Debulking Eliminates Need for Hospitalization Prior to Initiating Frontline Venetoclax Therapy in Previously Untreated CLL Patients: A Phase 3b Study

BACKGROUND: Venetoclax is an effective oral agent for frontline treatment of patients with chronic lymphocytic leukemia (CLL). Due to the rapid induction of cell death caused by the targeted activity of venetoclax, some patients require inpatient monitoring for tumor lysis syndrome (TLS) at initiation of therapy. In the recent CLL14 study, 64% and 22% of venetoclax-treated patients were medium and high risk for TLS, respectively. This study used disease re-staging every two cycles to explore the efficacy of using of obinutuzumab, with or without bendamustine prior to initiation of venetoclax, to reduce tumor burden and thus eliminate the need for hospitalizations, as well as reduce the risk for TLS at the initiation of venetoclax therapy.

METHODS: This is a single arm open-label, phase 3b trial (NCT03406156). Patients had previously untreated CLL/SLL (excluding those with 17p deletion), an Eastern Cooperative Oncology Group (ECOG) performance score of ≤1, and a medium (any lymph node 5 - <10 cm or absolute lymphocyte count [ALC] ≥25 × 10⁹ /L) or high (any lymph node ≥10 cm or ALC ≥25 × 10⁹ /L and any lymph node ≥5 cm) tumor burden. Patients had tumor debulking (with obinutuzumab or obinutuzumab plus bendamustine) for a maximum of six 28-day cycles until low tumor burden (ALC <25 × 10⁹ /L and all lymph nodes <5 cm) was achieved, at which point treatment with venetoclax plus obinutuzumab was initiated. The primary endpoints of the study were (1) the percentage of patients achieving low tumor burden after 2, 4, and 6 cycles of obinutuzumab, with or without bendamustine; and (2) the response rates of patients treated with venetoclax.

RESULTS: A majority of patients were <75 years old (87%, 60/69) with ALC ≥25 × 10⁹ /L (81%, 56/69), medium TLS risk (81%, 56/69), and RAI stage 1/2 (52%, 36/69; 32% had RAI stage 3/4). Of 69 patients treated, 50 had debulking with obinutuzumab alone, and 19 with added bendamustine (11% [2/19] added bendamustine at cycle 3+); 51 patients completed debulking and 18 are ongoing. After two cycles of debulking, 77% (40/52) of evaluable patients achieved low tumor burden; after four cycles, 94% (45/48); and after six cycles, 98% (46/47) [Figure]. ALC was reduced to less than 25 × 10⁹ /L in 98% (50/51) of evaluable patients after two cycles of obinutuzumab, without (100%; 43/43) or with bendamustine (7/8). Amongst those that received obintuzumab alone, 4 of 5 evaluable patients with lymph nodes 5-10 cm were debulked to <5 cm by 4 cycles of therapy. For patients started with obinutuzumab plus bendamustine, all 4 evaluable patients with lymph nodes 5-10 cm were debulked to <5 cm within 2 cycles, and 3 of 4 evaluable patients with nodes >10 cm were debulked to <5 cm by 4 cycles of therapy. Safety signals were consistent with the known profiles of bendamustine, obinutuzumab and venetoclax; the most frequently reported any-grade AEs (>30%) were infusion-related reactions (71%; all grade 1-2), nausea (39%), headache (35%) and fatigue (32%). Neutropenia (28%) and thrombocytopenia (10%) were the most frequently reported Grade 3+ AEs. AEs of TLS were reported in the debulking phase in 7% (5/69) of patients. A retrospective analysis using Howard criteria for TLS identified three additional patients with laboratory TLS: two occurred during the debulking phase and one during the venetoclax phase, all driven by phosphate and uric acid. Uric acid levels were below the institutional upper limit of normal for the patient with TLS during venetoclax treatment and did not require management. No patients were hospitalized during venetoclax ramp up.

CONCLUSIONS: Two cycles of obinutuzumab prior to initiation of venetoclax was an effective debulking strategy for patients with ALC >25 × 10⁹ /L and lymph nodes <5 cm, with over 98% success rate; the addition of bendamustine increased effective debulking for patients with nodes 5-10 cm. Patients with nodes >5 cm treated with obinutuzumab or >10 cm treated with obinutuzumab plus bendamustine may need >2 cycles to achieve low tumor burden. Debulking via obinutuzumab, with or without bendamustine, may allow more patients to be administered venetoclax in the outpatient setting, eliminating the need for hospitalization during venetoclax initiation.

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