Aggressive Lymphomas

Treatment with the ALK-inhibitor crizotinib produced high response rates in pediatric patients with ALK-positive anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMTs), according to phase 2 trial results.

“The robust and sustained clinical responses to crizotinib in patients with relapsed or refractory ALK-driven ALCL and IMT highlight the importance of this oncogene and the sensitivity to ALK inhibition in these diseases,” said Yaël P. Mossé, MD, of Children’s Hospital of Philadelphia, and her associates.

Twenty-six patients with recurrent ALCL and 14 with unresectable IMTs – not older than 22 years – were enrolled. Six of the ALCL patients were treated at 165 mg/m² (ALCL165) and 20 at 280 mg/m² (ALCL280), which was found to be the recommended phase 2 dose. Ten of the ALCL280 patients had been treated at an equivalent to this dose in phase 1 and they were included in the phase 2 analysis. Those in the ALCL280 group tended to be older, at a median age of 12.2 years, than the other patients in the study, the investigators reported (J Clin Oncol. 2017 Aug 8 doi: 10.1200/JCO.2017.73.4830).

Eight of the IMT patients were enrolled in a dose-escalation portion of the study, with one receiving a 100 mg/m² dose, one receiving 165 mg/m², and the other six receiving 280 mg/m². The other six were treated at 280 mg/m². All of the IMT patient results are presented as one pool because those at the lower doses had toxicity and responses similar to those in patients given the higher dose.

Sixteen of 20 patients in the ALCL280 group – 80% – had a complete response, two had a partial response, and two were found to have stable disease. The median duration of treatment in this group was 0.4 years, and the median time to the first partial or complete response was 27 days. In the ALCL165 group, five of six, or 83%, had a complete response, along with one found to have stable disease. This group had a median treatment duration of 2.79 years, and the median time to the first partial or complete response was 26.5 days.

In the IMT group, 5 of 14, or 36%, had a complete response; 7, or 50%, had a partial response, and 2 had stable disease. They received treatment for a median of 1.63 years, and the median time to the first partial or complete response was 28.5 days.

Investigators reported that at least one grade 3 or 4 adverse event occurred in 83% of patients in the ALCL165 group, in all of the patients in the ALCL280 group, and in 71% in the IMT group. Adverse events considered possibly, probably, or definitely related to the study treatment occurred in 33% of the ALCL165 group, in 85% of the ALCL280 group, and in 57% of the IMT group. The most common adverse event was a decreased neutrophil count.

“Notable objective and sustained responses were observed in patients with ALK fusion-positive ALCL and IMT,” the investigators wrote, “establishing a precedent in pediatric oncology for studying the early-phase activity of a targeted agent in a biomarker-selected and histology-independent cohort of patients.

“In the cohort of patients with ALK-positive unresectable IMTs,” they continued, “ALK inhibition was a highly effective therapy and supports consideration of frontline therapy with crizotinib, a strategy that could also be relevant to adults with this rare disease.”

[email protected]

Treatment with the ALK-inhibitor crizotinib produced high response rates in pediatric patients with ALK-positive anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMTs), according to phase 2 trial results.

“The robust and sustained clinical responses to crizotinib in patients with relapsed or refractory ALK-driven ALCL and IMT highlight the importance of this oncogene and the sensitivity to ALK inhibition in these diseases,” said Yaël P. Mossé, MD, of Children’s Hospital of Philadelphia, and her associates.

Twenty-six patients with recurrent ALCL and 14 with unresectable IMTs – not older than 22 years – were enrolled. Six of the ALCL patients were treated at 165 mg/m² (ALCL165) and 20 at 280 mg/m² (ALCL280), which was found to be the recommended phase 2 dose. Ten of the ALCL280 patients had been treated at an equivalent to this dose in phase 1 and they were included in the phase 2 analysis. Those in the ALCL280 group tended to be older, at a median age of 12.2 years, than the other patients in the study, the investigators reported (J Clin Oncol. 2017 Aug 8 doi: 10.1200/JCO.2017.73.4830).

Eight of the IMT patients were enrolled in a dose-escalation portion of the study, with one receiving a 100 mg/m² dose, one receiving 165 mg/m², and the other six receiving 280 mg/m². The other six were treated at 280 mg/m². All of the IMT patient results are presented as one pool because those at the lower doses had toxicity and responses similar to those in patients given the higher dose.

Sixteen of 20 patients in the ALCL280 group – 80% – had a complete response, two had a partial response, and two were found to have stable disease. The median duration of treatment in this group was 0.4 years, and the median time to the first partial or complete response was 27 days. In the ALCL165 group, five of six, or 83%, had a complete response, along with one found to have stable disease. This group had a median treatment duration of 2.79 years, and the median time to the first partial or complete response was 26.5 days.

In the IMT group, 5 of 14, or 36%, had a complete response; 7, or 50%, had a partial response, and 2 had stable disease. They received treatment for a median of 1.63 years, and the median time to the first partial or complete response was 28.5 days.

Investigators reported that at least one grade 3 or 4 adverse event occurred in 83% of patients in the ALCL165 group, in all of the patients in the ALCL280 group, and in 71% in the IMT group. Adverse events considered possibly, probably, or definitely related to the study treatment occurred in 33% of the ALCL165 group, in 85% of the ALCL280 group, and in 57% of the IMT group. The most common adverse event was a decreased neutrophil count.

“Notable objective and sustained responses were observed in patients with ALK fusion-positive ALCL and IMT,” the investigators wrote, “establishing a precedent in pediatric oncology for studying the early-phase activity of a targeted agent in a biomarker-selected and histology-independent cohort of patients.

“In the cohort of patients with ALK-positive unresectable IMTs,” they continued, “ALK inhibition was a highly effective therapy and supports consideration of frontline therapy with crizotinib, a strategy that could also be relevant to adults with this rare disease.”

[email protected]

Treatment with the ALK-inhibitor crizotinib produced high response rates in pediatric patients with ALK-positive anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMTs), according to phase 2 trial results.

“The robust and sustained clinical responses to crizotinib in patients with relapsed or refractory ALK-driven ALCL and IMT highlight the importance of this oncogene and the sensitivity to ALK inhibition in these diseases,” said Yaël P. Mossé, MD, of Children’s Hospital of Philadelphia, and her associates.

Twenty-six patients with recurrent ALCL and 14 with unresectable IMTs – not older than 22 years – were enrolled. Six of the ALCL patients were treated at 165 mg/m² (ALCL165) and 20 at 280 mg/m² (ALCL280), which was found to be the recommended phase 2 dose. Ten of the ALCL280 patients had been treated at an equivalent to this dose in phase 1 and they were included in the phase 2 analysis. Those in the ALCL280 group tended to be older, at a median age of 12.2 years, than the other patients in the study, the investigators reported (J Clin Oncol. 2017 Aug 8 doi: 10.1200/JCO.2017.73.4830).

Eight of the IMT patients were enrolled in a dose-escalation portion of the study, with one receiving a 100 mg/m² dose, one receiving 165 mg/m², and the other six receiving 280 mg/m². The other six were treated at 280 mg/m². All of the IMT patient results are presented as one pool because those at the lower doses had toxicity and responses similar to those in patients given the higher dose.

Sixteen of 20 patients in the ALCL280 group – 80% – had a complete response, two had a partial response, and two were found to have stable disease. The median duration of treatment in this group was 0.4 years, and the median time to the first partial or complete response was 27 days. In the ALCL165 group, five of six, or 83%, had a complete response, along with one found to have stable disease. This group had a median treatment duration of 2.79 years, and the median time to the first partial or complete response was 26.5 days.

In the IMT group, 5 of 14, or 36%, had a complete response; 7, or 50%, had a partial response, and 2 had stable disease. They received treatment for a median of 1.63 years, and the median time to the first partial or complete response was 28.5 days.

Investigators reported that at least one grade 3 or 4 adverse event occurred in 83% of patients in the ALCL165 group, in all of the patients in the ALCL280 group, and in 71% in the IMT group. Adverse events considered possibly, probably, or definitely related to the study treatment occurred in 33% of the ALCL165 group, in 85% of the ALCL280 group, and in 57% of the IMT group. The most common adverse event was a decreased neutrophil count.

“Notable objective and sustained responses were observed in patients with ALK fusion-positive ALCL and IMT,” the investigators wrote, “establishing a precedent in pediatric oncology for studying the early-phase activity of a targeted agent in a biomarker-selected and histology-independent cohort of patients.

“In the cohort of patients with ALK-positive unresectable IMTs,” they continued, “ALK inhibition was a highly effective therapy and supports consideration of frontline therapy with crizotinib, a strategy that could also be relevant to adults with this rare disease.”

[email protected]

Image by Andre E.X. Brown

Patients newly diagnosed with cancer may have a short-term increased risk of arterial thromboembolism, according to a new study.

The research showed that, within 6 months of their diagnosis, cancer patients had a rate of arterial thromboembolism that was more than double the rate in matched control patients without cancer.

However, the risk of arterial thromboembolism varied by cancer type.

Babak B. Navi, MD, of Weill Cornell Medicine in New York, New York, and his colleagues reported these findings in the Journal of the American College of Cardiology.

The researchers used the Surveillance Epidemiology and End Results–Medicare linked database to identify patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011.

The team matched these patients (by demographics and comorbidities) to Medicare enrollees without cancer, collecting data on 279,719 pairs of subjects. The subjects were followed through 2012.

Arterial thromboembolism

The study’s primary outcome was the cumulative incidence of arterial thromboembolism, defined as any inpatient or outpatient diagnosis of myocardial infarction or ischemic stroke.

The incidence of arterial thromboembolism at 3 months was 3.4% in cancer patients and 1.1% in controls. At 6 months, it was 4.7% and 2.2%, respectively. At 1 year, it was 6.5% and 4.2%, respectively. And at 2 years, it was 9.1% and 8.1%, respectively.

The hazard ratios (HRs) for arterial thromboembolism among cancer patients were 5.2 at 0 to 1 month, 2.1 at 1 to 3 months, 1.4 at 3 to 6 months, 1.1 at 6 to 9 months, and 1.1 at 9 to 12 months.

The risk of arterial thromboembolism varied by cancer type, with the greatest excess risk observed in lung cancer. The 6-month cumulative incidence was 8.3% in lung cancer patients and 2.4% in matched controls (P<0.001).

In patients with non-Hodgkin lymphoma, the 6-month cumulative incidence of arterial thromboembolism was 5.4%, compared to 2.2% in matched controls (P<0.001).

Myocardial infarction

The cumulative incidence of myocardial infarction at 3 months was 1.4% in cancer patients and 0.3% in controls.

At 6 months, it was 2.0% and 0.7%, respectively. At 1 year, it was 2.6% and 1.4%, respectively. And at 2 years, it was 3.7% and 2.8%, respectively.

The HRs for myocardial infarction among cancer patients were 7.3 at 0 to 1 month, 3.0 at 1 to 3 months, 1.8 at 3 to 6 months, 1.3 at 6 to 9 months, and 1.0 at 9 to 12 months.

Ischemic stroke

The cumulative incidence of ischemic stroke at 3 months was 2.1% in cancer patients and 0.8% in controls.

At 6 months, it was 3.0% and 1.6%, respectively. At 1 year, it was 4.3% and 3.1%, respectively. And at 2 years, it was 6.1% and 5.8%, respectively.

The HRs for ischemic stroke among cancer patients were 4.5 at 0 to 1 month, 1.7 at 1 to 3 months, 1.3 at 3 to 6 months, 1.0 at 6 to 9 months, and 1.1 at 9 to 12 months.

The researchers said these findings raise the question of whether patients with newly diagnosed cancer should be considered for antithrombotic and statin medicines for primary prevention of cardiovascular disease.

The team stressed that because patients with cancer are also prone to bleeding due to frequent coagulopathy and invasive procedures, carefully designed clinical trials are needed to answer these questions.

Image by Andre E.X. Brown

Patients newly diagnosed with cancer may have a short-term increased risk of arterial thromboembolism, according to a new study.

The research showed that, within 6 months of their diagnosis, cancer patients had a rate of arterial thromboembolism that was more than double the rate in matched control patients without cancer.

However, the risk of arterial thromboembolism varied by cancer type.

Babak B. Navi, MD, of Weill Cornell Medicine in New York, New York, and his colleagues reported these findings in the Journal of the American College of Cardiology.

The researchers used the Surveillance Epidemiology and End Results–Medicare linked database to identify patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011.

The team matched these patients (by demographics and comorbidities) to Medicare enrollees without cancer, collecting data on 279,719 pairs of subjects. The subjects were followed through 2012.

Arterial thromboembolism

The study’s primary outcome was the cumulative incidence of arterial thromboembolism, defined as any inpatient or outpatient diagnosis of myocardial infarction or ischemic stroke.

The incidence of arterial thromboembolism at 3 months was 3.4% in cancer patients and 1.1% in controls. At 6 months, it was 4.7% and 2.2%, respectively. At 1 year, it was 6.5% and 4.2%, respectively. And at 2 years, it was 9.1% and 8.1%, respectively.

The hazard ratios (HRs) for arterial thromboembolism among cancer patients were 5.2 at 0 to 1 month, 2.1 at 1 to 3 months, 1.4 at 3 to 6 months, 1.1 at 6 to 9 months, and 1.1 at 9 to 12 months.

The risk of arterial thromboembolism varied by cancer type, with the greatest excess risk observed in lung cancer. The 6-month cumulative incidence was 8.3% in lung cancer patients and 2.4% in matched controls (P<0.001).

In patients with non-Hodgkin lymphoma, the 6-month cumulative incidence of arterial thromboembolism was 5.4%, compared to 2.2% in matched controls (P<0.001).

Myocardial infarction

The cumulative incidence of myocardial infarction at 3 months was 1.4% in cancer patients and 0.3% in controls.

At 6 months, it was 2.0% and 0.7%, respectively. At 1 year, it was 2.6% and 1.4%, respectively. And at 2 years, it was 3.7% and 2.8%, respectively.

The HRs for myocardial infarction among cancer patients were 7.3 at 0 to 1 month, 3.0 at 1 to 3 months, 1.8 at 3 to 6 months, 1.3 at 6 to 9 months, and 1.0 at 9 to 12 months.

Ischemic stroke

The cumulative incidence of ischemic stroke at 3 months was 2.1% in cancer patients and 0.8% in controls.

At 6 months, it was 3.0% and 1.6%, respectively. At 1 year, it was 4.3% and 3.1%, respectively. And at 2 years, it was 6.1% and 5.8%, respectively.

The HRs for ischemic stroke among cancer patients were 4.5 at 0 to 1 month, 1.7 at 1 to 3 months, 1.3 at 3 to 6 months, 1.0 at 6 to 9 months, and 1.1 at 9 to 12 months.

The researchers said these findings raise the question of whether patients with newly diagnosed cancer should be considered for antithrombotic and statin medicines for primary prevention of cardiovascular disease.

The team stressed that because patients with cancer are also prone to bleeding due to frequent coagulopathy and invasive procedures, carefully designed clinical trials are needed to answer these questions.

Image by Andre E.X. Brown

Patients newly diagnosed with cancer may have a short-term increased risk of arterial thromboembolism, according to a new study.

The research showed that, within 6 months of their diagnosis, cancer patients had a rate of arterial thromboembolism that was more than double the rate in matched control patients without cancer.

However, the risk of arterial thromboembolism varied by cancer type.

Babak B. Navi, MD, of Weill Cornell Medicine in New York, New York, and his colleagues reported these findings in the Journal of the American College of Cardiology.

The researchers used the Surveillance Epidemiology and End Results–Medicare linked database to identify patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011.

The team matched these patients (by demographics and comorbidities) to Medicare enrollees without cancer, collecting data on 279,719 pairs of subjects. The subjects were followed through 2012.

Arterial thromboembolism

The study’s primary outcome was the cumulative incidence of arterial thromboembolism, defined as any inpatient or outpatient diagnosis of myocardial infarction or ischemic stroke.

The incidence of arterial thromboembolism at 3 months was 3.4% in cancer patients and 1.1% in controls. At 6 months, it was 4.7% and 2.2%, respectively. At 1 year, it was 6.5% and 4.2%, respectively. And at 2 years, it was 9.1% and 8.1%, respectively.

The hazard ratios (HRs) for arterial thromboembolism among cancer patients were 5.2 at 0 to 1 month, 2.1 at 1 to 3 months, 1.4 at 3 to 6 months, 1.1 at 6 to 9 months, and 1.1 at 9 to 12 months.

The risk of arterial thromboembolism varied by cancer type, with the greatest excess risk observed in lung cancer. The 6-month cumulative incidence was 8.3% in lung cancer patients and 2.4% in matched controls (P<0.001).

In patients with non-Hodgkin lymphoma, the 6-month cumulative incidence of arterial thromboembolism was 5.4%, compared to 2.2% in matched controls (P<0.001).

Myocardial infarction

The cumulative incidence of myocardial infarction at 3 months was 1.4% in cancer patients and 0.3% in controls.

At 6 months, it was 2.0% and 0.7%, respectively. At 1 year, it was 2.6% and 1.4%, respectively. And at 2 years, it was 3.7% and 2.8%, respectively.

The HRs for myocardial infarction among cancer patients were 7.3 at 0 to 1 month, 3.0 at 1 to 3 months, 1.8 at 3 to 6 months, 1.3 at 6 to 9 months, and 1.0 at 9 to 12 months.

Ischemic stroke

The cumulative incidence of ischemic stroke at 3 months was 2.1% in cancer patients and 0.8% in controls.

At 6 months, it was 3.0% and 1.6%, respectively. At 1 year, it was 4.3% and 3.1%, respectively. And at 2 years, it was 6.1% and 5.8%, respectively.

The HRs for ischemic stroke among cancer patients were 4.5 at 0 to 1 month, 1.7 at 1 to 3 months, 1.3 at 3 to 6 months, 1.0 at 6 to 9 months, and 1.1 at 9 to 12 months.

The researchers said these findings raise the question of whether patients with newly diagnosed cancer should be considered for antithrombotic and statin medicines for primary prevention of cardiovascular disease.

The team stressed that because patients with cancer are also prone to bleeding due to frequent coagulopathy and invasive procedures, carefully designed clinical trials are needed to answer these questions.

Micrograph showing DLBCL

Results from the SCHOLAR-1 study revealed poor outcomes of salvage therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL).

This retrospective study included data on patients enrolled in 2 randomized trials and 2 academic databases.

The patients had primary refractory disease, were refractory to second-line or later therapy, or had relapsed within 12 months of autologous stem cell transplant (ASCT).

Twenty-six percent of patients responded to salvage therapy, with 7% achieving a complete response (CR).

The median overall survival (OS) was 6.3 months, and 20% of patients were still alive at 2 years’ follow-up.

Christian Gisselbrecht, MD, of Saint Louis Hospital in Paris, France, and his colleagues reported these findings in Blood. SCHOLAR-1 was funded through an unrestricted grant from Kite Pharma.

“SCHOLAR-1 demonstrates the uniformly poor treatment outcomes for patients with aggressive non-Hodgkin lymphoma and emphasizes the need for breakthrough therapies for these refractory patients,” Dr Gisselbrecht said.

Patient characteristics

The study included pooled, patient-level data from 2 phase 3 trials and 2 databases:

• The Canadian Cancer Trials Group study LY.12 (n=219)
• The Lymphoma Academic Research Organization’s CORAL study  (n=170)
• A cohort from MD Anderson Cancer Center (n=165)
• A cohort from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (n=82).

There were a total of 636 patients who met criteria for refractory DLBCL, which included primary mediastinal B-cell lymphoma and transformed follicular lymphoma.

Twenty-eight percent of patients were primary refractory, 50% were refractory to second-line or later therapy, and 22% had relapsed within 12 months of transplant.

The patients’ median age was 55 (range, 19-81), and 64% were male. Seventy-three percent had an ECOG performance status of 0-1, 14% had a status of 2-4, and 13% were missing this data. Seventy-two percent of patients had stage III-IV disease, 27% had stage I-II disease, and less than 1% were missing this data.

Treatments

The MD Anderson cohort included patients who were relapsed/refractory to initial rituximab-containing chemotherapy, had failed salvage platinum-containing chemotherapy, and received a second salvage therapy at MD Anderson.

The University of Iowa/Mayo Clinic cohort included unselected, newly diagnosed patients with lymphoma who entered prospective documentation of primary and subsequent treatments and outcomes.

In the LY.12 study, patients were enrolled upon relapse after anthracycline-containing therapy and randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.

The CORAL study enrolled patients in their first relapse or whose lymphoma was refractory to first-line therapy. They were randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.

In the LY.12 and CORAL studies, eligible patients with CD20+ lymphoma were randomized to rituximab maintenance or observation post-ASCT.

Response

In all, 523 patients were evaluated for response. The overall response rate (ORR) was 26%, with a 7% CR rate and an 18% partial response rate.

Among patients with primary refractory disease, the ORR was 20%, and the CR rate was 3%.

Among patients who were refractory to second-line or later therapy, the ORR was 26%, and the CR rate was 10%.

Among patients who relapsed after transplant, the ORR was 34%, and the CR rate was 15%.

Survival

A total of 603 patients were evaluated for survival.

The median OS from the start of salvage therapy was 6.3 months (range, 5.9-7.0). The 1-year OS rate was 28%, and the 2-year OS was 20%.

Among primary refractory patients, the median OS was 7.1 months (range, 6.0-8.1), 1-year OS was 29%, and 2-year OS was 24%.

Among patient who were refractory to second-line or later therapy, the median OS was 6.1 months (range, 5.2-7.0), 1-year OS was 26%, and 2-year OS was 17%.

Among patients who relapsed after transplant, the median OS was 6.2 months (range, 5.2-7.6), 1-year OS was 32%, and 2-year OS was 19%.

“Although 60% to 70% of non-Hodgkin lymphoma patients survive 5 years after rituximab-based chemotherapy and autologous stem cell transplant, nearly half of them either do not respond or relapse shortly after transplant,” Dr Gisselbrecht noted.

“SCHOLAR-1 provides a rigorous measure of outcomes for these patients who do not benefit from currently available therapies, and this landmark study will serve as an important historical control for evaluating new therapeutic candidates in the field of non-Hodgkin lymphoma.”

Micrograph showing DLBCL

Results from the SCHOLAR-1 study revealed poor outcomes of salvage therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL).

This retrospective study included data on patients enrolled in 2 randomized trials and 2 academic databases.

The patients had primary refractory disease, were refractory to second-line or later therapy, or had relapsed within 12 months of autologous stem cell transplant (ASCT).

Twenty-six percent of patients responded to salvage therapy, with 7% achieving a complete response (CR).

The median overall survival (OS) was 6.3 months, and 20% of patients were still alive at 2 years’ follow-up.

Christian Gisselbrecht, MD, of Saint Louis Hospital in Paris, France, and his colleagues reported these findings in Blood. SCHOLAR-1 was funded through an unrestricted grant from Kite Pharma.

“SCHOLAR-1 demonstrates the uniformly poor treatment outcomes for patients with aggressive non-Hodgkin lymphoma and emphasizes the need for breakthrough therapies for these refractory patients,” Dr Gisselbrecht said.

Patient characteristics

The study included pooled, patient-level data from 2 phase 3 trials and 2 databases:

• The Canadian Cancer Trials Group study LY.12 (n=219)
• The Lymphoma Academic Research Organization’s CORAL study  (n=170)
• A cohort from MD Anderson Cancer Center (n=165)
• A cohort from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (n=82).

There were a total of 636 patients who met criteria for refractory DLBCL, which included primary mediastinal B-cell lymphoma and transformed follicular lymphoma.

Twenty-eight percent of patients were primary refractory, 50% were refractory to second-line or later therapy, and 22% had relapsed within 12 months of transplant.

The patients’ median age was 55 (range, 19-81), and 64% were male. Seventy-three percent had an ECOG performance status of 0-1, 14% had a status of 2-4, and 13% were missing this data. Seventy-two percent of patients had stage III-IV disease, 27% had stage I-II disease, and less than 1% were missing this data.

Treatments

The MD Anderson cohort included patients who were relapsed/refractory to initial rituximab-containing chemotherapy, had failed salvage platinum-containing chemotherapy, and received a second salvage therapy at MD Anderson.

The University of Iowa/Mayo Clinic cohort included unselected, newly diagnosed patients with lymphoma who entered prospective documentation of primary and subsequent treatments and outcomes.

In the LY.12 study, patients were enrolled upon relapse after anthracycline-containing therapy and randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.

The CORAL study enrolled patients in their first relapse or whose lymphoma was refractory to first-line therapy. They were randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.

In the LY.12 and CORAL studies, eligible patients with CD20+ lymphoma were randomized to rituximab maintenance or observation post-ASCT.

Response

In all, 523 patients were evaluated for response. The overall response rate (ORR) was 26%, with a 7% CR rate and an 18% partial response rate.

Among patients with primary refractory disease, the ORR was 20%, and the CR rate was 3%.

Among patients who were refractory to second-line or later therapy, the ORR was 26%, and the CR rate was 10%.

Among patients who relapsed after transplant, the ORR was 34%, and the CR rate was 15%.

Survival

A total of 603 patients were evaluated for survival.

The median OS from the start of salvage therapy was 6.3 months (range, 5.9-7.0). The 1-year OS rate was 28%, and the 2-year OS was 20%.

Among primary refractory patients, the median OS was 7.1 months (range, 6.0-8.1), 1-year OS was 29%, and 2-year OS was 24%.

Among patient who were refractory to second-line or later therapy, the median OS was 6.1 months (range, 5.2-7.0), 1-year OS was 26%, and 2-year OS was 17%.

Among patients who relapsed after transplant, the median OS was 6.2 months (range, 5.2-7.6), 1-year OS was 32%, and 2-year OS was 19%.

“Although 60% to 70% of non-Hodgkin lymphoma patients survive 5 years after rituximab-based chemotherapy and autologous stem cell transplant, nearly half of them either do not respond or relapse shortly after transplant,” Dr Gisselbrecht noted.

“SCHOLAR-1 provides a rigorous measure of outcomes for these patients who do not benefit from currently available therapies, and this landmark study will serve as an important historical control for evaluating new therapeutic candidates in the field of non-Hodgkin lymphoma.”

Micrograph showing DLBCL

Results from the SCHOLAR-1 study revealed poor outcomes of salvage therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL).

This retrospective study included data on patients enrolled in 2 randomized trials and 2 academic databases.

The patients had primary refractory disease, were refractory to second-line or later therapy, or had relapsed within 12 months of autologous stem cell transplant (ASCT).

Twenty-six percent of patients responded to salvage therapy, with 7% achieving a complete response (CR).

The median overall survival (OS) was 6.3 months, and 20% of patients were still alive at 2 years’ follow-up.

Christian Gisselbrecht, MD, of Saint Louis Hospital in Paris, France, and his colleagues reported these findings in Blood. SCHOLAR-1 was funded through an unrestricted grant from Kite Pharma.

“SCHOLAR-1 demonstrates the uniformly poor treatment outcomes for patients with aggressive non-Hodgkin lymphoma and emphasizes the need for breakthrough therapies for these refractory patients,” Dr Gisselbrecht said.

Patient characteristics

The study included pooled, patient-level data from 2 phase 3 trials and 2 databases:

• The Canadian Cancer Trials Group study LY.12 (n=219)
• The Lymphoma Academic Research Organization’s CORAL study  (n=170)
• A cohort from MD Anderson Cancer Center (n=165)
• A cohort from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (n=82).

There were a total of 636 patients who met criteria for refractory DLBCL, which included primary mediastinal B-cell lymphoma and transformed follicular lymphoma.

Twenty-eight percent of patients were primary refractory, 50% were refractory to second-line or later therapy, and 22% had relapsed within 12 months of transplant.

The patients’ median age was 55 (range, 19-81), and 64% were male. Seventy-three percent had an ECOG performance status of 0-1, 14% had a status of 2-4, and 13% were missing this data. Seventy-two percent of patients had stage III-IV disease, 27% had stage I-II disease, and less than 1% were missing this data.

Treatments

The MD Anderson cohort included patients who were relapsed/refractory to initial rituximab-containing chemotherapy, had failed salvage platinum-containing chemotherapy, and received a second salvage therapy at MD Anderson.

The University of Iowa/Mayo Clinic cohort included unselected, newly diagnosed patients with lymphoma who entered prospective documentation of primary and subsequent treatments and outcomes.

In the LY.12 study, patients were enrolled upon relapse after anthracycline-containing therapy and randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.

The CORAL study enrolled patients in their first relapse or whose lymphoma was refractory to first-line therapy. They were randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.

In the LY.12 and CORAL studies, eligible patients with CD20+ lymphoma were randomized to rituximab maintenance or observation post-ASCT.

Response

In all, 523 patients were evaluated for response. The overall response rate (ORR) was 26%, with a 7% CR rate and an 18% partial response rate.

Among patients with primary refractory disease, the ORR was 20%, and the CR rate was 3%.

Among patients who were refractory to second-line or later therapy, the ORR was 26%, and the CR rate was 10%.

Among patients who relapsed after transplant, the ORR was 34%, and the CR rate was 15%.

Survival

A total of 603 patients were evaluated for survival.

The median OS from the start of salvage therapy was 6.3 months (range, 5.9-7.0). The 1-year OS rate was 28%, and the 2-year OS was 20%.

Among primary refractory patients, the median OS was 7.1 months (range, 6.0-8.1), 1-year OS was 29%, and 2-year OS was 24%.

Among patient who were refractory to second-line or later therapy, the median OS was 6.1 months (range, 5.2-7.0), 1-year OS was 26%, and 2-year OS was 17%.

Among patients who relapsed after transplant, the median OS was 6.2 months (range, 5.2-7.6), 1-year OS was 32%, and 2-year OS was 19%.

“Although 60% to 70% of non-Hodgkin lymphoma patients survive 5 years after rituximab-based chemotherapy and autologous stem cell transplant, nearly half of them either do not respond or relapse shortly after transplant,” Dr Gisselbrecht noted.

“SCHOLAR-1 provides a rigorous measure of outcomes for these patients who do not benefit from currently available therapies, and this landmark study will serve as an important historical control for evaluating new therapeutic candidates in the field of non-Hodgkin lymphoma.”

Solid organ transplant recipients contribute a disproportionate fraction of pediatric non-Hodgkin lymphoma (NHL) cases, especially diffuse large B-cell lymphoma cases (DLBCL), according to an analysis of data drawn from transplant and cancer registries.

Investigators calculated that the incidence of NHL for the pediatric transplant population was 257 times higher than the general population, after analysis from the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012. The incidence of NHL for the pediatric transplant population was 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general population. Furthermore, transplant recipients made up a much larger proportion of general population DLBCL cases (7.62%; 95% CI, 6.35%-8.88%).

In the general population, the most common subtypes were DLBCL (25% of cases), Burkitt lymphoma (24%), and precursor cell lymphoblastic lymphoma (20%). Among NHLs diagnosed in transplant recipients, 65% were DLBCL, and 9% were Burkitt lymphoma, whereas there were no cases of precursor cell lymphoblastic lymphoma, reported Elizabeth L. Yanik, PhD, of Washington University, St. Louis, and her associates (Cancer. 2017 Jul 31. doi: 10.1002/cncr.30923).

The increased risk of NHL and other cancers for organ transplant recipients is primarily the result of the immunosuppressant medications administered after transplantation, leading to an increased risk of infection-related cancers, the authors said.

“NHL cases are largely attributable to EBV [Epstein-Barr virus] infections that occur while recipients are immunosuppressed, as evidenced by the high prevalence of EBV detectable in NHL tumors and particularly in cases diagnosed during the heavily immunosuppressed period early after transplantation,” wrote Dr. Yanik and her colleagues. “Patients who experience a primary EBV infection after transplantation are particularly susceptible because transplant recipients have a higher NHL risk if they are seronegative for EBV before transplantation.”

Among those at risk, Dr. Yanik and fellow investigators found transplant patients younger than 5 years were the most susceptible to NHL, making up 19.79% of those diagnosed with DLBCL.

The proportion of NHL in solid organ transplant recipients within the entire pediatric NHL population has risen over time, from 1.66% of the NHL population during 1990-1994 to 3.73% during 2010-2012.

“This trend is driven by the rising prevalence of transplant recipients in the general population and not by increases in NHL risk among transplant recipients,” noted Dr. Yanik and her coauthors. “The proportion of NHL diagnoses attributable to transplant recipients has grown over time, and it is likely that this population will be an important source of pediatric NHL cases in the future.”

This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.

[email protected]

On Twitter @eaztweets

Solid organ transplant recipients contribute a disproportionate fraction of pediatric non-Hodgkin lymphoma (NHL) cases, especially diffuse large B-cell lymphoma cases (DLBCL), according to an analysis of data drawn from transplant and cancer registries.

Investigators calculated that the incidence of NHL for the pediatric transplant population was 257 times higher than the general population, after analysis from the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012. The incidence of NHL for the pediatric transplant population was 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general population. Furthermore, transplant recipients made up a much larger proportion of general population DLBCL cases (7.62%; 95% CI, 6.35%-8.88%).

In the general population, the most common subtypes were DLBCL (25% of cases), Burkitt lymphoma (24%), and precursor cell lymphoblastic lymphoma (20%). Among NHLs diagnosed in transplant recipients, 65% were DLBCL, and 9% were Burkitt lymphoma, whereas there were no cases of precursor cell lymphoblastic lymphoma, reported Elizabeth L. Yanik, PhD, of Washington University, St. Louis, and her associates (Cancer. 2017 Jul 31. doi: 10.1002/cncr.30923).

The increased risk of NHL and other cancers for organ transplant recipients is primarily the result of the immunosuppressant medications administered after transplantation, leading to an increased risk of infection-related cancers, the authors said.

“NHL cases are largely attributable to EBV [Epstein-Barr virus] infections that occur while recipients are immunosuppressed, as evidenced by the high prevalence of EBV detectable in NHL tumors and particularly in cases diagnosed during the heavily immunosuppressed period early after transplantation,” wrote Dr. Yanik and her colleagues. “Patients who experience a primary EBV infection after transplantation are particularly susceptible because transplant recipients have a higher NHL risk if they are seronegative for EBV before transplantation.”

Among those at risk, Dr. Yanik and fellow investigators found transplant patients younger than 5 years were the most susceptible to NHL, making up 19.79% of those diagnosed with DLBCL.

The proportion of NHL in solid organ transplant recipients within the entire pediatric NHL population has risen over time, from 1.66% of the NHL population during 1990-1994 to 3.73% during 2010-2012.

“This trend is driven by the rising prevalence of transplant recipients in the general population and not by increases in NHL risk among transplant recipients,” noted Dr. Yanik and her coauthors. “The proportion of NHL diagnoses attributable to transplant recipients has grown over time, and it is likely that this population will be an important source of pediatric NHL cases in the future.”

This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.

[email protected]

On Twitter @eaztweets

Solid organ transplant recipients contribute a disproportionate fraction of pediatric non-Hodgkin lymphoma (NHL) cases, especially diffuse large B-cell lymphoma cases (DLBCL), according to an analysis of data drawn from transplant and cancer registries.

Investigators calculated that the incidence of NHL for the pediatric transplant population was 257 times higher than the general population, after analysis from the U.S. transplant registry and 16 cancer registries from around the country between 1990 and 2012. The incidence of NHL for the pediatric transplant population was 306 cases per 100,000 person-years (95% CI, 271-344), compared to 1.19 cases per 100,000 person-years (95% CI, 1.12-1.27) in the general population. Furthermore, transplant recipients made up a much larger proportion of general population DLBCL cases (7.62%; 95% CI, 6.35%-8.88%).

In the general population, the most common subtypes were DLBCL (25% of cases), Burkitt lymphoma (24%), and precursor cell lymphoblastic lymphoma (20%). Among NHLs diagnosed in transplant recipients, 65% were DLBCL, and 9% were Burkitt lymphoma, whereas there were no cases of precursor cell lymphoblastic lymphoma, reported Elizabeth L. Yanik, PhD, of Washington University, St. Louis, and her associates (Cancer. 2017 Jul 31. doi: 10.1002/cncr.30923).

The increased risk of NHL and other cancers for organ transplant recipients is primarily the result of the immunosuppressant medications administered after transplantation, leading to an increased risk of infection-related cancers, the authors said.

“NHL cases are largely attributable to EBV [Epstein-Barr virus] infections that occur while recipients are immunosuppressed, as evidenced by the high prevalence of EBV detectable in NHL tumors and particularly in cases diagnosed during the heavily immunosuppressed period early after transplantation,” wrote Dr. Yanik and her colleagues. “Patients who experience a primary EBV infection after transplantation are particularly susceptible because transplant recipients have a higher NHL risk if they are seronegative for EBV before transplantation.”

Among those at risk, Dr. Yanik and fellow investigators found transplant patients younger than 5 years were the most susceptible to NHL, making up 19.79% of those diagnosed with DLBCL.

The proportion of NHL in solid organ transplant recipients within the entire pediatric NHL population has risen over time, from 1.66% of the NHL population during 1990-1994 to 3.73% during 2010-2012.

“This trend is driven by the rising prevalence of transplant recipients in the general population and not by increases in NHL risk among transplant recipients,” noted Dr. Yanik and her coauthors. “The proportion of NHL diagnoses attributable to transplant recipients has grown over time, and it is likely that this population will be an important source of pediatric NHL cases in the future.”

This study was partially funded by the National Cancer Institute. One coauthor reported being an employee at GRAIL Inc. No other relevant financial disclosures were reported.

[email protected]

On Twitter @eaztweets

Mantle cell lymphoma

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

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

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

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

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

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

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

Mantle cell lymphoma

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

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

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

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

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

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

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

Mantle cell lymphoma

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

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

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

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

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

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

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

Photo by Aaron Logan

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

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

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

The team reported these findings in Nature Communications.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Photo by Aaron Logan

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

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

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

The team reported these findings in Nature Communications.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Photo by Aaron Logan

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

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

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

The team reported these findings in Nature Communications.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Photo from Business Wire

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

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

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

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

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

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

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

AETHERA trial

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

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

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

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

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

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

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

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

Photo from Business Wire

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

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

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

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

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

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

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

AETHERA trial

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

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

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

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

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

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

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

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

Photo from Business Wire

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

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

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

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

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

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

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

AETHERA trial

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

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

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

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

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

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

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

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

Micrograph showing CLL

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

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

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

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

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

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

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

Treatment

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

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

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

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

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

ORR, MRD, and survival

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

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

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

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

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

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

Adverse events

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

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

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

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

Micrograph showing CLL

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

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

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

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

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

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

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

Treatment

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

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

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

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

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

ORR, MRD, and survival

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

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

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

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

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

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

Adverse events

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

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

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

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

Micrograph showing CLL

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

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

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

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

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

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

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

Treatment

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

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

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

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

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

ORR, MRD, and survival

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

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

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

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

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

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

Adverse events

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

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

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

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

Micrograph showing FL

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

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

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

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

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

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

GALLIUM trial

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

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

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

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

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

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

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

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

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

Micrograph showing FL

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

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

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

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

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

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

GALLIUM trial

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

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

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

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

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

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

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

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

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

Micrograph showing FL

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

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

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

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

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

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

GALLIUM trial

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

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

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

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

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

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

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

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

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

Image by Joshua Stokes

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

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

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

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

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

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

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

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

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

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

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

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

Next steps

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

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

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

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

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

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

Image by Joshua Stokes

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

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

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

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

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

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

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

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

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

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

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

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

Next steps

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

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

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

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

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

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

Image by Joshua Stokes

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

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

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

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

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

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

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

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

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

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

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

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

Next steps

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

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

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

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

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

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