Blinatumomab Evokes Nearly 70% Response Rate in Non-Hodgkin Lymphoma

Journal of Clinical Oncology.

“Our results confirm data from the study’s interim analysis by showing that in this heavily pretreated population of patients with relapsed/refractory NHL, continuous intravenous infusion of single-agent blinatumomab is feasible up to the maximum-tolerated dose (MTD) of 60 µg/m2/day and results in antilymphoma activity with durable complete responses and partial responses,” lead author Maria-Elisabeth Goebeler, MD, Würzburg University Hospital in Germany, and coauthors wrote.

The dose-escalation study enrolled 76 heavily pretreated patients with relapsed/refractory NHL between 2004 and 2011. This cohort included 14 patients with diffuse large B-cell lymphoma (DLBCL), 28 with follicular lymphoma (FL), 24 with mantle cell lymphoma (MCL), and 10 with other NHL subtypes.

The median patient age was 65 years (range, 20-80 years) and 75% (n = 57) of the patients were male. Patients had received a median of 3 prior treatment regimens (range, 1-10), including 93% (n = 71) with at least 1 prior rituximab regimen, 30% (n = 23) with prior fludarabine, and 30% (n = 23) having received autologous HSCT.

Of those patients, 26% (n = 20) were rituximab refractory, with 13% (n = 10) and 12% (n = 9) having relapsed after prior CHOP and HSCT, respectively.  

Forty-two of the 76 patients were enrolled in the dose-escalation phase of the trial and received 1 of 7 doses of blinatumomab, ranging from 0.5 to 90 µg/m2/day, along with the investigator’s choice of concomitant steroids. Patients received blinatumomab at a constant flow rate for 4 to 8 weeks until dose-limiting toxicity or progressive disease.

Among the 35 patients who received the MTD of 60 µg/m2/day, the overall response rate (ORR) was 69% (n = 24), including 8 complete responses, 5 unconfirmed CRs (CRu), and 11 partial responses (PR). Five patients had stable disease and 5 patients had progressive disease. The ORR was 55% (6/11), 71% (5/7), and 80% (12/15), among patients with DLBCL, MCL, and FL, respectively. The median duration of response was 404 days (95% CI, 207-1129).

In the overall 76-patient study population, the most common all-grade adverse events (AEs) were lymphopenia (80%), pyrexia (76%), increased C-reactive protein level (49%), fatigue (46%), leukopenia (46%), increased weight (42%), and headache (42%). The most frequent grade ≥3 AEs included lymphopenia (79%), increased C-reactive protein level (20%), leukopenia (20%), neutropenia (17%), hyperglycemia (12%), and thrombocytopenia (12%). There were 3 patient deaths, 2 of which were potentially treatment-related (sepsis and Pneumocystis jirovecii infection).

Neurologic AEs were the most common dose-limiting toxicities and the most frequent cause of treatment discontinuation. Twenty-two percent of patients had grade 3 neurologic AEs, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade ≥4 neurologic AEs.

“We speculate that neurologic events associated with blinatumomab treatment may be due to cytokine-releasing T cells that migrate into the CNS; however, they cannot be correlated to the rather mild and transient cytokine elevations in serum at treatment start,” the researchers wrote.

Wurzburg et al examined various approaches to mitigating neurologic AEs in a study extension phase in which 34 patients were treated with the MTD. The most promising approaches that emerged included single-stepwise dose escalation plus pentosan polysulfate SP54 (PPS) and double-stepwise dose escalation, both administered with corticosteroid prophylaxis.

An ongoing phase II trial (NCT01741792) is examining blinatumomab in relapsed/refractory DLBCL.

Blinatumomab is a recombinant, single-chain monoclonal antibody that possesses antigen-recognition sites for CD3 and CD19. The CD3 complex consists of T cell surface glycoproteins, while CD19 is a tumor-associated antigen. The combination of these recognition sites into 1 therapy is thought to promote cytotoxic T lymphocyte and helper T lymphocyte activity against CD19-expressing B lymphocytes.

In December 2014, the FDA granted an accelerated approval to blinatumomab for the treatment of patients with acute lymphoblastic leukemia (ALL) based on phase II data. Amgen, the manufacturer of blinatumomab, recently announced that the phase III confirmatory TOWER trial has met its primary endpoint, with blinatumomab having improved overall survival versus standard chemotherapy in patients with Philadelphia chromosome—negative relapsed or refractory B-cell precursor ALL.

References

1. Goebeler M-E, 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 [published online February 16, 2016]. J Clin Oncol. doi:10.1200/JCO.2014.59.1586.