Elsevier

The Lancet Haematology

Volume 3, Issue 7, July 2016, Pages e317-e329
The Lancet Haematology

Articles
Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial

https://doi.org/10.1016/S2352-3026(16)30045-XGet rights and content

Summary

Background

In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens.

Methods

In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m2 every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234.

Findings

Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7–42·8) for the rituximab group and 34·0 months (25·4–41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5–incalculable) than with observation alone (35·5 months, 95% CI 25·7–46·3; hazard ratio [HR] 0·50, 95% CI 0·33–0·75, p=0·00077). The incidence of grade 3–4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3–4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3–4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]).

Interpretation

Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases.

Funding

Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

Introduction

For a large proportion of patients with chronic lymphocytic leukaemia requiring treatment according to the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria,1 chemoimmunotherapy with a regimen of an anti-CD20 antibody plus chemotherapeutic agents is now standard first-line treatment.2 Combining rituximab with chemotherapy increases the efficacy of treatment versus chemotherapy alone.3 The triple combination of fludarabine, cyclophosphamide, and rituximab was pioneered by physicians at the MD Anderson Cancer Center.4, 5 In randomised trials, this combination showed better efficacy than fludarabine plus cyclophosphamide alone both in patients who had not previously received chemotherapy6 and in those who had relapsed following chemotherapy7 with an adequate performance score and without contraindications such as decreased creatinine clearance or an unfavourable Cumulative Illness Rating Score. Recent updates confirm an overall survival benefit for the addition of rituximab to fludarabine and cyclophosphamide when used upfront, but also an increase in toxicity.6 Reducing the dose of chemotherapeutic while simultaneously increasing the rituximab dose reduced grade 3 and 4 neutropenia in one phase 2 trial,8 but clear conclusions about efficacy as compared with the full combination regimen were not possible. Overall, chemoimmunotherapeutic approaches using a backbone of fludarabine plus cyclophosphamide require careful selection of patients. Phase 2 data with a bendamustine–rituximab combination suggested a beneficial side-effect profile compared with fludarabine, cyclophosphamide, and rituximab, but no randomised comparison regarding efficacy was available at the time of initiation of our trial.9

Research in context

Evidence before this study

We did a literature search on Jan 27, 2016, for data available before the finalisation of the protocol of this trial in October, 2009, using the terms “rituximab”, “maintenance”, and “CLL” or “chronic lymphocytic leuk(a)emia”. Searches in PubMed (all publications until Oct 31, 2009) retrieved nine hits, searches in abstracts of the annual meetings of the American Society of Hematology (Jan 1, 2004, to Oct 31, 2009) retrieved 19 hits, and searches in the abstracts of the annual meetings of the American Society of Clinical Onoclogy (Jan 1, 2004, to Oct 31, 2009) retrieved four hits. The complete Cochrane Library (Cochrane Central Register of Controlled Trials) was also searched, but yielded no results. No evidence was found of published data from phase 3 randomised clinical trials of rituximab maintenance therapy.

Added value of this study

To the best of our knowledge, this is the first randomised trial to investigate rituximab maintenance in patients with chronic lymphocytic leukaemia sensitive to rituximab-containing chemoimmunotherapy. Our findings of this final analysis demonstrate that rituximab maintenance significantly increases tumour control as shown by prolongation of progression-free survival, increased conversion rate to complete response (with or without complete bone marrow recovery) and minimal residual disease negativity, time to next treatment, and event-free survival compared with observation across a broad spectrum of clinical covariates and induction regimens. This increase in progression-free survival is accompanied by an increase in mostly moderate infections.

Implications of all the available evidence

Our findings support a role for inclusion of anti-CD20 antibodies in maintenance treatments for patients with chronic lymphocytic leukaemia who respond to induction with chemoimmunotherapy.

There is strong evidence that the achievement of a negative status for minimal residual disease (MRD) is the single most important factor predictive of final outcome in patients with chronic lymphocytic leukaemia treated with chemoimmunotherapy,10 thus making pronounced suppression of the malignant clone essential for further improvements in disease control. In fact, even progression-free survival curves of patients achieving a complete response (CR) display a steady rate of relapse, and chronic lymphocytic leukaemia remains incurable in all except those relatively few patients who are eligible for, and successfully undergo, allogeneic stem-cell transplantation.11

The goal of deeper treatment responses as a prerequisite and surrogate marker for improved outcomes could potentially be reached by different approaches. Increasing the intensity of induction regimens, for example12 by adding a further cytotoxic agent such as mitoxantrone, could lead to deeper responses, albeit at the price of a considerable increase in toxicity and potential long-term complications. Continuing to administer rituximab to patients who respond to rituximab-based induction is another possible option. This strategy could allow more patients to achieve further tumour suppression and prolonged progression-free survival; in patients who cannot tolerate the combination of fludarabine, cyclophosphamide, and rituximab, addition of rituximab to lower-efficacy regimens might deepen remission in patients not achieving CR.

The randomised, phase 3 CLL-8a Mabtenance trial of the Arbeitsgemeinschaft Medikamentöse Tumortherapie GmbH (AGMT) evaluated the efficacy and safety of rituximab maintenance therapy as a means of prolonging progression-free survival. Before the design of the trial in 2009, studies in follicular lymphoma had shown increased response duration and overall survival in patients who received rituximab maintenance therapy.13, 14 Additionally, preliminary data from small observational and uncontrolled, early-phase consolidation and maintenance trials seemed promising.15, 16 Here, we report the final analysis of the AGMT CLL-8a Mabtenance trial.

Section snippets

Study design and participants

AGMT CLL-8a Mabtenance is an international, randomised, open-label, phase 3 clinical trial. 29 centres in Austria, the Czech Republic, Slovakia, Bulgaria, and Romania recruited 263 patients who fulfilled the following inclusion criteria: chronic lymphocytic leukaemia according to IWCLL criteria;1 age 18 years or older; Eastern Cooperative Oncology Group performance score (ECOG PS) of 0–2; CR, CR with incomplete bone marrow recovery (CRi), or partial response (PR), according to IWCLL criteria,1

Results

Of 276 patients screened for eligibility, 263 were enrolled and randomly assigned between April 1, 2010, and Dec 23, 2013 (figure 1). Ten patients did not meet inclusion criteria, two patients declined to participate, and one patient was not randomised due to other reasons. During the course of the trial (2 years of maintenance therapy or observation), 37 patients discontinued prematurely for reasons other than progression (figure 1). In those patients, assessments for toxicity and progression

Discussion

In our study of the role of rituximab maintenance therapy for patients with chronic lymphocytic leukaemia, we saw improved progression-free survival, time to mext treatment, and event-free survival for patients receiving rituximab, but no difference in overall survival. Simultaneous treatment with rituximab and chemotherapy has been shown to significantly increase remission, progression-free survival, and overall survival compared with chemotherapy alone in a wide variety of CD20-positive

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