Abstract: Background: HMAs improve survival of pts with higher-risk MDS; however, the role of HMAs is less clear in pts with lower-risk MDS. These pts have a heterogeneous prognosis, and some may benefit from early HMA therapy. To test the hypothesis that low-dose HMA therapy would be safe and effective in pts with lower-risk MDS, we treated pts with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS with low-dose HMA regimens using 3 days of either 5-azacytidine (AZA) or decitabine (DAC). Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts were treated with AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), CR with insufficient hematologic recovery (CRi) and hematologic improvement (HI). Secondary outcomes included safety profile, duration of response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myelogenous leukemia (AML) or death from any cause. Chi-square test was performed to evaluate differences in response rates. EFS and OS were calculated using Kaplan-Meier estimates and compared using the log-rank test. Results: Between 11/2012 and 6/2015, 88 pts with lower-risk MDS were treated; 83 of them are currently evaluable for response assessment (65 MDS, 15 CMML and 3 MDS/MPN). Thirty pts received AZA (36%) and 53 pts (64%) received DAC. Median time from diagnosis to treatment was 5 weeks (range 1-272 weeks). Median age was 71 years (range 44-85 years). Sixteen pts (19%) had therapy-related MDS. Thirty-eight pts (46%) were transfusion-dependent for RBCs and/or platelets at baseline, and 17 pts (20%) had received prior growth factor support with erythropoietin-stimulating agents or G-CSF. By IPSS, 13 pts (16%) had low-risk and 70 pts (84%) had intermediate-1-risk disease. By the MDACC lower-risk scoring system, 38 pts (46%) had high-risk, 38 pts (46%) had intermediate-risk and 7 pts (8%) had low-risk disease. Twenty-seven pts (33%) had ≥5% bone marrow blasts. By IPSS, cytogenetics were good-risk in 55 pts (66%), intermediate-risk in 20 pts (24%) and poor-risk in 8 pts (10%). Mutation analysis was performed in 76 pts at the time of enrollment, 43 (57%) of whom had at least one molecular mutation. TET2 mutation was identified in 17 pts (22%), RUNX1 in 8 pts (11%), TP53 in 6 pts (8%), ASXL1 in 5 pts (7%), IDH1/2 in 5 pts (7%) and DNMT3A in 4 pts (5%). The median follow-up was 13 months (range 2-30 months) and median number of cycles received was 9 (range 2-29 cycles). The OIR for the entire cohort was 61%; 32 pts (39%) achieved CR, 11 (13%) achieved CRi and 8 (10%) achieved HI. Of the 38 transfusion-dependent pts at baseline, 9 (24%) became transfusion-independent. The median time to best response was 2.2 months (range 0.8 to 19.6 months). Median duration of response has not been reached with 71% of responders still on study. Low-dose HMA therapy was well-tolerated with only 6 pts (7%) requiring dose reduction and 19 pts (23%) requiring dose delay. AML developed in 4 pts (5%), and 17 pts (20%) have died. For the entire cohort, the 1-year EFS rate was 67%, and the 1-year OS rate was 86%. The median EFS and OS have not been reached. When stratified by IPSS and the MDACC lower-risk scoring systems, there was not a significant difference in OIR, EFS or OS among various risk groups (Table 1). Conclusions: Among pts with low- and intermediate-1-risk MDS, low-dose HMA therapy was well-tolerated and resulted in an OIR of 61%. Response rates, EFS and OS did not differ when pts were stratified by IPSS or the MDACC lower-risk scoring system. A randomized trial of low-dose AZA vs. DAC vs. best supportive care in lower-risk MDS is ongoing. Table 1. Response and survival rates by risk stratification Risk Stratification Risk Group N OIR (%) P (OIR) 1-year EFS rate (%) P (EFS) 1-year survival rate (%) P (OS) IPSS Low 13 54 0.540 83 0.751 86 0.295 Intermediate-1 70 63 65 85 MDACC Lower-Risk Scoring System Low 7 71 0.851 67 0.925 100 0.179 Intermediate 38 61 77 92 High 38 61 58 78 All Patients 83 61 67 86 Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Onconova: Consultancy. DiNardo:Novartis: Research Funding. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Verstovsek:Incyte Corporation: Research Funding.

Abstract: INTRODUCTION: Frequency of NPM1 mutations in patients with myelodysplastic syndromes (MDS) is 〈 1%. Patients with acute myeloid leukemia and NPM1 mutations have favorable outcomes and high complete response (CR) rate with chemotherapy. In this study we analyzed the characteristics and clinical outcomes of patients with MDS and NPM1 mutations. METHODS: We analyzed the clinical characteristics of all patients with MDS and NPM1mut treated at MD Anderson Cancer Center from 2009 until 2016. Detection of exon 12 NPM1 mutations (W288fs*12) was performed by Sanger sequencing from 2009 until 2012 and by a 28 or 53 gene panel PCR-based next generation sequencing platform from 2012 to 2016. All clinical and demographic characteristics were obtained from clinical records. Response was defined following 2006 IWG criteria. The Kaplan-Meir product limit method was used to estimate the median overall survival (OS) and leukemia-free survival (LFS). Univariate Cox proportional hazards were used to identify association between variables and outcomes. RESULTS: A total of 22 patients with MDS had detectable W288fs*12 NPM1 mutations. Patient characteristics are detailed in Table 1. Median age was 58 years (range 19-86). Thirteen (59%) patients were classified as Int-1 and 9 (41%) as Int-2 by IPSS. Two (9%) patients had CMML and the remaining had MDS. Nineteen (82%) patients had normal karyotype. All patients had available FLT3, NRAS and KIT mutational evaluation with an additional 2 (9%) patients having sequencing data on 28 genes and 11 (50%) on 53 genes. A total of 2 (9%) patients had co-occurring FLT3-ITD mutations and 1 (4.5%) had a co-occurring FLT3 D835 mutation. Other detectable mutations included NRAS in 6/22 (27%) patients, DNMT3A and WT1 in 4/13 (31%), PTPN11, TET2 and IDH2 in 2/13 (15%) and RUNX1 and IDH1 in 1/13 (8%). A total of 15 (68%) patients were treated with azacitidine or decitabine based therapy, 6 (27%) with intensive chemotherapy and 1 (4.5%) with lenalidomide. Patients treated with chemotherapy tended to be younger (44 vs 62 years, p=0.023) and have higher bone marrow blasts (14% vs 8%, p=0.018). Seven (33%) patients underwent allogeneic stem-cell transplantation: 4 of the treated with chemotherapy and 3 of the patients treated with hypomethylating agents (p=0.12). Patients treated with chemotherapy had higher overall response rates (100% vs 38%, p=0.015) and complete response rates (84% vs 13%, OR 32.5, 95% CI 2.38-443.14, p=0.006) than patients treated with hypomethylating agents. A total of 6 patients had transformation to AML. Median follow up was 10 months (range 1-115). Median OS of all the population was not reached at current follow up. Median leukemia-free survival (LFS) was not reached at current follow up. Chemotherapy was associated with a trend to improved OS compared with hypomethylating agents (NR vs 58 months, p=0.086) as shown in Figure 1A. Allogeneic stem-cell transplant was associated with improved OS irrespective of treatment (NR vs 58 months, p=0.034) as shown in Figure 1B. By univariate analysis, presence of either FLT3-ITD or D835 mutation was associated with shorter median OS (6.9 vs 115.9 months, HR = 7.42, 95% CI: 1.03-53.45, p=0.047). No other mutations were found to significantly impact outcome. CONCLUSIONS: NPM1 mutations are extremely rare in the context of MDS and tend to appear in younger patients with excess blasts and normal karyotype. Our results suggest treatment of this subset of patients with AML-type chemotherapy followed by stem-cell transplantation could be associated with improved outcomes. Confirmation in larger studies is required. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Novartis: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding.

Abstract: INTRODUCTION: Mutations in TP53 can be detected in up to 16-19% patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). TP53 mutations confer adverse prognosis irrespective of currently available therapies. The clinical impact of the type, clonality and number of TP53 abnormalities is unclear. Preclinical data suggests some TP53 mutations may be associated with additional transactivation activity and increased oncogenicity. METHODS: We evaluated 1401 patients with previously untreated AML or MDS treated at The University of Texas MD Anderson Cancer Center from 2012 to 2016. Sequencing data was obtained by use of a 28 or 53-gene targeted PCR-based next generation sequencing platform. The following mutations in TP53 where defined as GOF based on available in vitro data: R172H, R175H, R270H, G245S, R248W, G248Q and R273H. Response was defined following 2003 IWG criteria for patients with AML and 2006 revised IWG criteria for patients with MDS. Generalized linear models were used to study the association of overall response (OR), complete response (CR) and risk factors. Kaplan-Meier produce limit method was used to estimate the median overall survival (OS). RESULTS: A total of 593 (42%) patients had MDS and 808 (56%) had AML. In a total of 984 (70%) patients, data on therapy with sufficient follow up and response evaluation was available, with 494 (35%) patients receiving therapy with hypomethylating agents (HMAs) and 373 (27%) with chemotherapy regimens. Among evaluated MDS pts, based on the Revised-IPSS prognostic model, 62 (11%) had very-low risk, 149 (25%) had low, 121 (20%) intermediate, 109 (18%) high and 152 (26%) very-high risk. A total of 167 (28%) pts with MDS and 223 (26%) pts with AML had complex karyotype. A total of 405 mutations in TP53 were detected among 151 (26%) and 161 (20%) patients with MDS and AML, respectively. Mutations included 332 (82%) missense, 26 (6%) nonsense, 34 (8%) frameshift insertions or deletions and 13 (3%) splice-site mutations. The most prevalent mutation was R273H (MDS: n=10, AML: n=9) followed by R248W (MDS: n=8, AML: n=8), Y220C (MDS: n=7, AML: n=8) and R175H (MDS: n=7, AML: n=6). Median variant allele frequency (VAF) of TP53 mutations was 39% (range 1-94). Among patients with TP53-mutant disease: 1 TP53 mutation was identified in 105 (70%) and 126 (78%) MDS and AML pts respectively, 2 in 44 (29%) and 34 (21%) and 3 in 2 (1%) and 1 (1%) respectively. The median difference in VAF among detectable mutations in pts with 2 TP53 mutations was 3.9% [95% CI 4.9-14%]. Among double TP53-mutant pts, known GOF mutations where always found in association with a LOF mutation with no pts having 2 detectable GOF mutations. Additionally, 66 (11%) MDS and 105 (13%) AML patients had TP53 deletions evidenced by presence of monosomy 17 or del(17p). Presence of a TP53 mutation was associated with loss of TP53 locus by cytogenetic abnormality (r=0.492, p 〈 0.001). However, patients with multiple detectable TP53 mutations were less likely to have co-occurring chr17 abnormalities (79% vs 21%, OR 0.48, CI 0.29-0.81, p=0.01). Sequential bone marrow sequencing through the course of disease evolution was available in 75 pts. Dynamics of TP53 VAF at time or response and subsequent relapse in evaluable pts is shown in Figure A. Median follow up was 10.4 months (range 0-167 months) for MDS pts and 7.8 months (range 0-50) in AML pts. Presence of TP53 mutations with high VAF (defined as VAF 〉 median VAF) was associated with significantly worse median OS (Figure B). Presence of more than 1 TP53 abnormality was not associated with worse OS, LFS or PFS in pts with MDS but predicted for shorter OS in pts with AML (Figure C). In addition, GOF were associated with worse OS than LOF mutations in pts with AML (Figure D), but not in MDS. Presence and number of TP53 mutations did not predict for response to HMAs. In addition, clearance of mutation at the time of response was associated with improved OS (HR 0.26, 95% CI 0.08-0.78, p=0.016). CONCLUSION: Presence of multiple TP53 abnormalities can be observed in up to 13% of patients with MDS or AML. The number of TP53 abnormalities does not seem to affect the survival of patients with MDS, but is associated with worse OS in AML. In addition, although GOF mutations do not seem to affect outcome of pts with MDS, these mutations were associated with worse OS than LOF in pts with AML. Clonal size of TP53 mutations as well as their clearance in therapy correlate with survival outcomes. Figure Figure. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Kadia:Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; BMS: Research Funding; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy. Ravandi:Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Xencor: Research Funding. Cortes:novartis: Research Funding. Daver:Novartis: Research Funding; Incyte: Consultancy; Karyopharm: Research Funding; Pfizer: Consultancy; ImmunoGen: Consultancy; Daiichi-Sankyo: Research Funding; Otsuka: Consultancy; BMS: Research Funding; Sunesis: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Celgene: Honoraria; Agios: Consultancy; Abbvie: Honoraria. Jabbour:novartis: Research Funding. Pemmaraju:daiichi sankyo: Research Funding; samus: Research Funding; cellectis: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; novartis: Research Funding; plexxikon: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding. Konopleva:cellectis: Research Funding; Immunogen: Research Funding; Stemline Therapeutics: Research Funding; abbvie: Research Funding. Colla:Abbvie: Research Funding. Andreeff:Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; Celgene: Consultancy; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Consultancy, Research Funding; SentiBio: Equity Ownership.

Abstract: Background: Older patients (pt) with acute myeloid leukemia (AML) and patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia (HR MDS/CMML) have poor outcomes. We showed that 10-day decitabine with venetoclax (DEC10-VEN) is a safe and effective strategy and offers potentially better outcomes compared to intensive chemotherapy in older pts with newly diagnosed (ND) AML, as well as relapsed or refractory (R/R) AML (DiNardo et al. Lancet Haematol 2020; Maiti et al. Am J Hematol 2021; Maiti et al. Cancer 2021). We here in present updated results of this prospective phase II trial (NCT03404193). Methods: Eligibility criteria included ECOG PS ≤3, WBC ≤10 x10 9/L, and adequate organ function. Decitabine dose was 20 mg/m 2 IV daily on D1-10 until CR/CRi, followed by 5-day cycles. Venetoclax was given on D1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the D21 bone marrow (BM) had ≤5% blasts. Venetoclax dose was 400 mg PO daily or equivalent with concomitant azole antifungals as previously described (DiNardo et al. Lancet Haematol. 2020). Venetoclax duration could be reduced to 14 to 7 days in subsequent cycles in cases of prolonged myelosuppression. All pts received cytoreduction prior to start, tumor lysis syndrome (TLS) prophylaxis and antimicrobial prophylaxis. Concomitant FLT3 tyrosine kinase inhibitors were allowed in FLT3-mutated AML. Pts could proceed to allogeneic stem-cell transplantation (SCT) after response, if eligible. Primary objective was overall response rate and secondary objectives included safety and overall survival. Outcomes and endpoints were defined per ELN2017 criteria. Measurable residual disease (MRD) was assessed using multiparametric flow cytometry (sensitivity 0.1%) and reported for all responding pts with evaluable MRD sample. Results: Between January 2018 and April 2021 we enrolled 219 pts with ND AML (n=83), untreated sAML (n=20), treated sAML (n=25), R/R AML (n=71) and HR MDS/CMML (n=20). This high-risk cohort included 54% of pts ≥70 yrs (n=119), 57% pts were men, 29% pts had ECOG PS ≥2, and 57% pts had adverse-risk AML (Table 1). The 30 mortality was 1% for ND pts and 3.6% for all pts. There were 346 treatment-related adverse events in 181 patients including infections with grade 3/4 neutropenia (40%), febrile neutropenia (29%), and infection with unknown ANC (17%, Table 2). There were 11 grade 5 events including infections with grade 3/4 neutropenia (n=6), infections with unknown ANC (n=4), and renal failure (n=1). The CR/CRi rate in ND AML was 83%, in untreated sAML was 65%, in treated sAML was 40%, in R/R AML was 42% and in HR-MDS/CMML was 20% (Table 3). Rates of negative measurable residual disease (MRD) by flow cytometry (0.1%) in ND AML was 73%, in untreated sAML was 53%, in treated sAML was 65%, and in R/R AM was 58%. After a median follow-up of 24.7 months (mo), the median OS in ND AML was 16.2 mo, in untreated sAML was 10.7 mo, in treated sAML was 5.8 mo, in R/R AML was 7.8 mo, and in HR-MDS/CMML was 10.1 mo (Fig. 1a). The 1-yr OS in ND AML was 54%, in untreated sAML was 41%, in treated sAML was 36%, in R/R AML was 41%, and in HR MDS/CMML was 35%. Median RFS for pts with ND AML was 10.9 mo, in the untreated sAML was 6.7 mo, in treated sAML was 11.4 mo, and in R/R AML was 8.4 mo (Fig. 1b). 44 pts underwent SCT after achieving response including ND AML (n=17), untreated sAML (n=4), treated sAML (n=3), R/R AML (n=16), and HR-MDS/CMML (n=4). The 100-day post-SCT mortality was 9% (n=4). Median OS after SCT in pts with previously untreated AML was 31.1 mo and in previously treated AML was 15.0 mo (Fig. 1c) 199 pts (91%) have discontinued treatment and 69 pts (32%) are alive. The most common reasons for treatment discontinuation included refractory disease in 49 pts (22%), relapse in 45 pts (21%), SCT in 44 pts (20%). Conclusions: DEC10-VEN is an effective therapy for older pts with ND and R/R AML. Transition to SCT after response with DEC10-VEN may offer long-term survival advantage in this older/unfit population with both ND and R/R AML. The trial continues to accrue. Based on these findings we have initiated a phase II trial of 10-day oral decitabine (ASTX727) with venetoclax in R/R AML (NCT04975919). Figure 1 Figure 1. Disclosures DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Pemmaraju: DAVA Oncology: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; Samus: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Celgene Corporation: Consultancy; Incyte: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy. Ravandi: Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Prelude: Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Sun Pharma: Consultancy, Research Funding. Kadia: AbbVie: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Genfleet: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Liberum: Consultancy; Astellas: Other; AstraZeneca: Other; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Dalichi Sankyo: Consultancy; Ascentage: Other; Pulmotech: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Aglos: Consultancy; Amgen: Other: Grant/research support. Short: Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Jain: Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Wierda: Janssen: Research Funding; Karyopharm: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma Inc.: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Burger: AstraZeneca: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Verstovsek: CTI BioPharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Andreeff: Glycomimetics: Consultancy; Aptose: Consultancy; AstraZeneca: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Syndax: Consultancy; Medicxi: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Senti-Bio: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Thompson: Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Agios: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Cellectis: Other: grant support; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support.

Abstract: Background: Treated secondary acute myeloid leukemia (ts-AML), defined as AML arising from previously treated antecedent hematologic disorder, is a high-risk disease with dismal outcomes. CPX-351 is approved for the treatment of secondary AML, although it did not improve outcomes within the subgroup of patients (pts) with secondary AML with prior exposure to hypomethylating agents (HMAs). In clinical practice, either chemotherapy or HMA plus venetoclax (Ven) are often used for pts with ts-AML, although there are little data to guide the optimal therapy in this setting Methods: We conducted a retrospective analysis of pts with AML arising from either MDS or CMML who received first AML therapy at our institution from 6/2004 to 1/2021 and who had prior HMA exposure for preceding MDS/CMML. Pts treated with prior intensive chemotherapy (IC) or Ven were excluded. Treatment regimens were classified as IC, low-intensity chemotherapy (LIC), or HMA plus Ven. Results: Among 562 pts with ts-AML, 271 (47%) were treated with IC, 237 (41%) with LIC, 54 (9%) with HMA+Ven. Baseline characteristics were similar between pts treated with different treatment regimens (Table 1), although pts treated with IC were significantly younger than those treated with LIC or HMA+Ven (median age: 65 vs. 72 years, P & lt;0.0001). The median number of prior therapies for previous MDS/CMML diagnosis was 1 (range, 1-5). The entire cohort was enriched with adverse risk mutations, including ASXL1 (IC-41%, LIC-28%, HMA+Ven-52%), RUNX1 (IC-22%, LIC-35%, HMA+Ven-56%), and TP53 (IC-45%, LIC-24%, HMA+Ven-40%). In the entire cohort, the CR/CRi rate was 26% and the overall response rate (ORR; defined as CR+CRi+MLFS) was 34%. CR/CRi rates and ORR were similar between IC and LIC (CR/CRi rates: 24% vs 26%; ORR: 30% vs 35%, respectively). Compared with IC/LIC, treatment with HMA+Ven was associated with higher CR/CRi rates (39% vs 25%; P=0.03) and ORR (54% vs 33%; P=0.002). 60-day mortality was similar between the treatment groups (IC-14%, LIC-9%, HMA+Ven-13%). Hematopoietic stem cell transplant rates for pts who received IC, LIC and HMA+Ven were 13%, 5%, and 9%, respectively. In the entire cohort, the median overall survival (OS) was 4.8 months (m), and relapse-free survival (RFS) was 5.9m. OS was similar between those treated with IC or LIC (median OS 4.5m vs. 4.8m; 1-year [yr] OS 14% vs. 22%; P=0.16) but was superior for those who received HMA+Ven compared with those who received IC/LIC (median OS 5.8m vs. 4.7m; 1-yr OS 35% vs. 17%; P=0.05 (Figure 1). RFS was also numerically higher in pts who received HMA+Ven compared with those treated with IC/LIC (median RFS 14.4m vs. 5.4m; 1-yr RFS 59% vs. 29%; P=0.17). The impact of therapies on outcomes in ts-AML was influenced by karyotype. In those with adverse risk karyotype, the outcomes were dismal regardless of treatment approach. ORR was similar between IC/LIC and HMA+Ven (24% vs 28%, P=0.66) and these groups also had similar OS (median OS: 3.3m vs. 4.1m; 1-yr OS 8% vs. 11%; P=0.41). However, among those with non-adverse risk karyotype, HMA+Ven was associated with significantly higher CR/CRi rates (57% vs 30%; P=0.008) and ORR (78% vs 39%, P=0.0003) compared with IC/LIC. HMA+ven also resulted in superior OS in this non-adverse risk group (13.7m vs 5.5m, 1-yr OS 24% vs. 55%, respectively; P=0.04) (Figure 2). The superior outcomes with HMA+Ven were also observed when the comparison was restricted to those treated with IC (P=0.01). Then we evaluated the impact of age specifically in pts treated with IC (stratified into & lt;60 and ≥60 yrs) and HMA+Ven (of any age). Pts treated with HMA+Ven (93% of whom were ≥60 yrs of age) had significantly higher OS compared with pts ≥60 yrs of age who received IC (5.8m vs 4.1m, 1-yr OS 35% vs. 12%; P=0.009) (Figure 3). Although not statistically significant, there was also a trend towards superior OS with HMA+Ven compared to IC in pts & lt;60 yrs of age who received IC (5.8m vs 5.0m, 1-yr OS 35% vs. 16%; P=0.16). Conclusion: For pts with ts-AML and prior HMA exposure, HMA+Ven yielded significantly higher ORR rates and improved OS compared to IC/LIC, particularly in pts with non-adverse risk karyotype and in pts ≥60 yrs of age. These results suggest that HMA+Ven should be preferentially considered for pts with ts-AML and prior HMA exposure, rather than chemotherapy-based approaches. Our results also highlight the very poor outcomes of ts-AML, a poor-risk subgroup of AML for which novel, effective therapies are still needed. Figure 1 Figure 1. Disclosures Kadia: Amgen: Other: Grant/research support; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Liberum: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Ravandi: Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding; Taiho: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. DiNardo: ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Pfizer: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy; Ryvu: Research Funding; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Agios: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Astellas Health: Honoraria; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: Novartis: Honoraria; NGMBio: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria.

Abstract: INTRODUCTION: Despite the limited number of patients with chronic myelomonocytic leukemia (CMML) included in the clinical trials that resulted in the approval of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS), HMA (azacitidine and decitabine) remain the most commonly used therapeutic intervention for patients with CMML. We present our experience with HMA in the treatment of CMML. METHODS: We retrospectively reviewed 153 patients diagnosed with CMML following the 2006 WHO classification and treated with frontline HMA between 2004 and 2015 at a single institution. Clinical and demographic data were obtained from our electronic database. Response was assessed by modified 2006 International Working Group (IWG) criteria. Statistical analyses were performed with the IBM SPSS Statistics 23.0 software. Overall survival (OS) and leukemia free survival were defined as the time between treatment onset and death or leukemia (or last contact), respectively. Data were summarized using median, range, and percentage. Censored endpoints were estimated by the nonparametric Kaplan-Meier method and compared using the log-rank test. All tests were 2-sided with significance set at p 〈 0.05. RESULTS: Baseline characteristics are shown in Table 1. 45 (30%) patients were female. Median age at diagnosis was 69 years (range 50-88). According to the CMML-specific prognostic scoring system (CPSS), 17 patients (11%) belonged to the low risk group, 45 (29%) to the intermediate-1 risk group, 45 (29%) to the intermediate-2 risk group, and 11 (7%) to the high risk group. Following the FAB criteria, 66 of the patients (43%) had CMML-MD and 87 (57%) had CMML-MP. By WHO classification, 99 patients (65%) were CMML-1 and 54 patients (35%) were CMML-2. Karyotype was available in 150 patients (abnormal in 50 [33%]), and according to the Spanish Haematological Cytogenetics Working Group, 106 (69%) belonged to the good-risk category, 24 (16%) to the intermediate-risk category, and 19 (12%) to the poor-risk category. 35 (23%) patients received azacitidine in monotherapy (AZA), 74 (48%) decitabine in monotherapy (DAC), and 44 (29%) were treated with combinations. The overall response rate (ORR) was 71% (108/153), with 56% (86/153) of the patients achieving complete response (CR). The median duration of response was 10 months (range 1-86 months). No differences were observed in ORR or CR between CMML-MD and CMML-MP (73% vs 69%, p=0.613, for ORR and 61% vs 53%, p=0.340, for CR), CMML-1 and CMML-2 (68% vs 76%, p=0.285; 56% vs 57%, p=0.825) or CPSS score (p=0.133). Median OS was 23 months (Fig.1A), and the cumulative probability of AML transformation was 30% at 5 years. There were statistically significant OS differences between responders and non-responders: 35 vs. 18 months, respectively (p 〈 0.01) (Fig.1B); CMML-MD and CMML-MP: 37 months vs. 25 (p=0.008) (Fig.1C); and good, intermediate, and poor risk cytogenetics: 34, 19, and 17 months, respectively (p=0.001) (Fig.1D). No differences were observed in terms of OS between CMML-1 and CMML-2: 30 and 29 months (p=0.974). Considering only the patients treated with AZA or DAC in monotherapy, CR was significantly higher in those patients treated with DAC (74.3%) when compared with patients treated with AZA (37.1%) (p 〈 0.001). Despite the fact that DAC shows a trend toward be better than AZA in terms of ORR (79.7% and 62.9%, respectively; p=0.06), leukemia free survival (LFS) (median 22 and 12 months, p=0.367) and OS (median 34 and 24 months, p=0.231), no statistical differences were observed. The only difference observed between groups was hemoglobin level (11.4 g/dl vs 10.4 g/dl, p=0.027). No other significant differences in terms of white blood cells, platelets, neutrophils, number of bone marrow blast, CMML-1 vs CMML-2, CMML-MD vs CMML-MP, CPSS and cytogenetic risk groups were observed between patients treated with AZA vs DAC. CONCLUSION: Here, we present the largest series of CMML treated with HMA. As previously published, HMA are clinically effective in the treatment of patients with CMML, providing ORR of 71% with 56% of CR. Better OS was observed in responders compared with non-responders, in CMML-MD compared with CMML-MP, and in those with low risk cytogenetics. In our cohort, CR was significantly higher in those patients treated with DAC when compared with patients treated with AZA. These results need to be confirmed in larger numbers of patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Celgene: Research Funding; Novartis: Research Funding; Agios: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Abstract: Introduction Gene mutations carry a significant prognostic value and influence the management of MDS and AML. However, until now, data on the impact of the type and functional effects of mutations on outcome, especially in genes lacking a hotspot such as TP53, are limited. TP53 mutation (TP53mut) is an independent predictor of poor outcome in MDS/AML. Majority of TP53mut are missense, few are nonsense, frameshift and splice-site. These occur across the entire coding region, and result in either loss-of-function, gain-of-function (GOF) or exert dominant negative effect on wild-type allele. Until now, there is limited data on the impact of the different types of TP53mut on the outcome in MDS/AML. There are several quantitative predictors to assess the molecular effect of TP53mut. Evolutional Action (EA) scoring system quantifies the deleterious effect of missense TP53mut based on the location of AA residue involved by the mutation and the effect of the AA change. Within head and neck cancer, this scoring system has identified a subset of mutations that have an adverse outcome. In this study, we assessed the impact of different parameters of TP53mut and the utility of EA score in well-characterized MDS and AML cohorts. Methods A total of 593 MDS, 139 CMML and 808 AML patients were selected for analysis. Coding region of TP53 was assessed by NGS for mutations by targeted amplicon-based NGS panel. Gain-of-function (GOF) mutations were defined as R172H, R175H, R270H, G245S, R248W, G248Q or R273H. Overall survival (OS) was calculated from the time of diagnosis to death or last follow-up. Event-free survival (EFS) was calculated from the time from therapy to progression/death. Various parameters of TP53mut, including the number, VAF, location, functional effect were correlated to outcome. In patients with missense TP53mut, EA score was correlated to outcome. Results Among a total of 732 MDS/CMML patients, 208 TP53 mutations were identified in 159 (21.7%) patients [99 men; 60 women; median age of 68 years (range, 18-98)]. The median VAF of TP53 mutations was 36.7% (range, 1.0-93.6). These included 164 missense, 21 frameshift, 17 nonsense and 6 splice-site mutations. Majority (n=149, 94%) involved DNA-binding domain (DBD). Twenty-four (15%) patients had a GOF type mutation. The median EA score was 76.7 (range, 16.6-97.7). The median OS was 33 months (12 months in TP53mut, 112 months in TP5wt; p 〈 0.001). The presence of complex karyotype (CK) with TP53mut showed worse OS compared to TP53mut alone (median 22 months vs. 12 months; p=0.010). The presence of deletion 17p did not affect OS in TP53 mutated patients (del17p + TP53mut, 14 months versus TP53mut alone, 12 months; p=0.789). By univariate analysis, the prognostic factors for OS and EFS included the presence and VAF of TP53mut; in addition, EA score was prognostic for EFS (p=0.04). Using statistical approach, a mathematical EA score of 〉 87.4 could predict a significantly worse EFS in MDS/CMML (p=0.01). Among 808 AML patients, 197 TP53 mutations were identified in 161 (~20%) patients [90 men, 71 women; median age of 70 years (range, 20-90)]. The median VAF of TP53 mutations was 42.7% (range, 1.2-94.4). These included 171 missense, 13 frameshift, 6 nonsense and 7 splice-site mutations. Majority (n=151, 77%) involved DBD. Twenty-six (16%) were of GOF type. The median EA score was 78.5 (range, 4.2-97.6). 139 TP53 mutated patients had a complex karyotype. The median OS was 16 months (6 month, TP53mut; 20 months, TP53wt; p 〈 0.001). Patients with 〉 1 TP53mut showed worse OS than patients with one mutation (7 months, single; 7 months, multiple; p=0.006). The presence of CK with TP53mut showed worse OS compared to TP53mut alone (median 5 months vs. 11 months; p=0.002). The presence of deletion 17p did not affect OS in TP53mut patients (del17p + TP53mut, 5 months versus TP53mut alone 7 months; p=0.136). By univariate analysis, the presence, number (2 vs. 1) and VAF of TP53 mutation(s) were prognostic factors for OS, EFS and LFS. GOF type mutation was prognostic for EFS but showed a trend for OS and LFS. EA score and site of mutation did not influence the outcome in AML. In AML, EA score of 〉 57.7 could predict a significantly worse OS (EA score 〈 57.7, 5 months versus 〉 57.7, 9 months; p=0.02). Conclusion The presence, number and VAF of TP53 mutation(s) are associated with worse outcome in AML and MDS. EA score can be helpful to further stratify MDS and AML patients with missense mutations. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Kadia:Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding. Ravandi:Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Xencor: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Xencor: Research Funding.