Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia

Tadeusz Robak, Andrzej Hellmann, Janusz Kloczko, Javier Loscertales, Ewa Lech-Maranda, John M Pagel, Anthony Mato, John C Byrd, Farrukh T Awan, Holger Hebart, Jose A Garcia-Marco, Brian T Hill, Michael Hallek, Amy J Eisenfeld, Scott C Stromatt, Ulrich Jaeger, Tadeusz Robak, Andrzej Hellmann, Janusz Kloczko, Javier Loscertales, Ewa Lech-Maranda, John M Pagel, Anthony Mato, John C Byrd, Farrukh T Awan, Holger Hebart, Jose A Garcia-Marco, Brian T Hill, Michael Hallek, Amy J Eisenfeld, Scott C Stromatt, Ulrich Jaeger

Abstract

Otlertuzumab (TRU-016) is a humanized anti-CD37 protein therapeutic that triggers direct caspase-independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles and IV bendamustine (70 mg/m2 ) on Days 1 and 2 of each cycle for up to six 28-day cycles or bendamustine alone. Thirty-two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone. Overall response rate according to the International Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the otlertuzumab and bendamustine arm and 39% in the bendamustine alone arm (P = 0·025). Median progression-free survival (PFS) was 15·9 months in the otlertuzumab and bendamustine arm and 10·2 months in the bendamustine alone arm (P = 0·0192). There was a higher incidence of pyrexia (34% vs. 12%) and neutropenia (59% vs. 39%) with the combination but this did not result in a higher incidence of severe (grade 3/4) infections (13% vs. 27%). This combination significantly increased the response rate and prolonged the PFS over single agent bendamustine in patients with relapsed or refractory CLL.

Keywords: CLL; bendamustine; otlertuzumab.

© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Odds ratio and 95% confidence intervals for overall response rate (per IWCLL criteria; Hallek et al, 2008) by characteristic. In this graph, ORR is shown by baseline characteristic. Points to the right of the vertical line indicate higher ORR in the combination arm compared to the control arm. The odds ratio is indicated by a black circle, and the 95% CI is indicated by a horizontal line. B2M, β2‐microglobulin; CI, confidence interval; Line CT, prior line(s) of chemotherapy; ECOG, Eastern Cooperative Oncology Group performance score; IWCLL, International Workshop on Chronic Lymphocytic Leukaemia; ORR, overall response rate.
Figure 2
Figure 2
Kaplan–Meier curves are shown for progression free survival (A) and overall survival (B). Median progression free survival was significantly longer (P = 0·0192) in the combination arm (15·9 months) compared to the control arm (10·2 months). Median overall survival was not reached in either arm. The numbers below the graphs are the number of subjects at risk at the corresponding time points. B, bendamustine; HR, hazard ratio; O, otlertuzumab; OS, overall survival; PFS, progression‐free survival. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Mean otlertuzumab cncentrations over time. The mean half‐life is 10·0 days. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
CD19+CD5+ counts at baseline and end of treatment.

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