Godley, Lucy A.

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.

Abstract Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.

Abstract The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Abstract Decitabine (Dacogen®), a hypomethylating agent, is FDA-approved for treatment of patients (pts) with all FAB subtypes of MDS. The approved regimen of 15 mg/m2 intravenously (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days repeating q 6 wks demonstrated an overall improvement rate (CR+PR+HI) of 30% in MDS pts. An alternative regimen, in which decitabine is administered 20 mg/m2 IV over 1 hr once daily for 5 consecutive days repeating q 4 wks not only permits outpatient therapy, but also showed promising efficacy in a pilot study (Blood2007:109:52). This alternate regimen was evaluated in a multicenter study and preliminary results from this open-label single-arm Phase 2 study are reported. Eligible pts were ≥18 years (yrs) of age with MDS (de novo or secondary) of any FAB subtype (including chronic myelomonocytic leukemia with white count <12,000/μL) and International Prognostic Scoring System (IPSS) score ≥ 0.5 (Intermediate-1 (Int-1), Intermediate-2 (Int-2) and High-risk groups) as determined by complete blood counts, bone marrow assessment, and cytogenetics within 28 days of enrollment. Responses, the primary endpoint of the study, were assessed using International Working Group (IWG) criteria (Blood2000;96:3671), which existed at study initiation and also used in the Phase 3 trial with the FDA-approved 3-day regimen. Secondary objectives included evaluation of hematologic improvement, cytogenetic response, overall survival, time to acute myeloid leukemia progression or death, transfusion requirements, and toxicity. Ninety-nine pts enrolled: median age 72 yrs, 72% male, 89% de novo MDS, median time from diagnosis 153 days, and 29% with prior therapy for MDS. The distribution of IPSS risk groups was as follows: Low, 1%; Int-1, 53%; Int-2, 23%; and High, 23%. Pts have thus far been followed for one year after enrollment of the last pt, and the preliminary data are reported here. Investigator assessments of response, using pathology results at the individual study sites along with laboratory findings, demonstrated an overall improvement rate of 43%; central confirmation of results is ongoing. Pts received a median of 5 cycles of decitabine (range 1–17). Median survival has not been reached; a total of 62 pts continue to be followed. The most frequent adverse events were fatigue, fever, constipation, nausea, and neutropenia. Decitabine administered daily for 5 days in the outpatient setting demonstrated clinical activity with manageable toxicity profile in Int-1 to High risk MDS, suggesting that both the 3- and 5-day regimens provide meaningful clinical benefit to patients.

Key Points The ClinGen MM-VCEP has specified RUNX1-specific curation rules to address gene function, gene-specific domains, and phenotypic criteria. RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the need for expert variant curation.

Abstract Background: It has been known for approximately 19 years that germline mutations in RUNX1, lead to familial platelet disorder with predisposition to myeloid malignancy (FPD-MM, OMIM 601399). Since that time researchers have identified a broad range of different RUNX1 mutations, in over 100 families. In large families, the diagnosis of malignancy shows variable penetrance among family members with the same mutation; some carriers of RUNX1 mutations do not develop malignancy. The causes of this heterogeneity are currently not known, complicating counselling and risk analysis for individual carriers. Recent advances in genetic sequencing technology applied by many FPD-MM research groups around the world have highlighted their value in understanding the somatic genetic changes that are associated with development of malignancies in germline RUNX1 mutation carriers. Collectively this information could lead to powerful insights essential for more precise risk assessment, monitoring, and therapeutic intervention. Specifically, a growing catalogue of somatic mutations associated with germline RUNX1 malignancy offers the opportunity for informed monitoring of asymptomatic RUNX1 carriers for additional high-risk somatic mutations, in turn providing the possibility for early therapeutic intervention to arrest the leukemic process. The challenge in advancing these goals for FPD-MM is the relative rarity of the disorder in individual populations. Global data sharing in a highly interactive FPD-MM research community offers a solution to this problem that benefits all patients world-wide. Aims: To create a global RUNX1 network through identifying and contacting researchers and clinicians with known and novel germline RUNX1 families, seeking their collaboration to share genomics data. To create a RUNX1.db portal to collectively house and analyse genomics data from germline RUNX1 carriers, with associated phenotype and clinical information, such that researchers have an ongoing means by which to combine their data with those generated by other groups around the world. Methods: RUNX1 network : Through existing collaborative networks, a systematic review of the literature, and referrals from initial contacts, we have identified a global network of researchers managing FPD-MM cases and families. RUNX1.db: We have adapted a custom-built variant analysis platform, VariantGrid, that is a visual web application and database designed to help scientists manage and analyse DNA variants that can be used to aggregate and analyse multiple datasets. Results: Preliminary analysis of aggregated data from the literature suggests there are features of germline RUNX1 syndrome that can be ascertained. These include frequent somatic mutation of RUNX1 in malignancy development, as well as mutations in genes associated with clonal hematopoiesis that may precede development of overt leukemia. This analysis also suggests that different types of germline RUNX1 mutations may be associated with different combinations of somatic mutations in the tumour. To further this analysis, we have identified over 70 groups internationally that either manage RUNX1 families or have identified potential germline carriers through genomics initiatives. This represents a large and growing resource for both scientific studies and clinical programs to benefit individuals with FPD-MM. Many of these groups have generated NGS data sets from patient samples which will be available for analysis through this portal. Further details and activities of the network, and results from the genomics aggregation database will be presented. Conclusion: We have created a global RUNX1 network, aggregated their data, and generated a RUNX1.db genomics portal for the continuous curation of genomics data from germline RUNX1 carriers. A preliminary analysis has already identified specific features of germline RUNX1 mutated malignancies that have clinical importance. Ongoing scientific and clinical studies through the RUNX1 network will enhance the power of aggregated data analysis, with RUNX1.db providing a central link, driving new insights that benefit patients. Disclosures Natsoulis: Imago BioSciences, Inc.: Consultancy, Equity Ownership. Guzman:Cellectis: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Abbvie: Honoraria. Borate:Novartis: Consultancy; Agios: Consultancy. Wei:Amgen: Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau. Dokal:MRC, Bloodwise, Telomerase Activator Sciences: Research Funding; The Gary Woodward Dyskeratosis Congenita Trust: Membership on an entity's Board of Directors or advisory committees; Action Medical Research, European School of Haematology: Membership on an entity's Board of Directors or advisory committees; Barts and The London School of Medicine and Dentistry, Queen Mary University of London,: Employment, Research Funding; Telomerase Activator Sciences: Research Funding; Barts and The London, Queen Mary University of London: Employment; Gary Woodward Dyskeratois Congenita Trust: Membership on an entity's Board of Directors or advisory committees. Hiwase:Novartis: Research Funding; Celgene: Research Funding. Branford:Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Owen:Merck: Honoraria; Teva: Honoraria; AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding. Fitzgibbon:Epizyme: Consultancy, Research Funding; Gilead: Consultancy. Rienhoff:Imago BioSciences, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kurokawa:Astellas Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eizai: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Teijin Pharma: Research Funding; Chugai Pharmaceutical: Research Funding.

Abstract Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of tissue mast cells (MC) in various organ systems, including bone marrow (BM). Indolent and advanced forms of SM have been described. Whereas patients with ISM have a normal or near normal life-expectancy, patients with advanced SM, including those suffering from mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic MC are usually resistant against conventional drugs and various targeted drugs. In rapidly progressive aggressive SM (ASM) and MCL, polychemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHCT) has been proposed. However, outcome of alloHCT in advanced SM is unknown, and it also remains uncertain whether clinically relevant graft-versus-SM (GVSM) effects may occur in these patients, as only sporadic case reports have been published. We performed a retrospective multi-center analysis to evaluate the outcome of alloHCT in patients with advanced SM. Fifty-four advanced SM patients receiving SCT in 32 transplantation centers in Europe and America were identified between 1990 and 2013. The median patient age was 45 years. Donors were: HLA identical siblings (31), unrelated donors (URD) (15), umbilical cord blood donors (UCB) (2), and haploidentical donors (1). In 5 patients, stem cell source was not defined (5). Thirty-four patients received myeloablative conditioning (MAC) and 18 received reduced intensity conditioning regimens (RIC). In 2 patients, conditioning regimen was not specified. Indications for alloHCT were SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) (n=32), MCL (n=13, including one with MCL-AHNMD), 8 with ASM and 1 with myelomastocytic leukemia (MML). The most prevalent AHNMD was acute myeloid leukemia (AML, n=16). With follow-up of 35-6180 (median 365) days, SM responses (defined as ≥50% decrease in BM mast cells ± decrease in serum tryptase ± regression of other organ manifestations) were observed in 39 patients (72%), including complete responses (CR) documented in 12 patients (22%). Eleven patients had stable disease, whereas 4 patients (7%) progressed immediately after alloHCT (primary resistance). In addition, 10 patients progressed (5 of them within 100 days) after an initial response. Progression was most frequently seen in MCL patients (n=6, 50%). In the AHNMD group, only 8 patients relapsed/progressed (25%). The overall survival (OS) and SM progression-free survival (PFS) at 1 year were 63% and 50% for all patients, 77% and 68% for SM-AHNMD, 63% and 50% for ASM, and 25% and 17% for MCL, respectively. The strongest predictive variable associated with inferior survival was a diagnosis of MCL. Other factors associated with poor outcome were: Karnofsky performance status ≤70%, ≥2 SM regimens given before alloHCT (e.g., steroids, cladribine, chemotherapy, tyrosine kinase inhibitor), donor source (alternative donors-UCB and haploidentical compared to sibling or URD), SM progression within the first 100 days, normal cytogenetics (compared to t(8;21) (q22;q22), and RIC (compared to MAC). The following variables were not associated with poor outcome: patient and donor age, recipient-donor sex match status, graft source (BM vs. peripheral stem cells), BM mast cell percentage at time of alloHCT, and CR status of AML or SM response at time of alloHCT. This largest multi-center analysis of results in advanced SM provides evidence for clinical efficacy of alloHCT, presumably because of a GVSM effect of alloHCT (achieving CR, and response to donor-lymphocyte infusions and RIC alloHCT). However, responses varied among different SM categories: while patients with SM-AHNMD enjoyed excellent outcomes, the OS for MCL patients in general, was poor. Nevertheless it is remarkable that 3 of 13 patients with MCL – an otherwise fatal disease with a median survival of <12 months – became long-term survivors after alloHCT. In summary, our results support development of a prospective alloHCT study, with the aim to optimize therapy and to improve overall outcome in advanced SM. Based on our pilot study, alloHCT should also be considered in practice for eligible and fit patients with SM-AHNMD (if treatment of AHNMD component needs alloHCT or SM component is aggressive), rapidly progressing ASM, MCL and MML when a suitable HLA-matched sibling donor or URD is available. Disclosures: Vercellotti: Sangart Inc.: Research Funding; Seattle Genetics: Research Funding. Akin:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding.

Abstract Background: Patients (pts) withHR-MDS have a median OS of 4 to 6 months (mo) after HMA failure (Prebet et al, J Clin Oncol 2011) and no approved salvage therapy. Development of new therapeutics for this population will benefit from the availability of surrogate endpoints and markers that can predict survival. Gore et al established response to azacitidine (Vidaza®) in first-line therapy for HR-MDS as a reasonable surrogate to predict survival (Gore et al, Haematologica 2013). Rigosertib, a novel dual PI3K/PLK pathway inhibitor, has been shown to reduce bone marrow blasts (BMBL) in these pts (Seetharam et al, Leuk Res 2012). Silverman et al described complete or partial bone marrow (BM) response, or stabilization after 4-8 weeks (wks) of treatment with rigosertib as a potential surrogate for predicting survival in pts with HR-MDS after failure of primary HMA therapy (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized Phase III trial. Methods:Pts with HR-MDS were randomly assigned 2:1 to rigosertib or best supportive care (BSC) after progressing on, failing to respond to, or relapsing after HMA treatment. BM aspirates were assessed pretreatment, at 4 weeks and at 8-week intervals thereafter. Central slide review was undertaken in a representative population of samples. The BMBL response at each time point was assessed using the following definitions: bone marrow complete response (mCR) = BMBL ≤ 5% and decrease of ≥ 50% from baseline; bone marrow partial response (mPR) = BMBL decrease from baseline of ≥ 50%, but BMBL still > 5%; stable disease (SD) = BMBL decrease or increase from baseline of < 50%; progressive disease (PD) = BMBL increase from baseline of ≥ 50% by an absolute minimum of 5%; Not evaluable (NE). Results:Bone marrow assessment was carried out in 156 patients (pts) on the rigosertib arm and 24 pts on the BSC arm at 4 wks after enrollment, and in 86 and 20 pts, respectively, at 12 wks. The invasive BM procedure was optional on the BSC arm, which accounts for the low number of assessments in this group. BM responses at the 2 time points are presented in Table 1. Since no difference in overall survival was noted between pts who had objective BM response and those who did not progress (ie, stable disease), a landmark analysis was conducted that separated pts who were alive at the 4-wk landmark time into two 4-wk response categories: BM response + SD vs. PD. Results of this analysis in rigosertib-treated patients were statistically significant at p = 0.011, with a hazard ratio (HR) of 0.62 and a median OS (from 4 wks onward) of 9.8 months in the mCR + mPR + SD group vs. 4.6 months in the PD group (Figure 1). Another landmark analysis was conducted at 12-wks. Results of this analysis were also significant (p < 0.001) in rigosertib-treated patients, with an HR of 0.39 and a median OS (from 12 wks onward) of 10.4 months in the mCR + mPR + SD group vs.7.5 months in the PD group (Figure 2). A time-dependent Cox regression of OS by 4-wk BMBL response reinforced the validity of the 4-wk and 12-wk BM assessments as surrogate biomarkers for survival (Table 2). Conclusions: These data suggest that BMBL response at 4 or 12 weeks was correlated with OS in this population of pts with HR-MDS treated with rigosertib after HMA failure and are consistent with previous observations in Phase II studies. Table 1 4- and 12-week Bone Marrow Blast Response (Intention-to-Treat Population) Number (%) of Patients 4-wk BMBL Response 12-wk BMBL Response Rigosertib N = 199 BSC N = 100 Rigosertib N = 199 BSC N = 100 Pts with BMBL assessment 156 (78) 24 (24)* 86 (43) 20 (20)* BM complete response (mCR) 22 4 11 5 BM partial response (mPR) 8 2 9 2 Stable disease (SD) 77 9 32 8 Progressive disease (PD) 49 9 34 5 * Bone marrow assessment was not required on the BSC arm. Figure 1 Figure 1. Figure 2 Figure 2. Table 2 Time-dependent Cox Regression of Overall Survival by Bone Marrow Blast Response Analysis Rigosertib BSC Wald P-value Hazard Ratio (95% Confidence Interval) Wald P-value Hazard Ratio (95% Confidence Interval) By 4-wk BMBL response 0.051 0.72 (0.51 - 1.00) 0.56 0.83 (0.45 - 1.54) By 12-wk BMBL response 0.0005 0.55 (0.39 - 0.77) 0.16 0.68 (0.39 - 1.17) *Stratified by pretreatment BMBL: 5%-19% vs. 20%-30% Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Azarnia:Onconova Therapeutics, Inc: Employment.

Abstract Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [<30% bone marrow blasts (BMBL)] who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment were stratified on BMBL count and randomized 2:1 to receive rigosertib (199 pts) or BSC (100 pts). Rigosertib was administered at 1800 mg/24 hr for 72-hr as a continuous intravenous (CIV) ambulatory infusion, every 2 weeks for the first 16 weeks, and then every 4 weeks. The primary endpoint was overall survival (OS), analyzed on an intention-to-treat (ITT) basis using the Kaplan-Meier method stratified on BMBL (5% to 19% vs. 20% to 30%). The trial had a 95% power to detect a 13-wk increase in median OS from 17 wks on BSC, with a 2-sided alpha = 0.05. The following results are based on 242 deaths: 161 in the rigosertib arm and 81 in the BSC arm. Results : Overall, the 2 arms were balanced in terms of baseline characteristics, with the majority of pts being male (66%), and White (82%). Age ranged from 50-90 yrs in the rigosertib arm and 55-86 years in the BSC arm (median, 74 yrs). The majority of pts (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. The median duration of the last HMA therapy was 8.8 months (mo) in the rigosertib arm and 10.3 mo in the BSC arm; 127 (64%) of rigosertib pts and 57% of BSC pts were classified as “primary HMA failure” (ie, they failed to respond to or progressed during HMA therapy, as defined by Prebet et al, J Clin Oncol, 2011). A 2.3-mo improvement in median OS was found in the overall (ITT) population (8.2 mo rigosertib vs. 5.9 mo BSC) (Figure 1). The ITT survival for rigosertib was similar to that noted in Phase I/II studies (35 weeks). The stratified log-rank p-value was 0.33. The stratified hazard ratio was 0.87, which was quite different from the ratio of medians (5.9/8.2 = 0.72), due to the fact that the 2 survival curves converged at 15 mo. Notably, among the 184 patients with primary HMA failure, the median OS was 8.6 mo in the rigosertib arm (N = 127) vs. 5.3 mo in the BSC arm (N = 57), HR= 0.69, p= 0.040 (Figure 2). Multivariate Cox regression, adjusting for pretreatment prognostic factors, showed little change in the treatment effect. The following subgroups were correlated with better OS: pts with failure of/progression on HMA treatment, pts with duration of HMA treatment ≤ 9 mo, pts < 75 years of age, and pts with very high risk per IPSS-R (Figure 3). Rigosertib was well tolerated, with a median dose intensity of 92%. There were no significant compliance or operations issues related to ambulatory continuous infusion. Protocol-defined dose reductions were reported in 5% of pts, with 24% experiencing dose delays of >7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.