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1307 MRD-Driven Time Limited Therapy with Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Previously Untreated Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Session: 642. CLL: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Biological, antibodies, Therapies, Combinations, Clinically relevant, molecular testing
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Jacob D. Soumerai, MD1, Anthony R. Mato, MD2, Jason Carter, MPH, PA-C2*, Ahmet Dogan, MD, PhD3, Ephraim P Hochberg, MD4*, Jeffrey A Barnes, MD, PhD4, Audrey Hamilton, MD5*, Jeremy S Abramson, MD, MMSc4, Connie Lee Batlevi, MD, PhD2, Erel Joffe, MD, MSc5, Matthew J Matasar, MD, MS6, Ariela Noy, MD2, Colette Owens, MD5, M. Lia Palomba, MD2, Tak Takvorian, MD4*, Venkatraman Seshan, PhD7*, Kelsey Flaherty2*, Lauren Ramos4*, Morgan Choma2*, Chaya Friedman2*, Puja Chadha2*, Elizabeth Simkins4*, Daneal Portman4*, Neena Majahan, NP2*, Rosalba Martignetti, RN4*, Joanna Mi, NP2*, Krista J Scorsune, NP4*, Julia M Lynch, NP4*, Brianne McGree, NP4*, Stephanie Y Hughes2*, Clare Grieve2*, Lindsey E Roeker, MD2, Omar Abdel-Wahab, MD 2 and Andrew D Zelenetz, MD, PhD5

1Massachusetts General Hospital, Boston, MA
2Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
4Massachusetts General Hospital Cancer Center, Boston, MA
5Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
6Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center/New York Presbyterian, New York, NY
7Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY


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.


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).


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).


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.

Disclosures: Soumerai: Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; GlaxoSmithKine: Research Funding; Genentech/Roche: Research Funding; BostonGene: Research Funding; Beigene: Consultancy, Research Funding. Mato: Janssen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy. Dogan: Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding; Takeda: Consultancy; AbbVie: Consultancy; EUSA Pharma: Consultancy. Hochberg: Intervention Insights: Consultancy; Leuko: Consultancy. Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Joffe: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Matasar: Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Immunovaccine Technologies: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Noy: Pharmacyclics: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; NIH: Research Funding. Palomba: Genentech: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Regeneron: Research Funding; Novartis: Honoraria; Merck: Honoraria; Celgene: Honoraria; Pharmacyclics: Honoraria. Roeker: AbbVie: Other: spouse with minority ownership interest ; Abbott Laboratories: Other: spouse with minority ownership interest ; American Society of Hematology: Research Funding. Abdel-Wahab: Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Zelenetz: MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Zanubrutinib is not FDA approved in CLL.

*signifies non-member of ASH