B Cell Lymphoma

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

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

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

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

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

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.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

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.

Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.

The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.

While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.

Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
 

Longer follow-up needed

The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.

Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.

“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.

Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.

Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.

“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
 

Ongoing responses at 9 months

The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.

Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.

As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.

The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.

Median duration of response, progression-free survival, and overall survival have not been reached, he added.

Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.

All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.

ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
 

SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.

Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.

The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.

While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.

Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
 

Longer follow-up needed

The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.

Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.

“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.

Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.

Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.

“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
 

Ongoing responses at 9 months

The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.

Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.

As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.

The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.

Median duration of response, progression-free survival, and overall survival have not been reached, he added.

Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.

All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.

ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
 

SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.

Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.

The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.

While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.

Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
 

Longer follow-up needed

The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.

Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.

“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.

Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.

Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.

“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
 

Ongoing responses at 9 months

The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.

Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.

As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.

The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.

Median duration of response, progression-free survival, and overall survival have not been reached, he added.

Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.

All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.

ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
 

SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.

Adolescents and young adults with aggressive mature B-cell non-Hodgkin lymphomas appear to have better outcomes when they’re treated under pediatric protocols rather than adult regimens, Canadian investigators say.

Results of a study of patients from the ages of 15 to 21 years with either diffuse large B-cell lymphoma (DLBCL) or Burkitt’s lymphoma treated at regional or community cancer centers in the province of Ontario indicated that adolescents and young adult (AYA) patients treated at adult centers had a more than fourfold risk for disease relapse or progression, compared with their counterparts who were treated at pediatric centers, reported Sumit Gupta, MD, PhD, from the Hospital for Sick Children in Toronto and colleagues.

“Our data suggest that pediatric approaches are associated with improved event-free survival and overall survival, primarily due to a decrease in the risk of relapse or progression, while still using lower cumulative doses of chemotherapy,” he said in an oral abstract presented at the American Society of Hematology annual meeting, held virtually.

The findings echo those seen in the treatment of patients with acute lymphoblastic leukemia (ALL). As previously reported, a study from Nordic and Baltic countries showed that young adults with ALL who were treated with a pediatric regimen had a 4-year event-free survival rate of 73%, compared with 42% for historical controls.

Similarly, a prospective U.S. study reported in 2014 showed that AYA with ALL treated with a pediatric regimen had better overall and event-free survival rates, compared with historical controls.

As with ALL, pediatric and adult regimens for treatment of patients with aggressive mature B-cell NHL differ substantially, with pediatric patients receiving more intensive short-term therapy with lower cumulative doses.

In addition, while pediatric regimens for DLBCL and Burkitt’s lymphoma are identical, adult regimens differ substantially between the two histologies, Dr. Gupta pointed out.

Adult regimens for DLBCL most often incorporate CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP), whereas Burkitt’s lymphoma in adults is generally treated with more aggressive multidrug regimens, in combination with rituximab.

Rituximab was incorporated into adults’ regimens far earlier than in pediatric regimens, with Food and Drug Administration approval of rituximab in frontline therapy of adults with DLBCL in 2006, “whereas the first pediatric large-scale randomized controlled trial of rituximab in pediatric mature B-cell lymphoma was only published earlier this year,” he noted.
 

Population-based study

To see how treatment patterns for AYA patients with aggressive mature B-cell non-Hodgkin lymphomas differ between pediatric and adult centers, Dr. Gupta and colleagues conducted a population-based study of all AYA in Ontario diagnosed with Burkitt’s or DLBCL from the ages of 15 to 21 years from 1992 through 2012.

AYA from the ages of 15 to 18 years who were treated at pediatric centers were identified through the Provincial Pediatric Oncology Registry, which includes data on demographics, disease treatment, and outcomes from each of Ontario’s five childhood cancer treatments centers.

Adolescents and young adults from 15 to 21 years who were treated at adult centers with adult regimens were identified through the Ontario Cancer Registry using chart abstraction by trained personnel at all treatment centers, with all data validated by clinician reviewers.

A total of 176 patients were identified, 129 with DLBCL and 47 with Burkitt’s lymphoma. In all, 62 of the 176 patients (35.2%) were treated in pediatric centers. Not surprisingly, multivariable analysis showed that AYA treated in adult centers were older, and more likely to have been treated earlier in the study period.

Comparing treatment patterns by locus of care, the investigators found that patients with DLBCL in pediatric centers received half of the cumulative anthracycline doses as those in adult centers (150 mg/m² vs. 300 mg/m²; P < .001) and about 75% of cumulative alkylating agent doses (3,300 mg/m² vs. 4,465 mg/m²; P = .009).

Patients with Burkitt’s lymphoma had identical exposures to anthracyclines in pediatric vs. adult centers (120 mg/m²), but those treated in pediatric centers had half the exposure to alkylators as those treated in adult centers (3,300 mg/m² vs. 6,600 mg/m²; P = .03).

Among patients with DLBCL, none of those treated at pediatric centers received rituximab, compared with 32.3% of those treated at adult centers (P < .001), whereas only a handful of patients with Burkitt’s lymphoma received rituximab in both pediatric and adult centers (nonsignificant).

Among all patients. 5-year event-free survival was 82.3% for those treated in pediatric centers, compared with 66.7% for those treated in adult centers (P = .02). Respective 5-year overall survival rates were 85.5% and 71.1% (P = .03).

Looking at survival by histology, the investigators saw that 5-year event-free survival for patients with DLBCL was 83.3% when they were treated like children vs. 66.7% when they were treated like adults (P = .04). Respective 5-year overall survival rates were 88.9% and 72% (P = .04).

Both event-free survival (80.8% vs. 66.7%) and overall survival (80.8% vs. 66.7%) were numerically but not statistically higher among patients with Burkitt’s treated at pediatric vs. adult centers.

An analysis adjusting for disease histology, stage, and time period of diagnosis showed that treatment at an adult center was associated with higher risk for death, with a hazard ratio of 2.4 (P = .03).

Additionally, an analysis adjusted for age, disease stage, and histology showed that patients treated in adult centers had a significantly increased risk of relapse or progression, compared with a HR of 4.4 (95% confidence interval; P = .008).

There were no significant differences in the risk of treatment-related mortality between the center types, however.

“It is important to note, however, that pediatric approaches to mature B-cell NHL [non-Hodgkin lymphoma] are associated with increased inpatient needs as compared to adult approaches, and with greater supportive care requirements. Thus the safety of such approaches in adults centers need to be established,” Dr. Gupta said.
 

Lower doses, better outcomes

In the question and answer session following the presentation, Jennifer Teichman, MD, MSc, a fellow in hematology at the University of Toronto who was not involved in the study asked why patients treated at adult centers would have higher relapse rates despite receiving higher doses of chemotherapy, noting that the poorer outcomes in those patients were not attributable to treatment-related mortality.

“I think one of the distinctions is that higher cumulative doses versus higher intensity of treatment over a shorter period of time are two different things, perhaps, and so giving lower cumulative doses but over a short period of time, and so giving higher intensity within that short period of time, may be what explains the higher success rate in pediatric trials,” Dr. Gupta said.

R. Michael Crump, MD, from the Princess Margaret Cancer Center, also in Toronto, asked whether the study results could have been influenced by differences between the pediatric center and adult center datasets in regard to pathology review, staging information, and International Prognostic Index.

Dr. Gupta acknowledged that, while the pediatric data were captured prospectively at each center by pediatric cancer registry staff and adult data were extracted retrospectively by trained chart reviewers, “the information that we were collecting was relatively basic – basic stage, basic histology, and that is a limitation.”

He also noted that clinicians reviewed the submitted retrospective data for completeness and had the ability to request chart extractors to return to a particular record for additional information or to correct potential errors.

The study was supported by the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.

SOURCE: Gupta S et al. ASH 2020, Abstract 708.

Adolescents and young adults with aggressive mature B-cell non-Hodgkin lymphomas appear to have better outcomes when they’re treated under pediatric protocols rather than adult regimens, Canadian investigators say.

Results of a study of patients from the ages of 15 to 21 years with either diffuse large B-cell lymphoma (DLBCL) or Burkitt’s lymphoma treated at regional or community cancer centers in the province of Ontario indicated that adolescents and young adult (AYA) patients treated at adult centers had a more than fourfold risk for disease relapse or progression, compared with their counterparts who were treated at pediatric centers, reported Sumit Gupta, MD, PhD, from the Hospital for Sick Children in Toronto and colleagues.

“Our data suggest that pediatric approaches are associated with improved event-free survival and overall survival, primarily due to a decrease in the risk of relapse or progression, while still using lower cumulative doses of chemotherapy,” he said in an oral abstract presented at the American Society of Hematology annual meeting, held virtually.

The findings echo those seen in the treatment of patients with acute lymphoblastic leukemia (ALL). As previously reported, a study from Nordic and Baltic countries showed that young adults with ALL who were treated with a pediatric regimen had a 4-year event-free survival rate of 73%, compared with 42% for historical controls.

Similarly, a prospective U.S. study reported in 2014 showed that AYA with ALL treated with a pediatric regimen had better overall and event-free survival rates, compared with historical controls.

As with ALL, pediatric and adult regimens for treatment of patients with aggressive mature B-cell NHL differ substantially, with pediatric patients receiving more intensive short-term therapy with lower cumulative doses.

In addition, while pediatric regimens for DLBCL and Burkitt’s lymphoma are identical, adult regimens differ substantially between the two histologies, Dr. Gupta pointed out.

Adult regimens for DLBCL most often incorporate CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP), whereas Burkitt’s lymphoma in adults is generally treated with more aggressive multidrug regimens, in combination with rituximab.

Rituximab was incorporated into adults’ regimens far earlier than in pediatric regimens, with Food and Drug Administration approval of rituximab in frontline therapy of adults with DLBCL in 2006, “whereas the first pediatric large-scale randomized controlled trial of rituximab in pediatric mature B-cell lymphoma was only published earlier this year,” he noted.
 

Population-based study

To see how treatment patterns for AYA patients with aggressive mature B-cell non-Hodgkin lymphomas differ between pediatric and adult centers, Dr. Gupta and colleagues conducted a population-based study of all AYA in Ontario diagnosed with Burkitt’s or DLBCL from the ages of 15 to 21 years from 1992 through 2012.

AYA from the ages of 15 to 18 years who were treated at pediatric centers were identified through the Provincial Pediatric Oncology Registry, which includes data on demographics, disease treatment, and outcomes from each of Ontario’s five childhood cancer treatments centers.

Adolescents and young adults from 15 to 21 years who were treated at adult centers with adult regimens were identified through the Ontario Cancer Registry using chart abstraction by trained personnel at all treatment centers, with all data validated by clinician reviewers.

A total of 176 patients were identified, 129 with DLBCL and 47 with Burkitt’s lymphoma. In all, 62 of the 176 patients (35.2%) were treated in pediatric centers. Not surprisingly, multivariable analysis showed that AYA treated in adult centers were older, and more likely to have been treated earlier in the study period.

Comparing treatment patterns by locus of care, the investigators found that patients with DLBCL in pediatric centers received half of the cumulative anthracycline doses as those in adult centers (150 mg/m² vs. 300 mg/m²; P < .001) and about 75% of cumulative alkylating agent doses (3,300 mg/m² vs. 4,465 mg/m²; P = .009).

Patients with Burkitt’s lymphoma had identical exposures to anthracyclines in pediatric vs. adult centers (120 mg/m²), but those treated in pediatric centers had half the exposure to alkylators as those treated in adult centers (3,300 mg/m² vs. 6,600 mg/m²; P = .03).

Among patients with DLBCL, none of those treated at pediatric centers received rituximab, compared with 32.3% of those treated at adult centers (P < .001), whereas only a handful of patients with Burkitt’s lymphoma received rituximab in both pediatric and adult centers (nonsignificant).

Among all patients. 5-year event-free survival was 82.3% for those treated in pediatric centers, compared with 66.7% for those treated in adult centers (P = .02). Respective 5-year overall survival rates were 85.5% and 71.1% (P = .03).

Looking at survival by histology, the investigators saw that 5-year event-free survival for patients with DLBCL was 83.3% when they were treated like children vs. 66.7% when they were treated like adults (P = .04). Respective 5-year overall survival rates were 88.9% and 72% (P = .04).

Both event-free survival (80.8% vs. 66.7%) and overall survival (80.8% vs. 66.7%) were numerically but not statistically higher among patients with Burkitt’s treated at pediatric vs. adult centers.

An analysis adjusting for disease histology, stage, and time period of diagnosis showed that treatment at an adult center was associated with higher risk for death, with a hazard ratio of 2.4 (P = .03).

Additionally, an analysis adjusted for age, disease stage, and histology showed that patients treated in adult centers had a significantly increased risk of relapse or progression, compared with a HR of 4.4 (95% confidence interval; P = .008).

There were no significant differences in the risk of treatment-related mortality between the center types, however.

“It is important to note, however, that pediatric approaches to mature B-cell NHL [non-Hodgkin lymphoma] are associated with increased inpatient needs as compared to adult approaches, and with greater supportive care requirements. Thus the safety of such approaches in adults centers need to be established,” Dr. Gupta said.
 

Lower doses, better outcomes

In the question and answer session following the presentation, Jennifer Teichman, MD, MSc, a fellow in hematology at the University of Toronto who was not involved in the study asked why patients treated at adult centers would have higher relapse rates despite receiving higher doses of chemotherapy, noting that the poorer outcomes in those patients were not attributable to treatment-related mortality.

“I think one of the distinctions is that higher cumulative doses versus higher intensity of treatment over a shorter period of time are two different things, perhaps, and so giving lower cumulative doses but over a short period of time, and so giving higher intensity within that short period of time, may be what explains the higher success rate in pediatric trials,” Dr. Gupta said.

R. Michael Crump, MD, from the Princess Margaret Cancer Center, also in Toronto, asked whether the study results could have been influenced by differences between the pediatric center and adult center datasets in regard to pathology review, staging information, and International Prognostic Index.

Dr. Gupta acknowledged that, while the pediatric data were captured prospectively at each center by pediatric cancer registry staff and adult data were extracted retrospectively by trained chart reviewers, “the information that we were collecting was relatively basic – basic stage, basic histology, and that is a limitation.”

He also noted that clinicians reviewed the submitted retrospective data for completeness and had the ability to request chart extractors to return to a particular record for additional information or to correct potential errors.

The study was supported by the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.

SOURCE: Gupta S et al. ASH 2020, Abstract 708.

Adolescents and young adults with aggressive mature B-cell non-Hodgkin lymphomas appear to have better outcomes when they’re treated under pediatric protocols rather than adult regimens, Canadian investigators say.

Results of a study of patients from the ages of 15 to 21 years with either diffuse large B-cell lymphoma (DLBCL) or Burkitt’s lymphoma treated at regional or community cancer centers in the province of Ontario indicated that adolescents and young adult (AYA) patients treated at adult centers had a more than fourfold risk for disease relapse or progression, compared with their counterparts who were treated at pediatric centers, reported Sumit Gupta, MD, PhD, from the Hospital for Sick Children in Toronto and colleagues.

“Our data suggest that pediatric approaches are associated with improved event-free survival and overall survival, primarily due to a decrease in the risk of relapse or progression, while still using lower cumulative doses of chemotherapy,” he said in an oral abstract presented at the American Society of Hematology annual meeting, held virtually.

The findings echo those seen in the treatment of patients with acute lymphoblastic leukemia (ALL). As previously reported, a study from Nordic and Baltic countries showed that young adults with ALL who were treated with a pediatric regimen had a 4-year event-free survival rate of 73%, compared with 42% for historical controls.

Similarly, a prospective U.S. study reported in 2014 showed that AYA with ALL treated with a pediatric regimen had better overall and event-free survival rates, compared with historical controls.

As with ALL, pediatric and adult regimens for treatment of patients with aggressive mature B-cell NHL differ substantially, with pediatric patients receiving more intensive short-term therapy with lower cumulative doses.

In addition, while pediatric regimens for DLBCL and Burkitt’s lymphoma are identical, adult regimens differ substantially between the two histologies, Dr. Gupta pointed out.

Adult regimens for DLBCL most often incorporate CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP), whereas Burkitt’s lymphoma in adults is generally treated with more aggressive multidrug regimens, in combination with rituximab.

Rituximab was incorporated into adults’ regimens far earlier than in pediatric regimens, with Food and Drug Administration approval of rituximab in frontline therapy of adults with DLBCL in 2006, “whereas the first pediatric large-scale randomized controlled trial of rituximab in pediatric mature B-cell lymphoma was only published earlier this year,” he noted.
 

Population-based study

To see how treatment patterns for AYA patients with aggressive mature B-cell non-Hodgkin lymphomas differ between pediatric and adult centers, Dr. Gupta and colleagues conducted a population-based study of all AYA in Ontario diagnosed with Burkitt’s or DLBCL from the ages of 15 to 21 years from 1992 through 2012.

AYA from the ages of 15 to 18 years who were treated at pediatric centers were identified through the Provincial Pediatric Oncology Registry, which includes data on demographics, disease treatment, and outcomes from each of Ontario’s five childhood cancer treatments centers.

Adolescents and young adults from 15 to 21 years who were treated at adult centers with adult regimens were identified through the Ontario Cancer Registry using chart abstraction by trained personnel at all treatment centers, with all data validated by clinician reviewers.

A total of 176 patients were identified, 129 with DLBCL and 47 with Burkitt’s lymphoma. In all, 62 of the 176 patients (35.2%) were treated in pediatric centers. Not surprisingly, multivariable analysis showed that AYA treated in adult centers were older, and more likely to have been treated earlier in the study period.

Comparing treatment patterns by locus of care, the investigators found that patients with DLBCL in pediatric centers received half of the cumulative anthracycline doses as those in adult centers (150 mg/m² vs. 300 mg/m²; P < .001) and about 75% of cumulative alkylating agent doses (3,300 mg/m² vs. 4,465 mg/m²; P = .009).

Patients with Burkitt’s lymphoma had identical exposures to anthracyclines in pediatric vs. adult centers (120 mg/m²), but those treated in pediatric centers had half the exposure to alkylators as those treated in adult centers (3,300 mg/m² vs. 6,600 mg/m²; P = .03).

Among patients with DLBCL, none of those treated at pediatric centers received rituximab, compared with 32.3% of those treated at adult centers (P < .001), whereas only a handful of patients with Burkitt’s lymphoma received rituximab in both pediatric and adult centers (nonsignificant).

Among all patients. 5-year event-free survival was 82.3% for those treated in pediatric centers, compared with 66.7% for those treated in adult centers (P = .02). Respective 5-year overall survival rates were 85.5% and 71.1% (P = .03).

Looking at survival by histology, the investigators saw that 5-year event-free survival for patients with DLBCL was 83.3% when they were treated like children vs. 66.7% when they were treated like adults (P = .04). Respective 5-year overall survival rates were 88.9% and 72% (P = .04).

Both event-free survival (80.8% vs. 66.7%) and overall survival (80.8% vs. 66.7%) were numerically but not statistically higher among patients with Burkitt’s treated at pediatric vs. adult centers.

An analysis adjusting for disease histology, stage, and time period of diagnosis showed that treatment at an adult center was associated with higher risk for death, with a hazard ratio of 2.4 (P = .03).

Additionally, an analysis adjusted for age, disease stage, and histology showed that patients treated in adult centers had a significantly increased risk of relapse or progression, compared with a HR of 4.4 (95% confidence interval; P = .008).

There were no significant differences in the risk of treatment-related mortality between the center types, however.

“It is important to note, however, that pediatric approaches to mature B-cell NHL [non-Hodgkin lymphoma] are associated with increased inpatient needs as compared to adult approaches, and with greater supportive care requirements. Thus the safety of such approaches in adults centers need to be established,” Dr. Gupta said.
 

Lower doses, better outcomes

In the question and answer session following the presentation, Jennifer Teichman, MD, MSc, a fellow in hematology at the University of Toronto who was not involved in the study asked why patients treated at adult centers would have higher relapse rates despite receiving higher doses of chemotherapy, noting that the poorer outcomes in those patients were not attributable to treatment-related mortality.

“I think one of the distinctions is that higher cumulative doses versus higher intensity of treatment over a shorter period of time are two different things, perhaps, and so giving lower cumulative doses but over a short period of time, and so giving higher intensity within that short period of time, may be what explains the higher success rate in pediatric trials,” Dr. Gupta said.

R. Michael Crump, MD, from the Princess Margaret Cancer Center, also in Toronto, asked whether the study results could have been influenced by differences between the pediatric center and adult center datasets in regard to pathology review, staging information, and International Prognostic Index.

Dr. Gupta acknowledged that, while the pediatric data were captured prospectively at each center by pediatric cancer registry staff and adult data were extracted retrospectively by trained chart reviewers, “the information that we were collecting was relatively basic – basic stage, basic histology, and that is a limitation.”

He also noted that clinicians reviewed the submitted retrospective data for completeness and had the ability to request chart extractors to return to a particular record for additional information or to correct potential errors.

The study was supported by the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.

SOURCE: Gupta S et al. ASH 2020, Abstract 708.

The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.

Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.

Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.

For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.

Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.

This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.

“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
 

Durability with further follow-up

Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.

In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.

In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.

In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.

In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.

Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.

Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).

No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.

No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
 

More research needed

Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.

“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.

“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.

A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.

The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
 

SOURCE: Bannerji R et al. ASH 2020, Abstract 400.

The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.

Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.

Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.

For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.

Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.

This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.

“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
 

Durability with further follow-up

Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.

In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.

In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.

In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.

In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.

Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.

Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).

No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.

No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
 

More research needed

Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.

“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.

“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.

A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.

The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
 

SOURCE: Bannerji R et al. ASH 2020, Abstract 400.

The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.

Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.

Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.

For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.

Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.

This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.

“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
 

Durability with further follow-up

Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.

In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.

In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.

In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.

In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.

Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.

Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).

No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.

No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
 

More research needed

Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.

“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.

“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.

A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.

The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
 

SOURCE: Bannerji R et al. ASH 2020, Abstract 400.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.

The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.

Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
 

Common etiology?

Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.

The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.

Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.

These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.

“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.

The study was sponsored by the French government. The authors stated that they had no conflicts of interest.

[email protected]

SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.

Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.

The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.

Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
 

Common etiology?

Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.

The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.

Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.

These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.

“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.

The study was sponsored by the French government. The authors stated that they had no conflicts of interest.

[email protected]

SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.

Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.

The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.

Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
 

Common etiology?

Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.

The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.

Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.

These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.

“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.

The study was sponsored by the French government. The authors stated that they had no conflicts of interest.

[email protected]

SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.