Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax.
Authors: Soumerai Jacob Drobnyk , Mato Anthony R. , Carter Jason , Dogan Ahmet , Hochberg Ephraim , Barnes Jeffrey A. , Hamilton Audrey M. , Abramson Jeremy S. , Batlevi Connie Lee , Joffe Erel , Matasar Matthew J. , Noy Ariela , Owens Colette Ngozi , Palomba Maria Lia , Takvorian Tak , Flaherty Kelsey , Ramos Lauren , Roeker Lindsey Elizabeth , Abdel-Wahab Omar Ibrahim , Zelenetz Andrew David 
Published: May 2020

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Background: Venetoclax (Ven)-Obinutuzumab (O) is approved for chronic lymphocytic leukemia (CLL) achieving frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven-Ibrutinib is synergistic with frequent uMRD but with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment (tx) with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. Methods: In this multicenter, investigator initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring tx per iwCLL, ECOG PS <2, ANC >1, PLT >75 (ANC >0, PLT >20 if due to CLL). BOVen was administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10−4) starting C7D1 then every 2 cycles. Once PB uMRD was determined and confirmed in bone marrow (BM), tx continued 2 additional cycles. Adverse events (AE) were assessed per CTCAE v5. Median (med) time to uMRD (primary endpoint) was estimated using the Kaplan-Meier method. Results: The study accrued 39 pts (3-10/19): med age 59 years (23-73), 3:1 male, CLL IPI >4 26/39 (67%), unmutated IGHV 28/39 (72%), 17p del/ TP53 mutated 4/39 (10%), all pts were evaluable for toxicity with 37 evaluable for efficacy. At a med follow up of 8 months (mo; 3-10), 25/37 (68%) pts achieved PB uMRD. Med time to PB uMRD is 6 mo (4-8+). Another 8/37 (22%) had PB MRD < 0.1%. Of 25 with PB uMRD, 19 had BM uMRD with 10/19 completing 2 additional cycles and discontinued; 3 had BM MRD (all <0.02%); 3 pending. The most common tx emergent AEs were neutropenia (49%), infusion related reaction (41%), bruising (39%), and diarrhea (39%). Grade ≥3 AEs in ≥5% pts were neutropenia (13%), thrombocytopenia (5%), rash (5%), and pneumonia (5%). Of 17 pts at high risk for TLS on C1D1, 2 cycles of BO reduced TLS risk to low/medium at Ven initiation in 15 (88%). No pts had laboratory/clinical TLS (Howard). Conclusions: BOVen is well tolerated and achieves rapid uMRD: currently 68% PB uMRD and 51% BM uMRD with limited follow up (to be updated on presentation). Ten (27%) have discontinued treatment thus far. The value of MRD directed treatment duration will be evaluated with continued follow up. Clinical trial information: NCT03824483 .