2016 - Long-term follow-up of multicenter phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in previously untreated patients with chronic lymphocytic leukemia: Impact of early MRD kinetics on posttreatment outcomes

Background:
Venetoclax plus obinutuzumab induces durable undetectable MRD (median time from end-of-therapy (EOT) to MRD conversion ≥10-4 of 21 months) in previously untreated CLL (Al-Sawaf et al, J Clin Oncol 2021) and zanubrutinib is a second-generation BTK inhibitor with a favorable safety profile and superior progression-free survival compared with ibrutinib (Brown et al, N Eng J Med 2023). BOVen appeared well-tolerated and achieved frequent uMRD in CLL (Soumerai et al, Lancet Haematology 2021). However, longer follow-up was needed to evaluate the MRD-driven treatment strategy. Herein, we present the initial report on long-term follow-up of BOVen in CLL.

Methods:
In this multicenter, phase 2 trial (NCT03824483), eligible patients had CLL/SLL requiring first-line treatment per iwCLL 2018 guidelines, ECOG performance status ≤2, absolute neutrophil count (ANC) ≥1,000/ul and platelet (PLT) count ≥75,000/ul (PLT ≥20,000 and no ANC requirement if due to CLL). Informed consent was obtained from all patients.

BOVen was administered in 28-day cycles: Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab was administered at 1000 mg intravenously (IV) on days 1 (split days 1-2 if lymphocyte count ≥25,000/ul or LN ≥5 centimeters), 8, and 15 of cycle 1, and day 1 of cycles 2-8; Venetoclax ramp up was initiated on cycle 3 day 1 (target 400 mg PO daily).

MRD was evaluated by flow cytometry (MRD-FC) with uMRD defined as ≤10-4 for the primary endpoint. ΔMRD400 was evaluated by immunosequencing in 35 of the first 39 patients enrolled (pending in final 13 pending) and defined as ≥400-fold reduction in the peripheral blood (PB) MRD level from baseline to cycle 5 day 1.

Treatment consisted of 8-24 cycles with duration determined by prespecified MRD-FC criteria. Beginning on cycle 7 day 1 then every 2 cycles, patients with PB uMRD-FC underwent bone marrow (BM) within 14 days. If BM uMRD-FC was confirmed, PB MRD-FC was repeated after 2 additional cycles. Patients with confirmed uMRD-FC in both PB and BM discontinued therapy.

All-cause adverse events (AE) were assessed per CTCAE v5. Median time to MRD-FC conversion (≥10-4) was calculated from EOT (Kaplan–Meier method).

Results:
The study accrued 52 pts (3/19-10/19; 7/20-4/21): median age 62 (range, 23-77), 75% (39/52) male, 71% (37/52) IGHV unmutated, 17% (9/52) del17p/TP53M. All patients are evaluable for safety and 50 are evaluable for efficacy.

With median follow up of 40 months (4.1-47.4) and treatment duration of 10 cycles (interquartile range [IQR] 8-14), 96% (48/50) were uMRD-FC in PB, and 92% (46/50) were uMRD in PB and BM after a median of 8 months (IQR 6-11.5).

The most common AEs were thrombocytopenia (55.8%), fatigue (55.8%), neutropenia (53.8%), diarrhea (46.2%), bruising (44.2%), infusion related reaction (36.5%). The most common grade ≥3 AE were neutropenia (23.1%), thrombocytopenia (7.7%), lung infection (5.8%). No laboratory or clinical TLS occurred (Howard criteria).

Of 46 patients meeting MRD-FC criteria to end treatment, MRD-FC free survival was 29.8 months (3.6-35.1; Figure 1). Of patients with EOT PB uMRD-FC who were evaluable for ΔMRD400, MRD-FC free survival was longer in ΔMRD400 achievers (NR vs 18.1 mo, log-rank p=0.003; Figure 2) despite fewer median cycles of therapy (8 vs 13, p < 0.001).

Conclusion:
Long-term follow up of BOVen demonstrate high rates of durable uMRD-FC. A phase II trial of BOVen with ΔMRD400-directed treatment duration is planned, and we hypothesize that longer duration of therapy for pts who fail ΔMRD400 (24 vs 10 mo) will further improve uMRD duration in these pts.