ALBERT

Description: Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations.

Description: Background: The Hyper-CVAD regimen is safe and effective in the frontline treatment of B-ALL. The addition of rituximab to the Hyper-CVAD regimen (HCVAD-R) improved the 3-year overall survival (OS) to 60% in pts with B-ALL. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of the CD20 molecule and has greater in vitro potency and increased complement-mediated cell lysis compared to rituximab. We hypothesized that ofatumumab plus Hyper-CVAD may increase the rates of complete remission (CR) and measurable residual disease negativity (MRD-) and improve survival by decreasing relapse rates. Methods: Pts were eligible if they had newly diagnosed untreated or minimally treated (≤ 1 cycle) Philadelphia chromosome (Ph)-negative CD20+ B-ALL. CD20 positivity was defined as ≥ 1% positive B-ALL cells. Pts received 8 alternating cycles of Hyper-CVAD and high-dose methotrexate/cytarabine (MTX/AraC). Ofatumumab was administered on days 1 and 11 of cycles 1 and 3; and days 1 and 8 of cycles 2 and 4. Pts then received POMP maintenance on cycles 1-5, 8-17 and 20-30 and late intensifications on cycles 6-7 and 18-19 (Hyper-CVAD + ofatumumab followed by MTX + peg-asparaginase). Pts received a total of 8 intrathecal injections of MTX and AraC for CNS prophylaxis. The primary endpoint was relapse-free survival (RFS) and secondary endpoints include CR rates, MRD negativity rates and OS. On a subset of 27 patient samples, transcriptome sequencing (RNA-seq) was performed to identify translocations and RNA expression signature for Ph-like ALL. We also performed a comprehensive detection of fusions and mutations reported in Ph-like ALL on RNA from these 27 samples using a multiplex fusion and mutation detection assay (Archer® FusionPlex® ALL). Results: Between August 2011 and May 2017, 69 pts were enrolled, including 4 already in CR at baseline after receiving 1 cycle of chemotherapy. Pts characteristics are summarized in Table 1. The median age was 41 years (18-71) and 48% pts were in the adolescent and young adult (AYA) age category (18-39 year-old). 7 of the 27 pts (26%) who had RNA-seq had Ph-like ALL gene expression signature. Among the 7 pts; 5 had Ph-like ALL fusions identified by Archer and/or RNA-seq-based fusion detection, including 2 P2RY8-CRLF2, 1 IGH-CRLF2, 1 BCR-FGFR1, and 1 ATF71P-PDGFRB. One patient had high CRLF2 expression with an unknown fusion partner. The remaining case lacked a fusion by either platform. Pts with Ph-like ALL had a higher median WBC of 41 x 109/L (range, 2 - 184). 43 pts (62%) had CD20 expression on ≥20% of the leukemic cells. 10/44 tested pts (23%) had TP53 mutation and 10/37 (27%) had CRLF2 overexpression by flow cytometry (4/5 CRLF2 rearrangement confirmed by Archer). 4 pts (6%) had low-hypodiploidy / near triploidy (Ho-Tr) and 2 (3%) pts had complex karyotype (CK). All but 1 pt (98%) achieved CR (2 after 2 cycles); only 1 pt (2%) died during induction. The MRD- rate was 65% after cycle 1 and 93% overall. These rates were 14% and 71%, respectively for pts with Ph-like ALL. The median time to MRD- was 0.7 month (range, 0.4-8 months) overall and 3 months (range, 0.7-6.5 months) for pts with Ph-like ALL. A total of 13 pts (19%) underwent allogeneic stem cell transplantation for adverse-risk cytogenetics (CK or Ho-Tr), Ph-like ALL (n=1/7), or persistent MRD+. The most common non-hematologic grade 3-4 toxicity was infection which occurred in 56% and 81% of pts, during induction and consolidation, respectively. With a median follow-up of 44 months, 46 pts (64%) are alive, including 37 pts (54%) in CR1. The median RFS and OS were 52 months (95% CI, 43 - NR) and not reached (95% CI, 65 - NR), respectively. The estimated 4-yr RFS and OS rates were 60% (95% CI, 49 - 73%) and 68% (95% CI, 58 - 81%), respectively (Figure 1A-1B). For AYA pts, the 4-yr OS rate was 74% (95% CI, 60 - 91%) (Figure 2A). The 4-yr OS rates were 54% (95%, 26 - 100%) for pts with Ph-like ALL compared to 74% (95% CI, 57 - 97%) for pts without Ph-like ALL (Figure 2B). There was no difference in OS according to the CD20 expression level (20% cut-off; p = 0.31). Using historical control pts, there was a trend towards improved OS with HCVAD-O versus HCVAD-R for pts with CD20 ≥ 20% (4-yr OS rate 63% vs 49%, p = 0.16) and HCVAD-O versus HCVAD alone for pts with CD20 1-19% (4-yr OS rate 73% vs 62%, p = 0.46). Conclusion: HCVAD-O is a safe and highly effective regimen in pts with CD20+ Ph-negative B-ALL. This regimen achieves excellent outcomes in the AYA population. Disclosures Kantarjian: BMS: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Kisoji: Consultancy, Honoraria; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding. Jain:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding. Mullighan:Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Amgen: Honoraria, Other: speaker, sponsored travel. O'Brien:AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Celgene: Consultancy; Kite: Research Funding; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. OffLabel Disclosure: Ofatumumab is not approved by the FDA for treatment of B-cell acute lymphoblastic leukemia.

Description: Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p

Description: Background: The addition of midostaurin to induction therapy has become a standard approach in newly diagnosed FLT3-mu AML. Second gen FLT3i's quizartinib and gilteritinib demonstrated single-agent CR/CRi rates of 45-55% in pts with R/R FLT3-mu AML in phase II/III trials. The majority of pts in these trials were prior FLT3 inhibitor naïve, a population likely to become obsolete soon. The response rates to second and third FLT3i exposure remain poorly defined. This will be an important clinical question as multiple FLT3i are approved. Methods: Adult pts with FLT3-ITD mu AML who received at least one FLT3i based therapy at MDACC from 2007 to 2018 were included. Single agent FLT3i and FLT3i combinations with cytotoxic chemotherapy (CCT) and low intensity therapy (LIT) (hypomethylating agents and low-dose cytarabine) were included. FLT3 testing was performed as previously reported (Luthra R et al., Haematologica 2014). All FLT3-ITD positive pts were included irrespective of the allelic frequency. Results: 217 pts with FLT3-ITD mu AML received one FLT3i therapy, 109 pts received a second FLT3i, 29 received a third FLT3i, and 4 received a fourth FLT3i (Table.1). Overall response rates (ORRs) (ORR = CR+CRp+CRi+PR) were 49%, 27%, 17% and 25% with the first, second, third, and fourth FLT3i (composite CR (CRc) rates of 49%, 27%, 13% and 25%), respectively (Table.1A). The median OS was 8.7, 4.2, 3.5 and 3.9 months with the first, second, third, and fourth FLT3i, respectively. In the first FLT3i exposure, the ORRs with CCT, LIT, and single-agent FLT3i were 57%, 62%, and 32%. The median (med) prior AML treatment in this group was 1 (range, 0 - 7), however none had received a prior FLT3i. In the second FLT3i exposure, the ORRs with CCT, LIT, and single-agent FLT3i were 27%, 46%, and 15%, respectively. The med prior AML treatments in this group were 3 (range, 1 - 8), including one prior FLT3i. In the third FLT3i exposure, the ORRs with CCT, LIT, and single-agent FLT3i were 0%, 29%, and 18%. The med prior AML treatments in this group were 4 (range, 2 - 10), including two prior FLT3i's. Only 4 pts received a fourth FLT3i and 1 had a CRi. Analyzing by individual FLT3i, 359 FLT3i's were used at different time points, excluding duplication of FLT3i's in any pt. The most frequently used was quizartinib (131 pts, 37% of all pts). Quizartinib was used in combination with LIT (63 pts) or as a single-agent (68 pts) only, with ORRs in all FLT3i exposure groups of 73% and 38% (CRc 70% and 38%), respectively. In the first (n=102), second (n=23), and third (n=6) FLT3i exposures, ORRs with quizartinib-based therapies were 59%, 39%, and 50% (CRc 59%, 35%, and 33%), respectively (Fig.1B). Quizarinib is a potent FLT3i. Switching to another FLT3i after failing first line quizartinib (n=33) still produced ORRs of 24% (CRc 21%). The second commonest used FLT3i was sorafenib (108 patients, 30% of all pts). Sorafenib was used in combination with CCT (n=38), LIT (n=57), and as single-agent (n=13) with ORRs in all FLT3i exposure groups of 54%, 42%, and 7% (CRc 54%, 39%, and 7%). Single agent sorafenib was not as effective. In the first (n=69), second (n=33), and third (n=6) FLT3i exposures, ORRs with sorafenib-based therapies were 49%, 30%, and 17% (CRc 46%, 30%, and 17%), respectively. Quizartinib-based therapies had an ORR of 37% (32% CR/CRi) as second line post-sorafenib (Fig.1C). Gilteritinib was used in 12 pts as a single-agent. 3, 8 and 1 pts received gilteritinib in first, second and third FLT3i exposures with ORRs of 67%, 38% and 100% (all CRc responses), respectively. Midostaurin was always used in combination, with CCT (n=2) or LIT (n=10) with ORRs of 50% and 40% (all CRc responses) in all FLT3i groups, respectively. In this small set, post-midostaurin ORRs to second FLT3i's were 57% (all CRc). Conclusions: ORRs dropped from 49% to 27% to 17% with first, second, and third FLT3i-based therapies. Combining FLT3is with low or high intensity chemotherapy appeared superior to single agent in all exposure groups. LIT (HMA and LDAC)-based combinations had encouraging ORRs of 46% and 29% in the second and third FLT3i exposure, likely because many pts received CCT-based combinations as initial therapy. Quizartinib and gilteritinib were effective with ORR of 35-40% even when used as a second FLT3i. This is a first attempt at identifying benchmark response rates for second and third FLT3i exposures, for developing novel FLT3i combinations and expectations with sequential FLT3i usage. Disclosures Ravandi: Xencor: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Sunesis: Honoraria. Konopleva:Stemline Therapeutics: Research Funding. Kadia:Novartis: Consultancy; Takeda: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Research Funding. DiNardo:Karyopharm: Honoraria; Bayer: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Pemmaraju:SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Short:Takeda Oncology: Consultancy. Andreeff:United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Oncolyze: Equity Ownership; Celgene: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SentiBio: Equity Ownership; Jazz Pharma: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Consultancy, Research Funding; Reata: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Daver:Alexion: Consultancy; ImmunoGen: Consultancy; Novartis: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Kiromic: Research Funding; Incyte: Research Funding; Incyte: Consultancy; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding.

Description: Introduction: Approximately 77% of younger pts and 49% of older pts with newly diagnosed AML achieve CR after induction chemotherapy (chemo). The majority of pts who achieve CR eventually relapse, with only approximately 30% of pts maintaining CR for 3 yrs or longer. Long-term outcomes in pts maintaining 1st CR for at least 3 yrs (AML survivors) remain largely unknown. The purpose of this study was to investigate long-term outcomes in this subset of pts. Methods: We performed a chart review of pts with AML treated at our institution from 2000-2015 who achieved CR for at least 3 yrs after their initial chemo ± allogeneic stem cell transplant (ASCT) to analyze their long-term outcomes. Results: 2779 pts with AML were treated between 2000 and 2015 at our institution with 1686 (61%) pts achieving CR. Among them, 455 (27%; 16% of all treated) maintained 1st CR for at least 3 years and constitute the focus of this analysis. Among them 309 received chemo alone and 146 chemo followed by ASCT. The median time from the initiation of induction chemo to the first CR was 29 days [10-207] for the entire cohort, and it was similar for pts treated with chemo only versus those who later received ASCT. Baseline characteristics for AML survivors were as follows: hypertension (HTN) in 27% of pts; dyslipidemia (DLD) in 16%; pulmonary disease in 10%; cardiac disease in 9%; diabetes mellitus (DM) in 9%; depression in 5%, renal disease in 5%; gastroesophageal reflux disease (GERD) in 5%; hypothyroidism in 5%; anxiety in 4%; osteopenia/osteoporosis in 1%. Late relapses (i.e., after 3 years in CR) occurred in 11% of pts - 14% treated with chemo alone and 6% treated with ASCT. Such relapses occurred after a median CR duration of 6 yrs (3-12) and 7 yrs (4-12) respectively. A change in karyotype compared to the original karyotype was seen in 51% of relapsed chemo pts and 56% of relapsed ASCT pts. The most common new cytogenetic abnormalities were 7q del (22%), Trisomy 8 (11%), and 5q del (7%). The two most common mutational status changes seen in relapsed pts were FLT3-ITD appearing in 5% of chemo pts while disappearing in 11% of ASCT pts and FLT3-D835 appearing in 5% of chemo pts while disappearing in 2% of chemo pts. Patients treated with ASCT did not display a change in FLT3-D835. At relapse, TP53 mutation was seen in 7% of pts; however, TP53 status at the time of diagnosis was unknown. A 2nd complete remission (CR2) was achieved in 54% of late relapse pts: 51% of chemo only pts and 67% of ASCT pts. The median CR2 duration was 18 months (mo) [3-127] and 15 [7-23] respectively. The median survival after relapse was 10 mo in chemo only pts and 14 mo in ASCT pts. Of chemo pts who relapsed, 30% underwent an ASCT and 4 ASCT pts received a 2nd ASCT. New comorbidities that were present at or after the 3 yr mark included: HTN in 15%; osteopenia/osteoporosis in 15%; renal disease in 14%; pulmonary disease in 11%; hematologic complications in 11%; DLD in 9%; GERD in 8%; cardiac ailments in 7%; depression and anxiety in 7% and 6% respectively; DM in 6%; hypothyroidism in 4%. Osteopenia/osteoporosis was seen in 39% of ASCT pts and 3% of chemo pts. Renal disease was seen in 23% of ASCT pts and 10% of chemo pts. Pulmonary disease was seen in 16% of ASCT pts and 9% of chemo pts. Second malignancies occurred in 17% of pts with the most common being skin cancer (7%), prostate cancer (2%), breast cancer (1%), and lymphoma (1%). Skin cancer occurred in 12% of ASCT pts and 5% of chemo pts. The median survival for the entire cohort starting from 3 yrs in CR is 10.7 yrs (0.1-14.3) with chemo pts having a median survival of 10.7 yrs (0.1-14.3) and 12.7 yrs (0.1-12.7) for ASCT pts (Fig 1). The most common causes of death (COD) for relapse ASCT pts was relapsed AML (33%), complications secondary to 2nd ASCT (22%), and infection (11%); the most common COD for relapse chemo pts was relapsed AML (47%), complications secondary to ASCT (14%), and second malignancy (2%). The most common COD for CR1 ASCT pts was ASCT-related complications (2%), malignancy (

Description: Introduction: Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor which has transformed the management of several B-cell malignancies, particularly chronic lymphocytic leukemia (CLL). B-cell malignancies inherently confer increased risk of infections due to defects in innate and adaptive immunity. Recent studies have provided conflicting data regarding the risk of infection with ibrutinib therapy, with some reports suggesting an increased risk of infection owing to BTK inhibition while others suggesting decreased risk due to B-cell recovery and humoral reconstitution. We conducted a systematic review and meta-analysis of all phase III randomized controlled trials (RCT) to determine the relative risk of infection associated with the ibrutinib. Methods: We performed a systematic search of Embase, PubMed, Web of Science, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov with appropriate keywords through 07/10/18, to find all RCTs comparing ibrutinib with other agents or placebo in patients with B-cell malignancies and also reporting infection as a treatment-emergent adverse event. The search strategy, study selection, data extraction, and analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. We pooled the point estimates using random effects model of the generic inverse-variance method described by Der Simonian and Laird. Statistical analyses were performed using the Stata/SE 15.1 (StataCorp LP, College Station, TX, USA). Results: A total of 6 phase III RCTs randomizing 1811 patients (pt; 935 on ibrutinib arms and 876 in the control arms) were included in the final analysis. Four trials were conducted in pts with CLL, one in pts with Waldenstrom macroglobulinemia and the other one in pts with mantle cell lymphoma. Characteristics of these trials are shown in Table 1. In 4 RCTs ibrutinib was compared with an active agent (i.e., ofatumumab, chlorambucil, temsirolimus, and rituximab) and in the other two trials, it was compared with placebo. Ibrutinib was administered as a 1st-line therapy in the RESONATE-2 trial and both as 1st line and in refractory disease in the iNNOVATE trial. The median duration of treatment across studies with ibrutinib was 17.7 months (range 9.4-38.7 months). Ibrutinib was associated with a statistically significant increased incidence of total infections (any grade) in pts with B-cell malignancies [pooled risk ratio (RR) = 1.34, 95% confidence interval (CI): 1.06-1.69, p=0.015, I2=73.2%, fig. 1A]. Pneumonia and upper respiratory tract infection (URTI) were two most commonly reported infection in pts across trials. The incidence of pneumonia (grade 3-5) and URTI (any grade) with ibrutinib was not significantly different from the same in the control arm (pooled RR = 1.30, 95% CI: 0.84-2.02, p=0.237, I2=0.0%, fig. 1B, and pooled RR =1.26, 95%CI: 0.94-1.70, p=0.122, I2=34.5%, fig. 1C respectively). In subgroup analysis of trials (n=4) in pts with CLL only, ibrutinib was associated with a trend towards increased incidence of total infection (any grade) in pts with CLL, but the result was not statistically significant (pooled RR =1.24, 95% CI: 0.99-1.54, p=0.061, I2=75.7%, fig. 2A). No statistically significant difference was noted in the incidence of pneumonia (grade 3-5) and URTI (any grade) in pts with CLL on ibrutinib, as compared to their counterparts in the control arms (pooled RR =1.19, 95%CI: 0.76-1.88, p=0.448, I2=0.0% fig. 2B, and pooled RR =1.16, 95%CI: 0.86-1.56, p=0.341, I2=25.4%, fig. 2C, respectively). No publication bias was observed across all the studies included in final analysis. Conclusion: In this meta-analysis, ibrutinib was associated with significantly increased risk of infection in pts with B-cell malignancies, whereas this risk was not significantly increased when the analysis was limited to patients with CLL. Future well-designed prospective trials with longer duration of follow up are needed to truly evaluate the association of ibrutinib and infections in pts with B-cell malignancies. Disclosures Short: Takeda Oncology: Consultancy. Maiti:Celgene Corporation: Other: Research funding to the institution.

Description: Background: Patients (pt) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are elderly, or have secondary AML (sAML), or relapsed/refractory (R/R) disease have poor outcomes. Venetoclax (VEN), an oral BCL2 inhibitor, has shown activity in R/R AML as single-agent and in combination with hypomethylating agents (HMA) in newly diagnosed unfit AML. We designed a phase II trial to evaluate the safety and efficacy of VEN with 10-days (D) of decitabine (DEC) in AML and high risk MDS. Methods: Eligible AML pts included those who had failed prior therapy, or were newly diagnosed (ND) elderly pts (〉60 years), or had sAML. ECOG score ≤3, WBC count ≤10 x109/L, and adequate organ function were required. VEN was given on day 1-28 in cycle (cy) 1 and D1-21 in cy 2 onwards; and was interrupted on C1D21 if the 21D bone marrow showed clearance of blasts, until count recovery. VEN was dosed 200 mg PO daily (50% dose reduction) in pts needing CYP3A4 inhibitors. DEC was given 20 mg/m2 IVdaily on D1-10 until CR/CRi, followed by 5-day cycles. Hydroxyurea or ara-C could be used for cytoreduction prior to starting therapy. Prophylactic antimicrobials were used until neutrophil recovery. Tyrosine kinase inhibitors could be used in applicable patients. Primary objective was to determine overall response rate (ORR) including complete remission (CR), CR with incomplete blood count recovery (CRi), partial remission (PR), and morphologic leukemia-free state in pts with AML. Secondary objectives were to determine safety of the combination; duration of response (DOR), disease-free survival (DFS) and overall survival (OS). Results: 48 pts were enrolled between January and May 2018 (Table 1). 24 pts (50%) had ND AML, 7 pts (15%) had sAML, and 16 pts (33%) had R/R AML. Prior therapies are listed in Table 1. The overall CR/CRi rate was 71% (34/48). CR/CRi rate for ND, sAML and R/R AML were 92%, 71% and 44%, respectively (Table 2). Negative minimal residual disease (MRD-) by flow cytometry at the time of response was achieved in 16/33 responding pts (49%). CR/CRi with MRD- was achieved in 11/21 pts with ND AML (52%), 2/5 pts with sAML (40%), and 3/6 pts w R/R AML (50%). CR/CRi rate in TP53 mutated pts was 67% (8/12, Table 2). Additional therapies included ponatinib in 1 pt with AML and t(9;22) who achieved a CRi; and sorafenib in 5 pts (4 FLT3-ITD, 1 FLT3 S749L variant) of which 2 ITD pts achieved CRi and 3 pts did not respond. Median time to first response was 43D (range 20-110) with a median of 1 cy to best response (range 1-3). At a median follow-up of 2.3 months (mo; range 1.4-5.7), pts had received a median of 2 cy (range 2-5) and 32 pts continue on study. Reasons for discontinuation are shown in Table 3. Median OS has not been reached (NR) for ND and sAML pts (NR, range 1.8 mo-NR) and R/R AML (NR, range 0.4 mo-NR, Fig 1a). Median DFS (Fig 1b) and DOR for ND and sAML pts are also NR (range 0.9 mo-NR). Median DFS and DOR for R/R AML pts were 3.3 mo (range 0.5-NR). 10 pts received GCSF. 59 treatment-emergent adverse events (TEAE) occurred in 31 pts, out of which 48 were grade (gr) 3/4. The most frequent gr 3/4 TEAE were infections, with gr 3/4 neutropenia (53%), febrile neutropenia (14%), and tumor lysis syndrome (TLS, n=2, 4%). 1 pt with WBC count 12 x109/L developed TLS on C1D2 which resolved with rasburicase and holding VEN; another pt with WBC count 28 x109/L developed TLS on C1D2 needing hemodialysis for 12 days, prompting study amendment to the current baseline WBC≤10 x109/L. Time to blood count recovery are shown in Table 4. There were total 6 deaths, all in pts with R/R AML (n=5) and treated sAML (n=1), including 3 deaths in hospice, 2 early deaths in relapsed AML pts due to infection; and 1 early death in a relapsed MDS pt due to pneumonia and acute kidney injury unrelated to therapy. There were no deaths in the ND AML pts. 30D and 60D mortality rates were 8% and 10%, respectively. Preliminary BH3 profiling data in R/R cohort showed BCL-2 priming (by assessing cytochrome C release to recombinant BAD peptide and ABT-199) in 7/8 pts irrespective of their response; however, pts who failed to achieve CR/CRi demonstrated co-dependence on other anti-apoptotic proteins MCL-1, BCL-XL and A1 (Fig 2). Additional BH3 profiling and CyTOF analyses are ongoing. Conclusion: The DEC10-VEN regimen had an acceptable safety profile and excellent response rates with CR/CRi of 92% in ND AML, 71% in sAML, and 44% in R/R AML with MRD- in 52% of ND AML, 40% of sAML and 50% of R/R AML. Trial is continuing to accrue (NCT03404193). Disclosures Maiti: Celgene Corporation: Other: Research funding to the institution. DiNardo:AbbVie: Consultancy, Other: Advisory role; Agios: Consultancy, Other: Advisory role; Bayer: Other: Advisory role; Celgene: Other: Advisory role; Medimmune: Other: Advisory role; Karyopharm: Other: Advisory role. Cortes:Novartis: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Pemmaraju:plexxikon: Research Funding; novartis: Research Funding; Affymetrix: Research Funding; samus: Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; abbvie: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding. Kadia:Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; BMS: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding. Ravandi:Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Xencor: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Short:Takeda Oncology: Consultancy. Daver:BMS: Research Funding; ImmunoGen: Consultancy; Incyte: Consultancy; Otsuka: Consultancy; Daiichi-Sankyo: Research Funding; Incyte: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Alexion: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Kiromic: Research Funding; ARIAD: Research Funding; Novartis: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pharmacyclics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Genentech: Research Funding; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; BMS: Research Funding; Servier: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jabbour:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Research Funding. Andreeff:AstraZeneca: Research Funding. Konopleva:Stemline Therapeutics: Research Funding.

Description: Background Multi-agent combination chemotherapy regimens for the treatment of ALL are considered a cancer success story in the pediatric setting. For adults, the same magnitude of success has not been realized using similar strategies. These regimens produce high complete remission (CR) rates of 80-90% but the cure rates are 40-50%. The incorporation of targeted agents (tyrosine kinase inhibitors and monoclonal antibodies) has improved survival and cure rates in adult ALL subsets. Blinatumomab, a bispecific T-cell engaging (BiTE) CD19-CD3 antibody, is effective in patients with relapsed/refractory disease and in patients with measurable residual disease (MRD). Better outcomes were obtained when blinatumomab was administered earlier in the course of the disease. We hypothesized that incorporating blinatumomab in sequential combination with Hyper-CVAD in previously untreated patients with ALL would improve the eradication of MRD, decrease the need for intensive chemotherapy, and improve survival. Methods Patients were eligible to participate in this phase 2 single-arm study if they were at least 14 years old, had newly diagnosed untreated Philadelphia-negative B-ALL or B-cell lymphoblastic lymphoma, had ECOG performance status (PS) of 0-3, and normal liver, kidney and cardiac function. Patients in CR after one prior course of chemotherapy were also eligible. Therapeutic regimen consisted of 4 alternating cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone, cycles 1 & 3) and high-dose methotrexate/cytarabine (cycles 2 & 4) followed by 4 consecutive cycles of blinatumomab (4 weeks every 6 week-cycle). All patients received 8 prophylactic intrathecal injections with methotrexate and cytarabine during the first 4 cycles of treatment. Additionally, patients with CD20+ ALL (≥ 1% cells) received a total of 8 doses of rituximab (375 mg/m2) or ofatumumab (2000 mg) during the hyper-CVAD cycles. Maintenance phase consisted of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) on cycles 1-3, 5-7, 9-11 and 13-15 alternating with blinatumomab on cycles 4, 8 and 12. The primary outcome was relapse-free survival (RFS) and secondary outcomes were overall survival (OS), overall response rate and MRD negativity rate. Results To date, 17 patients were treated, three of them enrolled in CR after 1 cycle of Hyper-CVAD. Patient's characteristics are summarized in Table 1. Median age is 43 years (range, 20-59). All but one patient had CD20 expression. Six patients (35%) had TP53 mutations. Four patients (24%) had low hypodiploidy-near triploidy. One patient (6%) had CRLF2 overexpression. All 14 evaluable patients achieved CR for an overall response rate of 100%. Minimal residual disease (MRD) negativity, assessed by 6-color multicolor flow, was achieved in 93% of the patients after one cycle of therapy. No early death within 6 weeks was reported. Patients have received a median of 4 cycles (1-4) of chemotherapy and 4 cycles (0-4) of blinatumomab. Two patients had early relapse during the Hyper-CVAD cycles after 2 and 4 cycles, respectively. Three patients underwent allogeneic stem cell transplantation (HSCT) (1 with histiocytic proliferation in the bone marrow, 1 with t(4;11) and 1 with CRLF2+ ALL). A total of 14 patients have initiated the blinatumomab phase. Nine patients received the total 8 courses of hyper-CVAD and blinatumomab and are currently receiving maintenance in CR. The treatment was well tolerated. Grade 3-4 adverse events attributed to blinatumomab occurred in 2 patients (12%) and were manageable and reversible. One patient developed transient Grade 3 cytokine release syndrome and one had Grade 3 ataxia. Both recovered after holding blinatumomab therapy and dexamethasone administration. Treatment was resumed thereafter with no recurrence. With a median follow up of 14 months (range, 3-20 months), 16 patients (94%) are alive (14 of them in first CR); one patient died after HSCT of a transplant-related complication. The 1-year RFS rate was 77% (95% CI 42-93%) (Figure 1A) and the 1-year OS rate was 90% (95% CI 47-99%) (Figure 1B). Conclusion The sequential combination of Hyper-CVAD and blinatumomab in newly diagnosed adult patients with B-ALL is safe and highly effective. These early results are favorable. The study continues to accrue patients. Disclosures Short: Takeda Oncology: Consultancy. Ravandi:Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria. Cortes:Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Jain:BMS: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Servier: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Verastem: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Jabbour:Abbvie: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.