Bewersdorf, Jan Philipp

AbstractGilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3‐mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen‐activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Abstract Background: Clonal cytopenia of undetermined significance (CCUS) is defined as persistent unexplained cytopenia with evidence of clonality [myeloid-associated somatic mutations (MTs) or cytogenetic [CG] abnormalities] but without definitive evidence of myeloid neoplasms (MN). The outcomes in CCUS patients (pts) are not well understood. Methods: The CCUS International Study database includes pts from 17 institutions who meet the criteria of CCUS and do not have other causes of cytopenia. Pts with MDS defining CG abnormalities were excluded. We collected baseline clinical data, laboratory parameters, CGs, molecular genetics, treatment, and disease course. Diverse gene panels from different institutions were collated to include a total of 70 myeloid-related somatic genes (30 genes in common). 2018 IWG MDS response criteria were used to determine response rate (RR). Disease progression (DP) is defined by progression to MN. The relationship between independent variables and DP and death was assessed using Cox proportional hazards models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. All statistical analysis was performed using SAS. Results: A total of 258 pts were captured by July 2021. The median age was 71 (IQR 63-77) years, and 66% were male. Among 73 (28%) pts with known malignancy history, 27 (37%) pts received previous chemo- or radiation therapy. 27 (10%) pts had non-malignant hematology comorbidities. 91 (35%) had cardiovascular disease, and 33 (13%) had inflammatory disease. (Table 1) The red blood cell and platelet transfusion-dependent rates were 7.3% and 2.3%, respectively. The median number of MTs was 2 (IQR 1-3), with 221 (86%) pts had ≥1 MT, of which 116 (53%) had ≥ 2 MTs. The most common 5 MTs were TET2 (n=78, 30%), SRSF2 (n=50, 19%), DNMT3A (n=47, 18%), ASXL1 (n=40, 16%), and U2AF1 (n=22, 9%) (Figure 1). The median VAF (mVAF) was 28% (IQR: 9.2%, 43%) with VAF &lt; 10% in 47 (18%) and VAF ≥40% in 78 (30.2%) of the MTs. mVAF of the all genes are shown in Figure 2. Among pts with CG abnormalities (n=62, 24%), trisomy 8 and -Y are the most common karyotypes (n=15 for each, 24%) (Table 2). Eighty one (31%) patients received various treatments for CCUS with modest RR, including growth factors (n=47, 18.2%, RR: 25.5%), supportive care (n=23, 9%, RR: 26%), immunoglobulin/immunosuppressive therapy (n=15, 6%, RR: 40%), and DNMTi (n=8, 3%, RR=13%). The median length of follow-up was 15.6 (IQR 6.9-30.6) months. 24 pts progressed to MN, 14 (58.3%) of which were MDS, 8 (33.3%) CMML, and 2 (8.3%) AML. The 2-year PFS was 86.1% (95% CI: 80-93%) with a median PFS of 16.3 (IQR: 3.7, 21) months. In the multivariable model, positive MT of KRAS (HR: 8.4, 95% CI: 1.9-36.9, p=0.005) and CBL (HR: 16.5, 95% CI: 3.7-73.8, p=0.003) were significantly associated with DP. In the functional pathway analysis, having at least 1 splicing factor MT was significantly associated with DP (HR: 2.6, 95% CI:1.2-5.9, p=0.02). TP53 was not significantly associated with DP (HR: 1.2, 95% CI: 0.2-8.7, p=0.88). Having &gt;1 MT (HR: 3.57, 95% CI: 1.19-10.7, p=0.02) compared to a single MT was significantly associated with DP (Figure 3). Over the follow-up period, 35 pts died. The 2-year OS was 81% (95% CI: 74.9-87.9%). In the multivariable model, MT of KRAS (HR: 6.1, 95% CI: 1.8-20, p=0.003), CBL (HR: 7.3, 95% CI: 1.7-31, p=0.007), and FLT3 (HR: 19.9, 95% CI: 2.5-155, p=0.004) were significantly associated with inferior survival. In the functional pathway analysis, MTs in activated signaling pathway were significantly associated with death (HR: 4.1, 95% CI: 1.8-9, p&lt;0.001). None of the pts with TP53 MT died. Having &gt;1 MT was not statistically significantly associated with higher risk of death (HR: 1.5, 95% CI: 0.7-3.0, p=0.28) (Figure 4). After adjustment for co-MT status and comorbidities, baseline Hb&lt;10 g/dL (HR: 3.7, 95% CI: 1.8-7.9, p&lt;0.001) was significantly associated with greater mortality. Conclusion: This large retrospective study summarizes the CCUS pts' characteristics, with different MT patterns and VAF. We confirmed the impact of having &gt;1 MT on DP, but not OS. Genes involved in activated signaling had a significant impact on both DP and OS. TP53 MT was not associated with worse outcome. Findings may be due to limited cases in the particular genes and different gene panels from multiple institutions. A longer follow-up is planned to further describe the predictors for outcome in this ongoing study. Figure 1 Figure 1. Disclosures Komrokji: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy. Zeidan: BioCryst: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Geron: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Janssen: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; AstraZeneca: Consultancy; Agios: Consultancy; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Astex: Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; Astellas: Consultancy; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foran: trillium: Research Funding; actinium: Research Funding; kura: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; abbvie: Research Funding; aptose: Research Funding; pfizer: Honoraria; novartis: Honoraria; servier: Honoraria; bms: Honoraria; revolution medicine: Honoraria; OncLive: Honoraria; gamida: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Desai: Astex: Research Funding; Janssen R&D: Research Funding; Kura Oncology: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy. Ades: ABBVIE: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; TAKEDA: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Brunner: Novartis, Celgene, Takeda, AstraZeneca: Research Funding; Celgene, Forty Seven Inc, Jazz: Other: Advisory Board. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Prebet: BMS: Research Funding; BMS, Curios, Daichi: Consultancy. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Abstract Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of leukemia-associated driver mutations (MT). These MT predominantly involve epigenetic regulators such as DNMT3A, ASXL1, and TET2 (DAT, 75%). CHIP is a disease of aging and is associated with increased all-cause mortality. Clonal Hematopoiesis (CH), when present in the context of unexplained cytopenias and MT variant allele fractions (VAF) &gt;20%, is termed as clonal cytopenias of undetermined significance (CCUS). Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by TET2, ASXL1, and SRSF2MT as well as sustained monocytosis. It usually arises in the setting of existing CH and clonal monocytosis. Here, we assessed the clonal compositions involving DAT genes in patients (pts) with CHIP, CCUS, and CMML. Methods: We included 1008 pts: 54 (5%) with CHIP, 334 (33%) with CCUS, and 620 (62%) with CMML. Demographics, laboratory parameters, and mutational spectrum at diagnosis were collected. We characterized and compared DAT MT in all three cohorts and assessed correlations with clinical parameters. MT locus and type along with protein sequences were analyzed using ProteinPaint. All statistical analyses were performed using R. Results: Of the 1008 pts, 427 (42%) had DAT MT; 36 had CHIP (67%); 96 had CCUS (29%), and 296 had CMML (48%). The median age was 71 years (IQR 65-76), and 68% were male. CMML pts had higher white blood cell counts, absolute neutrophil counts, absolute monocyte counts, and lower hemoglobin and platelet counts in comparison to CCUS and CHIP pts. The distribution of age and sex were similar among the three groups. After a median follow-up of 11 months (IQR 9.5-12.8), there were no myeloid progressions in the CHIP group and 17 (18%) in the CCUS group (8 of which developed CMML, Table 1). There were 738 protein-altering or splice-site DATMT in 495 unique MT hotspots. Pts with TET2MT were older (71 years, compared to DNMT3AMT: 69 years and ASXL1MT: 69 years , p&lt;0.022). ASXL1MT were more common in males (75%, compared to DNMT3AMT: 52% and TET2MT: 66%, p=0.005). The mean VAF (mVAF) were 15.5% for DNMT3AMT, 35% for ASXL1MT and 39.2% TET2MT, respectively (p&lt;0.001). We then compared DATMT characteristics in CHIP, CCUS, and CMML groups: DNMT3AMT were most common in CHIP, followed by CCUS, and were very rare in CMML (35% vs. 15% vs. 3%, p&lt;0.001), with mVAF of DNMT3AMT increasing across this spectrum (CHIP: 6.5% vs. CCUS: 17.1% vs. CMML: 43.4%, p&lt;0.0001). While DNMT3A missense MTs were most common (n=62, 67.4%), the AML-associated R882 hotspot MT was seen in 26 (28%) pts (CHIP: n=3, 5%, CCUS: n=10, 16%, and CMML n=13, 21%, Figure 1a). None of the DNMT3AMT CHIP and CCUS pts progressed to CMML.ASXL1MT were most frequently seen in CMML (n=178, 28.6%), followed by CHIP (n=4, 7.4%), and CCUS (n=17, 5%, p&lt;0.001). The mVAF of ASXL1MT was significantly lower in CHIP, followed by CCUS, and CMML (11% vs. 34% vs. 36%, p&lt;0.0001). Truncating ASXL1 MTs were most common (n=205, 53%). Mutational hotspots included G646W (n=81, CCUS: n=6, 3%, CMML: n=75, 37%) and E635 (n=27, CHIP: n=1, 0.5%, CCUS: n=1, 0.5%, CMML: n=27, 13%, Figure 1b). Four ASXL1MT CCUS pts transformed to CMML (R965, E635, G646W, Q910*, and Q925*); of which 2 co-mutated with TET2MT, one with SRSF2MT, and one with an additional ASXL1MT.TET2MT were frequently encountered in CMML, followed by CCUS and CHIP pts (CMML: n=205, 33% vs. CCUS: n=88, 26.3% vs. CHIP: n=15, 27.8%, p=0.02). The mVAF of TET2MT progressively increased across the 3 groups (CHIP: 14.1%, CCUS: 31.9%, CMML: 45.5%, p&lt;0.001). TET2MT occurred across the span of the gene, with no clear hotspots identified, with nonsense MT being most frequent (n=150, 37.3%, Figure 1c). Among the nonsense and frameshift TET2MT (n=209), 131 (63%) involved the N terminal region, and 78 (37%) involved the catalytic domain. Among 8 CCUS pts that transformed to CMML, 6 had TET2MT, including 4 with spliceosome co-MT. Conclusion: While CMML, a disease of aging, arises in the background of CH, the most common CH MT, DNMT3AMT, plays a minor role in this process, and in fact, DNMT3AMT tend to occur at younger ages. While DNMT3A MT and ASXL1MT are preferentially observed in hotspots, TET2MT span the entire gene. Clonal compositions largely involving truncating TET2MT and frameshift ASXL1MT, in conjunction with splicing MT, shape the CMML genotype. Figure 1 Figure 1. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Agios: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria. Zeidan: Genentech: Consultancy; BeyondSpring: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Amgen: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Astex: Research Funding; Epizyme: Consultancy; Geron: Other: Clinical Trial Committees; Boehringer Ingelheim: Consultancy, Research Funding; AstraZeneca: Consultancy; Acceleron: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Agios: Consultancy; Aprea: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; ADC Therapeutics: Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Jasper: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; BioCryst: Other: Clinical Trial Committees. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Griffiths: Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Jazz Pharma: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savona: CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Litzow: AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

Abstract Background: CML is managed by life-long TKI therapy in most pts which can be associated with chronic toxicities and substantial costs. Discontinuation of TKI in some pts can result in sustained therapy-free remission (TFR); however only a minority are candidates for discontinuation approaches; of those most still relapse and must restart TKI. High expression of programmed death receptor-1 (PD-1) and its ligand PD-L1 on CML-specific cytotoxic T-cells and CML cells, respectively, suggests that PD-1/PD-L1-mediated immune escape contribute to CML persistence and relapse after TKI discontinuation. We designed the BLAST MRD CML trial (NCT#03516279) to study whether adding anti-PD-1 antibody pembrolizumab to TKI therapy is safe and tolerable and increases rate of conversion to undetectable minimal residual disease (UMRD). We present data from the early safety cohort from this ongoing trial with a data cut-off date June 15th, 2021. Methods: BLAST MRD CML-1 is an ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial that enrolls adults with chronic phase CML who achieved a major molecular response (MR 3) but not UMRD while on a stable dose of up to three lines of TKI therapy. UMRD was defined as an undetectable BCR-ABL by central RQ-PCR (assay sensitivity of 4.5 [MR 4.5]) on 2 consecutive samples separated by ≥4 weeks. Once enrolled, pts continue on TKI and concurrently receive pembrolizumab 200mg IV on day (D)1 of each 21-D cycle with central MRD assessment every 4 cycles for 17 cycles. Pts who achieve UMRD at or prior to C17 discontinue pembrolizumab, while those with persistent MRD continue TKI + pembrolizumab for another 18 cycles. TKI is discontinued one year following first documentation of UMRD. After TKI discontinuation, BCR-ABL is monitored at defined intervals for 24 months. Primary endpoint is proportion of CML pts on stable-dose TKI who convert to UMRD within 2 years (yrs) of combined TKI + pembrolizumab therapy. Secondary endpoints include rates of TKI discontinuation and proportion of pts achieving 2-year TFR, MRD kinetics, and safety. Immune related and other adverse events (AE) were assessed and graded according to CTCAE v 5.0. Results: As of cut-off date, 6 pts enrolled in safety cohort. Median age was 43 yrs (range 32-65). TKIs received on trial included imatinib (N=2), dasatinib (N=3), and nilotinib (N=1). All 6 pts were on 2 nd line TKI. Median exposure to pembrolizumab was 20 doses (range, 5-36). Five pts were still on combined pembrolizumab + TKI treatment, while the 6 th pt has completed combined therapy for 2 yrs and then continued TKI monotherapy on trial after achievement of UMRD (pt has to be in UMRD for 1 yr before TKI can be discontinued). The combination of TKI and pembrolizumab was safe and well tolerated (Table 1). Only 3 pts experienced grade (G) 1/2 AEs as the worst non-hematologic AE while on trial. Hematologic toxicity reported was also generally minimal with only one G 1/2 anemia AE. The only reported G3 AE was a lipase elevation (283 U/L, normal range 11 - 55 U/L) noted on routine laboratory assessment in a pt receiving nilotinib at 400mg BID dose after 48 weeks of starting on trial combined therapy. Amylase was also elevated at G2. No baseline lipase levels were available as protocol at that time did not require baseline assessments. The pt had no symptoms and CT imaging showed no radiologic evidence of pancreatitis. The lipase and amylase levels normalized with holding of both nilotinib and pembrolizumab for 7 weeks, and the AE did not recur with resumption of combined therapy at same dose of pembrolizumab but with nilotinib reduced to 400mg daily. No G4 or 5 AEs occurred. No other dose-adjustments or treatment discontinuation/interruptions due to AEs occurred. No immune-related AEs (IRAEs) have been reported. Discussion: Data from the early safety cohort suggest that the combination of TKI and pembrolizumab is safe and well tolerated. The AEs observed were mild and generally G1/2. No pt discontinued trial therapy due to AEs. Only one G3 AE (asymptomatic lipase elevation) was reported, which could have been related to nilotinib therapy and could have predated trial entry as no baseline lipase value was available and was fully reversible with a temporary hold of therapy. No IRAEs have been reported to date. Work is ongoing on an amendment to study protocol to enhance accrual. Efficacy results will be reported as they mature. Figure 1 Figure 1. Disclosures Zeidan: Boehringer Ingelheim: Consultancy, Research Funding; Ionis: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Astex: Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BeyondSpring: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BioCryst: Other: Clinical Trial Committees; Janssen: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Geron: Other: Clinical Trial Committees; Astellas: Consultancy; ADC Therapeutics: Research Funding; Agios: Consultancy; Jazz: Consultancy; Pfizer: Other: Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bhatt: National Marrow Donor Program: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Research Funding; Jazz: Research Funding; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: Omeros: Other: Advisory Board; Astellas: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Pembrolizumab has not been approved for the treatment of CML

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p &lt;0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p&lt;0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p&lt;0.001) and alloHCT in CR1 (p&lt;0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p&lt;0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. &lt; 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Background: Gilteritinib is approved for the treatment of relapsed/refractory (R/R) AML and FLT3-mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) enrolled prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or post-transplant FLT3inhibitor (FLT3i) maintenance. Some mechanisms of drug resistance can be shared across FLT3i's, suggesting response to gilteritinib might differ in patients treated with frontline FLT3i. A better understanding of how prior therapy modulates response to gilteritinib is necessary to clarify this novel agent's role in the current FLT3-mutated AML treatment algorithm. Methods: This is an ongoing multi-institutional analysis from 13 US centers identifying patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. Patients who received gilteritinib as a part of an ongoing trial were excluded. Response criteria were identical to the ADMIRAL trial. For patients with available data and a composite complete remission (CRc), we defined clinically measurable residual disease (cMRD) negative status by bone marrow flow cytometry using a cutoff of &lt;1 x 10x105 cells as well as polymerase chain reaction (PCR) for FLT3 mutation with a minimum sensitivity of 5%. Survival from the time of gilteritinib initiation was recorded. Multivariate analysis included all variables collected to determine interaction with patient outcome (CR and survival data). Kaplan-Meier curves and log rank test were used for survival analysis after gilteritinib initiation. Results: 72 patients treated with prior FLT3i exposure received gilteritinib for treatment of R/R FLT3mut+ AML. Patient characteristics are presented in table-1 with 46 (64%) previously receiving midostaurin, 19 (26%) sorafenib, and 7 (10%) other FLT3i. 8 (11%) received more than one prior TKI. NGS at diagnosis were available in 66 patients (92%) and co-mutations in DNMT3A, NPM1 and NRAS were observed in more than 10% of patients. Average duration of gilteritinib therapy was 5.7 months (range: 0.2-25 months). 27 (37.5%) received stem cell transplant (SCT) before gilteritinib and 15 (21%) underwent SCT after gilteritinib. The composite CR rate (CRc, defined as CR + CRi + CRp) was 51.4% (n= 37 patients). With regard to specific FLT3i's, we found no significant difference in median survival (7.1 months and 6.4 months for midostaurin and sorafenib, respectively) or remission rates (CRc 54% and 47% for prior midostaurin and sorafenib, respectively). The CRc rate for patients who received only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. A trend toward higher CRc rate was noted in patients treated with gilteritinib in combination regimens rather than as a single agent (64% vs 43%, respectively, p=0.09 using Chi-square test). No survival advantage for combination therapy was seen over single agent. Survival was longest in patients who obtained a CR, particularly a cMRD negative response; this remained significant after censoring at the time of SCT (figures 1&2). Patients who received SCT after gilteritinib had significantly longer survival than non-transplanted patients (9.3 months vs 5.6 months, respectively, HR 0.44, 95% CI 0.2-0.8)(figure-3). Patients with concurrent mutations of NPM1/DNMT3A had a trend toward a higher CRc compared to FLT3 mutation alone (71% vs 50%, p= 0.2) but similar survival. With regard to mutations associated with drug resistance to other FLT3i's, patients with both FLT3-ITD and FLT3-D835 mutation had similar response and survival to FLT3-ITD alone. However, patients with MAPK pathway activating mutations (e.g. NRAS and PTPN11) had lower CRc (37.5% vs 59.5%) and poorer median survival than other patients (3.3 months vs 7.5 months) (HR 2.2- 95% CI 1.1-4.4) p value &lt;0.01(figure-4). Conclusions: In this multi-center, retrospective analysis, gilteritinib remains a clinically active agent after treatment failure of prior FLT3i's (midostaurin or sorafenib). Mutations activating MAPK pathway have been implicated in secondary gilteritinib resistance but are seldom co-mutated at initial FLT3mut+ AML diagnosis. While further study is required, we hypothesize that their detection after frontline FLT3i therapy may represent treatment-emergent clones with propensity for pan-FLT3i resistance. Disclosures Zeidan: Cardiff Oncology: Consultancy, Honoraria, Other; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; MedImmune/Astrazeneca: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Daver:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perl:Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Biomed Valley Discoveries: Research Funding; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Syndax: Consultancy, Honoraria; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; New Link Genetics: Honoraria, Other; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; Takeda: Honoraria, Other: Travel costs for meeting. Altman:Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; PeerView: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; Fujifilm: Research Funding. OffLabel Disclosure: Some of the patients we are reporting on received gilteritinib in combination with other agents which is off-label use.

Background: Chronic myeloid leukemia (CML) is driven by the activity of the oncogenic BCR-ABL tyrosine kinase, which can be effectively inhibited by tyrosine kinase inhibitors (TKIs) leading to prolonged overall and disease-free survival. Despite their effectiveness, disease can progress on TKI therapy, and lifelong treatment with TKI can have substantial negative effects on quality of life and financial health. Studies assessing the safety of TKI discontinuation in CML patients in molecular remission showed that TKIs can be discontinued in up to 45% of patients without disease recurrence. Programmed death receptor-1 (PD-1) is an inhibitory immune checkpoint receptor expressed by T-cells that can be inhibited by the anti-PD-1 monoclonal antibody pembrolizumab. Preclinical data have shown that PD-1 is highly expressed on CML-specific cytotoxic T-cells and PD-1 ligand (PD-L1) is present on CML cells. In murine CML models, the administration of anti-PD-L1 antibodies prolonged survival. As these studies suggest that disease relapse might be due to PD-1/PD-L1 mediated immune escape by CML cells, we designed the BLAST MRD CML 1 trial to study whether adding pembrolizumab to TKI is safe, increases the rate of conversion to undetectable minimal residual disease (UMRD) and allows a higher rate of TKI discontinuation. Methods: The primary endpoint of this ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial is to assess the proportion of CML patients on stable-dose TKI who convert to UMRD during or within 2 years of initiating pembrolizumab therapy (NCT#03516279). Secondary endpoints are (I) the proportion of CML patients who maintain UMRD for 6 months and 12 months, (II) the proportion of CML patients who discontinue TKI after achieving UMRD, (III) the proportion of patients who maintain UMRD off TKI at 2 years after first determined UMRD, and (IV) the incidence of grade 3 or 4 immune related adverse events related to pembrolizumab treatment during the first 2 years after registration. UMRD state is defined as an undetectable BCR-ABL using the central RQ-PCR assay with a sensitivity of 4.5 [MR4.5] on 2 consecutive occasions separated by at least 4 weeks with the date of achievement of UMRD constituting the date of first test. Immune related and other adverse events will be assessed according to CTCAE v 5.0 terminology and grading. Adult (≥18 years) patients with pathologically-confirmed CML and who have achieved major molecular response (MR3) but not UMRD at time of screening are eligible. Eligibility was recently expanded to allow third line TKI. Therefore, currently eligible patients must have been on first, second, or third line TKI therapy with either dasatinib, imatinib, nilotinib, or bosutinib for at least 2 years prior to enrolment. Patients with accelerated or blast phase CML or who have received prior allogeneic hematopoietic stem cell transplant or anti-PD-1/PD-L1 therapy are excluded. Patients will continue a standard dose of TKI therapy and receive pembrolizumab at 200 mg IV every 21 days (Figure 1). MRD status will be assessed centrally every 4 cycles. Patients who achieve UMRD at or prior to cycle 17 will discontinue TKI and pembrolizumab. If MRD remains positive prior to cycle 17, TKI and pembrolizumab will be continued for an additional 18 cycles. If MRD is still detectable after the second year of combined therapy, patients will come off study. If patients are in an UMRD state by the end of year 1 or 2 of pembrolizumab therapy, pembrolizumab will be discontinued. Patients who remain in UMRD status for one year after the first UMRD result will discontinue TKI therapy. Once TKI is discontinued, BCR-ABL will monitored q4 weeks for the first six months post TKI discontinuation, then q8 weeks for the subsequent six months, then q12 weeks for another year. Assuming that the addition of pembrolizumab to TKI will increase the conversion rate to UMRD from 20% to 40%, enrollment of 36 patients (40 patients to allow for 10% drop-out) would give this trial 91% power with a one-sided type-I error of 0.089. The combination therapy will be considered promising if 11 or more patients meet the criteria for TKI discontinuation. Toxicity will be monitored and reviewed every six months. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cardinal Health: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Taiho: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; ADC Therapeutics: Research Funding. Radich:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Bhatt:Incyte: Consultancy, Research Funding; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Research Funding; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Hoffman La Roche: Research Funding; Ariad: Research Funding; Biosight: Research Funding.