ALBERT

Description: Background: The majority of adult patients (pts) with B-cell precursor acute lymphoblastic leukemia (B-ALL) can achieve complete remission (CR) with conventional multi-agent chemotherapy regimens, with only 30 to 50% of them achieving a long-term cure. Persistence of minimal/measurable residual disease (MRD) is associated with poor event-free and overall survival. Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, is capable of eradicating MRD in precursor B-ALL, and possibly prolong survival. We aimed to evaluate blinatumomab in pts with precursor B-ALL who did not achieve MRD negativity after initial therapy or who had MRD relapse. Methods: This is an open-label, single-arm, phase II trial including pts with B-ALL in CR who had either not achieved MRD negativity or had MRD-positive relapse, starting any time after ≥3 months (mo) of frontline therapy, or in CR2 and beyond after at least 1 mo of salvage therapy. Positive MRD was defined as ≥1 x 10-4 by 6-color multi-parameter flow cytometry. MRD for pts with Philadelphia chromosome positive (Ph+) ALL was defined as BCR-ABL1 to ABL1 transcripts ratio of ≥ 0.1% IS by RT-PCR. Pts received continuous IV infusion of blinatumomab 28 µg/day over 4 weeks followed by 2 weeks treatment-free interval. For the first cycle, blinatumomab was initiated at 9 µg/day for 1 week and then escalated to 28 µg/day, if tolerated. A TKI of treating physician's choice was added to the regimen for pts with Ph+ ALL. Responders could receive up to 4 additional consolidation cycles, and subsequent allogeneic stem cell transplantation (ASCT) was offered depending on donor availability. Pts who do not proceed with ASCT may receive blinatumomab maintenance therapy with one cycle every 3 mo for up to 4 cycles (9 cycles total). Relapse-free survival (RFS) was the primary endpoint. Secondary endpoints were the MRD negativity rate at any time and after cycle 1, event-free survival, overall survival (OS), and safety profile. Results: Between 12/2015 and 05/2017, we enrolled 17 pts with precursor-B ALL in CR. Baseline characteristics are shown in Table 1. Three pts (18%) had Ph+ ALL. Twelve pts (70%) were in CR1, and 5 pts (30%) were in CR2 and beyond. Eleven (65%) pts had persistent MRD, and 6 (35%) pts had MRD relapse. Pts received a median of 2 cycles (range, 1-5) of blinatumomab. Thirteen out of the 17 pts (76%) achieved MRD negative status at a median time of 41 days (range, 29-92), 3 pts did not achieve a response after 2 cycles, and 1 pt progressed during the first cycle. Of the 13 responders, 12 pts (92%) responded after the first cycle; 1 pt responded after the second cycle. Of them, 6 pts (46%) proceeded to ASCT with median time from enrollment to ASCT of 3 mo (range, 2-6 mo). Therapy was well tolerated. Blinatumomab-related adverse events of any grade were observed in 6 pts (35%). These adverse events included cytokine release syndrome in 3 pts (grade 3, n=1; grade 2, n=2), grade 3 encephalopathy (n=1), grade 3 psychosis (n=1), and grade 1 confusion (n=1). All resolved with supportive management. No pts discontinued blinatumomab due to adverse events. With a median follow-up of 14 mo (range, 2-30 mo), 12 pts (71%) are alive. 8 pts (62%) have remained in remission for more than one year, 5 of them had received ASCT. The 1-year OS and RFS rates were 75% and 68%, respectively (Figure 1). Conclusion: Blinatumomab is well tolerated and is highly effective in eradicating MRD in pts with precursor B-ALL who have persistent MRD or who experience MRD relapse after intensive chemotherapy. Disclosures Short: Takeda Oncology: Consultancy. Konopleva:Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Stemline Therapeutics: Research Funding. Daver:ARIAD: Research Funding; Novartis: Consultancy; BMS: Research Funding; Incyte: Consultancy; Sunesis: Research Funding; Pfizer: Research Funding; Kiromic: Research Funding; Karyopharm: Research Funding; ImmunoGen: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Alexion: Consultancy; Novartis: Research Funding. Jain:ADC Therapeutics: Research Funding; Pfizer: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; ADC Therapeutics: 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; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Novimmune: 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; Incyte: Research Funding; BMS: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologioes: Research Funding; Incyte: Research Funding; Pharmacyclics: 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; Celgene: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; 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; Janssen: 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; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ravandi:Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding. O'Brien:Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy; Acerta: Research Funding; Kite Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Alexion: Consultancy; Astellas: Consultancy. Jabbour:novartis: Research Funding.

Description: Background: Relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL) is an aggressive malignant disease with poor long-term outcomes. Blinatumomab, a bispecific T-cell engager (BiTe) CD3-CD19 antibody, showed improved overall survival compared to standard chemotherapy. This is a long-term follow-up analysis evaluating outcomes of adult patients with R/R B-ALL treated in a phase 2 trial of blinatumomab at a single institution. Methods: Adult patients with R/R Philadelphia negative B-ALL were enrolled in this open-label single arm phase 2 trial from January 2012 until January 2015. During screening period, patients who had high tumor burden were given 10 mg/m2/day of dexamethasone for up to 5 days until 3 days prior to treatment initiation in order to prevent cytokine release syndrome. Patients received continuous IV infusion of blinatumomab 28 µg/day over 4 weeks (wk) followed by 2 wk treatment-free interval. For the first cycle, blinatumomab was initiated at 9 µg/day for 1 wk and then escalated to 28 µg/day, if tolerated. Patients who achieved response within 2 cycles received up to 3 additional cycles of consolidation treatment (total of 5 cycles). Allogeneic stem cell transplantation (ASCT) was offered to responding patients at the discretion of the investigators. The primary objective of the trial was to evaluate efficacy as well as safety of blinatumomab in patients with R/R B-ALL. During long-term follow-up, hematological relapse, treatment received after blinatumomab failure and survival data were collected. Overall survival was defined as the time elapsed from the date of start of treatment until death or date of last follow-up. Results: A total of 35 patients received blinatumomab, with baseline characteristics summarized in Table 1. The median number of cycles received was 2 (range, 1-5 cycles). The overall response rate was 54% (19/35), with only 2 achieving response after 2 cycles. The median time to response was 28 days (range, 14-69 days). Complete remission (CR), CR with partial hematologic recovery (CRp), CR with incomplete hematologic recovery (CRi) were achieved in 13 (37%), 4 (11%), and 2 (5%) patients, respectively. Sixteen out of 19 (84%) responding patients achieved negative minimal residual disease (MRD) by flow cytometry. Treatment was well tolerated with most adverse events being transient. Cytokine release syndrome was observed in 17 (49%) patients, all were of grade 2 toxicity. Neurotoxicity of grade 1 and 2 were observed in 9 (26%) patients; 5 patients had tremors, 3 had confusion, and 1 had seizure. Of all patients, 17 (49%) underwent subsequent ASCT: 6 (32%) had ASCT as consolidation after blinatumomab; of them 3 remained in continuous MRD negativity post ASCT for a median of 53.6 months (range, 2.4-57). Of the 19 responding patients, 16 relapsed after a median of 3 months (range, 0.5 to 26.1); 4 of them (25%) with CD19-negative disease. Eleven patients received subsequent ASCT after other salvage strategies. Anti-CD19 therapies were given to 8 (23%) patients after failure. Two patients received an anti-CD19 drug conjugate, and 6 other patients received anti-CD19 CAR T cells (2 patients for relapsed disease after ASCT and 4 patients as consolidation post-ASCT). None of the patients was re-challenged with blinatumomab after relapse. After a median follow-up of 11 months, 5 patients (14%) remained alive. The median OS was 10.6 months (range, 0.2-68). The 2-year and 3-year OS were 23% and 14% respectively. Outcomes of long-term survivors (i.e. 〉2 years) are summarized in Table 2. Conclusion: Blinatumomab followed by ASCT confers good long-term survival among patients with heavily pretreated R/R ALL. Long-term survival of more than 2 years was only observed in those who received subsequent ASCT. Disclosures Short: Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Jazz: Honoraria; Jazz: Honoraria. Sasaki:Otsuka Pharmaceutical: Honoraria. Cortes:Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Alexion: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Astellas: Consultancy; Celgene: Consultancy; Aptose Biosciences Inc.: Consultancy; Janssen: Consultancy; Kite Pharma: Research Funding; GlaxoSmithKline: Consultancy; Sunesis: Consultancy, Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Acerta: Research Funding; Amgen: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding.

Description: Introduction Venetoclax (VEN), a potent BCL2 inhibitor, demonstrated favorable outcomes combined with hypomethylating agents and low dose cytarabine (AraC) in elderly patients (pts) newly diagnosed (ND) with acute myeloid leukemia (AML). In order to improve both remission rates and survival in fit AML pts, we evaluated the combination of VEN with FLAG-IDA regimen in fit pts with ND or relapsed/refractory (R/R) AML. Objectives This phase (Ph) Ib/II single center clinical trial has dual primary objectives: (1) Safety and tolerability of the combination for pts with R/R AML (Ph Ib), and (2) Overall response rate (ORR) by modified IWG AML criteria in pts ND or R/R AML (Ph II). Secondary analyses include duration of response (DOR) and overall survival (OS). Methods Eligibility includes medically fit, ND or R/R AML pts of any age with adequate organ function, PS ≤ 2, and WBC 〈 25x109/L. Only R/R AML pts were eligible for Ph Ib dose escalation. Pts receive FLAG-IDA induction/consolidation (ind/cons), with VEN orally daily. The original FLAG-IDA ind consisted of fludarabine 30 mg/m2 IV D2-6, AraC 2 g/m2 IV D2-6, idarubicin 6 mg/m2 IV D4-6 (8 mg/m2 IV D4-6 for ND pts), and filgrastim 5 mcg/kg daily D1-7 (or pegfilgrastim 6 mg after day 5 to replace remaining injections). The 3+3 algorithm was applied for dose escalation. The first cohort (dose -1, n=8) received FLAG-IDA with VEN 200 mg on days 1-21 of ind, incorporating a 2-day VEN dose ramp up. After the observation of gram negative bacteremia and/or sepsis in 5 of 6 pts during cycle 1 nadir, an amended dose level -1 ind was designed with reduced AraC 1.5 g/m², with VEN 200 mg on D1-14 and dose level 0 with VEN 400mg on D1-14. After completion of ind/cons, single agent VEN at 400 mg continuously is provided as maintenance for pts not proceeding to alloSCT. The data cutoff was 6.10.2019. Results At data cutoff, 34 pts with a median age of 47 yrs (range, 21-72) have been enrolled: 16 pts in the Ph Ib, and 18 pts in Ph II (11 in ND, and 7 in R/R cohort). 23 pts had R/R AML with a median of 2 (range, 1-4) prior therapies, and 10 (43%) pts had received prior alloSCT. Additional demographics including molecular profile at study enrollment are provided in Table 1. The median number of cycles received is 2 (range, 1-4). VEN 400 mg on D1-14 was considered safe for Ph II dose expansion. Serious adverse events regardless of causality were infections (n=26), bacteremia (n=12), sepsis (n=5), hypotension (n=4) and typhlitis (n=3). No tumor lysis syndrome was identified. 30-day mortality was 0%, 60-day mortality was 0% in ND cohort and 13% in R/R cohort (2 pts died from progression and 1 pt from fungal pneumonia). All enrolled pts were evaluable for response. Of 23 R/R pts, 17 pts (74%) achieved a best response of CR/CRi (12 CR, 5 CRi: 3 CRh + 2 CRp). 12 (52%) pts attained MRD negative status by flow cytometry. 15 pts attained a best response after one cycle, and two attained blast reduction after cycle 1 followed by CR after re-induction. Among responders, 9 pts proceeded to alloSCT, 2 remain on study, 3 pts relapsed, and 3 pts died in CR at 1.7, 3.4 and 4.6 months on treatment. Median time to ANC recovery 〉 500/ul and platelet recovery 〉 50K in responders was 27 days (range, 20-90) and 33 days (range, 20-54) respectively. With a median follow-up of 5 months, median DOR is not reached and OS is 7.1 months. Median OS for pts in salvage 1, 2, and ≥ 3 is 9.4, 10, and 4.9 months, respectively. Of 11 ND pts, 10 pts (91%) achieved ORR (9 CR, 1 CRh) and all 10 pts became MRD negative by flow cytometry: 3 pts proceeded to alloSCT, and 7 pts remain on active treatment. Median time to ANC and platelet recovery with induction was 23 days (range, 19-31) and 25 days (range, 18-31) respectively. Both DOR and OS are not estimable. Of interest, responding pts demonstrated higher apoptosis priming, as shown by depolarization in response to Bid, PUMA and Bim peptides by BH3 profiling (Fig 1). Conclusions FLAG-IDA with VEN demonstrates notable activity in both R/R and ND medically fit pts. Improved safety and tolerability without decreasing efficacy was achieved by decreasing AraC to 1.5 g/m2, and administering VEN for 14 days in ind, and 7 days in cons cycles. Neither prolonged cytopenias nor early mortality were observed. Ph II portion for R/R and ND pts is ongoing. Correlative studies with genomic annotation, CyTOF analysis and BH3 profiling are being analyzed, with higher apoptosis priming identified in responding pts. Longer follow-up is necessary to establish long term survival benefit. Table 1 Disclosures Konopleva: Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Calithera: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. Kadia:Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: 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; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Garcia-Manero: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; Amphivena: Consultancy, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Biopath: Consultancy; BiolineRx: Consultancy, Research Funding; Merus: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy, Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding. DiNardo:celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria.

Description: Background: Treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been revolutionized after the introduction of tyrosine kinase inhibitors (TKIs) to the backbone multi-agent chemotherapy regimens. While the majority of patients (pts) achieve complete remission (CR) following initial therapy, a significant proportion relapse. Here we examine the predictors of outcomes in pts with Ph+ ALL at first morphological relapse. Methods: Clinical data from adult pts with Ph+ ALL who received frontline hyperCVAD chemotherapy with TKI at our institution between 4/2001 and 5/2018 were reviewed. Pts who had morphological relapse after first CR, defined as recurrence of BM blasts to ≥ 5% and/or development of central nervous system (CNS) or other extramedullary leukemia, were evaluated for predictors of second response and survival. Relapse free survival-2 (RFS2) was defined as the time from the date of second CR to the date of second relapse or death (censored at last f/u). Overall survival-2 (OS2) was defined as the time from the date of first relapse until death (censored at last f/u). The Kaplan Meier method was used to estimate RFS2 and OS2. Univariate and multivariate Cox proportional hazards models were used to determine associations between prognostic covariates and outcomes. Results: We identified 233 pts with Ph+ ALL who received frontline hyperCVAD with TKI on clinical trials. 57 (25%) pts had morphological relapse after a median of 15.9 months (mo) from first CR (range: 5.3-94). Among these, only 5 pts had received an allogeneic hematopoietic cell transplantation (alloHCT) in first CR. Baseline characteristics of all pts are summarized in table 1. Salvage treatments for relapsed pts were re-challenge with hyperCVAD in 18 (32%) pts, other cytarabine-based regimens in 10 (18%) pts, asparaginase-based regimens in 7 (12%) pts, intrathecal chemotherapy alone in 6 (11%) pts, blinatumomab in 4 (7%) pts, and inotuzumab in 4 (7%) pts. 43 (75%) pts received a TKI in combination with their salvage treatment; of them, 19 (44%) continued with their initial TKI, while 24 (56%) pts changed to another TKI. CR2 was achieved in 41 of 49 (84%) evaluable pts. 8 pts were not evaluable; early death in 4 pts or loss of f/u in the other 4 pts. Among pts achieving CR2, 23 pts were negative for minimal residual disease (MRD) by flow cytometry at time of CR2. 20 pts achieved major molecular response (MMR, defined as BCR-ABL PCR ratio of less than 0.1% IS) after a median of 2.2 mo (range, 0.5-5.1) from start of salvage treatment. 10 pts achieved complete molecular remission. The median number of cycles to CR2 was 1 cycle. 17 (30%) pts underwent alloHCT in CR2. Among the 41 pts achieving CR2, 22 had a second relapse after a median of 13.3 mo (range, 0.7-78). The median duration of CR2 in pts who had alloHCT was not reached versus 12.4 months (p=0.01) in pts who continued on maintenance chemotherapy. Median RFS2 was 10.5 mo (range, 0.2-81). 1-year and 2-year OS2 were 41% and 20% respectively (Figure 1). At last f/u, 47 (82%) pts had died; 28 (60%) died from disease progression, 7 (15%) from transplant related complications (GVHD,VOD), 4 (8%) from infections in CR, and 8 (17%) from other causes (such as myelodysplastic syndrome, motor vehicle accident). 10 pts are still alive after a median f/u of 30.4 mo, and are in continuous CR (7 pts in CR2, and 3 pts in CR3). On univariate analysis, patients with first remission duration of more than 12 mo had longer OS with a hazard ratio (HR) of 0.5 (95% CI, 0.28-0.92, p=0.03). Pts who relapsed with LDH ≥ 1200 U/L, or performance status of 2 or 3, or received either no TKI or imatinib had worse OS with a HR of 2.07 (95% CI, 1.06-4.05), 2.41 (95% CI, 1.17-4.96), and 3.82 (95% CI, 2-7.31), respectively. Achievement of MMR after salvage treatment was associated with better outcomes with HR of 0.39 (95% CI, 0.2-0.73) for OS2, and 0.43 (95% CI, 0.22-0.82) for RFS2 (p =0.01 for both). After adjusting for all other variables, LDH, achievement of MMR and the use of second or third generation TKI had a significant effect on OS. Conclusion: The majority of pts with first relapsed Ph+ ALL will respond to subsequent salvage chemotherapy in combination with TKI. AlloHCT is feasible in CR2 and is associated with increased remission duration, but not survival. LDH less than 1200 at relapse, the use of second or third generation TKIs in salvage treatment and achievement of MMR predicted for improved survival. Disclosures Short: Takeda Oncology: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Jain:Astra Zeneca: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Servier: Research Funding; Cellectis: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Servier: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Astra Zeneca: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Infinity: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Abbvie: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Verastem: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Astra Zeneca: 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; 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; Abbvie: 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; Astra Zeneca: 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; Verastem: 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; Novartis: 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; 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. O'Brien:Aptose Biosciences Inc.: Consultancy; Pfizer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Sunesis: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Celgene: Consultancy; Kite Pharma: Research Funding; Astellas: Consultancy; Regeneron: Research Funding; Abbvie: Consultancy; Acerta: Research Funding; Alexion: Consultancy. Kadia:Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Celgene: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Jabbour:Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding. Ravandi:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Xencor: Research Funding.

Description: Background: Crenolanib is a type I oral pan-FLT3 inhibitor with high potency and selectivity against FLT3-ITD and FLT3-tyrosine kinase domain (TKD) mutations. Crenolanib has demonstrated a clinical activity as a single agent in heavily treated acute myeloid leukemia (AML) patients (pts). Preclinical studies have shown an antileukemic synergistic effect of the combination of crenolanib with cytotoxic agents. We report here the final analysis of an open label, dose escalation, two-arm, phase I/II trial of crenolanib combined with standard chemotherapy in pts with relapsed/refractory (R/R) FLT3 mutant AML. Methods: Adult pts with a diagnosis of R/R FLT3 mutant AML were enrolled. Pts were assigned per physician's choice to either crenolanib in combination with higher intensity salvage chemotherapy (Arm1) or crenolanib with 5-azacitidine (Arm2). Higher intensity chemotherapy options consisted of either IA (Idarubicin (Ida) 12 mg/m2 for 3 days (d) with cytarabine (AraC) 1.5 g/m2 for 4 d (3 d if age 〉 60 yrs)). On a later amendment two other options were added: FLAG-Ida (Fludarabine 30 mg/m2, AraC 2g/m2 each for 5 d, and Ida 8 mg/m2 for 3 d), or MEC (Mitoxantrone 8 mg/m2, etoposide 100 mg/m2, AraC 1g/m2 all for 5 d). 5-azacitidine was given at 75 mg/m2/d for 7d each cycle. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3d before the next cycle. Responding pts were eligible to proceed to allogeneic hematopoietic cell transplant (alloHCT) or consolidation with AraC (750 mg/m2 for 3d) and Ida (8 mg/m2 for 2d) followed by crenolanib up to 6 cycles. Pts could continue on maintenance with single-agent crenolanib up to 1 year. Pts on Arm2 could continue combination therapy until progression or unacceptable toxicity. The primary objective was to determine the dose limiting toxicity (DLT) and maximal tolerated dose of crenolanib-based combinations, as well as overall response rates (ORR), including complete remission (CR), CR with incomplete blood count recovery (CRi), and partial remission (PR). Secondary objectives are duration of response, relapse free survival, and overall survival. Results: Total 28 pts were treated. Baseline characteristics are summarized in Table 1. All 3 dose escalation cohorts have been completed. 20 pts received crenolanib in combination with salvage chemotherapy, and 8 with 5-azacitidine. 16 (57%) pts had received prior FLT3 inhibitors including sorafenib (n=11), quizartinib (n=3), E6201 (n=2). The median number of cycles received was 1 (range, 1-14). No DLTs were observed at any of the dose levels explored. Non-hematologic adverse events possibly related to crenolanib were all grade 1 or 2 in severity, including nausea (n=1), vomiting (n=2), fatigue (n=2), diarrhea (n=1), abdominal pain (n=1), muscular weakness (n=1), hypotension (n=1). No deaths were attributed to crenolanib. The ORR in 24 pts evaluable for response was 11 (46%) including CR (n=3), CRi (n=7), and PR (n=1). Three (11%) pts had hematologic improvement with bone marrow blast count reduction of at least 50%. Four pts were not evaluable for response due to early death3 from infection, 1 stopped therapy early for unrelated reasons). The median time to response was 29 days (range, 19-116). Among responders, 4 (36%) pts achieved negative minimal residual disease by flow cytometry after a median of 3.2 mo (range, 0.7-3.7). Five pts received consolidation with alloHCT, and 2 other pts had alloHCT after subsequent salvage therapy. One pt received crenolanib maintenance after transplant. The median OS (mOS) was 4.7 (0.4-27) mo (Figure 1); median RFS was 4 (1-23) mo. Of 18 pts who received one or 2 prior therapies, 9 (50%) pts achieved CR/CRi (including 3 of 9 pts with prior exposure to FLT3 inhibitors) and 5 (28%) received subsequent alloHCT. The mOS for pts who received ≤ 2 prior therapies was 6.2 mo versus 1.5 mo for pts who received ≥ 3 prior therapies (p=0.0002). OS by treatment arm and prior therapies is shown in Figure 2. Conclusion: Full dose crenolanib (100 mg TID) can be safely combined with chemotherapy in R/R FLT3 mutant AML. ORR can reach up to 50% with the combination, even with prior exposure to FLT3 inhibitors, and particularly among Arm 1 pts with ≤ 2 prior therapies (mOS=8.6 mo). The study was terminated at the sponsor's request. Disclosures Jabbour: Takeda: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Daver:ImmunoGen: Consultancy; Alexion: Consultancy; Pfizer: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Sunesis: Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Kiromic: Research Funding; BMS: Research Funding; ARIAD: Research Funding; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Andreeff:SentiBio: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Celgene: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Consultancy, Research Funding; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership. Pemmaraju:cellectis: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; novartis: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding. Kadia:Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding.

Description: Background: New drug combinations and higher intensity therapy have led to significant improvements in complete remission (CR) rates for patients (pts) with acute myeloid leukemia (AML). However, many pts with high-risk AML who respond to initial induction/consolidation chemotherapy and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with very poor outcomes. With the exception of ASCT, long-term maintenance treatment in AML is still not part of the standard treatment approach. NK cells as part of the immune microenvironment are important mediators of immune surveillance in AML. Lenalidomide can enhance NK cell activity and immune synapse formation, and has anti-leukemia activity in AML. Here, we evaluated the efficacy of low intensity, continuous dosing of lenalidomide in pts with high-risk AML in remission. Methods: Adult pts with high-risk AML who have achieved first or second CR after induction chemotherapy and at least one consolidation cycle within 12 months of enrollment and who are not candidates for immediate ASCT were enrolled in this phase 2 trial. High-risk features for AML included adverse cytogenetics, FLT3 mutation, prior myeloid neoplasm or dysplasia (secondary AML, s-AML), therapy related AML, primary refractory AML, or minimal residual disease (MRD) persistence at any point after initial induction chemotherapy. Pts were treated continuously with lenalidomide 10 mg orally daily on days 1-28 of a 28-day cycle for up to 24 cycles. After cycle 1, stepwise dose escalations were allowed to 20 mg daily in pts who were tolerating their dose and have presence of minimal residual or morphologically detectable disease. The primary objective is to assess relapse free survival (RFS). Secondary objectives are duration of remission, overall survival (OS) and safety profile. Results: A total of 28 pts were enrolled in this study with a median age of 61 years (range, 24-87). Baseline characteristics of all pts are summarized in Table 1. All pts were in CR at the time of enrollment, with 22 (79%) pts in CR1 and 6 (21%) in CR2. Patient started lenalidomide maintenance after a median of 8.8 months (range, 4-19.3) from the start of induction chemotherapy. High-risk features at the time of enrollment were as follows (some are overlapping): 7 (25%) pts with history of prior myeloid neoplasm, 15 (54%) persistent MRD, 7 (25%) adverse mutational profile, 6 (21%) adverse cytogenetics, 3 (11%) CR2 status, 2 (7%) therapy related AML and 2 (7%) primary refractory disease. The median number of cycles was 6 (range, 1-24). Six (21%) pts completed 24 months of maintenance treatment, and 8 pts are still receiving lenalidomide on study. Overall, lenalidomide was well tolerated; Serious adverse events of grade 3 or 4 were observed in 11 (39%) pts including rash (n=6), thrombocytopenia (n=4), neutropenia (n=4), fatigue (n=2), febrile neutropenia (n=1), nausea (n=1), vomiting (n=1). Nine (32%) pts continued on 10 mg dosing, 2 (7%) had successfully increased the dose to 15 mg daily, 15 (54%) had dose reduction to 5 mg daily mainly due to rash (n=6), thrombocytopenia (n=3), neutropenia (n=2), nausea (n=1), fatigue (n=2), and diarrhea (n=1). Two pts discontinued treatment because of recurrent rash despite dose reduction. At the time of lenalidomide initiation, 5 (18%) pts had detectable MRD with a median of 0.1% of aberrant blasts (range, 0.02-1.6%) detected by flow cytometry. Of them, four pts relapsed within 3.7 months (range, 1.2-5.7), and one received ASCT due to persistent MRD and continues in remission. With a median follow-up of 12.1 months (range, 3-39), 11 (39%) pts relapsed after a median of 2.9 months (range, 0.7-23); of them, 7 pts had a prior myeloid neoplasm (n=6) or therapy related AML (n=1). The median duration of remission for all pts was 8.9 months (range, 0.7-38). The 1-year OS and RFS from time of enrollment were 67% and 52%, respectively (figure 1). The median RFS in pts with prior myeloid neoplasm (n=7) or therapy related AML (n=2) was only 10 months versus not yet reached in pts with other high-risk categories (p=0.01) (figure 1). Conclusion: Lenalidomide is a safe and feasible maintenance strategy in high-risk AML pts who are not candidates for ASCT. This trial continues to surpass the pre-specified expected rate of RFS of high-risk pts based on a historical cohort. Pts with secondary treated or therapy related AML remain with poor outcomes. Disclosures Ravandi: Xencor: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Daver:Alexion: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy; ImmunoGen: Consultancy; Pfizer: Consultancy; Incyte: Research Funding; Incyte: Consultancy; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; BMS: Research Funding; Novartis: Consultancy; ARIAD: Research Funding; Otsuka: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Oncolyze: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Oncolyze: Equity Ownership; SentiBio: Equity Ownership; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding. DiNardo:Bayer: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Celgene: Honoraria. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; cellectis: Research Funding; samus: Research Funding; novartis: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding. Jain:Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: 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; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Servier: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Cellectis: Research Funding; Astra Zeneca: Research Funding; Adaptive Biotechnologioes: Research Funding; Servier: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: 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; ADC Therapeutics: 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; 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; Astra Zeneca: 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; Verastem: 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; 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. Cortes:Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy.