Blinatumomab Demonstrates Durable Complete, Partial Responses in Relapsed/Refractory Non-Hodgkin Lymphoma

In a recent open-label, multicenter, dose-escalation, phase I study of blinatumomab in heavily pretreated patients with relapsed/refractory non-Hodgkin lymphoma (NHL), patients treated with the maximum tolerated dose (MTD) of the bispecific anti-CD19/CD3 antibody experienced a response rate of 69 percent, according to a report published in the Journal of Clinical Oncology.

Maria-Elisabeth Goebeler, MD, from the Würzburg University Hospital in Germany, and colleagues assessed the efficacy of blinatumomab in 76 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

Patients were enrolled from nine locations in Germany between 2004 and 2011. Patient diagnoses included:

  • Diffuse large B-cell lymphoma (DLBCL; n=14)
  • Follicular lymphoma (FL; n=28)
  • Mantle cell lymphoma (MCL; n=24)
  • Other NHL subtypes (n=10)

The median patient age was 65 years (range = 20-80 years) and most (75%) were male. Patients had received a median of three prior therapies (range = 1-10 therapies); the majority of patients were treated with rituximab (93%), though many (26%) were refractory to it.

The study consisted of two parts: a dose-escalation phase and an extension phase. In the dose-escalation phase, 42 patients received blinatumomab via continuous intravenous infusion over four or eight weeks at seven different dose levels (between 0.5 and 90 μ/m2 per day). Patients continued treatment until toxicity or disease progression. The researchers determined that the MTD was 60 μ/m2 per day; 35 patients received the MTD.

Next, 34 patients went on to the extension phase to evaluate anti-lymphoma activity and strategies for mitigating neurologic events at the pre-specified MTD.

Among the patients treated at the MTD, the ORR was 69 percent (n=24/35), with eight complete responses (CRs), five unconfirmed CRs, and 11 partial responses. Five patients had stable disease and another five had progressive disease.

Among the different NHL diagnoses, ORR was greatest among patients with FL (80%), followed by MCL (71%) and DLBCL (55%).

The responses were “durable,” the authors wrote, with a median duration of response of 404 days (95% CI 207-1,129) among all patients.

In the entire study population, the most common adverse events (AEs) were lymphopenia (80%), pyrexia (76%), increased C-reactive protein level (49%), fatigue (46%), leukopenia (46%), weight gain (42%), and headache (42%).

Neurologic AEs were the most common cause of dose-limiting toxicities and the most common cause of treatment discontinuation in the entire study population. Twenty-two percent of patients experienced grade 3 neurologic AEs, including encephalopathy (8%), aphasia (4%), and headache (3%).

However, in the extension phase, Dr. Goebeler and colleagues found that stepwise dosing (5 to 60 μg/m2 per day) plus use of pentosan polysulfate SP54 (n=3) resulted in no treatment discontinuations. Single-step dosing (n=5) and double-step dosing (n=24) strategies also mitigated treatment discontinuation due to neurologic AEs, resulting in two and seven treatment discontinuations, respectively.

Three deaths occurred among the study population, of which two were reported as potentially treatment-related.

“Continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible … and showed anti-lymphoma activity,” Dr. Goebeler and co-authors concluded.

The small patient population is a limitation of this study, and further studies will have to confirm the findings among the specific disease subtypes. Although the stepwise dosing helped mitigate treatment discontinuations due to neurologic AEs, nine patients discontinued treatment, suggesting that additional strategies are needed to curb the neurologic toxicity associated with blinatumomab. An ongoing phase II study is in progress to evaluate blinatumomab in relapsed/refractory DLBCL.


Reference

Goebeler ME, Knop S, Viardot A, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: Final results from a phase I study. J Clin Oncol. 2016 February 16. [Epub ahead of print]

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