Drug shows early promise for rel/ref NHL

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”