Follicular Lymphoma

Photo by Etan J. Tal

New research has revealed factors that may increase the risk of B-cell non-Hodgkin lymphoma (B-NHL) in Israelis and Palestinians.

This large-scale, epidemiological study indicated that each group had its own unique risk factors.

However, in both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a hematopoietic malignancy were all associated with B-NHL.

A team of Palestinian and Israeli researchers reported these findings in PLOS ONE.

The researchers noted that Israelis and Palestinians share the same ecosystem but differ in terms of lifestyle, health behaviors, and medical systems. Yet both populations report high incidences of NHL.

To gain some insight into this phenomenon, the team conducted a study examining risk factors for B-NHL and its subtypes in these two populations.

The researchers looked at medical history, environmental factors, and lifestyle factors in 823 B-NHL patients and 808 healthy controls.

There were 516 Israeli Jews with B-NHL and 307 Palestinian Arabs with B-NHL. The mean age at diagnosis was 60 and 51, respectively.

The proportion of patients with diffuse large B-cell lymphoma was 71% of Palestinian Arabs and 41% of Israeli Jews. The proportion of patients with follicular lymphoma was 14% and 28%, respectively. And the proportion of patients with marginal zone lymphoma was 2% and 14%, respectively.

Using data from questionnaires, pathology review, serology, and genotyping, the researchers uncovered potential risk factors for B-NHL common to both populations and other factors unique to each population.

Results

The data showed that, in both Palestinian Arabs and Israeli Jews, B-NHL was associated with:

• Recreational sun exposure (odds ratio [OR]=1.4)
• Black hair-dye use (OR=1.70)
• A history of hospitalization for infection (OR=1.68)
• Having a first-degree relative with a hematopoietic malignancy (OR=1.69).

Smoking was associated with follicular lymphoma in both populations (OR=1.46). And greater-than-monthly indoor pesticide use was associated with diffuse large B-cell lymphoma in both populations (OR=2.01).

There was an inverse association between alcohol use and B-NHL for both populations (OR=0.46).

Among Palestinian Arabs only, risk factors for B-NHL included gardening (OR=1.93) and a history of herpes (OR=3.73), mononucleosis (OR=6.34), rubella (OR=2.86), and blood transfusion (OR=2.53).

Risk factors that applied to Israeli Jews only included growing fruits and vegetables (OR=1.87) and self-reported autoimmune diseases (OR=1.99).

The researchers said differences in risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by B-NHL subtypes suggest specific causal factors for different types of disease. However, these findings require further investigation to reveal their mechanisms.

“Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions,” said study author Ora Paltiel, of Hadassah-Hebrew University Medical Organization in Jerusalem, Israel.

“The study provided opportunities for training Palestinian and Israeli researchers and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations.” 

Photo by Etan J. Tal

New research has revealed factors that may increase the risk of B-cell non-Hodgkin lymphoma (B-NHL) in Israelis and Palestinians.

This large-scale, epidemiological study indicated that each group had its own unique risk factors.

However, in both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a hematopoietic malignancy were all associated with B-NHL.

A team of Palestinian and Israeli researchers reported these findings in PLOS ONE.

The researchers noted that Israelis and Palestinians share the same ecosystem but differ in terms of lifestyle, health behaviors, and medical systems. Yet both populations report high incidences of NHL.

To gain some insight into this phenomenon, the team conducted a study examining risk factors for B-NHL and its subtypes in these two populations.

The researchers looked at medical history, environmental factors, and lifestyle factors in 823 B-NHL patients and 808 healthy controls.

There were 516 Israeli Jews with B-NHL and 307 Palestinian Arabs with B-NHL. The mean age at diagnosis was 60 and 51, respectively.

The proportion of patients with diffuse large B-cell lymphoma was 71% of Palestinian Arabs and 41% of Israeli Jews. The proportion of patients with follicular lymphoma was 14% and 28%, respectively. And the proportion of patients with marginal zone lymphoma was 2% and 14%, respectively.

Using data from questionnaires, pathology review, serology, and genotyping, the researchers uncovered potential risk factors for B-NHL common to both populations and other factors unique to each population.

Results

The data showed that, in both Palestinian Arabs and Israeli Jews, B-NHL was associated with:

• Recreational sun exposure (odds ratio [OR]=1.4)
• Black hair-dye use (OR=1.70)
• A history of hospitalization for infection (OR=1.68)
• Having a first-degree relative with a hematopoietic malignancy (OR=1.69).

Smoking was associated with follicular lymphoma in both populations (OR=1.46). And greater-than-monthly indoor pesticide use was associated with diffuse large B-cell lymphoma in both populations (OR=2.01).

There was an inverse association between alcohol use and B-NHL for both populations (OR=0.46).

Among Palestinian Arabs only, risk factors for B-NHL included gardening (OR=1.93) and a history of herpes (OR=3.73), mononucleosis (OR=6.34), rubella (OR=2.86), and blood transfusion (OR=2.53).

Risk factors that applied to Israeli Jews only included growing fruits and vegetables (OR=1.87) and self-reported autoimmune diseases (OR=1.99).

The researchers said differences in risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by B-NHL subtypes suggest specific causal factors for different types of disease. However, these findings require further investigation to reveal their mechanisms.

“Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions,” said study author Ora Paltiel, of Hadassah-Hebrew University Medical Organization in Jerusalem, Israel.

“The study provided opportunities for training Palestinian and Israeli researchers and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations.” 

Photo by Etan J. Tal

New research has revealed factors that may increase the risk of B-cell non-Hodgkin lymphoma (B-NHL) in Israelis and Palestinians.

This large-scale, epidemiological study indicated that each group had its own unique risk factors.

However, in both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a hematopoietic malignancy were all associated with B-NHL.

A team of Palestinian and Israeli researchers reported these findings in PLOS ONE.

The researchers noted that Israelis and Palestinians share the same ecosystem but differ in terms of lifestyle, health behaviors, and medical systems. Yet both populations report high incidences of NHL.

To gain some insight into this phenomenon, the team conducted a study examining risk factors for B-NHL and its subtypes in these two populations.

The researchers looked at medical history, environmental factors, and lifestyle factors in 823 B-NHL patients and 808 healthy controls.

There were 516 Israeli Jews with B-NHL and 307 Palestinian Arabs with B-NHL. The mean age at diagnosis was 60 and 51, respectively.

The proportion of patients with diffuse large B-cell lymphoma was 71% of Palestinian Arabs and 41% of Israeli Jews. The proportion of patients with follicular lymphoma was 14% and 28%, respectively. And the proportion of patients with marginal zone lymphoma was 2% and 14%, respectively.

Using data from questionnaires, pathology review, serology, and genotyping, the researchers uncovered potential risk factors for B-NHL common to both populations and other factors unique to each population.

Results

The data showed that, in both Palestinian Arabs and Israeli Jews, B-NHL was associated with:

• Recreational sun exposure (odds ratio [OR]=1.4)
• Black hair-dye use (OR=1.70)
• A history of hospitalization for infection (OR=1.68)
• Having a first-degree relative with a hematopoietic malignancy (OR=1.69).

Smoking was associated with follicular lymphoma in both populations (OR=1.46). And greater-than-monthly indoor pesticide use was associated with diffuse large B-cell lymphoma in both populations (OR=2.01).

There was an inverse association between alcohol use and B-NHL for both populations (OR=0.46).

Among Palestinian Arabs only, risk factors for B-NHL included gardening (OR=1.93) and a history of herpes (OR=3.73), mononucleosis (OR=6.34), rubella (OR=2.86), and blood transfusion (OR=2.53).

Risk factors that applied to Israeli Jews only included growing fruits and vegetables (OR=1.87) and self-reported autoimmune diseases (OR=1.99).

The researchers said differences in risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by B-NHL subtypes suggest specific causal factors for different types of disease. However, these findings require further investigation to reveal their mechanisms.

“Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions,” said study author Ora Paltiel, of Hadassah-Hebrew University Medical Organization in Jerusalem, Israel.

“The study provided opportunities for training Palestinian and Israeli researchers and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations.” 

Follicular lymphoma

The European Commission has approved a biosimilar rituximab product, Truxima™, for all the same indications as the reference product, MabThera.

This means Truxima (formerly called CT-P10) is approved for use in the European Union to treat patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

Truxima, a product of Celltrion Healthcare Hungary Kft, is the first biosimilar monoclonal antibody approved in an oncology indication worldwide.

The approval is based on data submitted to the European Medicines Agency.

The agency’s Committee for Medicinal Products for Human Use (CHMP) said the evidence suggests Truxima and MabThera are similar in terms of efficacy, safety, immunogenicity, pharmacodynamics, and pharmacokinetics in patients with RA and advanced follicular lymphoma (FL).

Therefore, the European Commission approved Truxima for the following indications.

Non-Hodgkin lymphoma 

Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV FL.

Truxima maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.

Truxima monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.

Chronic lymphocytic leukemia

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.

The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.

RA, GPA, and MPA 

Truxima in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.

Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.

Truxima studies

There are 3 ongoing, phase 3 trials of Truxima in patients with RA (NCT02149121), advanced FL (NCT02162771), and low-tumor-burden FL (NCT02260804).

Results from the phase 1/3 trial in patients with newly diagnosed, advanced FL suggest that Truxima and the reference rituximab are similar with regard to pharmacokinetics, immunogenicity, and safety (B Coiffier et al. ASH 2016, abstract 1807).

Results from the phase 3 study of RA patients indicate that Truxima is similar to reference products (EU and US-sourced rituximab) with regard to pharmacodynamics, safety, and efficacy for up to 24 weeks (DH Yoo et al. 2016 ACR/ARHP Annual Meeting, abstract 1635).  

Follicular lymphoma

The European Commission has approved a biosimilar rituximab product, Truxima™, for all the same indications as the reference product, MabThera.

This means Truxima (formerly called CT-P10) is approved for use in the European Union to treat patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

Truxima, a product of Celltrion Healthcare Hungary Kft, is the first biosimilar monoclonal antibody approved in an oncology indication worldwide.

The approval is based on data submitted to the European Medicines Agency.

The agency’s Committee for Medicinal Products for Human Use (CHMP) said the evidence suggests Truxima and MabThera are similar in terms of efficacy, safety, immunogenicity, pharmacodynamics, and pharmacokinetics in patients with RA and advanced follicular lymphoma (FL).

Therefore, the European Commission approved Truxima for the following indications.

Non-Hodgkin lymphoma 

Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV FL.

Truxima maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.

Truxima monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.

Chronic lymphocytic leukemia

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.

The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.

RA, GPA, and MPA 

Truxima in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.

Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.

Truxima studies

There are 3 ongoing, phase 3 trials of Truxima in patients with RA (NCT02149121), advanced FL (NCT02162771), and low-tumor-burden FL (NCT02260804).

Results from the phase 1/3 trial in patients with newly diagnosed, advanced FL suggest that Truxima and the reference rituximab are similar with regard to pharmacokinetics, immunogenicity, and safety (B Coiffier et al. ASH 2016, abstract 1807).

Results from the phase 3 study of RA patients indicate that Truxima is similar to reference products (EU and US-sourced rituximab) with regard to pharmacodynamics, safety, and efficacy for up to 24 weeks (DH Yoo et al. 2016 ACR/ARHP Annual Meeting, abstract 1635).  

Follicular lymphoma

The European Commission has approved a biosimilar rituximab product, Truxima™, for all the same indications as the reference product, MabThera.

This means Truxima (formerly called CT-P10) is approved for use in the European Union to treat patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

Truxima, a product of Celltrion Healthcare Hungary Kft, is the first biosimilar monoclonal antibody approved in an oncology indication worldwide.

The approval is based on data submitted to the European Medicines Agency.

The agency’s Committee for Medicinal Products for Human Use (CHMP) said the evidence suggests Truxima and MabThera are similar in terms of efficacy, safety, immunogenicity, pharmacodynamics, and pharmacokinetics in patients with RA and advanced follicular lymphoma (FL).

Therefore, the European Commission approved Truxima for the following indications.

Non-Hodgkin lymphoma 

Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV FL.

Truxima maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.

Truxima monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.

Chronic lymphocytic leukemia

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.

The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.

RA, GPA, and MPA 

Truxima in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.

Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.

Truxima studies

There are 3 ongoing, phase 3 trials of Truxima in patients with RA (NCT02149121), advanced FL (NCT02162771), and low-tumor-burden FL (NCT02260804).

Results from the phase 1/3 trial in patients with newly diagnosed, advanced FL suggest that Truxima and the reference rituximab are similar with regard to pharmacokinetics, immunogenicity, and safety (B Coiffier et al. ASH 2016, abstract 1807).

Results from the phase 3 study of RA patients indicate that Truxima is similar to reference products (EU and US-sourced rituximab) with regard to pharmacodynamics, safety, and efficacy for up to 24 weeks (DH Yoo et al. 2016 ACR/ARHP Annual Meeting, abstract 1635).  

 

 

Richard Delarue, MD

Photo by Larry Young

 

SAN FRANCISCO—Treatment with 5-azacitidine (5-AZA) can produce a high response rate in patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), according to a small study.

The overall response rate (ORR) among AITL patients was 75%, and the complete response (CR) rate was 42%.

However, this study also included patients with other types of peripheral T-cell lymphoma (PTCL), and most of these patients did not respond to 5-AZA.

Richard Delarue, MD, of Necker University Hospital in Paris, France, presented these results at the 9th Annual T-cell Lymphoma Forum.

Results were also presented at the 2016 ASH Annual Meeting (abstract 4164). Dr Delarue reported receiving honoraria from Celgene.

Patients

The study included 19 patients with relapsed/refractory PTCL. Twelve patients had AITL, 3 had adult T-cell leukemia/lymphoma (ATLL), 2 had PTCL not otherwise specified, 1 had enteropathy-associated T-cell lymphoma, and 1 had transformed mycosis fungoides.

At diagnosis, the median age was 71 (range, 39-85) for AITL patients and 59 (range, 32-83) for the other PTCL patients. Seventy-five percent of AITL patients had an IPI score of 3 to 5 and a PIT score of 3 to 4. Eighty-six percent of the other PTCL patients had an IPI score of 3 to 5, and 57% had a PIT score of 3 to 4.

At the time of 5-AZA treatment, all patients had stage III/IV disease. The AITL patients had received a median of 2 (range, 0-6) prior lines of therapy, and the other PTCL patients had received a median of 3 (range, 0-7).

Two patients did not receive chemotherapy before 5-AZA because of the presence of associated chronic myelomonocytic leukemia (CMML) that required treatment first.

Ninety-two percent of AITL patients had TET2 mutations (n=11), 33% had DNMT3A mutations (n=4), and 0% had IDH2 mutations. One of the non-AITL patients had a TET2 mutation.

Treatment

Patients received a subcutaneous injection of 5-AZA at 75 mg/m² for 7 consecutive days every 28 days until progression or unacceptable toxicity. Six patients also received 4 to 8 infusions of rituximab because of EBV-DNA positivity.

The patients received a median of 3 cycles of 5-AZA. At the time of analysis, 4 patients were still receiving therapy.

The median follow-up was 84 days (range, 19 to 1236).

Toxicity

“Hematological toxicity was as expected with 5-azacitidine,” Dr Delarue said.

However, 2 patients had “unusual” adverse reactions. One patient had grade 2 polyneuropathy, which was considered related to a paraneoplastic syndrome.

The other patient had grade 3 diarrhea related to colitis of unknown origin, and this led to treatment interruption.

There were no treatment-related deaths.

Efficacy

Dr Delarue noted that the ORR was significantly higher in AITL patients than in patients with the other PTCL subtypes (P=0.0198).

The ORR was 53% in the entire cohort (10/19), 75% (9/12) among AITL patients, and 14% among patients with other PTCLs (1/7).

“The only patient with a response in the ‘other PTCL’ group was a patient with HTLV1-associated ATLL . . . , but he relapsed a couple of weeks after the second cycle,” Dr Delarue explained.

Among the AITL patients, the CR rate was 42% (5/12), the partial response rate was 33% (4/12), and the rate of stable disease was 25% (3/12).

Six AITL patients eventually progressed—after 2, 2, 3, 4, 4, and 20 cycles of therapy, respectively.

Two AITL patients are off therapy but remain in CR after 9 and 10 months (5 and 6 cycles of treatment), respectively.

The median progression-free survival for AITL patients was 16 months, and the median overall survival was 17 months.

Dr DeLarue noted that 4 of the AITL patients had CMML, 1 had non-CMML myelodysplastic syndrome, 3 had monocytosis without CMML, and 4 had normal monocyte counts.

He also said that, at present, it’s not possible to correlate the results observed in the AITL patients with their mutational status.

However, he and his colleagues are planning a prospective study of 5-AZA in patients with relapsed/refractory AITL and T follicular helper cell PTCL not otherwise specified. 5-AZA will be compared to investigator’s choice in this study.

Dr DeLarue said this trial will provide an opportunity to use the new oral formulation of 5-AZA (CC-486). And he and his colleagues welcome collaborators.

 

 

Richard Delarue, MD

Photo by Larry Young

 

SAN FRANCISCO—Treatment with 5-azacitidine (5-AZA) can produce a high response rate in patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), according to a small study.

The overall response rate (ORR) among AITL patients was 75%, and the complete response (CR) rate was 42%.

However, this study also included patients with other types of peripheral T-cell lymphoma (PTCL), and most of these patients did not respond to 5-AZA.

Richard Delarue, MD, of Necker University Hospital in Paris, France, presented these results at the 9th Annual T-cell Lymphoma Forum.

Results were also presented at the 2016 ASH Annual Meeting (abstract 4164). Dr Delarue reported receiving honoraria from Celgene.

Patients

The study included 19 patients with relapsed/refractory PTCL. Twelve patients had AITL, 3 had adult T-cell leukemia/lymphoma (ATLL), 2 had PTCL not otherwise specified, 1 had enteropathy-associated T-cell lymphoma, and 1 had transformed mycosis fungoides.

At diagnosis, the median age was 71 (range, 39-85) for AITL patients and 59 (range, 32-83) for the other PTCL patients. Seventy-five percent of AITL patients had an IPI score of 3 to 5 and a PIT score of 3 to 4. Eighty-six percent of the other PTCL patients had an IPI score of 3 to 5, and 57% had a PIT score of 3 to 4.

At the time of 5-AZA treatment, all patients had stage III/IV disease. The AITL patients had received a median of 2 (range, 0-6) prior lines of therapy, and the other PTCL patients had received a median of 3 (range, 0-7).

Two patients did not receive chemotherapy before 5-AZA because of the presence of associated chronic myelomonocytic leukemia (CMML) that required treatment first.

Ninety-two percent of AITL patients had TET2 mutations (n=11), 33% had DNMT3A mutations (n=4), and 0% had IDH2 mutations. One of the non-AITL patients had a TET2 mutation.

Treatment

Patients received a subcutaneous injection of 5-AZA at 75 mg/m² for 7 consecutive days every 28 days until progression or unacceptable toxicity. Six patients also received 4 to 8 infusions of rituximab because of EBV-DNA positivity.

The patients received a median of 3 cycles of 5-AZA. At the time of analysis, 4 patients were still receiving therapy.

The median follow-up was 84 days (range, 19 to 1236).

Toxicity

“Hematological toxicity was as expected with 5-azacitidine,” Dr Delarue said.

However, 2 patients had “unusual” adverse reactions. One patient had grade 2 polyneuropathy, which was considered related to a paraneoplastic syndrome.

The other patient had grade 3 diarrhea related to colitis of unknown origin, and this led to treatment interruption.

There were no treatment-related deaths.

Efficacy

Dr Delarue noted that the ORR was significantly higher in AITL patients than in patients with the other PTCL subtypes (P=0.0198).

The ORR was 53% in the entire cohort (10/19), 75% (9/12) among AITL patients, and 14% among patients with other PTCLs (1/7).

“The only patient with a response in the ‘other PTCL’ group was a patient with HTLV1-associated ATLL . . . , but he relapsed a couple of weeks after the second cycle,” Dr Delarue explained.

Among the AITL patients, the CR rate was 42% (5/12), the partial response rate was 33% (4/12), and the rate of stable disease was 25% (3/12).

Six AITL patients eventually progressed—after 2, 2, 3, 4, 4, and 20 cycles of therapy, respectively.

Two AITL patients are off therapy but remain in CR after 9 and 10 months (5 and 6 cycles of treatment), respectively.

The median progression-free survival for AITL patients was 16 months, and the median overall survival was 17 months.

Dr DeLarue noted that 4 of the AITL patients had CMML, 1 had non-CMML myelodysplastic syndrome, 3 had monocytosis without CMML, and 4 had normal monocyte counts.

He also said that, at present, it’s not possible to correlate the results observed in the AITL patients with their mutational status.

However, he and his colleagues are planning a prospective study of 5-AZA in patients with relapsed/refractory AITL and T follicular helper cell PTCL not otherwise specified. 5-AZA will be compared to investigator’s choice in this study.

Dr DeLarue said this trial will provide an opportunity to use the new oral formulation of 5-AZA (CC-486). And he and his colleagues welcome collaborators.

 

 

Richard Delarue, MD

Photo by Larry Young

 

SAN FRANCISCO—Treatment with 5-azacitidine (5-AZA) can produce a high response rate in patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), according to a small study.

The overall response rate (ORR) among AITL patients was 75%, and the complete response (CR) rate was 42%.

However, this study also included patients with other types of peripheral T-cell lymphoma (PTCL), and most of these patients did not respond to 5-AZA.

Richard Delarue, MD, of Necker University Hospital in Paris, France, presented these results at the 9th Annual T-cell Lymphoma Forum.

Results were also presented at the 2016 ASH Annual Meeting (abstract 4164). Dr Delarue reported receiving honoraria from Celgene.

Patients

The study included 19 patients with relapsed/refractory PTCL. Twelve patients had AITL, 3 had adult T-cell leukemia/lymphoma (ATLL), 2 had PTCL not otherwise specified, 1 had enteropathy-associated T-cell lymphoma, and 1 had transformed mycosis fungoides.

At diagnosis, the median age was 71 (range, 39-85) for AITL patients and 59 (range, 32-83) for the other PTCL patients. Seventy-five percent of AITL patients had an IPI score of 3 to 5 and a PIT score of 3 to 4. Eighty-six percent of the other PTCL patients had an IPI score of 3 to 5, and 57% had a PIT score of 3 to 4.

At the time of 5-AZA treatment, all patients had stage III/IV disease. The AITL patients had received a median of 2 (range, 0-6) prior lines of therapy, and the other PTCL patients had received a median of 3 (range, 0-7).

Two patients did not receive chemotherapy before 5-AZA because of the presence of associated chronic myelomonocytic leukemia (CMML) that required treatment first.

Ninety-two percent of AITL patients had TET2 mutations (n=11), 33% had DNMT3A mutations (n=4), and 0% had IDH2 mutations. One of the non-AITL patients had a TET2 mutation.

Treatment

Patients received a subcutaneous injection of 5-AZA at 75 mg/m² for 7 consecutive days every 28 days until progression or unacceptable toxicity. Six patients also received 4 to 8 infusions of rituximab because of EBV-DNA positivity.

The patients received a median of 3 cycles of 5-AZA. At the time of analysis, 4 patients were still receiving therapy.

The median follow-up was 84 days (range, 19 to 1236).

Toxicity

“Hematological toxicity was as expected with 5-azacitidine,” Dr Delarue said.

However, 2 patients had “unusual” adverse reactions. One patient had grade 2 polyneuropathy, which was considered related to a paraneoplastic syndrome.

The other patient had grade 3 diarrhea related to colitis of unknown origin, and this led to treatment interruption.

There were no treatment-related deaths.

Efficacy

Dr Delarue noted that the ORR was significantly higher in AITL patients than in patients with the other PTCL subtypes (P=0.0198).

The ORR was 53% in the entire cohort (10/19), 75% (9/12) among AITL patients, and 14% among patients with other PTCLs (1/7).

“The only patient with a response in the ‘other PTCL’ group was a patient with HTLV1-associated ATLL . . . , but he relapsed a couple of weeks after the second cycle,” Dr Delarue explained.

Among the AITL patients, the CR rate was 42% (5/12), the partial response rate was 33% (4/12), and the rate of stable disease was 25% (3/12).

Six AITL patients eventually progressed—after 2, 2, 3, 4, 4, and 20 cycles of therapy, respectively.

Two AITL patients are off therapy but remain in CR after 9 and 10 months (5 and 6 cycles of treatment), respectively.

The median progression-free survival for AITL patients was 16 months, and the median overall survival was 17 months.

Dr DeLarue noted that 4 of the AITL patients had CMML, 1 had non-CMML myelodysplastic syndrome, 3 had monocytosis without CMML, and 4 had normal monocyte counts.

He also said that, at present, it’s not possible to correlate the results observed in the AITL patients with their mutational status.

However, he and his colleagues are planning a prospective study of 5-AZA in patients with relapsed/refractory AITL and T follicular helper cell PTCL not otherwise specified. 5-AZA will be compared to investigator’s choice in this study.

Dr DeLarue said this trial will provide an opportunity to use the new oral formulation of 5-AZA (CC-486). And he and his colleagues welcome collaborators.

 

Obinutuzumab (Gazyva®)

 

Health Canada has approved the use of obinutuzumab (Gazyva®), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).

The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who relapsed after, or are refractory to, a rituximab-containing regimen.

Obinutuzumab is also approved in Canada for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.

Obinutuzumab is a product of Roche.

Health Canada’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial.

The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.

The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression). 

The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.

Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).

The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.

The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.

At last follow-up, the median overall survival had not been reached in either study arm.
 
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).

 

Obinutuzumab (Gazyva®)

 

Health Canada has approved the use of obinutuzumab (Gazyva®), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).

The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who relapsed after, or are refractory to, a rituximab-containing regimen.

Obinutuzumab is also approved in Canada for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.

Obinutuzumab is a product of Roche.

Health Canada’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial.

The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.

The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression). 

The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.

Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).

The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.

The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.

At last follow-up, the median overall survival had not been reached in either study arm.
 
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).

 

Obinutuzumab (Gazyva®)

 

Health Canada has approved the use of obinutuzumab (Gazyva®), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).

The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who relapsed after, or are refractory to, a rituximab-containing regimen.

Obinutuzumab is also approved in Canada for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.

Obinutuzumab is a product of Roche.

Health Canada’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial.

The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.

The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression). 

The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.

Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).

The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.

The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.

At last follow-up, the median overall survival had not been reached in either study arm.
 
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).

A newer technique aimed at detect circulating tumor DNA in the blood – cancer personalized profiling by deep sequencing (CAPP-Seq) – detected recurrence of diffuse large B cell lymphoma more than 6 months earlier than radiographic findings in a study at Stanford (Calif.) University, where the technique was invented.

The findings signal another win for “liquid biopsy,” the measurement of tumor DNA circulating in the blood, which is rapidly emerging as a quick and powerful tool for the diagnosis of a range of cancers and tumor subtypes, and prediction of tumor behavior and treatment response. Investigators at Stanford and elsewhere are studying liquid biopsy not only for lymphoma, but also for colorectal, thyroid, breast, prostate, and most other cancers. The Stanford team recently reported that its circulating DNA-detecting CAPP-Seq technique also helps in lung cancer.

In the new study, Stanford used CAPP-Seq (Cancer Personalized Profiling by deep Sequencing), which it called “an ultrasensitive capture-based targeted sequencing method” to analyze 166 plasma and 118 tissue samples from 92 patients with diffuse large B cell lymphoma (DLBCL) at diagnosis and various point afterward. The team compared the results to radiologic, and other standard diagnostic and monitoring techniques (Sci Transl Med. 2016 Nov 9;8[364]:364ra155).

At diagnosis, the amount of circulating DNA (ctDNA) correlated strongly with clinical indices and was independently predictive of patient outcomes; “whereas 100% of pretreatment samples had detectable ctDNA, only 37% of samples had abnormally high serum” lactate dehydrogenase, currently the most commonly used biomarker for DLBCL, said investigators, led by research fellow Florian Scherer, MD.

The group detected ctDNA in 73% of patients (8/11) who eventually relapsed a mean of 188 days before relapse was detected by standard-of-care radiologic techniques.

CAPP-Seq identified nine patients with a particular type of activated B cell-like tumor, for whom ibrutinib (Imbruvica) is particularly effective; ctDNA also predicted the transformation of indolent follicular lymphoma to DLBCL “with high sensitivity and specificity,” the group reported.

Stanford anticipates “ctDNA will have broad utility for dissecting tumor heterogeneity within and between patients with lymphomas and other cancer types, with applications for the identification of adverse risk groups, the discovery of resistance mechanisms to diverse therapies, and the development of risk-adapted therapeutics.”

The team said its approach “outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies.” Meanwhile, while biomarkers hold “great promise for risk stratification and therapeutic targeting,” they are “currently difficult to measure in clinical settings,” the investigators said.

Roche bought the rights to CAPP-Seq from Stanford in 2015. Several authors are coinventors on patent applications for CAPP-Seq and also Roche consultants. Two are employees. Dr. Scherer had no disclosures. The work was funded by Stanford, the American Society of Hematology, the National Cancer Institute, and others.

[email protected]

A newer technique aimed at detect circulating tumor DNA in the blood – cancer personalized profiling by deep sequencing (CAPP-Seq) – detected recurrence of diffuse large B cell lymphoma more than 6 months earlier than radiographic findings in a study at Stanford (Calif.) University, where the technique was invented.

The findings signal another win for “liquid biopsy,” the measurement of tumor DNA circulating in the blood, which is rapidly emerging as a quick and powerful tool for the diagnosis of a range of cancers and tumor subtypes, and prediction of tumor behavior and treatment response. Investigators at Stanford and elsewhere are studying liquid biopsy not only for lymphoma, but also for colorectal, thyroid, breast, prostate, and most other cancers. The Stanford team recently reported that its circulating DNA-detecting CAPP-Seq technique also helps in lung cancer.

In the new study, Stanford used CAPP-Seq (Cancer Personalized Profiling by deep Sequencing), which it called “an ultrasensitive capture-based targeted sequencing method” to analyze 166 plasma and 118 tissue samples from 92 patients with diffuse large B cell lymphoma (DLBCL) at diagnosis and various point afterward. The team compared the results to radiologic, and other standard diagnostic and monitoring techniques (Sci Transl Med. 2016 Nov 9;8[364]:364ra155).

At diagnosis, the amount of circulating DNA (ctDNA) correlated strongly with clinical indices and was independently predictive of patient outcomes; “whereas 100% of pretreatment samples had detectable ctDNA, only 37% of samples had abnormally high serum” lactate dehydrogenase, currently the most commonly used biomarker for DLBCL, said investigators, led by research fellow Florian Scherer, MD.

The group detected ctDNA in 73% of patients (8/11) who eventually relapsed a mean of 188 days before relapse was detected by standard-of-care radiologic techniques.

CAPP-Seq identified nine patients with a particular type of activated B cell-like tumor, for whom ibrutinib (Imbruvica) is particularly effective; ctDNA also predicted the transformation of indolent follicular lymphoma to DLBCL “with high sensitivity and specificity,” the group reported.

Stanford anticipates “ctDNA will have broad utility for dissecting tumor heterogeneity within and between patients with lymphomas and other cancer types, with applications for the identification of adverse risk groups, the discovery of resistance mechanisms to diverse therapies, and the development of risk-adapted therapeutics.”

The team said its approach “outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies.” Meanwhile, while biomarkers hold “great promise for risk stratification and therapeutic targeting,” they are “currently difficult to measure in clinical settings,” the investigators said.

Roche bought the rights to CAPP-Seq from Stanford in 2015. Several authors are coinventors on patent applications for CAPP-Seq and also Roche consultants. Two are employees. Dr. Scherer had no disclosures. The work was funded by Stanford, the American Society of Hematology, the National Cancer Institute, and others.

[email protected]

A newer technique aimed at detect circulating tumor DNA in the blood – cancer personalized profiling by deep sequencing (CAPP-Seq) – detected recurrence of diffuse large B cell lymphoma more than 6 months earlier than radiographic findings in a study at Stanford (Calif.) University, where the technique was invented.

The findings signal another win for “liquid biopsy,” the measurement of tumor DNA circulating in the blood, which is rapidly emerging as a quick and powerful tool for the diagnosis of a range of cancers and tumor subtypes, and prediction of tumor behavior and treatment response. Investigators at Stanford and elsewhere are studying liquid biopsy not only for lymphoma, but also for colorectal, thyroid, breast, prostate, and most other cancers. The Stanford team recently reported that its circulating DNA-detecting CAPP-Seq technique also helps in lung cancer.

In the new study, Stanford used CAPP-Seq (Cancer Personalized Profiling by deep Sequencing), which it called “an ultrasensitive capture-based targeted sequencing method” to analyze 166 plasma and 118 tissue samples from 92 patients with diffuse large B cell lymphoma (DLBCL) at diagnosis and various point afterward. The team compared the results to radiologic, and other standard diagnostic and monitoring techniques (Sci Transl Med. 2016 Nov 9;8[364]:364ra155).

At diagnosis, the amount of circulating DNA (ctDNA) correlated strongly with clinical indices and was independently predictive of patient outcomes; “whereas 100% of pretreatment samples had detectable ctDNA, only 37% of samples had abnormally high serum” lactate dehydrogenase, currently the most commonly used biomarker for DLBCL, said investigators, led by research fellow Florian Scherer, MD.

The group detected ctDNA in 73% of patients (8/11) who eventually relapsed a mean of 188 days before relapse was detected by standard-of-care radiologic techniques.

CAPP-Seq identified nine patients with a particular type of activated B cell-like tumor, for whom ibrutinib (Imbruvica) is particularly effective; ctDNA also predicted the transformation of indolent follicular lymphoma to DLBCL “with high sensitivity and specificity,” the group reported.

Stanford anticipates “ctDNA will have broad utility for dissecting tumor heterogeneity within and between patients with lymphomas and other cancer types, with applications for the identification of adverse risk groups, the discovery of resistance mechanisms to diverse therapies, and the development of risk-adapted therapeutics.”

The team said its approach “outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies.” Meanwhile, while biomarkers hold “great promise for risk stratification and therapeutic targeting,” they are “currently difficult to measure in clinical settings,” the investigators said.

Roche bought the rights to CAPP-Seq from Stanford in 2015. Several authors are coinventors on patent applications for CAPP-Seq and also Roche consultants. Two are employees. Dr. Scherer had no disclosures. The work was funded by Stanford, the American Society of Hematology, the National Cancer Institute, and others.

[email protected]

 

Germinal center (rectangle) in
the spleen of a mouse, showing
inactivated GSK3 (magenta)
in B cells (blue) near follicular
dendritic cells (green).
Image from the lab of
Robert Rickert, PhD

 

Research published in Nature Immunology helps explain how B-cell metabolism adapts to different environments.

The study suggests the protein GSK3 acts as a metabolic checkpoint regulator in B cells, promoting the survival of circulating B cells while limiting the growth and proliferation of B cells in germinal centers.

“Our research shows that the protein GSK3 plays a crucial role in helping B cells meet the energy needs of their distinct states,” said study author Robert Rickert, PhD, of Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California.

“The findings are particularly relevant for certain B-cell pathologies, including lymphoma subtypes, where there is an increased demand for energy to support the hyperproliferation of cells in a microenvironment that may be limited in nutrients.”

Dr Rickert and his colleagues noted that B cells predominate in a quiescent state until they encounter an antigen, which prompts the cells to grow, proliferate, and differentiate.

The team’s new study showed that GSK3 adjusts B-cell metabolism to match the needs of these different cell states.

In circulating B cells, GSK3 limits overall metabolic activity. In proliferating B cells in germinal centers, GSK3 slows glycolysis and the production of mitochondria.

In fact, GSK3 function is essential for B-cell survival in germinal centers. To understand why, the researchers looked at how B cells in these regions generate energy.

The team found that because these B cells are so metabolically active, they consume nearly all available glucose. That switches on glycolysis.

High glycolytic activity leads to an accumulation of toxic reactive oxygen species, as does rapid manufacture of mitochondria, which tend to leak the same chemicals.

Thus, by restraining the metabolism in specific ways, GSK3 prevents cell death induced by reactive oxygen species.

“Our results were really surprising,” Dr Rickert said. “Until now, we would have thought that slowing metabolism would only be important for preventing B cells from becoming cancerous, which it indeed may be. These studies provide insight into the dynamic nature of B-cell metabolism that literally ‘fuels’ differentiation in the germinal center to produce an effective antibody response.”

“It’s not yet clear whether or how GSK3 might be a target for future therapies for B cell-related diseases, but this research opens a lot of doors for further studies. To start with, we plan to investigate how GSK3 is regulated in lymphoma and how that relates to changes in metabolism. That research could lead to new approaches to treating lymphoma.”

This research was performed in collaboration with scientists at Eli Lilly and the Lunenfeld-Tanenbaum Research Institute at the University of Toronto. Funding was provided by the National Institutes of Health, the Lilly Research Award Program, the Arthritis National Research Foundation, and the Canadian Institutes of Health Research.

 

Germinal center (rectangle) in
the spleen of a mouse, showing
inactivated GSK3 (magenta)
in B cells (blue) near follicular
dendritic cells (green).
Image from the lab of
Robert Rickert, PhD

 

Research published in Nature Immunology helps explain how B-cell metabolism adapts to different environments.

The study suggests the protein GSK3 acts as a metabolic checkpoint regulator in B cells, promoting the survival of circulating B cells while limiting the growth and proliferation of B cells in germinal centers.

“Our research shows that the protein GSK3 plays a crucial role in helping B cells meet the energy needs of their distinct states,” said study author Robert Rickert, PhD, of Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California.

“The findings are particularly relevant for certain B-cell pathologies, including lymphoma subtypes, where there is an increased demand for energy to support the hyperproliferation of cells in a microenvironment that may be limited in nutrients.”

Dr Rickert and his colleagues noted that B cells predominate in a quiescent state until they encounter an antigen, which prompts the cells to grow, proliferate, and differentiate.

The team’s new study showed that GSK3 adjusts B-cell metabolism to match the needs of these different cell states.

In circulating B cells, GSK3 limits overall metabolic activity. In proliferating B cells in germinal centers, GSK3 slows glycolysis and the production of mitochondria.

In fact, GSK3 function is essential for B-cell survival in germinal centers. To understand why, the researchers looked at how B cells in these regions generate energy.

The team found that because these B cells are so metabolically active, they consume nearly all available glucose. That switches on glycolysis.

High glycolytic activity leads to an accumulation of toxic reactive oxygen species, as does rapid manufacture of mitochondria, which tend to leak the same chemicals.

Thus, by restraining the metabolism in specific ways, GSK3 prevents cell death induced by reactive oxygen species.

“Our results were really surprising,” Dr Rickert said. “Until now, we would have thought that slowing metabolism would only be important for preventing B cells from becoming cancerous, which it indeed may be. These studies provide insight into the dynamic nature of B-cell metabolism that literally ‘fuels’ differentiation in the germinal center to produce an effective antibody response.”

“It’s not yet clear whether or how GSK3 might be a target for future therapies for B cell-related diseases, but this research opens a lot of doors for further studies. To start with, we plan to investigate how GSK3 is regulated in lymphoma and how that relates to changes in metabolism. That research could lead to new approaches to treating lymphoma.”

This research was performed in collaboration with scientists at Eli Lilly and the Lunenfeld-Tanenbaum Research Institute at the University of Toronto. Funding was provided by the National Institutes of Health, the Lilly Research Award Program, the Arthritis National Research Foundation, and the Canadian Institutes of Health Research.

 

Germinal center (rectangle) in
the spleen of a mouse, showing
inactivated GSK3 (magenta)
in B cells (blue) near follicular
dendritic cells (green).
Image from the lab of
Robert Rickert, PhD

 

Research published in Nature Immunology helps explain how B-cell metabolism adapts to different environments.

The study suggests the protein GSK3 acts as a metabolic checkpoint regulator in B cells, promoting the survival of circulating B cells while limiting the growth and proliferation of B cells in germinal centers.

“Our research shows that the protein GSK3 plays a crucial role in helping B cells meet the energy needs of their distinct states,” said study author Robert Rickert, PhD, of Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California.

“The findings are particularly relevant for certain B-cell pathologies, including lymphoma subtypes, where there is an increased demand for energy to support the hyperproliferation of cells in a microenvironment that may be limited in nutrients.”

Dr Rickert and his colleagues noted that B cells predominate in a quiescent state until they encounter an antigen, which prompts the cells to grow, proliferate, and differentiate.

The team’s new study showed that GSK3 adjusts B-cell metabolism to match the needs of these different cell states.

In circulating B cells, GSK3 limits overall metabolic activity. In proliferating B cells in germinal centers, GSK3 slows glycolysis and the production of mitochondria.

In fact, GSK3 function is essential for B-cell survival in germinal centers. To understand why, the researchers looked at how B cells in these regions generate energy.

The team found that because these B cells are so metabolically active, they consume nearly all available glucose. That switches on glycolysis.

High glycolytic activity leads to an accumulation of toxic reactive oxygen species, as does rapid manufacture of mitochondria, which tend to leak the same chemicals.

Thus, by restraining the metabolism in specific ways, GSK3 prevents cell death induced by reactive oxygen species.

“Our results were really surprising,” Dr Rickert said. “Until now, we would have thought that slowing metabolism would only be important for preventing B cells from becoming cancerous, which it indeed may be. These studies provide insight into the dynamic nature of B-cell metabolism that literally ‘fuels’ differentiation in the germinal center to produce an effective antibody response.”

“It’s not yet clear whether or how GSK3 might be a target for future therapies for B cell-related diseases, but this research opens a lot of doors for further studies. To start with, we plan to investigate how GSK3 is regulated in lymphoma and how that relates to changes in metabolism. That research could lead to new approaches to treating lymphoma.”

This research was performed in collaboration with scientists at Eli Lilly and the Lunenfeld-Tanenbaum Research Institute at the University of Toronto. Funding was provided by the National Institutes of Health, the Lilly Research Award Program, the Arthritis National Research Foundation, and the Canadian Institutes of Health Research.

 

2016 ASH Annual Meeting
© Todd Buchanan 2016

 

SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.

Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.

And in transplant-naïve HL patients, the combination produced an ORR of 67%. 

“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.

“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”

“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”

Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
 
Checkpoint inhibitors

Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.

Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.

Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.

The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.

So the investigators added a combination cohort to CheckMate 039.

Combination cohort study design

Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).

Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.

Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.

The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.

Patient characteristics

The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.

HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).

“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.

Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.

B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.

T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.

MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.

Patient disposition

With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.

“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.

“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”

Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.

Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).

Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.

And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.

About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.

Safety

One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.

“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”

Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).

Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.

Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.

All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.

About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.

“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”

The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).

Efficacy

Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).

“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.

The ORR in the 18 transplant-naive patients was 67% (n=67).

The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.

B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.

T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.

Except for 1 patient with stable disease, MM patients did not respond to therapy.

Biomarker analysis

All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.

Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.

Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.

 

2016 ASH Annual Meeting
© Todd Buchanan 2016

 

SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.

Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.

And in transplant-naïve HL patients, the combination produced an ORR of 67%. 

“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.

“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”

“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”

Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
 
Checkpoint inhibitors

Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.

Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.

Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.

The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.

So the investigators added a combination cohort to CheckMate 039.

Combination cohort study design

Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).

Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.

Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.

The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.

Patient characteristics

The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.

HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).

“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.

Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.

B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.

T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.

MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.

Patient disposition

With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.

“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.

“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”

Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.

Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).

Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.

And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.

About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.

Safety

One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.

“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”

Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).

Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.

Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.

All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.

About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.

“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”

The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).

Efficacy

Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).

“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.

The ORR in the 18 transplant-naive patients was 67% (n=67).

The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.

B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.

T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.

Except for 1 patient with stable disease, MM patients did not respond to therapy.

Biomarker analysis

All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.

Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.

Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.

 

2016 ASH Annual Meeting
© Todd Buchanan 2016

 

SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.

Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.

And in transplant-naïve HL patients, the combination produced an ORR of 67%. 

“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.

“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”

“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”

Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
 
Checkpoint inhibitors

Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.

Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.

Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.

The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.

So the investigators added a combination cohort to CheckMate 039.

Combination cohort study design

Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).

Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.

Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.

The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.

Patient characteristics

The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.

HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).

“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.

Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.

B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.

T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.

MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.

Patient disposition

With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.

“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.

“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”

Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.

Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).

Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.

And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.

About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.

Safety

One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.

“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”

Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).

Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.

Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.

All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.

About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.

“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”

The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).

Efficacy

Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).

“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.

The ORR in the 18 transplant-naive patients was 67% (n=67).

The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.

B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.

T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.

Except for 1 patient with stable disease, MM patients did not respond to therapy.

Biomarker analysis

All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.

Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.

Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

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

Breakthrough 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.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

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

Breakthrough 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.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

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

Breakthrough 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.

 

 

Attendees at the

2016 ASH Annual Meeting

 

SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.

DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.

ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).

A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.

Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).

Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.

Earlier data from the phase 2 study have been reported in Hematology Times.

Phase 2 interim analysis

The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.

“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.

Patients then received a conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.

Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg.

“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”

Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.

The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.

The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.

At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.

Patient characteristics

Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.

The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.

Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.

Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.

Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.

Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.

Results

Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.

At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.

For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.

Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.

The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.

Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.

After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.

Adverse events

Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.

Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.

CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.

In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.

Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.

There were no cases of cerebral edema.

Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.

Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.

Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.

The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.

AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.

Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.

The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.

The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at the

2016 ASH Annual Meeting

 

SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.

DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.

ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).

A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.

Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).

Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.

Earlier data from the phase 2 study have been reported in Hematology Times.

Phase 2 interim analysis

The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.

“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.

Patients then received a conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.

Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg.

“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”

Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.

The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.

The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.

At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.

Patient characteristics

Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.

The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.

Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.

Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.

Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.

Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.

Results

Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.

At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.

For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.

Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.

The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.

Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.

After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.

Adverse events

Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.

Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.

CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.

In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.

Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.

There were no cases of cerebral edema.

Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.

Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.

Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.

The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.

AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.

Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.

The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.

The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at the

2016 ASH Annual Meeting

 

SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.

DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.

ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).

A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.

Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).

Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.

Earlier data from the phase 2 study have been reported in Hematology Times.

Phase 2 interim analysis

The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.

“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.

Patients then received a conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.

Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg.

“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”

Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.

The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.

The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.

At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.

Patient characteristics

Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.

The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.

Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.

Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.

Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.

Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.

Results

Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.

At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.

For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.

Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.

The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.

Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.

After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.

Adverse events

Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.

Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.

CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.

In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.

Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.

There were no cases of cerebral edema.

Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.

Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.

Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.

The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.

AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.

Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.

The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.

The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.

*Information in the abstract differs from that presented at the meeting.

 

 

Micrograph showing FL

 

Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal

dynamics,” according to researchers.

The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.

Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.

The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.

The team then classified the patients according to the following clinical endpoints:

• Patients who presented with transformation (n=15)
• Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
• Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).

The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.

Results showed that tumors that progress early evolve in different ways from those that transform.

The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.

In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.

Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.

The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.

The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.

The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.

The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.

The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.

 

 

Micrograph showing FL

 

Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal

dynamics,” according to researchers.

The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.

Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.

The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.

The team then classified the patients according to the following clinical endpoints:

• Patients who presented with transformation (n=15)
• Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
• Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).

The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.

Results showed that tumors that progress early evolve in different ways from those that transform.

The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.

In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.

Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.

The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.

The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.

The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.

The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.

The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.

 

 

Micrograph showing FL

 

Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal

dynamics,” according to researchers.

The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.

Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.

The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.

The team then classified the patients according to the following clinical endpoints:

• Patients who presented with transformation (n=15)
• Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
• Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).

The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.

Results showed that tumors that progress early evolve in different ways from those that transform.

The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.

In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.

Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.

The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.

The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.

The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.

The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.

The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.