July-August 2017, Volume 14, Issue 4
Can Chemoimmunotherapy Be Improved As Front-Line Therapy for CLL in Fit Patients?
Published on: July 01, 2017
Study Title: A Phase III Multicenter, Randomized, Prospective, Open-Label Trial of Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab Plus Venetoclax (RVe) Versus Obinutuzumab (GA101) Plus Venetoclax (GVe) Versus Obinutuzumab Plus Ibrutinib Plus Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without del(17p) or TP53 Mutation (CLL13/GAIA)
ClinicalTrials.Gov Identifier: NCT02950051
Sponsor: German CLL Study Group
Collaborators: Nordic CLL Group, HOVON and SAKK
Accrual Goal: 920 eligible patients
Participating Centers: 160 centers across Germany, Austria, Switzerland, The Netherlands, Belgium, Denmark, Sweden, Norway, and Finland
Study Design: This is a multi-arm phase III, randomized, open-label clinical trial that compares chemoimmunotherapy with three combinations of non-DNA damaging drugs as first-line therapy for fit patients. Standard chemoimmunotherapy is fludarabine, cyclophosphamide, and rituximab (FCR) for patients 65 years or younger, and bendumustine-rituximab (BR) for patients older than 65 years. Two of the experimental arms contain a combination of the BCL2 inhibitor, venetoclax, with an anti-CD20 antibody (either rituximab or obinutuzumab); the third also includes the BTK inhibitor ibrutinib with venetoclax and obinutuzumab. The co-primary endpoints are peripheral blood (PB) minimal residual disease (MRD) negativity at 15 months and progression-free survival (PFS); each will be tested independently, enabling superiority to be established for an experimental arm if either endpoint is significantly different in a favorable direction. The primary comparison for MRD negativity is between the chemoimmunotherapy and the obinutuzumab-venetoclax (GVe) arms. The primary comparison for PFS is between the chemoimmunotherapy and obinutuzumab-ibrutinib-venetoclax (GIVe) arms. The secondary outcomes are multiple and include complete response rates, duration of response, overall survival, safety, and quality-of-life. Efficacy outcomes may be compared among other arms in a predefined hierarchical sequence.
Rationale: The chemoimmunotherapy combination FCR was first reported as initial therapy in 20051 and was confirmed as the gold-standard front-line therapy for fit patients in 2010.2 The alternative BR regimen is less effective but is better tolerated and is a standard for older fit patients.3 Both produce significant acute toxicity and carry risks of late complications such as myelodysplastic syndromes or acute myeloid leukemia, and yet, for most patients, the treatment is not curative. Therefore, more effective therapies with less toxicity are needed. New targeted agents avoid some of the toxicities associated with DNA damage, show efficacy as single agents, and preliminary efficacy and tolerability in combination.
Prolonged survival without toxicity is the goal of therapy, but the prognosis of patients with CLL lacking either del(17p) or TP53 mutation is sufficiently favorable to require surrogate measures as primary endpoints in trials. PFS is an established surrogate for overall survival (OS) in this disease setting, and PB MRD–negativity is an independent predictor of PFS and OS with chemoimmunotherapy.4 Venetoclax in combination with an anti-CD20 antibody induces MRD negativity in the majority of patients with CLL in either the relapsed/refractory5 or front-line6 setting. The study therefore tests whether GVe induces a greater rate of PB MRD-negativity than standard therapy, as an early indicator of comparative efficacy. Ibrutinib induces a high rate of durable responses when given continuously and synergizes with venetoclax to kill CLL cells in vitro;7,8 its use for three years as an addition to GVe in the GIVe arm is anticipated to reduce the risk of relapse. Consequently, PFS is the primary endpoint for comparison between GIVe and chemoimmunotherapy.
Comment: Patients with CLL and their doctors are wanting more from first-line therapy. Treatment decisions are becoming increasingly complex and require consideration of disease genetics, age, fitness, comorbidities, and goals of treatment. Add to this the handful of new agents and combinations, and patients and their doctors could well be facing decision matrices akin to a Rubik’s cube as they strive toward personalized medicine. Patients who are fit for chemoimmunotherapy usually are looking to achieve long-term leukemia-free survival (or at least PFS) without the early and late toxicities induced by FCR.
The CLL13/GAIA study led by Dr. Barbara Eichhorst focuses on this large group of patients. While the long-term efficacy of chemoimmunotherapy is well understood, rituximab plus venetoclax (RVe), GVe and GIVe are new regimens, with only RVe having follow-up beyond two years.5 Consequently, the optimal duration of venetoclax in RVe and GVe, or ibrutinib and venetoclax in GIVe, is not known, but investigators are working on the premise that first line therapy for fit patients should be time-limited rather than indefinite until progression. So, the non-DNA damaging combinations chosen are based on preliminary data, including from those tested in ongoing German CLL Study Group trials.
The trial’s complex design combines pragmatism with sophistication, reflecting the tension between the large sample sizes needed to compare multiple regimens for multiple endpoints and the imperative to accrue rapidly and deliver answers in the shortest timeframes. It complements the first randomized study of a non-DNA-damaging regimen (ibrutinib-rituximab) versus chemoimmunotherapy (FCR) in fit patients 70 years of age or younger. The National Cancer Institute-sponsored U.S. intergroup study (NCT02048813) led by Dr. Tait Shanafelt and highlighted in the May/June 2015 issue of The Hematologist, completed accrual in June 2016, and the first interim analysis for its primary endpoint of PFS will be next year, two years after the last accrual.
Once we have the results of the primary analyses for both these trials, physicians and patients will know whether chemoimmunotherapy can be bettered as front-line therapy for CLL without TP53 dysfunction in fit patients. Of course, even if the trials are positive, important questions are likely to remain incompletely answered. For example, which non-DNA damaging regimen is best? What are the optimal durations of use for individual targeted therapy elements (time-limited, until MRD negativity is achieved, or indefinite)? Do the trial outcomes equally apply to specific genetic subgroups, which can be cured with FCR, such as IGHV-mutated CLL? In any case, the CLL13/GAIA trial is likely to shape the future of front-line therapy for fit patients with CLL for many years to come, and accrual should be strongly supported.
Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regiment of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088.
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.
Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928-942.
Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30:980-988.
Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230-240.
Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702-2705.
Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia. Clin Cancer Res. 2015;21:3705-3715.
Deng J, Isik E, Fernandes SM, et al. Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;doi:10.1038/leu.2017.32. [Epub ahead of print].
Conflict of Interests
Dr. Roberts has received research funding from AbbVie and Genentech (venetoclax), and Janssen (sponsor for ibrutinib outside the United States). He is employed part-time by the Walter and Eliza Hall Institute, which receives milestone and royalty payments for venetoclax but receives no financial benefits personally.
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