Can Chemoimmunotherapy Be Improved As Front-Line Therapy for CLL in Fit Patients?

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)

NCT02950051

German CLL Study Group

Nordic CLL Group, HOVON and SAKK

920 eligible patients

160 centers across Germany, Austria, Switzerland, The Netherlands, Belgium, Denmark, Sweden, Norway, and Finland

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.

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.

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.