MRD-Driven Time Limited Therapy with Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Previously Untreated Chronic Lymphocytic Leukemia

Background:

Venetoclax (Ven; BCL2 inhibitor) with obinutuzumab (O; CD20 antibody) is approved for patients with previously untreated chronic lymphocytic leukemia (CLL) and achieves frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven and Ibrutinib (BTK inhibitor; BTKi) appears synergistic with frequent uMRD but is associated with grade >3 neutropenia in 33-56% patients (pts; Jain NEJM 2019; Rogers ASH 2018; Tam ASH 2019). Zanubrutinib (BGB-3111; B) is a highly specific BTKi that showed 100% occupancy in lymphoid tissues, so may be a preferable BTKi to combine with O and Ven. We hypothesize that treatment with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD.

Methods:

In this multicenter, investigator-initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment per iwCLL, ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelet count (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent obtained from all pts.

BOVen was administered in 28 day (D) cycles (C): B 160 mg by mouth (PO) twice daily starting D1; O 1000 mg IV D1 (or split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg PO daily).

Treatment duration was determined by a prespecified uMRD endpoint (min 8 to max 24 cycles). Beginning C7D1 then every 2 cycles, pts with uMRD by flow cytometry at a sensitivity ≥10^-4 (uMRD-FC4) in peripheral blood (PB) underwent bone marrow (BM) in ≤14 days for MRD assessment, with PB MRD-FC4 reassessed after 2 additional cycles. Pts with uMRD-FC4 in PB on 2 consecutive measurements and in BM discontinued therapy and entered posttreatment surveillance.

The primary endpoint was rate of BM uMRD-FC4. Response was assessed per iwCLL 2018. Adverse events (AE; CTCAE v5) that were unlikely, possibly, probably or definitely related were tabulated. MRD was also assessed by immunosequencing (IS; ClonoSEQ; sensitivity, 10^–6 given sufficient input).

Results:

The study accrued 39 pts (03/19-10/19): median age was 59 (23-73), there was a 3:1 male predominance, 26/39 (67%) had CLL IPI high or very high risk, 28/39 (72%) had unmutated IGHV, 6/39 (15.4%) had 17p del and/or TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy.

At a median follow up of 14+ months (mo; 3-18+), the proportion of pts achieving uMRD-FC4 are 92% (34/37) in PB and 84% (31/37) in BM. Median time to BM uMRD-FC4 was 6 mo (6-16+; 4 mo of BOVen triplet). The frequency of pts achieving OR and CR/CRi were 100% (37/37) and 49% (18/37), respectively. Twenty-nine (77%) pts (55% CR/CRi, 45% PR) achieved the prespecified MRD endpoint and discontinued therapy after a median 10 mo (8-16+) therapy (8 mo of BOVen triplet). No recurrent MRD or progression events occurred.

The most common AEs (all grades, per pt) were neutropenia (56%), thrombocytopenia (49%), diarrhea (46%), bruising (41%), infusion related reaction (41%), nausea (26%), and myalgia (23%). Grade ≥3 AEs occurring in ≥5% pts were neutropenia (15%), thrombocytopenia (5%), rash (5%), and pneumonia (5%). Nine pts (23%) received G-CSF for grade 3-4 (5 pts) or grade 2 neutropenia (4 pts). Four (10%) pts had B (3) and/or Ven (4) reductions for diarrhea (3) or pneumonia (1). Of 16 pts at high risk for TLS on C1D1, BO reduced TLS risk to low/medium at Ven initiation in 14 (88%). No pts had laboratory/clinical TLS (Howard).

Of 35 pts with available PB MRD-IS at C5D1 (after 2 mo of triplet), 77% (27/35) had ≥2-log reduction in PB MRD-IS (δMRD) with a median δMRD of 2.8 (0.6-6). We undertook a post hoc analysis to identify a δMRD that predicts BM uMRD-FC4 in ≤8 mo. A ≥400-fold reduction (≥2.6-log) was selected using the Youden Index and was highly predictive of BM uMRD-FC4 at 8 mo or earlier (sensitivity 88%, specificity 100%, PPV 100%, NPV 79%).

Of 25 pts with PB uMRD-FC4 and paired IS completed, 96% (24/25) were uMRD-IS4 and 64% (16/25) uMRD-IS5. Of 20 pts with BM uMRD-FC and paired IS, 90% (18/20) were uMRD-IS4 with 40% (8/20) uMRD-IS5 (IS for remaining BM samples is pending).

Conclusion:

BOVen was well tolerated with a low rate of grade ≥3 neutropenia and achieved frequent and rapid uMRD: 92% PB uMRD and 84% BM uMRD at a median follow up of 14+ mo (3-18+). Twenty-nine (77%) pts achieved the prespecified MRD endpoint and discontinued treatment per protocol. The value of MRD directed treatment duration will be evaluated with continued follow up.