Abstract: The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.

Abstract: FcγRIIb-dependent internalization of therapeutic mAbs is dependent on antibody specificity. FcγRIIb can be activated in both cis and trans configurations.

Abstract: Introduction: Treatment-free remission (TFR) is an emerging treatment goal in chronic phase chronic myeloid leukemia (CP-CML). The NCCN guidelines suggest patients must meet the following criteria in order to be eligible for an attempt at TKI discontinuation: use of a TKI for at least 3 years with no history of TKI resistance who have maintained a deep molecular response (MR4 - BCR-ABL IS ≤0.01%) for at least 2 years. The aim of this study was to identify predictors of long-term TFR in CP-CML patients who discontinue TKI therapy at our institution. Methods: We retrospectively identified all CP-CML patients who had discontinued TKIs after meeting TKI discontinuation criteria at Moffitt Cancer Center. Patient charts were reviewed to collect data on demographics, disease characteristics, and outcomes. TFR was calculated from date of TKI discontinuation to date of molecular recurrence (defined as loss of MMR (BCR-ABL IS ≥0.1%) or date of last follow up). Statistical analysis was performed utilizing Kaplan-Meier curves and log rank (Mantel-Cox) test. Results: A total of 102 patients met TKI discontinuation criteria and stopped treatment to attempt TFR. The median age at diagnosis was 53.5 years (19-83 years). The median age at TKI discontinuation was 61 years (28-92 years). Fifty (49.5%) patients were male. Four patients (3.9%) had previously received interferon α. At a median follow up of 29 months, the TFR rate was 56.8%, with molecular recurrence occurring in 44 patients. 93 patients had a follow up of at least 6 months. Of the 44 patients with molecular recurrence, 37 (84%) recurred within 6 months and 41 (93%) within 12 months of TKI cessation. The rate of TFR at 12 months and 24 months was 58% (95% CI: 48-68%) and 53% (95% CI: 43-64%), respectively [Figure 1]. Baseline characteristics along with univariate analysis of the 102 patients included in the study are shown in Table 1. Age, BMI at discontinuation, gender, Sokol risk index, last TKI prior to discontinuation, lines of therapy, or duration on TKI prior to discontinuation did not significantly affect rates of TFR. Patients with sustained MR4.5 (BCR-ABL IS & lt;0.0032%) for 2 years prior to discontinuation showed a trend toward higher probability of TFR at 12 months compared to those in MR4 (62% vs 49%; p=0.055). Median time to regain MMR after restarting treatment in patients with molecular recurrence was 90 days (range 28-443 days). 32 patients (31%) developed TKI withdrawal syndrome with symptoms including headache, arthralgia, myalgia and fatigue. Conclusions: At our center, 102 CP-CML patients qualified for TKI cessation. The rate of TFR at 12 months was 58% which is consistent with published data from numerous TKI discontinuation clinical trials. We were unable to identify any factors that were predictive of successful TFR, however those patients with a deeper molecular response (MR 4.5) at the time of TKI cessation trended towards higher rates of TFR at 12 months, suggesting that the depth of response is important for achieving prolonged TFR. Identifying methods to further deepen molecular response in CP-CML patients may ultimately lead to higher rates of TFR in the future. Figure 1 Figure 1. Disclosures Nodzon: Takeda: Consultancy. Komrokji: Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; 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; Geron: Consultancy. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte: Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Padron: Blueprint: Honoraria; Incyte: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; BMS: Research Funding. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; PharmaEssentia: Honoraria. Lancet: Jazz: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background Hypomethylating agents (HMA) remain the backbone for treating higher risk myelodysplastic syndromes (MDS) patients (pts) with less than 20% of pts achieving complete response (CR) and median overall survival (OS) of 12-18 months. Ongoing studies in higher risk MDS are assessing the role of adding venetoclax (Ven) to HMA. Preliminary data have reported promising higher response rate as first line therapy (1L) HMA/Ven) as well as activity in relapsed/refractory MDS to HMA. (R/R MDS). Method We analyzed all higher risk MDS pts treated at Moffitt Cancer Center defined by revised international prognostic scoring system (R-IPSS) by ≥ intermediate risk who received HMA as first line therapy after diagnosis. We compared outcomes of those pts who received single agent IL HMA, 1L HMA/Ven combination and HMA with Ven add back strategy after HMA failure (R/R MDS HMA/Ven). OS was defined from time of diagnosis. Results We identified 1193 higher risk MDS pts who received HMA 1L, 1158 pts received single agent HMA (1L HMA) (1027 azacitidine (AZA) and 131 decitabine (DAC)), 35 pts received 1L HMA/Ven combination (26 AZA and 9 DAC backbone). Among pts treated with HMA alone as first line, 31 were treated subsequently with HMA/Ven combination for R/R MDS without transformation to AML. The median duration of follow up from diagnosis was 96 months (mo) for 1L HMA, 15 mo for 1L HMA/Ven and 36 mo for HMA/Ven R/R MDS. Focusing on first line therapy, 1127 received 1L HMA alone with no subsequent Ven add back and 35 pts 1L HMA/Ven. Table-1 summarizes baseline characteristics, 1L HMA/Ven pts were more likely to be MDS-EB2 and more pts harbored ASXL-1 somatic mutation (SM). The overall response rate (ORR) (HI+) was 77% for 1L HMA/Ven compared to 40% 1L HMA (p & lt;.005). The CR/marrow CR (mCR)/PR/HI were 34%/37%/3%/3% compared to 13%/11%/1%/15% for 1L HMA/Ven and IL HMA alone respectively, p & lt;.005. Among pts with ASXL-1 SM, The ORR was 87% (CR 44%) and 32% (CR 8%) for IL HMA/Ven and 1 L HMA alone respectively, p & lt; .005. Among pts with TP53 SM the ORR was 75% and 44% for IL HMA/Ven and 1 L HMA alone respectively, p = .038, however CR rates were 25% versus 17%, p = .47. The rate of AML transformation was 23% and 37% for IL HMA/Ven and 1 L HMA alone respectively, p = .08. The overall survival was 21 mo (95% CI 11-32) and 20 mo (95%CI 19-22) for IL HMA/Ven and 1 L HMA alone respectively, p= .86. Among patients who proceeded to allogeneic stem transplantation (AHSCT) (n=269) 13 pts received 1L HMA/Ven, the median OS was not reached compared to 38 mo (95%CI 27-50) among who received 1L HMA alone (p=.2). The 2-year survival probability rate was 91% and 51% for IL HMA/Ven and 1 L HMA alone who proceeded to AHSCT respectively. (Figure 1 A) Among pts who received 1L HMA alone as first line, 31 pts later received HMA/Ven for R/R MDS. The median number of 1L HMA therapy alone was 6 cycles. The ORR was 61% (CR 13% and mCR 48%). The median OS from time of diagnosis for pts who received HMA/Ven for R/R MDS was 33 mo (95% CI 31-36) compared to 21 mo (95% CI 11-32) for those who had IL HMA/Ven and 20 mo (95%CI 19-22) for those who received 1L HMA alone with no subsequent Ven therapy. (p=.02). (Figure-1 B) Nine of 31 pts who received HMA/Ven R/R MDS underwent AHSCT compared to 22 who did not proceed to transplant with median OS 31 and 33 mo respectively, (p = .7). Conclusions Among higher risk MDS patients, 1L HMA/Ven combination yields significantly higher complete response rates including ASXL-1 mutant MDS compared to 1L HMA alone. The OS survival benefit for 1L HMA/Ven in higher risk MDS pts can only be addressed in randomized clinical trial but our data suggest promising activity among those who received 1L HMA/Ven and proceeded to AHSCT (2-year OS 91%). Ven add back strategy to HMA after 1L HMA failure has clinical activity and was associated with OS benefit. Figure 1 Figure 1. Disclosures Komrokji: Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Abbvie: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Geron: Honoraria. Padron: Taiho: Honoraria; Stemline: Honoraria; BMS: Research Funding; Blueprint: Honoraria; Kura: Research Funding; Incyte: Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Protagonist: Consultancy, Research Funding; Pharmaessentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Blueprint: Honoraria; Incyte: Consultancy; Celgene/BMS: Honoraria; Abbvie: Honoraria. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Astellas: Consultancy; Jazz: Consultancy. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Venetoclax for treatment of myelodysplastic syndromes

Abstract: Introduction: Dasatinib is a second generation tyrosine kinase inhibitor (TKI) which is approved for treatment of chronic myeloid leukemia (CML). Pleural effusion (PE) is a unique toxicity associated with dasatinib use. The risk of development of PE with dasatinib was reported to be 6-9% per year in DASISION and 5-15% per year in CA180-034. At a 5 and 7 year follow up 28% and 33% of patients developed PE in DASISION and CA180-034, respectively (Cortes et. al. J Clin Onc 2016 and Shah et. al. Am J Hematol 2016). PE led to discontinuation of dasatinib in only 6% and 7% patients in DASISION and CA180-034, respectively. Alternative TKIs are required in these cases with the goal to avoid recurrence of PE. Recently, switching to bosutinib after development of a PE while on dasatinib has been shown to be associated with a 30% risk of developing a recurrent PE, higher than the reported rate in front line trials (Tribelli et. al. Ann Hematol 2019). Objective: The aim of this study was to identify the incidence of pleural effusions in a cohort of patients treated with dasatinib for chronic phase (CP)-CML, and the safety of switching therapy to bosutinib. Methods: A retrospective chart review of all patients who had received dasatinib for treatment of CP-CML between 1992 and 2020 at Moffitt Cancer Center was performed. Patient data including baseline characteristics, date of diagnosis, line of treatment, date of initiation and termination of treatment, reason for discontinuation and dose were collected. PE was graded according to the CTCAE v5.0 (common terminology criteria for adverse events). A descriptive analysis of the data collected is reported. Results: A total of 390 patients, 184 males and 206 females, were treated with dasatinib during their course of treatment for CP-CML. The median age of diagnosis of CML was 50 years. 79% of patients were Caucasian. Dasatinib was used as front line therapy in 150 (38.4%) patients, second line in 177 (45.3%) patients and third line or above in 63 (16.1%) patients. A total of 69 patients (17.6%) developed any grade of PE, with 33 (48%) patients considered to have CTCAE grade 2 PE, 34 (49%) patients grade 3, and only 1 patient developed grade 4 PE. The dose of dasatinib for the patients that developed PE was 140 mg (6%), 100 mg (71%), 70 mg BID (4.3%), 70 mg (3%), 20 mg (3%) and unknown (13%). Therapy was changed to another TKI without a dose modification in 43% patients, the dose was reduced in 46% patients and we do not have information about dose available for the other 11% patients. Recurrence of PE was observed in 34 (49%) patients. PE directed treatment included a combination of furosemide (49%), steroids (20%) and thoracentesis (49%). The median time from initiation of dasatinib to development of PE was 31 months. Only 12 patients (17.3%) continued dasatinib after development of PE, while the other 57 patients discontinued the drug. Median duration of therapy on dasatinib was 39 months in patients that developed PE. Therapy was switched to bosutinib in 13 patients out of whom 6 (46%) re-developed PE. The median time to re-accumulation of PE after switching to bosutinib was 9 months. While only 14.2% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. Conclusion: A change in TKI to bosutinib was associated with a 46% risk of recurrence of pleural effusion in patients who develop pleural effusion on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib. Further prospective studies are needed to determine the safety of bosutinib in this setting. Disclosures Nodzon: Takeda: Consultancy. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Takeda: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees. Padron: Stemline: Honoraria; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding; Taiho: Honoraria. Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: Jazz: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background The revised international prognostic scoring system (R-IPSS) incorporated severe neutropenia (SN) defined as absolute neutrophil count (ANC) & lt; 0.8 x10 9 /L as a prognostic variable. Among MDS patients (pts), 18% had ANC & lt; 0.8 x10 9 /L (Greenberg et al, Blood 2012). Current treatment guidelines recommend considering hypomethylating agents or immunosuppressive therapy for treating MDS patients (pts) with neutropenia with low neutrophil response reported in clinical studies ( & lt;20%). Recurrent infections remain a major cause of morbidity and mortality in MDS pts. Identification of the genomic landscape of MDS pts with SN is crucial given the large unmet clinical need in this patient population. Method We analyzed all MDS pts treated at Moffitt Cancer Center with known ANC values around time of diagnosis and who had next generation sequencing (NGS). We defined SN around time of diagnosis for the purpose of this study according to the R-IPSS cut off (ANC 0.8 x10 9 /L) and stratified pts into two groups based on this definition. Results We identified 1972 MDS pts with known ANC who underwent NGS testing among whom 466 pts (24%) had SN by R-IPSS definition. Table-1 summarizes baseline characteristics comparing SN and non-SN pts. Neutropenic pts were slightly younger, had higher myeloblasts percentage, lower platelets count, higher risk disease by R-IPSS and were more likely to be classified as MDS-EB subtypes based on WHO 2016 criteria. Ninety-three pts had isolated SN (Hgb & gt; 10 g/dl and platelets & gt; 100 x10 9 /L). IDH mutations (MT) (IDH-1/IDH-2) were the only MT observed at higher rate among neutropenic pts. Table-2 summarizes landscape of common MT observed comparing SN and non-SN pts in the whole group and stratified by R-IPSS (lower risk defined as very low to intermediate and higher risk as high and very high groups). There was no difference in other genes not included in the table (NRAS, SETBP1, ZRSR2, CBL, JAK-2, FLT-3, NPM-1 and PHF6). Among the whole cohort, 13% of MDS pts with SN harbored IDH MT compared to 6% in non-SN pts (p & lt; .005). Both IDH-1 and IDH-2 MT were more common in neutropenic pts and among both lower and higher risk R-IPSS groups. The most common observed hot spot in IDH-2 was R140, although the R172 hotspot was observed more in SN pts. Among pts with isolated SN, 18% harbored IDH MT compared to 12% in non-isolated SN (p=.1); however, IDH-1 MT were more common in pts with isolated SN (11% vs 4%; p=.01) but no difference in IDH-2 MT (8% in both isolated SN and non-isolated SN groups, p=.8). TP53 was observed in 26% compared to 19% respectively for SN and non-SN pts, p & lt;.005 but no statistical difference was observed when examined among R-IPSS risk groups. The median overall survival (mOS) was shorter (25 months (mo) vs 42 mo; p & lt;.005) and the rate of AML transformation higher (49% vs 26%; p & lt;.005) in SN vs non-SN pts respectively. The mOS was worse for SN IDH wild type (WT) compared to non-SN IDH-WT, (24 versus 43.5 mo, p & lt; .005) while there was no difference in mOS comparing SN IDH-MT compared to non-SN IDH MT (mOS 33 vs 30 mo; p=.3). Among SN pts, there was no difference in mOS among IDH MT compared to WT (mOS 33 vs 24 mo; p= .1). However, among non-SN pts IDH-MT was associated with worse OS with a mOS 31 mo compared to 42 mo for non-SN IDH-WT (p=.04). Given lack of effective treatment options, two symptomatic IDH1 SN lower risk MDS pts have been treated with ivosidenib. Both pts achieved a complete hematologic response within 2 weeks of initiation of therapy (ANC 0.3 to 2.8 and ANC 0.21 to 2.4), which has been durable for 5 and 26 months, respectively. Conclusions Severe neutropenia is present in almost one fourth of MDS pts and it is associated with worse outcome. IDH mutations are enriched among SN MDS pts regardless of R-IPSS risk group. In pts with isolated SN, IDH-1 but not IDH-2 were more frequently observed compared to non-isolated SN. IDH mutations were associated with worse outcome among non-neutropenic pts. Notably, in 2 of 2 IDH-1 MT SN pts, treatment with ivosidenib resulted in ongoing, durable complete hematologic responses. The underlying biology of this observation (likely differentiation block or inhibition of dioxygenase enzymes) and the role of IDH inhibitors as potential targeted therapy for MDS pts with neutropenia should be further explored. Figure 1 Figure 1. Disclosures Komrokji: BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau. Kuykendall: Prelude: Research Funding; Abbvie: Honoraria; BluePrint Medicines: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: BerGenBio: Consultancy; AbbVie: Consultancy; ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Millenium Pharma/Takeda: Consultancy; Agios: Consultancy; Jazz: Consultancy. Padron: Taiho: Honoraria; Blueprint: Honoraria; Kura: Research Funding; Incyte: Research Funding; BMS: Research Funding; Stemline: Honoraria. Sallman: Incyte: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Use of IDH inhibitors in MDS

Abstract: Background: There is a paucity of research on racial and ethnic disparities in myelodysplastic syndromes (MDS). Research focused on racial and ethnic disparities for MDS is essential to improve knowledge and understanding to deliver racial and ethnic sensitive care. There are limited studies that delineate the incidence of cytogenetic and molecular features of MDS by race and ethnicity (Yan, et al. 2021, Ramadan, et al.,2016). The aim of this abstract is to report the difference in clinical phenotype, genotype and outcomes of White, Black and Hispanics from a large MDS data base. Methods: Adult patients were identified through the Moffitt Cancer Center MDS data base and divided into racial/ethnic categories. Fisher exact test and chi-square tests were used to compare categorical variables. Univariate survival analysis was estimated using the Kaplan-Meier method. Results: From analysis of 4414 patients with MDS, 4131 (93%) were White, 116 (3%) Black and 167 (4%) Hispanic. Table-1 summarizes baseline characteristics. There were more Black and Hispanic women diagnosed with MDS (p & lt; .001). Black and Hispanic patients were younger at diagnosis (p & lt;0.01), Hispanic patients had a lower platelet count at baseline (p=0.02). There were no racial differences in WHO 2016 MDS classification or disease risk according to R-IPSS. Black MDS patients had less complex karyotype (p & lt;0.05) while abnormalities in chromosome 5 were more common in White patients 785(19.6%, p & lt;0.05). Table-2 summarizes somatic mutations (SM) landscape among the different racial groups, IDH2 SM (p=0. 01) and NPM-1 SM (p=.004) were more common in Black MDS patients. MPL (p & lt; 0.005) was observed more frequently among Hispanic patients. There was no difference in response to any modality of treatment based on race. Hispanic patients were more likely to undergo allogeneic hematopoietic stem cell transplant 50 (29.9%, p & lt;0.01). Clinical trial participation rates among the groups were similar. The median overall survival (mOS) was 35 months (mo), 31 mo, and 52.5 mo for White, Black and Hispanic patients respectively, p= .01 shown in Figure 1. For very low/low R-IPSS the mOS was 67.6, 52 and 93 mo respectively, p= .028, Figure 2a. For intermediate risk R-IPSS the mOS was 33, 30 and 51 mo respectively, p=0.2, and for high/very high-risk R-IPSS the mOS was 16.8, 21.7, and 25 mo respectively, p=.025. See Figures 2b and 2c. There was no difference in rate of AML transformation Conclusions: This large retrospective study revealed racial/ethnic differences in clinical and molecular features of MDS. Hispanic patients had better overall survival. Continued research in this area is recommended to better understand the phenotype and genotype of patients from diverse ethnic/racial backgrounds. Acknowledgement of Funding: NINR Grant # 1K23NR018488-01A Figure 1 Figure 1. Disclosures Tinsley-Vance: Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Taiho: Consultancy; Fresenius Kabi: Consultancy; Incyte: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Abbvie: Honoraria; Jazz: Consultancy, Speakers Bureau. Padron: Stemline: Honoraria; Blueprint: Honoraria; Kura: Research Funding; Taiho: Honoraria; Incyte: Research Funding; BMS: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Lancet: Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; Astellas: Consultancy; Agios: Consultancy; Jazz: Consultancy. Kuykendall: PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; Prelude: Research Funding; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman: Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: AbbVie: Consultancy; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau.

Abstract: Background: Patients with acute myeloid leukemia (AML) with myelodysplasia related changes (MRC) or therapy related myeloid neoplasm have poorer outcomes compared to patients with de novo AML. CPX-351 was approved by the Food and Drug Administration (FDA) in 2017 as an induction chemotherapy regimen for patients with AML-MRC or t-AML as defined by 2016 World Health Organization (WHO) classification. A large randomized phase 3 study that led to approval of CPX-351 included only the patients between age 60 and 75. However, the FDA approval extends to patients of age ≥18 years with limited data regarding its efficacy in a younger patient population. Methods: We performed a retrospective study of clinical and molecular data of 89 patients treated at Moffitt Cancer Center with CPX-351 as frontline induction chemotherapy regimen in patients with AML. Clinical data was abstracted in accordance with institutional review board approved protocol. Patients were then divided in two subgroups: Cohort A) Age 〈 60 years and cohort B) Age ≥60 years. We calculated overall response rate (ORR) defined as the proportion of patients achieving complete remission (CR), CR with incomplete count recovery (CRi) or morphologic leukemia free state (MLFS). We then calculated median overall survival (mOS) using Kaplan Meier method with log-rank test to determine significance. Fisher's Exact method was utilized to determine significance for categorical variables. All reported p-values are two sided. Results: Out of a total 89 patients included in the analysis, 17% (n=15) of patients were in cohort A and 83% (n=74) of patients were in cohort B. In cohort A, 40% of patients were female compared to 39% of patients in cohort B. Median age in cohort A was 56 years old (range: 42-59) and 70 years old in cohort B (range: 60-84). Overall, 71% of the patients had adverse risk disease as defined by European Leukemia Net (ELN) classification, which includes 80% of patients in cohort A and 69% of patients in cohort B. Baseline characteristics are described in Table 1. Among 83 patients evaluable for response, overall response rate (ORR) of the entire cohort was 51% (Table 2). ORR in cohort A was 40% compared to 53% in cohort B (p=0.41). ORR in ELN defined adverse risk group was 47% in the entire cohort and was not significantly different between cohort A and B (33% vs. 51%, p=0.34). Overall 30-day mortality rate of the entire cohort was 2.2%, 6.7% in cohort A and 0.1% in cohort B. Overall 60-day mortality rate of the entire cohort was 6.7%, 13.3% in cohort A and 5.4% in cohort B. Overall, 27% of patients proceeded to allogeneic stem cell transplant (allo-SCT), including 20% of patients in cohort A and 28% of patients in cohort B (p=0.75). We then evaluated ORR according to somatic mutations prior to initiation of therapy. The most common gene mutation was ASXL1 in 28% of patients followed by TET2 (25%) and RUNX1 (19%). Patients with IDH1/2 mutations had superior response rates compared to patients without IDH1/2 mutations (13/16 (81%) vs. 67/142 (47%), p=0.02). Among patients with TP53 mutated disease (n=12), which include 20% of patients in cohort A and 13% of patients in cohort B, ORR was 25% with 17% achieving CR and was not significantly different between cohort A and B (p=1.0). At median follow up of 13.0 months, mOS of the entire cohort was 11.1 months. Patients in cohort A did not have significantly different mOS to patients in cohort B (5.8 vs. 11.1 months, p=0.54) (Figure 1). Since there was a higher percentage of patients in cohort A with TP53 mutation than patients in cohort B (20% vs. 13%), we estimated mOS in patients without TP53 mutation and mOS was not different between cohorts A and B (13.4 vs. 11 months, p=0.59). Among responding patients, mOS was not reached in cohort A compared to 17.7 months in cohort B (p=0.59). Conclusion: We demonstrate that CPX-351 results in similar survival outcomes in both younger and older adults with AML with MRC or therapy-related AML. Our data suggests that CPX-351 is a viable treatment option for any age group where inherent disease biology dictates outcome rather than age. Disclosures Padron: Incyte: Research Funding. Kuykendall:Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Komrokji:Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Agios: Consultancy; JAZZ: Speakers Bureau; Novartis: Speakers Bureau. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria.

Abstract: Background: Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoiesis, and aberrant expression of this gene can facilitate leukemogenesis. RUNX1 mutations (RUNX1mut) are thought to carry a poor prognosis and have been recently incorporated into the risk stratification systems for acute myeloid leukemia (AML) by European LeukemiaNet (ELN) (Dohner et al. 2017) and National Comprehensive Cancer Network (NCCN et al. 2019). However, the clinical significance of this mutation after allogeneic stem cell transplantation (allo-SCT) is controversial with a recent study suggesting that allo-SCT may reverse the unfavorable influence of RUNX1mut(Qin et al. 2017). In this study, we describe the prognostic impact of RUNX1mutin patients with AML undergoing allo-SCT and compare the outcomes to ELN-defined adverse risk, RUNX1wtAML patients and patients with intermediate risk AML. Methods: We retrospectively reviewed our database of 407 patients who received allo-SCT at the Moffitt Cancer Center between 2013 and 2018. Only AML patients undergoing allo-SCT during first complete remission that had molecular information prior to transplant were included. This cohort was divided into three subgroups: 1) RUNX1mutAML 2) ELN-defined adverse risk, RUNX1wtAML and 3) ELN-defined intermediate risk AML. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Cumulative incidence function was performed as defined by the Fine and Gray model. Kaplan-Meier analysis with log-rank test was used to estimate median overall survival (mOS) from the time of diagnosis. Results: Among 407 AML patients reviewed, we identified 28 patients with RUNX1mut, 71 adverse risk RUNX1wtpatients, and 69 intermediate risk patients. Of the 28 patients (18 males/10 females) with RUNX1mut, 53.6% were under age 60, two-thirds had de novo AML (dAML), and 92.9% had intermediate risk cytogenetics as defined by ELN 2017 at diagnosis. Baseline characteristics are described in Table 1. Univariate analysis identified RUNX1mutto be predictive of inferior OS compared to the intermediate risk cohort (HR 2.29, 95% CI 1.12-4.64, p=0.022). Subsequent multivariate regression using covariates of age, sex, AML type, lines of therapy prior to allo-SCT, and conditioning regimen confirmed RUNX1mutas an independent covariate for reduced OS (HR 2.51, 95% CI: 1.18-5.33, p=0.016). At a median follow-up of 29.3 months for the entire cohort, Kaplan-Meier analysis confirmed an inferior mOS in patients with RUNX1mutcompared to the intermediate risk group (25.7 months vs. 59.8 months, p=0.029) and was not different from RUNX1wtadverse risk group (25.7 months vs. 45.7 months, p=0.872) (Figure 1A). Cumulative incidence of relapse after allo-SCT for patients with RUNX1mutis significantly higher than intermediate risk patients (p=0.005, Figure 1B); however, there was no difference compared to RUNXwtadverse risk AML (p=0.295). There was no difference in non-relapse mortality (NRM) between RUNX1mutand intermediate risk patients (p=0.789, Figure 1B) or RUNX1mutand RUNX1wtadverse risk AML (p=0.323). When impact of concomitant somatic mutations on disease recurrence in RUNX1mutcohort was assessed, no discernible trends were identified. RUNX1mutwas mutually exclusive with NPM1 and frequently co-occurred with DNMT3A (21.4%), IDH2 (17.9%), and SRSF2 (17.9%) (Figure 2). Interestingly, 92.9% of the patients with RUNX1muthad ELN-defined intermediate risk cytogenetics and only 7.1% of the cohort had ELN-defined adverse risk cytogenetics. Conclusions: Our findings indicate that allo-SCT AML patients with RUNX1muthave poor outcomes analogous to RUNX1wtadverse risk AML. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Agios: Honoraria. Kuykendall:Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria; Celgene: Honoraria. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Speakers Bureau; Agios: Consultancy; Incyte: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: BACKGROUND: Over the past 25 years research has shifted from predominantly focused on men to research that includes both men and women. In addition, myelodysplastic syndromes (MDS) have only been included in the SEER registry since 2001 and are largely understudied. This has resulted in a knowledge gap in the difference in clinical phenotype, genotype, and outcomes between men and women diagnosed with MDS. The aim of this abstract is to identify those gender-based differences. METHODS: This was a retrospective study using a large MDS database at Moffitt Cancer Center. We compared baseline clinical and molecular characteristics and outcomes based on gender. Chi-square tests were used for comparing categorical variables and t-test for continuous variables. Kaplan-Meier method was used to compare survival. RESULTS: The Moffitt Cancer Center MDS data base includes 4413 patients among whom 2922 (66%) were men and 1658 (34%) were women. Table-1 summarizes baseline characteristics based on gender. Women were slightly younger (mean age at diagnosis 66.5 versus 69 years for men, p & lt; 0.001). There were more Hispanic/black women than men (9% versus 5%, p = & lt;0.001). Women had slightly lower hemoglobin (mean Hgb 9.4 versus 9.8 g/dl for men, p=0.032) and higher platelet count (mean platelets count 171 versus 136, p & lt; 0.001). More women had del 5/monosomy abnormalities compared to men (p= & lt;0.001), with 353 women (25%) affected. Therapy-related MDS also occurred more often in women (p= & lt;0.001) 413 (25%). More women had isolated del5 q by WHO 2016. (6% vs 2%, p= & lt;0.001). There was no difference in disease risk based on R-IPSS. There were gender differences in molecular profile. (Table-2). SRSF2 mutation, U2AF1 mutation, ZRSR2 mutation, ASXL1 mutation, and RUNX1 mutations were observed more frequently in men. ZRSR2 was expected. The median overall Survival (mOS) was longer for women in lower-risk MDS, but not in higher-risk MDS. (Figure- 1 and 2) The overall mOS was 37.5 months (mo) for females compared to 35 mo for males, p=0.002). The mOS for very/low R-IPSS was 81 and 62 mo, for intermediate risk R-IPSS 35 mo vs 33 mo, and for high/very high-risk R-IPSS 16.7 versus 17.4 mo respectively for females and males (p & lt; 0.001). The rate of AML transformation was not different (32% and 34%, respectively for women and men, p =0.16). Women were more likely response to ATG/CSA than men (38% versus 19%, p= 0.04) There were no differences in response to erythroid stimulating agents, hypomethylating agents, lenalidomide treatment or rate of allogeneic hematopoietic stem cell transplant (AHSCT). CONCLUSION: This retrospective review of a large data base of MDS patients highlights important gender differences in clinical and molecular MDS disease features. We identified differences in rates of selected somatic mutations. Men had more splicing machinery mutations, ASXL-1, and RUNX-1 mutations. Women had better overall survival mainly in lower risk MDS and higher responses to immunosuppressive therapy. Acknowledgement of Funding: NINR Grant # 1K23NR018488-01A Figure 1 Figure 1. Disclosures Tinsley-Vance: Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Taiho: Consultancy; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Astellas: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Padron: Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria; BMS: Research Funding; Taiho: Honoraria; Incyte: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Daiichi Sankyo: Consultancy; Agios: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Celgene/BMS: Consultancy; Jazz: Consultancy. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman: Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Komrokji: Geron: Consultancy; Acceleron: Consultancy; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees.