Search

Summary Background We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. Methods This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2–8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8–24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [ clinicaltrials.gov ( NCT03824483 ). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. Findings Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52–70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0–27·3), 33 (89%) of 37 patients (95% CI 75–97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8–12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0–18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. Interpretation BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. Funding Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11], PPV 100% [21/21], NPV 79% [11/14]. As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.

Background: TP53 mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with chemoimmunotherapy (Eskelund Blood 2017) and there is no standard frontline treatment for this high-risk patient population. The combination of Bruton's Tyrosine Kinase (BTK) inhibition and the BCL2 inhibition have been shown to be synergistic and active in relapsed, refractory MCL, including in patients with TP53 mutation (Tam NEJM 2018). Obinutuzumab, ibrutinib, and venetoclax has been shown to be well tolerated and associated with high response rates in relapsed and untreated MCL patients (Le Gouill Blood 2021). We hypothesize that treatment with zanubrutinib (B; BGB-3111; BTK inhibitor), obinutuzumab (O; CD20 antibody), and venetoclax (Ven; BCL2 inhibitor) (BOVen) will be well tolerated and efficacious in untreated TP53 mutant MCL. Methods: In this multicenter, investigator-initiated phase 2 trial (NCT03824483), eligible pts had previously untreated MCL with TP53 mutation (any variant allele frequency allowed) and ECOG PS1, PLT >75, HGB >=9 (unless if due to MCL). BOVen is 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 is 2 years at minimum and primary endpoint is 2-year progression-free survival. Adverse events (AE) were assessed per CTCAE v5. Results: 12 patients have been enrolled of the 25 total planned accrual. The median age on study was 67.5 years (range 29 - 79); 83% were male (10/12); various histologic subtypes were included (9 conventional MCL, 2 non-nodal leukemic, and 1 blastoid variant); 100% stage IV (12/12); by MIPI: 75% high risk (9/12), 17% intermediate (2/12), and 8% low risk MIPI score (1/12); 90% Ki67 >=30% (n=9/10); 50% Ki67>=50% (n=5/10); and 50% 17p deletion (n=6/12). All 12 patients were evaluable for toxicity. The grade 3 treatment-related AEs were limited to infusion-related reaction (17%, n=2 pts), neutropenia (8%, n=1 pt) that resolved with GCSF support, and elevation of transaminases (8%, n=1 pt). The most common treatment-related AEs (occurred in more than 1 patient) were low-grade and included: infusion-related reaction (17%, grade 1-2, n=3), neutropenia (17%, grade 1-2, n=2), thrombocytopenia (25%, grade 1, n=3), nausea (33%, grade 1, n=4), elevation of transaminases, (17%, grade 1, n=2), and rash (17%, grade 1, n=2). There was one treatment-related serious adverse event of fever without neutropenia that occurred on C3D2 after BOVen treatment. Pt was discharged after brief hospitalization in stable condition with resolution of fever and negative infectious work up. No dose reductions or modifications were required. No pts had laboratory/clinical TLS (Howard). Median follow up was 4 months (0 - 11 months). One pt has progressed and eleven pts remain on study in continued response. Of the 10 patients who have undergone disease restaging by Lugano criteria at C3 post BO, 80% (n=8/10) achieved PET-CR which has been maintained in 2 patients at C7. One patient, who has TP53, CARD11, and SMARCA4 mutations, achieved stable disease at C3, converted to a partial response at C7, and is now progressing during C12. The other patient had progressive disease by Lugano criteria at C3 with a mixed response on PET/CT with some sites of tumor regression, but after the addition of venetoclax pt had resolution of bulky palpable adenopathy and systemic symptoms. All patients had baseline positive peripheral blood flow cytometry (PBFC) and at C3 90% (n=9/10) had negative PBFC. Conclusions: BOVen was well tolerated in untreated TP53 mutant MCL. The preliminary efficacy is promising in this high-risk subset of MCL, however, follow-up is limited. Updated response data, including minimal residual disease assessment using a next-generation immunosequencing (IS) assay, will be presented at the meeting. Disclosures Kumar: Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Abbvie Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding. Soumerai: AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Consultancy; BostonGene: Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Abramson: Morphosys: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; BeiGene: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Bluebird Bio: Consultancy; Genmab: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: Kite Pharma: Consultancy; TG Therapeutics: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; Dava Oncology: Honoraria; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Dogan: Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; Peer View: Honoraria; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy; Seattle Genetics: Consultancy. Falchi: Roche: Research Funding; Genmab: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genetech: Research Funding. Ho: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees. Khan: Seattle Genetics: Research Funding. Matasar: IGM Biosciences: Research Funding; Merck: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Juno Therapeutics: Consultancy; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; Takeda: Consultancy, Honoraria; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Bayer: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Abdel-Wahab: Foundation Medicine Inc: Consultancy; Prelude Therapeutics: Consultancy; Merck: Consultancy; LOXO Oncology: Consultancy, Research Funding; H3B Biomedicine: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Gilead: Honoraria, Research Funding; MEI Pharma: Honoraria, Research Funding; AstraZeneca: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Pharmacyclics: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Genentech/Roche: Honoraria, Research Funding; Verastem: Honoraria; Abbvie: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Beigene: Honoraria, Other, Research Funding; SecuraBio: Honoraria; LFR: Other; MethylGene: Research Funding; NCCN: Other.