User login
Optimizing CAR T-cell therapy in NHL
Photo from Fred Hutchinson
Cancer Research Center
Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).
Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.
Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.
The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.
Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.
About JCAR014
JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.
“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”
Patients and treatment
Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).
The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).
They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous
(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.
The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.
Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 105 CAR T cells/kg, 18 received 2 × 106 CAR T cells/kg, and 9 received 2 × 107 CAR T cells/kg.
Efficacy
In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).
Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).
The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.
Higher response rates were also observed in patients who received 2 × 106 CAR T cells/kg rather than the other 2 dose levels.
The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 106/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 106/kg after Cy or Cy/E.
Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 106 CAR T cells/kg, and 1 patient each had received the other 2 doses.)
“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.
“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”
Safety
Two patients who were treated with the highest CAR T-cell dose (2 × 107 cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.
This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.
Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.
Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.
Three of the 6 patients (50%) treated at 2 × 107 CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.
The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.
They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.
The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions. 
Photo from Fred Hutchinson
Cancer Research Center
Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).
Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.
Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.
The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.
Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.
About JCAR014
JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.
“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”
Patients and treatment
Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).
The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).
They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous
(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.
The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.
Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 105 CAR T cells/kg, 18 received 2 × 106 CAR T cells/kg, and 9 received 2 × 107 CAR T cells/kg.
Efficacy
In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).
Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).
The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.
Higher response rates were also observed in patients who received 2 × 106 CAR T cells/kg rather than the other 2 dose levels.
The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 106/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 106/kg after Cy or Cy/E.
Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 106 CAR T cells/kg, and 1 patient each had received the other 2 doses.)
“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.
“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”
Safety
Two patients who were treated with the highest CAR T-cell dose (2 × 107 cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.
This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.
Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.
Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.
Three of the 6 patients (50%) treated at 2 × 107 CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.
The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.
They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.
The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.
Photo from Fred Hutchinson
Cancer Research Center
Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).
Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.
Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.
The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.
Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.
About JCAR014
JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.
“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”
Patients and treatment
Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).
The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).
They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous
(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.
The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.
Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 105 CAR T cells/kg, 18 received 2 × 106 CAR T cells/kg, and 9 received 2 × 107 CAR T cells/kg.
Efficacy
In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).
Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).
The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.
Higher response rates were also observed in patients who received 2 × 106 CAR T cells/kg rather than the other 2 dose levels.
The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 106/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 106/kg after Cy or Cy/E.
Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 106 CAR T cells/kg, and 1 patient each had received the other 2 doses.)
“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.
“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”
Safety
Two patients who were treated with the highest CAR T-cell dose (2 × 107 cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.
This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.
Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.
Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.
Three of the 6 patients (50%) treated at 2 × 107 CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.
The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.
They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.
The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.
Metabolic tumor volume predicts outcome in follicular lymphoma
The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.
Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.
It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.
To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.
A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).
Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.
No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.
Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.
It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.
To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.
A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).
Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.
No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.
Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.
It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.
To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.
A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).
Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.
No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: At diagnosis, the total metabolic tumor volume of follicular lymphoma predicts treatment response and patient outcome.
Major finding: A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival.
Data source: A pooled analysis of three multicenter prospective studies involving 185 patients with a high burden of disease.
Disclosures: No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
New treatment option for relapsed/refractory NHL
Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.
The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based
therapy or stopped responding to it.
The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).
However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).
Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.
Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.
Patients and treatment
GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).
The patients were randomized to receive one of the following treatments:
- bendamustine alone (120 mg/m2/day on days 1 and 2 for up to six 28-day cycles)
- bendamustine (90 mg/m2/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).
The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.
Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.
Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.
The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.
Safety
Nearly all patients in both arms experienced at least 1 adverse event (AE).
Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).
Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).
Response
According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.
The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.
Survival
The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
At last follow-up, the median OS had not been reached in either arm (P=0.40).
There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).
Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).
Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).
Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.
Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.
The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based
therapy or stopped responding to it.
The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).
However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).
Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.
Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.
Patients and treatment
GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).
The patients were randomized to receive one of the following treatments:
- bendamustine alone (120 mg/m2/day on days 1 and 2 for up to six 28-day cycles)
- bendamustine (90 mg/m2/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).
The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.
Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.
Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.
The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.
Safety
Nearly all patients in both arms experienced at least 1 adverse event (AE).
Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).
Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).
Response
According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.
The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.
Survival
The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
At last follow-up, the median OS had not been reached in either arm (P=0.40).
There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).
Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).
Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).
Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.
Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.
The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based
therapy or stopped responding to it.
The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).
However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).
Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.
Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.
Patients and treatment
GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).
The patients were randomized to receive one of the following treatments:
- bendamustine alone (120 mg/m2/day on days 1 and 2 for up to six 28-day cycles)
- bendamustine (90 mg/m2/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).
The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.
Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.
Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.
The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.
Safety
Nearly all patients in both arms experienced at least 1 adverse event (AE).
Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).
Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).
Response
According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.
The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.
Survival
The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
At last follow-up, the median OS had not been reached in either arm (P=0.40).
There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).
Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).
Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).
Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.
Drug no longer in development for DLBCL, other cancers
ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.
In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.
Now, ProNAi has said it does not plan to resume development of the drug.
“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.
About PNT2258
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.
ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.
“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.
The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.
ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).
Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.
PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.
“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.
PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m2 through 150 mg/m2.
A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.
Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.
ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.
In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.
Now, ProNAi has said it does not plan to resume development of the drug.
“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.
About PNT2258
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.
ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.
“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.
The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.
ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).
Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.
PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.
“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.
PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m2 through 150 mg/m2.
A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.
Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.
ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.
In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.
Now, ProNAi has said it does not plan to resume development of the drug.
“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.
About PNT2258
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.
ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.
“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.
The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.
ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).
Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.
PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.
“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.
PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m2 through 150 mg/m2.
A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.
Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.
CAR T-cell therapy granted orphan designation
Photo courtesy of NIAID
The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).
The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.
ICG122 is being developed by iCell Gene Therapeutics.
The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.
“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.
“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Photo courtesy of NIAID
The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).
The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.
ICG122 is being developed by iCell Gene Therapeutics.
The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.
“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.
“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Photo courtesy of NIAID
The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).
The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.
ICG122 is being developed by iCell Gene Therapeutics.
The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.
“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.
“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Lenalidomide maintenance doesn’t improve OS in DLBCL
Photo courtesy of Celgene
Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.
Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.
REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.
The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.
However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.
Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.
“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.
“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”
The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:
- The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
- The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
- The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
- The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.
Photo courtesy of Celgene
Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.
Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.
REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.
The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.
However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.
Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.
“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.
“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”
The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:
- The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
- The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
- The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
- The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.
Photo courtesy of Celgene
Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.
Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.
REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.
The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.
However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.
Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.
“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.
“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”
The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:
- The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
- The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
- The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
- The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.
Combo doesn’t improve PFS in DLBCL
Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.
Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.
The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.
“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.
“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”
The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m2 every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.
The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.
In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.
Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.
Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.
Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.
Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.
The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.
“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.
“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”
The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m2 every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.
The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.
In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.
Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.
Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.
Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.
Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.
The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.
“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.
“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”
The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m2 every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.
The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.
In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.
Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.
Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.
Drug’s benefits outweigh risks, PRAC says
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.
However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.
And the committee updated its previous recommendations to manage this risk.
The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the review
The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
PRAC’s recommendations
The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.
Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.
Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.
Furthermore, idelalisib should not be started in patients with a generalized infection.
At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.
Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.
However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.
And the committee updated its previous recommendations to manage this risk.
The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the review
The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
PRAC’s recommendations
The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.
Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.
Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.
Furthermore, idelalisib should not be started in patients with a generalized infection.
At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.
Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.
However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.
And the committee updated its previous recommendations to manage this risk.
The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the review
The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
PRAC’s recommendations
The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.
Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.
Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.
Furthermore, idelalisib should not be started in patients with a generalized infection.
At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.
Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.
Obinutuzumab approved to treat FL
The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).
The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.
GADOLIN trial
The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.
Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.
Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).
The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.
The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.
The median overall survival has not yet been reached in either study arm.
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).
The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).
The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).
The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.
GADOLIN trial
The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.
Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.
Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).
The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.
The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.
The median overall survival has not yet been reached in either study arm.
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).
The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).
The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).
The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.
GADOLIN trial
The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.
Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.
Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).
The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.
The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.
The median overall survival has not yet been reached in either study arm.
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).
The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).
Follicular lymphoma with histologic transformation may merit ASCT
Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.
In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.
Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).
A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).
After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.
Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.
The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.
In just 3 years, prospective observational studies and [this] clever ancillary analysis of a prospective clinical trial have better informed the lymphoma community about the expected incidence and timing of transformation in patients with follicular lymphoma after being treated with modern management strategies. But we are still limited by clumsy predictive tools for identifying patients at highest risk. Deeper understanding of biologic and genetic factors of FL subclonal populations as well as the tumor microenvironment will allow for more precise identification of patients truly at risk and potentially will provide actionable targets for abrogating that risk. Future [studies of] transformed lymphoma will hopefully replace variables such as anthracyclines, the Follicular Lymphoma International Prognostic Index, lactate dehydrogenase, and ASCT with promising new variables such as IRF-4, miR-31, bcl-2, pleuripotency, and nuclear factor kappa B pathway genes or new therapies that target these variables. Future analyses should not simply prognosticate who is at risk for transformation, but should predict a specific intervention to either prevent or treat such an event.
Dr. Brian K. Link is at the University of Iowa, Iowa City. He reported ties to AbbVie, Gilead Sciences, Genentech, Sandoz, Pharmacyclics, Millennium Pharmaceuticals, Genentech, Kite Pharma, Seattle Genetics, and Dynavax Technologies. These comments are from his editorial accompanying the report (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.67.4234).
In just 3 years, prospective observational studies and [this] clever ancillary analysis of a prospective clinical trial have better informed the lymphoma community about the expected incidence and timing of transformation in patients with follicular lymphoma after being treated with modern management strategies. But we are still limited by clumsy predictive tools for identifying patients at highest risk. Deeper understanding of biologic and genetic factors of FL subclonal populations as well as the tumor microenvironment will allow for more precise identification of patients truly at risk and potentially will provide actionable targets for abrogating that risk. Future [studies of] transformed lymphoma will hopefully replace variables such as anthracyclines, the Follicular Lymphoma International Prognostic Index, lactate dehydrogenase, and ASCT with promising new variables such as IRF-4, miR-31, bcl-2, pleuripotency, and nuclear factor kappa B pathway genes or new therapies that target these variables. Future analyses should not simply prognosticate who is at risk for transformation, but should predict a specific intervention to either prevent or treat such an event.
Dr. Brian K. Link is at the University of Iowa, Iowa City. He reported ties to AbbVie, Gilead Sciences, Genentech, Sandoz, Pharmacyclics, Millennium Pharmaceuticals, Genentech, Kite Pharma, Seattle Genetics, and Dynavax Technologies. These comments are from his editorial accompanying the report (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.67.4234).
In just 3 years, prospective observational studies and [this] clever ancillary analysis of a prospective clinical trial have better informed the lymphoma community about the expected incidence and timing of transformation in patients with follicular lymphoma after being treated with modern management strategies. But we are still limited by clumsy predictive tools for identifying patients at highest risk. Deeper understanding of biologic and genetic factors of FL subclonal populations as well as the tumor microenvironment will allow for more precise identification of patients truly at risk and potentially will provide actionable targets for abrogating that risk. Future [studies of] transformed lymphoma will hopefully replace variables such as anthracyclines, the Follicular Lymphoma International Prognostic Index, lactate dehydrogenase, and ASCT with promising new variables such as IRF-4, miR-31, bcl-2, pleuripotency, and nuclear factor kappa B pathway genes or new therapies that target these variables. Future analyses should not simply prognosticate who is at risk for transformation, but should predict a specific intervention to either prevent or treat such an event.
Dr. Brian K. Link is at the University of Iowa, Iowa City. He reported ties to AbbVie, Gilead Sciences, Genentech, Sandoz, Pharmacyclics, Millennium Pharmaceuticals, Genentech, Kite Pharma, Seattle Genetics, and Dynavax Technologies. These comments are from his editorial accompanying the report (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.67.4234).
Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.
In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.
Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).
A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).
After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.
Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.
The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.
Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.
In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.
Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).
A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).
After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.
Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.
The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Histologic transformation of follicular lymphoma tends to occur early and may merit intensive salvage with autologous stem cell transplantation.
Major finding: Median overall survival was not reached among patients who received ASCT and was 1.7 years in those who didn’t have ASCT.
Data source: A study of 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial.
Disclosures: The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.