First-Line Time Limited Venetoclax Combinations in Chronic Lymphocytic Leukemia

SUMMARY: The American Cancer Society estimates that for 2023, about 18,740 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4490 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax, given along with anti-CD20 antibody Obinutuzumab or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation, and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Three BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.

In previously published studies, Venetoclax in combination with Obinutuzumab or Rituximab as first-line therapy led to a high incidence of undetectable Minimal Residual Disease (MRD) and long Progression-Free Survival, among patients who are not fit, and patients with relapsed disease. However, there is no data from prospective, randomized clinical trials evaluating the safety and efficacy of Venetoclax-Obinutuzumab combination in fit patients with CLL with normal renal function. Combining BCL2 inhibitors with BTK inhibitors have induced undetectable Minimal Residual Disease and improved disease control.

GAIA-CLL13 trial is a prospective, open-label, multicenter, four-group, Phase III trial, designed to evaluate the efficacy and safety of two fixed-duration regimens and one time-limited combination of Venetoclax plus anti-CD20 antibodies (Venetoclax-Rituximab, Venetoclax-Obinutuzumab, and Venetoclax-Obinutuzumab-Ibrutinib), as compared with chemoimmunotherapy, in the first-line treatment of young patients with CLL who are fit (low burden of coexisting conditions with no TP53 aberrations).

In this study, a total of 926 patients (N=926) were randomly assigned in a 1:1:1:1 ratio to receive six cycles of chemoimmunotherapy (N=229) or 12 cycles of treatment with either Venetoclax-Rituximab (N=237), Venetoclax-Obinutuzumab (N=229), or Venetoclax-Obinutuzumab-Ibrutinib (N=231). Chemoimmunotherapy consisted of Fludarabine 25 mg/m2 IV and Cyclophosphamide 250 mg/m2 IV, given on day 1-3 of each cycle, and patients older than 65 years of age received Bendamustine 90 mg/m2 IV on day 1 and 2 of each cycle. Rituximab 375 mg/m2 IV was added to chemotherapy on day 1 of cycle 1, and at a dose of 500 mg/m2 IV on day 1 of each of the next five cycles.

The three experimental regimens contained Venetoclax 400 mg orally daily for ten 28-day cycles after a 5-week ramp-up phase from day 22 in cycle 1 until the end of cycle 2. In the Venetoclax-Rituximab group, Rituximab was administered at a dose of 375 mg/m2 IV on day 1 of cycle 1 and at a dose of 500 mg/m2 on day 1 of each of the next five cycles. In the Obinutuzumab-containing regimens, Obinutuzumab was administered at a dose of 100 mg IV on day 1, 900 mg IV on day 2, and then 1000 mg IV on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, Obinutuzumab was administered at a dose of 1000 mg IV. In the triple-combination regimen (Venetoclax-Obinutuzumab-Ibrutinib), Ibrutinib 420 mg orally daily was initiated along with the first Obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment cycles, to which Venetoclax was added as described for the Venetoclax-Obinutuzumab regimen above. Ibrutinib was discontinued after two consecutive measurements of undetectable MRD or could be extended. The median patient age was 61 years and all the treatment groups were well balanced with respect to patient characteristics. The Primary end points were undetectable MRD ( less than 10−4, which meant less than 1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15, and Progression Free Survival.

At 15 months, the percentage of patients with undetectable MRD, the Primary endpoint, was significantly higher in the Venetoclax-Obinutuzumab group (86.5%) and the Venetoclax-Obinutuzumab–Ibrutinib group (92.2%), compared to the chemoimmunotherapy group (52.0%), P<0.001 for both comparisons. However, the Primary endpoint of undetectable MRD was not significantly higher in the Venetoclax-Rituximab group compared to the chemoimmunotherapy group (57% versus 52%; P=0.32).

At a median follow up of 38.8 months, the interim analysis of 3-year Progression Free Survival (the second Primary end point) was superior in the Venetoclax-Obinutuzumab-Ibrutinib group (90.5%; HR=0.32; P<0.001) and the Venetoclax-Obinutuzumab group (87.7%; HR=0.42; P<0.001), compared to the chemoimmunotherapy group (75.5%). This PFS benefit was not seen in the in the Venetoclax-Rituximab group when compared to chemoimmunotherapy (80.8%; HR=0.79, P=0.18). Grade 3 and 4 infections were more common with chemoimmunotherapy (18.5%) and Venetoclax-Obinutuzumab–Ibrutinib (21.2%) than with Venetoclax-Obinutuzumab (13.2%) and Venetoclax-Rituximab (10.5%).

It was concluded that Venetoclax-Obinutuzumab combination with or without Ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL, with higher rates of undetectable MRD and Progression Free Survival.

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. Eichhorst B, Niemann CU, Kater AP, et al., for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. N Engl J Med 2023; 388:1739-1754