Results of a Phase 2 Study of MEDI-551 and Bendamustine Vs Rituximab and Bendamustine in Relapsed or Refractory Chronic Lymphocytic Leukemia

Background: In patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), novel therapies are needed to prolong disease control. MEDI-551, an afucoslylated, affinity-optimized, anti-CD19 antibody, functions by antibody-dependent cellular cytotoxicity, with a 30% monotherapy response rate in CLL. A phase 2 randomized, open-label study (NCT01466153) is evaluating the clinical activity, efficacy, and safety of combination therapy with MEDI-551 + bendamustine compared with rituximab + bendamustine in R/R CLL patients.

Methods: Patients were initially randomized to receive bendamustine 70 mg/m² intravenously (IV) on days 1, 2 with either MEDI-551 2 or 4 mg/kg on days 2, 8 of cycle 1 (on day 1 of subsequent cycles) or rituximab 375 mg/m² IV on day 1 of cycle 1 (then 500 mg/m² IV on day 2 of subsequent cycles), for up to six 28-day cycles. The 4-mg/kg dose of MEDI-551 was selected for the final efficacy analysis against rituximab. Safety assessments included adverse events (AEs) and laboratory parameters. Disease response was determined using 2008 International Working Group criteria. Exploratory objectives included micro RNA (miRNA) expression levels before and after treatment.

Results: As of March 2014, the safety population comprised 147 patients across all treatment arms. The median age was 66 years (range 41–81), with 11% of patients with deletion (del) (17p), 20% with del (11q), 30% with del (13q), 12% with trisomy 12, and 39% with unmutated immunoglobulin heavy chains (IgVH). The median number of treatment cycles was 4 (range 1–6). Treatment-related AEs observed in ≥20% of patients included nausea, infusion-related reactions (IRRs), nausea, fatigue, pyrexia, neutropenia, and cough in the MEDI-551 arm vs nausea, fatigue, constipation, asthenia, pyrexia, and neutropenia in the rituximab arm. Grade 3/4 treatment-related AEs are listed in the table.

*Note: After 42 patients were enrolled in the study (all treatment groups), corticosteroid prophylaxis was recommended before patients receiving the initial dose of MEDI-551.

Discontinuation of study treatment because of AEs occurred in 26% of patients receiving MEDI-551/bendamustine (including neutropenia, thrombocytopenia, bradycardia, abdominal pain, asthenia, fatigue, cytokine release syndrome, hypersensitivity, pneumonia, infusion-related reactions, elevated liver function tests, dehydration, hyponatremia, headache, depression, epistaxis, hypoxia, rash, and hypotension) and in 20% of those receiving rituximab/bendamustine (including febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, cardiac failure, uveitis, small intestine obstruction, upper gastrointestinal hemorrhage, asthenia, fatigue, and systemic inflammatory response syndrome). No treatment-related deaths occurred in any treatment arm. Clinical activity was observed in both the MEDI-551 and rituximab arms, and a biomarker has been identified that may predict for MEDI-551 responders. Expression of a miRNA signature is specifically elevated in NHL patient samples. Low pretreatment levels of this miRNA signature in whole blood may predict for responders to MEDI-551. Three-fold lower levels (P<.0001) in pretreatment samples from MEDI-551 responders vs nonresponders were noted, but no differences in miRNA signature expression were noted between responders and nonresponders in the rituximab arm.

Conclusions: Data show evidence of clinical activity in R/R CLL patients, with comparable safety observed between the MEDI-551 and rituximab arms. Expression level of a miRNA signature is able to predict for those more likely to respond to MEDI-551, with MEDI-551 responders having low pretreatment miRNA signature expression.