Aggressive Lymphomas

Mantle cell lymphoma

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to acalabrutinib, a BTK inhibitor being developed to treat multiple B-cell malignancies.

The breakthrough designation applies to acalabrutinib as a treatment for patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

The FDA granted acalabrutinib breakthrough designation based on data from the drug’s development program, which includes data from the phase 2 ACE-LY-004 trial in patients with relapsed or refractory MCL.

Data from this trial have not yet been released to the public but are expected to be presented at an upcoming medical meeting.

Mantle cell lymphoma

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to acalabrutinib, a BTK inhibitor being developed to treat multiple B-cell malignancies.

The breakthrough designation applies to acalabrutinib as a treatment for patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

The FDA granted acalabrutinib breakthrough designation based on data from the drug’s development program, which includes data from the phase 2 ACE-LY-004 trial in patients with relapsed or refractory MCL.

Data from this trial have not yet been released to the public but are expected to be presented at an upcoming medical meeting.

Mantle cell lymphoma

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to acalabrutinib, a BTK inhibitor being developed to treat multiple B-cell malignancies.

The breakthrough designation applies to acalabrutinib as a treatment for patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

The FDA granted acalabrutinib breakthrough designation based on data from the drug’s development program, which includes data from the phase 2 ACE-LY-004 trial in patients with relapsed or refractory MCL.

Data from this trial have not yet been released to the public but are expected to be presented at an upcoming medical meeting.

Photo by Aaron Logan

Researchers say they have developed a new approach to model human immune variation that overcomes the limitations of traditional mouse models.

With this approach, the team identified genetic markers that directly correlate with the outcome of inflammatory and malignant diseases in humans, including chronic lymphocytic leukemia and Burkitt lymphoma.

The findings suggest that accounting for immune diversity is critical to the success of predicting disease outcomes based on immune cell measurements.

The team reported these findings in Nature Communications.

Traditionally, researchers have relied on inbred mouse strains to gain insight into human diseases while reducing experimental noise.

“If you take a black, a brown, or a white mouse, each one will give you a different answer in the same assay,” said Klaus Ley, MD, of La Jolla Institute for Allergy and Immunology in California.

“For example, if you vaccinate them, their responses will be different, which creates a lot of experimental noise. However, when you think about patients, or even healthy people, we are all different.”

To mine those differences for information, the researchers embraced the experimental noise. Instead of analyzing a single inbred mouse strain, they turned to the hybrid mouse diversity panel (HDMP).

The HDMP is a panel of about 100 different inbred mouse strains that mirror the breadth of genetic and immunological diversity found in the human population.

The researchers studied the natural variation in the activation pattern of abdominal macrophages. Macrophages isolated from 83 different mouse strains from the HDMP were exposed to lipopolysaccharide (LPS), a major component of the outer wall of gram-negative bacteria.

“Fundamentally, when the immune system is confronted with gram-negative bacteria, it can deal with the situation in 2 ways—either it gets very angry and tries to kill the bacteria or it can wall them off in an attempt to live with it,” explained Dr Ley. “Both strategies carry a certain risk, but a long evolutionary history has ensured that mice and people can survive with either strategy.”

The LPS-induced reactions of the macrophages covered the whole spectrum—from very aggressive (LPS+) to very tolerant (LPS-), depending on the mouse strain.

Next, the researchers asked which genes were active during each type of response to identify gene signatures that correlated with LPS responsiveness.

The team then ran these gene signatures across various human gene expression data sets and discovered they strongly correlated with human disease outcomes.

For example, macrophages isolated from healthy joints were enriched in LPS-tolerant genes, whereas macrophages from rheumatoid arthritis patients were strongly skewed toward LPS-aggressive.

Since it was known that mice and people with the aggressive phenotype are better at fighting cancer, the researchers specifically asked whether the level of LPS responsiveness could predict tumor survival.

After analyzing data from 18,000 biopsies across 39 different tumor types, the team found the LPS+ gene signature strongly correlated with survival, while the LPS- signature correlated with cancer death.

The pattern was significant across many types of cancer, including chronic lymphocytic leukemia, Burkitt lymphoma, osteosarcoma, melanoma, and large-cell lung carcinoma.

Photo by Aaron Logan

Researchers say they have developed a new approach to model human immune variation that overcomes the limitations of traditional mouse models.

With this approach, the team identified genetic markers that directly correlate with the outcome of inflammatory and malignant diseases in humans, including chronic lymphocytic leukemia and Burkitt lymphoma.

The findings suggest that accounting for immune diversity is critical to the success of predicting disease outcomes based on immune cell measurements.

The team reported these findings in Nature Communications.

Traditionally, researchers have relied on inbred mouse strains to gain insight into human diseases while reducing experimental noise.

“If you take a black, a brown, or a white mouse, each one will give you a different answer in the same assay,” said Klaus Ley, MD, of La Jolla Institute for Allergy and Immunology in California.

“For example, if you vaccinate them, their responses will be different, which creates a lot of experimental noise. However, when you think about patients, or even healthy people, we are all different.”

To mine those differences for information, the researchers embraced the experimental noise. Instead of analyzing a single inbred mouse strain, they turned to the hybrid mouse diversity panel (HDMP).

The HDMP is a panel of about 100 different inbred mouse strains that mirror the breadth of genetic and immunological diversity found in the human population.

The researchers studied the natural variation in the activation pattern of abdominal macrophages. Macrophages isolated from 83 different mouse strains from the HDMP were exposed to lipopolysaccharide (LPS), a major component of the outer wall of gram-negative bacteria.

“Fundamentally, when the immune system is confronted with gram-negative bacteria, it can deal with the situation in 2 ways—either it gets very angry and tries to kill the bacteria or it can wall them off in an attempt to live with it,” explained Dr Ley. “Both strategies carry a certain risk, but a long evolutionary history has ensured that mice and people can survive with either strategy.”

The LPS-induced reactions of the macrophages covered the whole spectrum—from very aggressive (LPS+) to very tolerant (LPS-), depending on the mouse strain.

Next, the researchers asked which genes were active during each type of response to identify gene signatures that correlated with LPS responsiveness.

The team then ran these gene signatures across various human gene expression data sets and discovered they strongly correlated with human disease outcomes.

For example, macrophages isolated from healthy joints were enriched in LPS-tolerant genes, whereas macrophages from rheumatoid arthritis patients were strongly skewed toward LPS-aggressive.

Since it was known that mice and people with the aggressive phenotype are better at fighting cancer, the researchers specifically asked whether the level of LPS responsiveness could predict tumor survival.

After analyzing data from 18,000 biopsies across 39 different tumor types, the team found the LPS+ gene signature strongly correlated with survival, while the LPS- signature correlated with cancer death.

The pattern was significant across many types of cancer, including chronic lymphocytic leukemia, Burkitt lymphoma, osteosarcoma, melanoma, and large-cell lung carcinoma.

Photo by Aaron Logan

Researchers say they have developed a new approach to model human immune variation that overcomes the limitations of traditional mouse models.

With this approach, the team identified genetic markers that directly correlate with the outcome of inflammatory and malignant diseases in humans, including chronic lymphocytic leukemia and Burkitt lymphoma.

The findings suggest that accounting for immune diversity is critical to the success of predicting disease outcomes based on immune cell measurements.

The team reported these findings in Nature Communications.

Traditionally, researchers have relied on inbred mouse strains to gain insight into human diseases while reducing experimental noise.

“If you take a black, a brown, or a white mouse, each one will give you a different answer in the same assay,” said Klaus Ley, MD, of La Jolla Institute for Allergy and Immunology in California.

“For example, if you vaccinate them, their responses will be different, which creates a lot of experimental noise. However, when you think about patients, or even healthy people, we are all different.”

To mine those differences for information, the researchers embraced the experimental noise. Instead of analyzing a single inbred mouse strain, they turned to the hybrid mouse diversity panel (HDMP).

The HDMP is a panel of about 100 different inbred mouse strains that mirror the breadth of genetic and immunological diversity found in the human population.

The researchers studied the natural variation in the activation pattern of abdominal macrophages. Macrophages isolated from 83 different mouse strains from the HDMP were exposed to lipopolysaccharide (LPS), a major component of the outer wall of gram-negative bacteria.

“Fundamentally, when the immune system is confronted with gram-negative bacteria, it can deal with the situation in 2 ways—either it gets very angry and tries to kill the bacteria or it can wall them off in an attempt to live with it,” explained Dr Ley. “Both strategies carry a certain risk, but a long evolutionary history has ensured that mice and people can survive with either strategy.”

The LPS-induced reactions of the macrophages covered the whole spectrum—from very aggressive (LPS+) to very tolerant (LPS-), depending on the mouse strain.

Next, the researchers asked which genes were active during each type of response to identify gene signatures that correlated with LPS responsiveness.

The team then ran these gene signatures across various human gene expression data sets and discovered they strongly correlated with human disease outcomes.

For example, macrophages isolated from healthy joints were enriched in LPS-tolerant genes, whereas macrophages from rheumatoid arthritis patients were strongly skewed toward LPS-aggressive.

Since it was known that mice and people with the aggressive phenotype are better at fighting cancer, the researchers specifically asked whether the level of LPS responsiveness could predict tumor survival.

After analyzing data from 18,000 biopsies across 39 different tumor types, the team found the LPS+ gene signature strongly correlated with survival, while the LPS- signature correlated with cancer death.

The pattern was significant across many types of cancer, including chronic lymphocytic leukemia, Burkitt lymphoma, osteosarcoma, melanoma, and large-cell lung carcinoma.

Photo from Business Wire

Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).

This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.

Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.

Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.

AETHERA trial

Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.

The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Photo from Business Wire

Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).

This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.

Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.

Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.

AETHERA trial

Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.

The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Photo from Business Wire

Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).

This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.

Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.

Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.

AETHERA trial

Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.

The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing FL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for obinutuzumab (Gazyvaro).

The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.

The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:

• In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
• In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
• In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.

GALLIUM trial

The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.

The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Micrograph showing FL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for obinutuzumab (Gazyvaro).

The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.

The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:

• In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
• In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
• In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.

GALLIUM trial

The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.

The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Micrograph showing FL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for obinutuzumab (Gazyvaro).

The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.

The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:

• In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
• In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
• In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.

GALLIUM trial

The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.

The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.

Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.

“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.

Neil Osterweil/Frontline Medical News

LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.

Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.

“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.

Neil Osterweil/Frontline Medical News

LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.

Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.

“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.

Neil Osterweil/Frontline Medical News

Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.

Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.

[email protected]

Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.

Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.

[email protected]

Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.

Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.

[email protected]

Research Center

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).

Research Center

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).

Research Center

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).

Photo courtesy of the CDC

Three case reports published in The New England Journal of Medicine describe the successful use of PD-1 inhibitors in gray zone lymphoma.

Two patients who had failed treatment with DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab) ultimately responded to treatment with pembrolizumab.

Another patient—who had previously received 2 chemotherapy regimens, monotherapy with brentuximab vedotin, and radiation—responded to treatment with nivolumab.

Pembrolizumab treatment

An 18-year-old woman with mediastinal gray-zone lymphoma initially had a partial response to DA-EPOCH-R. However, she progressed 6 weeks after salvage radiotherapy.

She went on to receive pembrolizumab, had a complete metabolic response, and proceeded to allogeneic transplant after 235 days of treatment.

A 76-year-old man with mediastinal gray-zone lymphoma also had a partial response to DA-EPOCH-R but later progressed.

He proceeded to pembrolizumab and had a complete metabolic response. He was still in remission on day 381 of treatment.

Nivolumab treatment

The patient who received nivolumab is Bobbie Flexer, an 80-year-old retired mathematics professor.

“For me, trying nivolumab was a binary choice: I could try the drug or I could give up,” Flexer said.

She had initially achieved a complete metabolic response to DA-EPOCH-R, but her disease progressed after 6 cycles of treatment.

“Given Bobbie’s age and her resistance to chemotherapy, it was difficult to simply increase her dose,” said Flexer’s oncologist, Manali Kamdar, MD, of the University of Colorado School of Medicine in Aurora.

“Bobbie’s tumor biopsy expressed a protein called CD30, and so we started her on brentuximab, which targets these CD30 cells. Unfortunately, Bobbie’s disease progressed through multiple cycles of brentuximab. Subsequently, we switched her to another combined chemotherapy—namely, gemcitabine with oxaliplatin [plus rituximab].”

When that regimen and mediastinal radiation both proved unsuccessful, Dr Kamdar started Flexer on nivolumab.

“Within one dose, she was in less pain, and she looked much better,” Dr Kamdar said.

A PET scan after 6 doses showed that Flexer’s disease was in complete remission, and she was still in remission on day 161 of treatment.

She did experience adverse effects, including 2 bouts of pneumonitis, which were successfully treated with prednisone.

Flexer also experienced an uptick in pancreas enzymes that caused high blood glucose levels. She is learning to treat that side effect with insulin. And dietitians helped her manage expected gut-related side effects of nivolumab.

To Dr Kamdar, Flexer’s case was striking enough to warrant submitting a report to NEJM.

Coincidentally, the journal had just received 2 similar case reports from the National Institutes of Health, in which researchers had used pembrolizumab to target gray zone lymphoma in a nearly identical way.

Together, these cases suggest a new strategy for treating gray zone lymphoma.

Photo courtesy of the CDC

Three case reports published in The New England Journal of Medicine describe the successful use of PD-1 inhibitors in gray zone lymphoma.

Two patients who had failed treatment with DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab) ultimately responded to treatment with pembrolizumab.

Another patient—who had previously received 2 chemotherapy regimens, monotherapy with brentuximab vedotin, and radiation—responded to treatment with nivolumab.

Pembrolizumab treatment

An 18-year-old woman with mediastinal gray-zone lymphoma initially had a partial response to DA-EPOCH-R. However, she progressed 6 weeks after salvage radiotherapy.

She went on to receive pembrolizumab, had a complete metabolic response, and proceeded to allogeneic transplant after 235 days of treatment.

A 76-year-old man with mediastinal gray-zone lymphoma also had a partial response to DA-EPOCH-R but later progressed.

He proceeded to pembrolizumab and had a complete metabolic response. He was still in remission on day 381 of treatment.

Nivolumab treatment

The patient who received nivolumab is Bobbie Flexer, an 80-year-old retired mathematics professor.

“For me, trying nivolumab was a binary choice: I could try the drug or I could give up,” Flexer said.

She had initially achieved a complete metabolic response to DA-EPOCH-R, but her disease progressed after 6 cycles of treatment.

“Given Bobbie’s age and her resistance to chemotherapy, it was difficult to simply increase her dose,” said Flexer’s oncologist, Manali Kamdar, MD, of the University of Colorado School of Medicine in Aurora.

“Bobbie’s tumor biopsy expressed a protein called CD30, and so we started her on brentuximab, which targets these CD30 cells. Unfortunately, Bobbie’s disease progressed through multiple cycles of brentuximab. Subsequently, we switched her to another combined chemotherapy—namely, gemcitabine with oxaliplatin [plus rituximab].”

When that regimen and mediastinal radiation both proved unsuccessful, Dr Kamdar started Flexer on nivolumab.

“Within one dose, she was in less pain, and she looked much better,” Dr Kamdar said.

A PET scan after 6 doses showed that Flexer’s disease was in complete remission, and she was still in remission on day 161 of treatment.

She did experience adverse effects, including 2 bouts of pneumonitis, which were successfully treated with prednisone.

Flexer also experienced an uptick in pancreas enzymes that caused high blood glucose levels. She is learning to treat that side effect with insulin. And dietitians helped her manage expected gut-related side effects of nivolumab.

To Dr Kamdar, Flexer’s case was striking enough to warrant submitting a report to NEJM.

Coincidentally, the journal had just received 2 similar case reports from the National Institutes of Health, in which researchers had used pembrolizumab to target gray zone lymphoma in a nearly identical way.

Together, these cases suggest a new strategy for treating gray zone lymphoma.

Photo courtesy of the CDC

Three case reports published in The New England Journal of Medicine describe the successful use of PD-1 inhibitors in gray zone lymphoma.

Two patients who had failed treatment with DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab) ultimately responded to treatment with pembrolizumab.

Another patient—who had previously received 2 chemotherapy regimens, monotherapy with brentuximab vedotin, and radiation—responded to treatment with nivolumab.

Pembrolizumab treatment

An 18-year-old woman with mediastinal gray-zone lymphoma initially had a partial response to DA-EPOCH-R. However, she progressed 6 weeks after salvage radiotherapy.

She went on to receive pembrolizumab, had a complete metabolic response, and proceeded to allogeneic transplant after 235 days of treatment.

A 76-year-old man with mediastinal gray-zone lymphoma also had a partial response to DA-EPOCH-R but later progressed.

He proceeded to pembrolizumab and had a complete metabolic response. He was still in remission on day 381 of treatment.

Nivolumab treatment

The patient who received nivolumab is Bobbie Flexer, an 80-year-old retired mathematics professor.

“For me, trying nivolumab was a binary choice: I could try the drug or I could give up,” Flexer said.

She had initially achieved a complete metabolic response to DA-EPOCH-R, but her disease progressed after 6 cycles of treatment.

“Given Bobbie’s age and her resistance to chemotherapy, it was difficult to simply increase her dose,” said Flexer’s oncologist, Manali Kamdar, MD, of the University of Colorado School of Medicine in Aurora.

“Bobbie’s tumor biopsy expressed a protein called CD30, and so we started her on brentuximab, which targets these CD30 cells. Unfortunately, Bobbie’s disease progressed through multiple cycles of brentuximab. Subsequently, we switched her to another combined chemotherapy—namely, gemcitabine with oxaliplatin [plus rituximab].”

When that regimen and mediastinal radiation both proved unsuccessful, Dr Kamdar started Flexer on nivolumab.

“Within one dose, she was in less pain, and she looked much better,” Dr Kamdar said.

A PET scan after 6 doses showed that Flexer’s disease was in complete remission, and she was still in remission on day 161 of treatment.

She did experience adverse effects, including 2 bouts of pneumonitis, which were successfully treated with prednisone.

Flexer also experienced an uptick in pancreas enzymes that caused high blood glucose levels. She is learning to treat that side effect with insulin. And dietitians helped her manage expected gut-related side effects of nivolumab.

To Dr Kamdar, Flexer’s case was striking enough to warrant submitting a report to NEJM.

Coincidentally, the journal had just received 2 similar case reports from the National Institutes of Health, in which researchers had used pembrolizumab to target gray zone lymphoma in a nearly identical way.

Together, these cases suggest a new strategy for treating gray zone lymphoma.