P637: time-limited treatment with acalabrutinib plus obinutuzumab in treatment-naïve chronic lymphocytic leukemia patients: early results of an ongoing phase 2 trial

Background: The Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib is approved for treatment of chronic lymphocytic leukemia (CLL). Acalabrutinib induces durable remissions in most patients with CLL, which mostly are partial remissions (PR), and therefore treatment typically is given as long-term monotherapy. As a potential alternative we developed a time-limited regimen, combining acalabrutinib with obinutuzumab. Here, we report early results from 20 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04505254) since Sep 2020 at MD Anderson Cancer Center. Aims: The primary objective is to determine the rate of treatment-free remissions 6 months after completion of 24 cycles of frontline therapy. The secondary objectives are to determine the durability of treatment-free remissions, efficacy of re-treatment in patients who relapse, and factors associated with prolonged remission. Methods: Patients with untreated CLL and indications for therapy by 2018 iwCLL criteria receive 100 mg acalabrutinib BID for 24 cycles, combined with 6, monthly obinutuzumab infusions, starting in cycle 3. Patients who do not achieve a complete remission (CR) after cycle 8 can receive additional 6 monthly doses of obinutuzumab during cycles 9 – 14. Treatment is discontinued after 24 cycles, and patients will be monitored. Undetectable measurable residual disease (MRD) is defined as presence of <0.01% clonal CLL cells as assessed by 4-color flow-cytometry. Results: The median age of the patients was 65 yrs (range, 40 – 83 yrs), 10% had del17p or TP53 mutation, 45% had unmutated IgHV and 65% advance stage disease (RAI stage III/IV). The median baseline absolute lymphocyte count (ALC) and β2-microglobulin were 30.8x109/L (range, 3.6 – 188.4 x 109/L) and 4.2 mg/L (range, 2.2 – 7.9 mg/L). After a median follow-up of 16 months, 18 (90%) of patients remain on study; one patient died (5%) due to complications from a presumed bacterial pneumonia, and one patient (5%) was taken off study due to cholecystitis and neutropenia. The estimated two-year PFS and OS for the cohort were 94.4%. Thirteen and twelve patients were evaluable for response assessment after 8 and 14 months of therapy. At 8 months, the responses were 15.4% CR, 76.9% PR, and 7.7% stable disease; at 14 months, 25% CR, 75% PR, accounting for the overall response rate was 92.3% and 100%, respectively. Five patients completed 24 cycles of therapy; at the last assessment, three of them achieved a CR (one with undetectable MRD), two – a PR. No patient had disease relapse or progression on study. The median level of bone marrow infiltration by CLL cells declined from 83.6% (range, 36.1 – 94.0%) at baseline to 2.0% (range, 0.0 – 63.2%) after 8, to 0.21% (range, 0.0 – 6.65%) after 14, and to 0.14% (range, 0.0 – 0.45%) after 24 months of therapy (Figure). Summary/Conclusion: Our preliminary data indicate that combination of acalabrutinib and obinutuzumab induces remissions with significant reduction in bone marrow disease. Longer treatment and follow-up are warranted to determine the durability of responses after therapy discontinuation. Figure: Bone marrow MRD levels during treatment with acalabrutinib and obinutuzumab.Keywords: B-CLL, Clinical trial