Follicular Lymphoma

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Blood sample collection

Photo by Juan D. Alfonso

 

A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.

Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.

This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.

Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.

They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.

The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.

In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.

The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.

Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.

Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.

Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.

 

 

Blood sample collection

Photo by Juan D. Alfonso

 

A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.

Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.

This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.

Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.

They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.

The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.

In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.

The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.

Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.

Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.

Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.

 

 

Blood sample collection

Photo by Juan D. Alfonso

 

A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.

Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.

This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.

Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.

They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.

The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.

In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.

The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.

Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.

Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.

Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.

 

 

Genome testing

Photo courtesy of the

National Institute

of General Medical Science

 

NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).

First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.

However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.

“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.

“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.

Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.

Demographic risk factors

Dr Slager noted that age, gender, and race are risk factors for CLL.

Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.

There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.

There is a higher incidence of CLL in Caucasians than Asians, for both males and females.

“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”

However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.

Beyond demographic factors

The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.

In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.

The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.

This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.

Medical history

Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.

However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.

The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.

“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.

Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.

Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.

Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.

“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”

Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.

“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”

For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”

Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.

 

 

Genome testing

Photo courtesy of the

National Institute

of General Medical Science

 

NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).

First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.

However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.

“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.

“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.

Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.

Demographic risk factors

Dr Slager noted that age, gender, and race are risk factors for CLL.

Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.

There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.

There is a higher incidence of CLL in Caucasians than Asians, for both males and females.

“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”

However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.

Beyond demographic factors

The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.

In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.

The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.

This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.

Medical history

Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.

However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.

The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.

“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.

Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.

Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.

Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.

“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”

Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.

“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”

For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”

Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.

 

 

Genome testing

Photo courtesy of the

National Institute

of General Medical Science

 

NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).

First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.

However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.

“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.

“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.

Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.

Demographic risk factors

Dr Slager noted that age, gender, and race are risk factors for CLL.

Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.

There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.

There is a higher incidence of CLL in Caucasians than Asians, for both males and females.

“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”

However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.

Beyond demographic factors

The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.

In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.

The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.

This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.

Medical history

Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.

However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.

The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.

“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.

Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.

Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.

Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.

“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”

Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.

“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”

For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”

Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.

 

 

Micrograph showing CMV

 

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) is recommending orphan designation for a cytomegalovirus-specific cytotoxic T-lymphocyte product (CMV-CTLs) intended to treat CMV infection in patients with impaired cell-mediated immunity.

The CMV-CTLs are designed to find and kill cells expressing CMV.

To create CMV-CTLs, T cells are collected from the blood of third-party donors and then exposed to CMV antigens.

The resulting activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

The CMV-CTLs are being developed by Atara Biotherapeutics, Inc.

The cells are currently under investigation in a pair of phase 2 trials (NCT01646645 and NCT02136797).

Results of a phase 1 trial (published in Biology of Blood and Marrow Transplantation in 2015) suggested CMV-CTLs are safe and can clear CMV infection in patients who have undergone allogeneic hematopoietic stem cell transplant.

The trial included 17 transplant recipients with CMV viremia or clinical infection that persisted despite prolonged treatment with antiviral drugs. Fourteen of the patients had received T-cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis.

Sixteen of the patients received CMV-CTLs created using cells derived from their transplant donor, and 1 patient received cells from a third-party donor.

Fifteen patients achieved clearance of CMV viremia, including 3 of the 5 patients with overt disease and the patient who received cells from a third-party donor.

In addition, the researchers said CMV-CTLs were well-tolerated. None of the patients experienced fever, alterations in vital signs, or other toxicities during the first 48 hours of observation.

None of the patients developed manifestations of de novo acute GVHD, and GHVD did not worsen in either of the 2 patients who had GVHD prior to infusion.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

 

 

Micrograph showing CMV

 

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) is recommending orphan designation for a cytomegalovirus-specific cytotoxic T-lymphocyte product (CMV-CTLs) intended to treat CMV infection in patients with impaired cell-mediated immunity.

The CMV-CTLs are designed to find and kill cells expressing CMV.

To create CMV-CTLs, T cells are collected from the blood of third-party donors and then exposed to CMV antigens.

The resulting activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

The CMV-CTLs are being developed by Atara Biotherapeutics, Inc.

The cells are currently under investigation in a pair of phase 2 trials (NCT01646645 and NCT02136797).

Results of a phase 1 trial (published in Biology of Blood and Marrow Transplantation in 2015) suggested CMV-CTLs are safe and can clear CMV infection in patients who have undergone allogeneic hematopoietic stem cell transplant.

The trial included 17 transplant recipients with CMV viremia or clinical infection that persisted despite prolonged treatment with antiviral drugs. Fourteen of the patients had received T-cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis.

Sixteen of the patients received CMV-CTLs created using cells derived from their transplant donor, and 1 patient received cells from a third-party donor.

Fifteen patients achieved clearance of CMV viremia, including 3 of the 5 patients with overt disease and the patient who received cells from a third-party donor.

In addition, the researchers said CMV-CTLs were well-tolerated. None of the patients experienced fever, alterations in vital signs, or other toxicities during the first 48 hours of observation.

None of the patients developed manifestations of de novo acute GVHD, and GHVD did not worsen in either of the 2 patients who had GVHD prior to infusion.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

 

 

Micrograph showing CMV

 

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) is recommending orphan designation for a cytomegalovirus-specific cytotoxic T-lymphocyte product (CMV-CTLs) intended to treat CMV infection in patients with impaired cell-mediated immunity.

The CMV-CTLs are designed to find and kill cells expressing CMV.

To create CMV-CTLs, T cells are collected from the blood of third-party donors and then exposed to CMV antigens.

The resulting activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

The CMV-CTLs are being developed by Atara Biotherapeutics, Inc.

The cells are currently under investigation in a pair of phase 2 trials (NCT01646645 and NCT02136797).

Results of a phase 1 trial (published in Biology of Blood and Marrow Transplantation in 2015) suggested CMV-CTLs are safe and can clear CMV infection in patients who have undergone allogeneic hematopoietic stem cell transplant.

The trial included 17 transplant recipients with CMV viremia or clinical infection that persisted despite prolonged treatment with antiviral drugs. Fourteen of the patients had received T-cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis.

Sixteen of the patients received CMV-CTLs created using cells derived from their transplant donor, and 1 patient received cells from a third-party donor.

Fifteen patients achieved clearance of CMV viremia, including 3 of the 5 patients with overt disease and the patient who received cells from a third-party donor.

In addition, the researchers said CMV-CTLs were well-tolerated. None of the patients experienced fever, alterations in vital signs, or other toxicities during the first 48 hours of observation.

None of the patients developed manifestations of de novo acute GVHD, and GHVD did not worsen in either of the 2 patients who had GVHD prior to infusion.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.

Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.

It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.

To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.

A TMTV threshold of 510 cm³ was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).

Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.

No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.

The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.

Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.

It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.

To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.

A TMTV threshold of 510 cm³ was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).

Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.

No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.

The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.

Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.

It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.

To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.

A TMTV threshold of 510 cm³ was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).

Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.

No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.

 

 

Follicular lymphoma

 

Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.

The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based

therapy or stopped responding to it.

The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).

However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).

Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.

Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.

Patients and treatment

GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).

The patients were randomized to receive one of the following treatments:

• bendamustine alone (120 mg/m²/day on days 1 and 2 for up to six 28-day cycles)
• bendamustine (90 mg/m²/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).

The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.

Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.

Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.

The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.

Safety

Nearly all patients in both arms experienced at least 1 adverse event (AE).

Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).

Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).

Response

According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.

The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.

Survival

The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.

According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).

At last follow-up, the median OS had not been reached in either arm (P=0.40).

There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).

Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).

Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).

Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.

 

 

Follicular lymphoma

 

Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.

The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based

therapy or stopped responding to it.

The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).

However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).

Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.

Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.

Patients and treatment

GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).

The patients were randomized to receive one of the following treatments:

• bendamustine alone (120 mg/m²/day on days 1 and 2 for up to six 28-day cycles)
• bendamustine (90 mg/m²/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).

The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.

Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.

Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.

The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.

Safety

Nearly all patients in both arms experienced at least 1 adverse event (AE).

Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).

Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).

Response

According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.

The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.

Survival

The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.

According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).

At last follow-up, the median OS had not been reached in either arm (P=0.40).

There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).

Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).

Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).

Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.

 

 

Follicular lymphoma

 

Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.

The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based

therapy or stopped responding to it.

The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).

However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).

Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.

Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.

Patients and treatment

GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).

The patients were randomized to receive one of the following treatments:

• bendamustine alone (120 mg/m²/day on days 1 and 2 for up to six 28-day cycles)
• bendamustine (90 mg/m²/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).

The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.

Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.

Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.

The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.

Safety

Nearly all patients in both arms experienced at least 1 adverse event (AE).

Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).

Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).

Response

According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.

The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.

Survival

The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.

According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).

At last follow-up, the median OS had not been reached in either arm (P=0.40).

There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).

Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).

Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).

Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.