Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study

doi:10.1016/S1470-2045(15)00143-6

The Lancet Oncology

Volume 16, Issue 13, October 2015, Pages 1370-1379

https://doi.org/10.1016/S1470-2045(15)00143-6 Get rights and content

Summary

Background

Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia.

Methods

This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0–2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00802737.

Findings

Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the allocated intervention (withdrawal of consent). The median follow-up was 19·1 months (IQR 10·3–28·8). Progression-free survival was improved in patients assigned to the ofatumumab group (29·4 months, 95% CI 26·2–34·2) compared with those assigned to observation (15·2 months, 11·8–18·8; hazard ratio 0·50, 95% CI 0·38–0·66; p<0·0001). The most common grade 3 or higher adverse events up to 60 days after last treatment were neutropenia (56 [24%] of 237 patients in the ofatumumab group vs 23 [10%] of 237 in the observation group) and infections (31 [13%] vs 20 [8%]). 20 (8%) of 237 patients in the ofatumumab group and three (1%) of 237 patients in the observation group had adverse events that led to permanent discontinuation of treatment. Up to 60 days after last treatment, two deaths related to adverse events occurred in the ofatumumab treatment group and five deaths related to adverse events occurred in the observation group; no deaths were attributed to the study drug.

Interpretation

These data are important for the development of optimum maintenance strategies in patients with relapsed chronic lymphocytic leukaemia, notably in the present era of targeted drugs, many of which are to be used until progression.

Funding

GlaxoSmithKline and Genmab.

Introduction

Although many treatments have become available in the past few years that effectively induce remission and improve progression-free survival, allogeneic stem-cell transplantation is still the only potentially curative treatment for chronic lymphocytic leukaemia.¹ Because allogeneic stem-cell transplantation is feasible in only a few patients with chronic lymphocytic leukaemia, prolonged progression-free survival and overall survival are the fundamental treatment goals for most patients.

Chronic lymphocytic leukaemia and follicular lymphoma are different diseases, yet they show similarities in their clinical behaviour, such as a long natural course, decreasing remission duration upon successive treatments, and incurability. In follicular lymphoma, maintenance treatment with the chimeric anti-CD20 monoclonal antibody rituximab has been shown to result in a significant and clinically relevant improvement in progression-free survival, both after first-line remission induction treatment² and after relapse.3, 4 As a corollary, maintenance treatment might also be beneficial in chronic lymphocytic leukaemia. In mostly small, phase 2 trials, consolidation or maintenance treatment with lenalidomide,5, 6 rituximab,7, 8, 9, 10 or alemtuzumab11, 12 for varying durations has been feasible. Results of a randomised phase 3 trial with 201 patients showed that maintenance treatment with rituximab for 2 years improved progression-free survival and overall survival only in the patients carrying chromosomal deletion 11q (del[11q]) or deletion 17p (del[17p]) who are at high risk of disease progression.¹³

Research in context

Evidence before this study

When the study protocol was developed in 2009, little data for the efficacy and safety of maintenance treatment in chronic lymphocytic leukaemia existed. We searched PubMed without restrictions of time of publication using the terms “CLL AND maintenance” and “CLL AND consolidation”, without time or language restrictions. We identified two studies, both in previously untreated patients: consolidation (4 months) and maintenance (12 months) with rituximab was assessed in a phase 2 trial, and consolidation (3 months) with alemtuzumab was tested in a phase 3 study. The phase 3 study was stopped prematurely because of severe infections.

Added value of this study

This study is the first large, randomised, phase 3 study of maintenance treatment in a population of patients with relapsed chronic lymphocytic leukaemia in remission after re-induction treatment. We show that 2 years of maintenance treatment with ofatumumab, a human anti-CD20 monoclonal antibody, prolonged progression-free survival and time to next treatment. Ofatumumab was well tolerated and did not cause unexpected toxicities. Importantly, we show that ofatumumab maintenance did not increase the risk of transformation.

Implications of all the available evidence

Our data are timely in the present era of novel treatment modalities for chronic lymphocytic leukaemia, notably the BTK and PI3K inhibitors. At present, continued treatment with these kinase inhibitors until relapse is recommended—ie, they are used as a prolonged maintenance treatment. Our data for the efficacy and safety of ofatumumab maintenance treatment are important for the determination of the optimum maintenance strategies in relapsed chronic lymphocytic leukaemia.

Ofatumumab is a human type I CD20 (IgG1-κ) monoclonal antibody, with potent in-vitro, complement-dependent cytotoxicity even in rituximab-refractory cells,14, 15 a higher antibody-dependent cytotoxicity than rituximab,¹⁶ and in-vivo efficacy in rituximab-refractory chronic lymphocytic leukaemia.¹⁷ The aim of this study was to compare ofatumumab maintenance treatment with observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia. Here we present the prespecified interim efficacy and toxicity analysis.

Section snippets

Study design and patients

PROLONG was an open-label, randomised, phase 3 study done at 130 centres in 24 countries worldwide (appendix). Eligible patients were aged 18 years or older with a diagnosis of chronic lymphocytic leukaemia in second or third complete or partial remission based on the International Workshop on Chronic Lymphocytic Leukaemia's (IWCLL) updated National Cancer Institute-sponsored working group (NCI-WG) criteria¹⁸ and a WHO performance status of 0–2. Patients were eligible for enrolment if it was 3

Results

Between May 6, 2010, and June 19, 2014, 559 patients were screened and 474 patients were enrolled: 238 patients were assigned to the ofatumumab maintenance group and 236 patients were assigned to the observation group (figure 1). Baseline demographics and clinical characteristics were generally well balanced between the groups (table 1). Type of previous treatment was also well balanced between the treatment groups (table 1). 380 (80%) of patients had received chemoimmunotherapy as their most

Discussion

Our data indicate that ofatumumab maintenance treatment improved both progression-free survival and time to next treatment in patients with relapsed chronic lymphocytic leukaemia who are in partial or complete remission after re-induction treatment. Ofatumumab was well tolerated when given intravenously once every 8 weeks at a dose of 1000 mg and did not cause unexpected toxic effects. The progression-free survival benefit was independent of baseline demographic characteristics, remission

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ArticlesOfatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Blood

Lancet

Blood

Leuk Res

Blood

Blood

Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study

J Clin Oncol

Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials

J Natl Cancer Inst

Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia

Cancer

NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment

Ann Hematol

Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients

Am J Hematol

Alemtuzumab maintenance may safely prolong chemotherapy-free intervals in chronic lymphocytic leukemia

Med Oncol

Articles
Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study