment with Abecma can cause severe side effects. The label carries a boxed warning regarding CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life threatening.

The most common side effects of Abecma are CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first 1-2 weeks after treatment, but some side effects may occur later.

The agency also noted that, to further evaluate the long-term safety of the drug, it is requiring the manufacturer to conduct a postmarketing observational study.

“The FDA remains committed to advancing novel treatment options for areas of unmet patient need,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

“While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual’s age and the stage of the condition at the time of diagnosis. Today’s approval provides a new treatment option for patients who have this uncommon type of cancer.”

A version of this article first appeared on Medscape.com.

Chimeric antigen receptor (CAR) T-cell therapy, described as a “living drug,” is now available for patients with relapsed/refractory multiple myeloma who have been treated with four or more prior lines of therapy.

The Food and Drug Administration said these patients represent an “unmet medical need” when it granted approval for the new product – idecabtagene vicleucel (ide-cel; Abecma), developed by bluebird bio and Bristol-Myers Squibb.

Ide-cel is the first CAR T-cell therapy to gain approval for use in multiple myeloma. It is also the first CAR T-cell therapy to target B-cell maturation antigen.

Previously approved CAR T-cell products target CD19 and have been approved for use in certain types of leukemia and lymphoma.

All the CAR T-cell therapies are customized treatments that are created specifically for each individual patient from their own blood. The patient’s own T cells are removed from the blood, are genetically modified and expanded, and are then infused back into the patient. These modified T cells then seek out and destroy blood cancer cells, and they continue to do so long term.

In some patients, this has led to eradication of disease that had previously progressed with every other treatment that had been tried – results that have been described as “absolutely remarkable” and “one-shot therapy that looks to be curative.”

However, this cell therapy comes with serious adverse effects, including neurologic toxicity and cytokine release syndrome (CRS), which can be life threatening. For this reason, all these products have a risk evaluation and mitigation strategy, and the use of CAR T-cell therapies is limited to designated centers.

In addition, these CAR T-cells products are phenomenally expensive; hospitals have reported heavy financial losses with their use, and patients have turned to crowdfunding to pay for these therapies.
 

‘Phenomenal’ results in MM

The FDA noted that approval of ide-cel for multiple myeloma is based on data from a multicenter study that involved 127 patients with relapsed/refractory disease who had received at least three prior lines of treatment.

The results from this trial were published Feb. 25 in the New England Journal of Medicine.

An expert not involved in the trial described the results as “phenomenal.”

Krina Patel, MD, an associate professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, said that “the response rate of 73% in a patient population with a median of six lines of therapy, and with one-third of those patients achieving a deep response of complete response or better, is phenomenal.

“We are very excited as a myeloma community for this study of idecabtagene vicleucel for relapsed/refractory patients,” Dr. Patel told this news organization at the time.

The lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

Both experts highlighted the poor prognosis for patients with relapsed/refractory disease. Recent decades have seen a flurry of new agents for myeloma, and there are now three main classes of agents: immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.

Nevertheless, in some patients, the disease continues to progress. For patients for whom treatments with all three classes of drugs have failed, the median progression-free survival is 3-4 months, and the median overall survival is 9 months.

In contrast, the results reported in the NEJM article showed that overall median progression-free survival was 8.8 months, but it was more than double that (20.2 months) for patients who achieved a complete or stringent complete response.

Estimated median overall survival was 19.4 months, and the overall survival was 78% at 12 months. The authors note that overall survival data are not yet mature.

The patients who were enrolled in the CAR T-cell trial had undergone many previous treatments. They had undergone a median of six prior drug therapies (range, 3-16), and most of the patients (120, 94%) had also undergone autologous hematopoietic stem cell transplant.

In addition, the majority of patients (84%) had disease that was triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% had disease that was penta-exposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% had disease that was penta-refractory.

In the NEJM article, the authors report that about a third of patients had a complete response to CAR T-cell therapy.

At a median follow-up of 13.3 months, 94 of 128 patients (73%) showed a response to therapy (P < .001); 42 (33%) showed a complete or stringent complete response; and 67 patients (52%) showed a “very good partial response or better,” they write.

In the FDA announcement of the product approval, the figures for complete response were slightly lower. “Of those studied, 28% of patients showed complete response – or disappearance of all signs of multiple myeloma – to Abecma, and 65% of this group remained in complete response to the treatment for at least 12 months,” the agency noted.

The FDA also noted that treatment with Abecma can cause severe side effects. The label carries a boxed warning regarding CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life threatening.

The most common side effects of Abecma are CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first 1-2 weeks after treatment, but some side effects may occur later.

The agency also noted that, to further evaluate the long-term safety of the drug, it is requiring the manufacturer to conduct a postmarketing observational study.

“The FDA remains committed to advancing novel treatment options for areas of unmet patient need,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

“While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual’s age and the stage of the condition at the time of diagnosis. Today’s approval provides a new treatment option for patients who have this uncommon type of cancer.”

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Patients with cancer are at significantly increased risk for COVID-19 and worse outcomes, a new review confirms. It also found that patients with leukemia, non-Hodgkin lymphoma, and lung cancer are at greatest risk.

Blacks with cancer are at even higher risk, and for patients with colorectal cancer and non-Hodgkin lymphoma, the risk is higher for women than for men. (This contrasts with findings in noncancer populations, where men are more at risk from COVID-19 and severe outcomes than women.)

These findings come from a huge review of electronic health records of 73.4 million patients in the United States. They “highlight the need to protect and monitor patients with cancer as part of the strategy to control the pandemic,” the authors wrote.

The review was published online Dec. 10 in JAMA Oncology.

The greater risk for COVID-19 among patients with cancer is well known, but breaking the risk down by cancer type is novel, wrote the investigators, led by Quanqiu Wang, MS, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland.

Cancer patients are immunocompromised and have more contact with the health care system, which increases their risk for COVID-19. But which bodily systems are affected by cancer seems to matter. In patients with blood cancer, for example, COVID-19 is probably more dangerous, because blood cancer weakens the immune system directly, the authors suggested.

The increased risk for infection and hospitalization with SARS-CoV-2 among Black patients with cancer might be because of biology, but it is more likely because of factors that weren’t captured in the database review. Such factors include social adversity, economic status, access to health care, and lifestyle, the researchers noted.

For this study, the investigators analyzed electronic health records held in the IBM Watson Health Explorys system, which captures about 15% of new cancer diagnoses in the United States.

The analysis found that, as of Aug. 14, 2020, 16,570 patients (0.02%) had been diagnosed with COVID-19; about 1,200 also had been diagnosed with cancer. Of those, 690 were diagnosed with cancer in the previous year, which counted as a recent cancer diagnosis in the analysis. The study included 13 common cancers, including endometrial, kidney, liver, lung, gastrointestinal, prostate, skin, and thyroid cancers, among others.

Patients with any cancer diagnosis (adjusted odds ratio, 1.46) as well as those with a recent cancer diagnosis (aOR, 7.14) had a significantly higher risk for COVID-19 than those without cancer, after adjusting for asthma, cardiovascular diseases, nursing home stays, and other risk factors.

The risk for COVID-19 was highest among patients recently diagnosed with leukemia (aOR, 12.16), non-Hodgkin lymphoma (aOR, 8.54), and lung cancer (aOR 7.66). The risk for COVID-19 was lower for patients with cancers associated with worse prognoses, including pancreatic (aOR, 6.26) and liver (aOR, 6.49) cancer. It was weakest for patients with thyroid cancer (aOR, 3.10; P for all < .001).

Hospitalization was more common in recent cancer patients with COVID-19 than in COVID-19 patients without cancer (47.46% vs. 24.6%), as was COVID-19–related death (14.93% vs. 5.26%). Among cancer patients who did not have COVID-19, 12.39% were hospitalized, and 4.03% died. The findings suggest a synergistic effect between the COVID-19 and cancer, the team noted.

Among patients recently diagnosed with cancer, Black patients – 10.3% of the overall study population – had a significantly higher risk for COVID-19 than White patients. The racial disparity was largest for patients with breast cancer (aOR, 5.44), followed by patients with prostate cancer (aOR, 5.10), colorectal cancer (aOR, 3.30), and lung cancer (aOR, 2.53; P for all < .001).

Hospitalizations were more common among Black patients with cancer and COVID-19 than White patients. There was also a trend toward higher mortality among Black patients (18.52% vs. 13.51%; P = .11)

However, these differences may not be related to race, oncologist Aakash Desai, MBBS, of the Mayo Clinic, Rochester, Minn., and colleagues noted in an accompanying commentary. “Interestingly, a previous study of hospitalized patients with COVID-19 without cancer demonstrated that mortality rates for Black patients were comparable to those for White patients after adjustment for both comorbidities and deprivation index, suggesting that observed differences are mainly owing to societal disparities rather than biology.”

The editorialists also noted that the finding that Black patients with cancer are at greater risk for COVID-19 (aOR, 1.58-5.44, depending on cancer) echoes the findings in the general population. The Centers for Disease Control and Prevention estimates a severalfold increased risk among Black patients. These higher rates may largely be explained by social determinants, they suggested. Such factors include increased burden of comorbidities, crowded living conditions (inner cities, multigenerational homes, etc.), dependence on public transportation or child care, and higher work-related exposures. “Until such societal disparities are accounted for, we cannot presume these findings are caused by any inherent differences among racial groups,” the editorialists wrote.

“Clearly, the haunting spotlight of COVID-19 has dramatically illuminated known U.S. health care and societal disparities,” Dr. Desai and colleagues wrote. “This situation should be a wake-up call that brings much-needed improvements in U.S. equity policies, including but not limited to better health care access. Nothing appears more critical for alleviating these disparate clinical outcomes in this time of crisis and beyond,” they declared.

The study was funded by the National Institutes of Health, the American Cancer Society, and other organizations. The investigators disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with cancer are at significantly increased risk for COVID-19 and worse outcomes, a new review confirms. It also found that patients with leukemia, non-Hodgkin lymphoma, and lung cancer are at greatest risk.

Blacks with cancer are at even higher risk, and for patients with colorectal cancer and non-Hodgkin lymphoma, the risk is higher for women than for men. (This contrasts with findings in noncancer populations, where men are more at risk from COVID-19 and severe outcomes than women.)

These findings come from a huge review of electronic health records of 73.4 million patients in the United States. They “highlight the need to protect and monitor patients with cancer as part of the strategy to control the pandemic,” the authors wrote.

The review was published online Dec. 10 in JAMA Oncology.

The greater risk for COVID-19 among patients with cancer is well known, but breaking the risk down by cancer type is novel, wrote the investigators, led by Quanqiu Wang, MS, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland.

Cancer patients are immunocompromised and have more contact with the health care system, which increases their risk for COVID-19. But which bodily systems are affected by cancer seems to matter. In patients with blood cancer, for example, COVID-19 is probably more dangerous, because blood cancer weakens the immune system directly, the authors suggested.

The increased risk for infection and hospitalization with SARS-CoV-2 among Black patients with cancer might be because of biology, but it is more likely because of factors that weren’t captured in the database review. Such factors include social adversity, economic status, access to health care, and lifestyle, the researchers noted.

For this study, the investigators analyzed electronic health records held in the IBM Watson Health Explorys system, which captures about 15% of new cancer diagnoses in the United States.

The analysis found that, as of Aug. 14, 2020, 16,570 patients (0.02%) had been diagnosed with COVID-19; about 1,200 also had been diagnosed with cancer. Of those, 690 were diagnosed with cancer in the previous year, which counted as a recent cancer diagnosis in the analysis. The study included 13 common cancers, including endometrial, kidney, liver, lung, gastrointestinal, prostate, skin, and thyroid cancers, among others.

Patients with any cancer diagnosis (adjusted odds ratio, 1.46) as well as those with a recent cancer diagnosis (aOR, 7.14) had a significantly higher risk for COVID-19 than those without cancer, after adjusting for asthma, cardiovascular diseases, nursing home stays, and other risk factors.

The risk for COVID-19 was highest among patients recently diagnosed with leukemia (aOR, 12.16), non-Hodgkin lymphoma (aOR, 8.54), and lung cancer (aOR 7.66). The risk for COVID-19 was lower for patients with cancers associated with worse prognoses, including pancreatic (aOR, 6.26) and liver (aOR, 6.49) cancer. It was weakest for patients with thyroid cancer (aOR, 3.10; P for all < .001).

Hospitalization was more common in recent cancer patients with COVID-19 than in COVID-19 patients without cancer (47.46% vs. 24.6%), as was COVID-19–related death (14.93% vs. 5.26%). Among cancer patients who did not have COVID-19, 12.39% were hospitalized, and 4.03% died. The findings suggest a synergistic effect between the COVID-19 and cancer, the team noted.

Among patients recently diagnosed with cancer, Black patients – 10.3% of the overall study population – had a significantly higher risk for COVID-19 than White patients. The racial disparity was largest for patients with breast cancer (aOR, 5.44), followed by patients with prostate cancer (aOR, 5.10), colorectal cancer (aOR, 3.30), and lung cancer (aOR, 2.53; P for all < .001).

Hospitalizations were more common among Black patients with cancer and COVID-19 than White patients. There was also a trend toward higher mortality among Black patients (18.52% vs. 13.51%; P = .11)

However, these differences may not be related to race, oncologist Aakash Desai, MBBS, of the Mayo Clinic, Rochester, Minn., and colleagues noted in an accompanying commentary. “Interestingly, a previous study of hospitalized patients with COVID-19 without cancer demonstrated that mortality rates for Black patients were comparable to those for White patients after adjustment for both comorbidities and deprivation index, suggesting that observed differences are mainly owing to societal disparities rather than biology.”

The editorialists also noted that the finding that Black patients with cancer are at greater risk for COVID-19 (aOR, 1.58-5.44, depending on cancer) echoes the findings in the general population. The Centers for Disease Control and Prevention estimates a severalfold increased risk among Black patients. These higher rates may largely be explained by social determinants, they suggested. Such factors include increased burden of comorbidities, crowded living conditions (inner cities, multigenerational homes, etc.), dependence on public transportation or child care, and higher work-related exposures. “Until such societal disparities are accounted for, we cannot presume these findings are caused by any inherent differences among racial groups,” the editorialists wrote.

“Clearly, the haunting spotlight of COVID-19 has dramatically illuminated known U.S. health care and societal disparities,” Dr. Desai and colleagues wrote. “This situation should be a wake-up call that brings much-needed improvements in U.S. equity policies, including but not limited to better health care access. Nothing appears more critical for alleviating these disparate clinical outcomes in this time of crisis and beyond,” they declared.

The study was funded by the National Institutes of Health, the American Cancer Society, and other organizations. The investigators disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with cancer are at significantly increased risk for COVID-19 and worse outcomes, a new review confirms. It also found that patients with leukemia, non-Hodgkin lymphoma, and lung cancer are at greatest risk.

Blacks with cancer are at even higher risk, and for patients with colorectal cancer and non-Hodgkin lymphoma, the risk is higher for women than for men. (This contrasts with findings in noncancer populations, where men are more at risk from COVID-19 and severe outcomes than women.)

These findings come from a huge review of electronic health records of 73.4 million patients in the United States. They “highlight the need to protect and monitor patients with cancer as part of the strategy to control the pandemic,” the authors wrote.

The review was published online Dec. 10 in JAMA Oncology.

The greater risk for COVID-19 among patients with cancer is well known, but breaking the risk down by cancer type is novel, wrote the investigators, led by Quanqiu Wang, MS, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland.

Cancer patients are immunocompromised and have more contact with the health care system, which increases their risk for COVID-19. But which bodily systems are affected by cancer seems to matter. In patients with blood cancer, for example, COVID-19 is probably more dangerous, because blood cancer weakens the immune system directly, the authors suggested.

The increased risk for infection and hospitalization with SARS-CoV-2 among Black patients with cancer might be because of biology, but it is more likely because of factors that weren’t captured in the database review. Such factors include social adversity, economic status, access to health care, and lifestyle, the researchers noted.

For this study, the investigators analyzed electronic health records held in the IBM Watson Health Explorys system, which captures about 15% of new cancer diagnoses in the United States.

The analysis found that, as of Aug. 14, 2020, 16,570 patients (0.02%) had been diagnosed with COVID-19; about 1,200 also had been diagnosed with cancer. Of those, 690 were diagnosed with cancer in the previous year, which counted as a recent cancer diagnosis in the analysis. The study included 13 common cancers, including endometrial, kidney, liver, lung, gastrointestinal, prostate, skin, and thyroid cancers, among others.

Patients with any cancer diagnosis (adjusted odds ratio, 1.46) as well as those with a recent cancer diagnosis (aOR, 7.14) had a significantly higher risk for COVID-19 than those without cancer, after adjusting for asthma, cardiovascular diseases, nursing home stays, and other risk factors.

The risk for COVID-19 was highest among patients recently diagnosed with leukemia (aOR, 12.16), non-Hodgkin lymphoma (aOR, 8.54), and lung cancer (aOR 7.66). The risk for COVID-19 was lower for patients with cancers associated with worse prognoses, including pancreatic (aOR, 6.26) and liver (aOR, 6.49) cancer. It was weakest for patients with thyroid cancer (aOR, 3.10; P for all < .001).

Hospitalization was more common in recent cancer patients with COVID-19 than in COVID-19 patients without cancer (47.46% vs. 24.6%), as was COVID-19–related death (14.93% vs. 5.26%). Among cancer patients who did not have COVID-19, 12.39% were hospitalized, and 4.03% died. The findings suggest a synergistic effect between the COVID-19 and cancer, the team noted.

Among patients recently diagnosed with cancer, Black patients – 10.3% of the overall study population – had a significantly higher risk for COVID-19 than White patients. The racial disparity was largest for patients with breast cancer (aOR, 5.44), followed by patients with prostate cancer (aOR, 5.10), colorectal cancer (aOR, 3.30), and lung cancer (aOR, 2.53; P for all < .001).

Hospitalizations were more common among Black patients with cancer and COVID-19 than White patients. There was also a trend toward higher mortality among Black patients (18.52% vs. 13.51%; P = .11)

However, these differences may not be related to race, oncologist Aakash Desai, MBBS, of the Mayo Clinic, Rochester, Minn., and colleagues noted in an accompanying commentary. “Interestingly, a previous study of hospitalized patients with COVID-19 without cancer demonstrated that mortality rates for Black patients were comparable to those for White patients after adjustment for both comorbidities and deprivation index, suggesting that observed differences are mainly owing to societal disparities rather than biology.”

The editorialists also noted that the finding that Black patients with cancer are at greater risk for COVID-19 (aOR, 1.58-5.44, depending on cancer) echoes the findings in the general population. The Centers for Disease Control and Prevention estimates a severalfold increased risk among Black patients. These higher rates may largely be explained by social determinants, they suggested. Such factors include increased burden of comorbidities, crowded living conditions (inner cities, multigenerational homes, etc.), dependence on public transportation or child care, and higher work-related exposures. “Until such societal disparities are accounted for, we cannot presume these findings are caused by any inherent differences among racial groups,” the editorialists wrote.

“Clearly, the haunting spotlight of COVID-19 has dramatically illuminated known U.S. health care and societal disparities,” Dr. Desai and colleagues wrote. “This situation should be a wake-up call that brings much-needed improvements in U.S. equity policies, including but not limited to better health care access. Nothing appears more critical for alleviating these disparate clinical outcomes in this time of crisis and beyond,” they declared.

The study was funded by the National Institutes of Health, the American Cancer Society, and other organizations. The investigators disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.