ALBERT

Description: Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.

Description: Introduction: MDS encompasses a heterogeneous group of clonal neoplastic hematopoietic stem cell diseases characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia (AML). While the advent of hypomethylating agent (HMA) therapy has modestly improved survival in higher-risk MDS, outcomes following HMA failure are dismal. The hedgehog (HH) signaling pathway is an important regulator of hematopoietic cell survival and differentiation, with upregulation of HH target genes and signaling proteins a frequent occurrence in MDS and AML. PF-04449913 (PF-04) is an orally bioavailable inhibitor of Smoothened (SMO), which demonstrated antileukemic activity in a prior phase 1 study. We performed a phase 2 study of PF-004449913 in patients with MDS following HMA failure. Objectives: 1) primary: to estimate overall IWG-2006 response rate (CR + PR + HI + marrow CR) to PF-04449913 in patients with relapsed/refractory MDS and CMML; 2) secondary: to assess safety , overall survival, time to AML transformation, and effect of PF-04 on HH target gene expression. Methods: This was a single center, open-label phase 2 study. Key eligibility criteria included: 1) patients age ≥ 18 with MDS, CMML, or AML (20-29% blasts) following failure of HMA; 2) ECOG 0-2; 3) Adequate kidney and hepatic function. Treatment consisted of PF-04 at 100 mg/day in 4-week cycles for 4 cycles, with continuation allowed for achievement of stable disease or better. Dose increase to 200 mg/day was permitted after cycle 2 for patients with stable disease. Bone marrow biopsy for response assessment occurred after cycle 2, cycle 4, and every 4th cycle thereafter. For correlative studies, total cellular RNA was isolated from ficolled mononuclear cells in baseline marrow samples, and qPCR performed for expression of GLI1, PTCH1, and SMO). Results: Thirty five patients were enrolled, 24M and 11F. Median age was 75 years (range 55-88). A majority of patients had higher-risk (54%) vs lower-risk (43%) MDS by IPSS at time of enrollment. A total of thirty four patients (97%) had received prior azacitidine for a median of 9 cycles (range 1-88), while 6 patients had received decitabine for a median of 4 cycles (5 of whom had also received azacitidine). The median number of cycles of PF-04 received was 3 (range 1-11). All 35 patients were evaluable for response. Two of 35 patients (6%) achieved response per MDS IWG 2006 criteria, including one patient with HI-N/HI-P and another with marrow CR and HI-N. Nineteen additional patients (54%) had stable disease following cycle 2 (8 weeks). With a median follow-up of 10.1 months, the median survival for all treated patients was 10.2 months (95% CI 6.8-13.6 mo)(Figure 1). Median survival for patients with low/INT-1 risk MDS was longer than for INT-2/high risk patients (22.4 mo vs 7.5 mo, p=0.013). Six patients (17%) died while on-treatment, but none of the deaths were considered related to PF-04. The most common treatment-emergent adverse events included myalgia/muscle cramps (65%), dysgeusia (60%), nausea (31%), anorexia (31%), oral mucositis (25%), and AST elevation (22%). The vast majority of these events were grade 1/2. Except for infection (11%), there were no treatment-emergent grade 3/4 events in 〉 10% of patients. Only 5 patients (14%) required dose reduction to 50 mg/day due to intolerance. In the pharmacodynamics analysis, responding patients had higher baseline expression of SMO, PTC ,and GLI1 than non-responders, while non-responders had higher post-treatment increases in these transcripts compared with responders. Conclusions: PF-04 was well tolerated in patients with advanced, HMA refractory MDS, but had limited efficacy in this unselected, heavily pre-treated patient population. The pharmacodynamic analysis suggests predictive potential of HH pathway gene expression for response warranting further investigation. Figure 1 Figure 1. Disclosures Komrokji: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy. Sweet:Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding.

Description: Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin 2 units/mo) with serum Epo 〉500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers. Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (〈 median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of 〉Grade 3, non-hematologic AEs. Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. Disclosures Bennett: Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

Description: 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.

Description: Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin 2 units/month) with serum Epo 〉500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a 〉2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Description: Background Hypomethylating agent (HMA) therapy represents the standard of care for patients with higher risk myelodysplastic syndromes (MDS) although only 50% of patients respond to treatment. Recent evidence from molecular profiling through next-generation sequencing (NGS) in myeloid diseases has been conflicting as to the value of somatic mutations as a biomarker for response to HMA. In particular, there have been conflicting data on response rates and outcomes in TP53 mutant (MT) MDS and acute myeloid leukemia (AML) based on azacitidine versus decitabine (Welch et al., NEJM 2016; Garcia-Manero et al., NEJM 2017). However, the TP53 mutant cohorts in these studies were small (median 23 patients, range 13-39) and heterogeneous based on treatment status (treatment naïve versus relapse/refractory). Therefore, our goal was to characterize outcomes of TP53 mutant MDS patients who received frontline HMA therapy. Patients and Methods TP53 MT MDS and oligoblastic AML (20-30% blasts) cases were retrospectively identified from the Moffitt Cancer Center MDS database. All patients had NGS of TP53 and up to 53 additional genes performed prior to the initiation of HMA. The lower limit of VAF detection was set at 5% and the minimum depth of coverage at each position was 500X. Clinical variables and outcomes of MDS patients were characterized at the time of sample procurement. Fisher's exact tests were used for comparative analyses. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of HMA initiation. Response rates and outcomes of TP53 MT patients were compared to a cohort of wildtype (WT) patients (n=63). Results From May 2013 to May 2018, a total of 71 patients with TP53 mutant MDS were identified with a median age of 68 years (39-82) and male predominance (66%). Fourteen patients (20%) had multiple mutations in TP53. Of the cohort, 82% of patients (n=58) were treated with azacitidine (88% (n=51) with AZA monotherapy; 12% (n=7) with AZA in combination (2 pts with lenalidomide and 5 pts with investigational agents)) with 18% (n=13) receiving decitabine. The median # of HMA cycles was 4 (range 1-33). Thirteen pts (18%) proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Of the cohort, 18% (n=13) obtained complete remission (CR) with 39% (n=28) overall response rate (ORR). There was no difference in CR or ORR in pts treated with AZA vs DAC (P=0.24 and P=0.2, respectively). At a median follow up 20 months, the median OS of the entire cohort was 9.7 months. There was no difference in median OS between AZA vs AZA combo vs DAC (7.6 vs 15.2 vs 12.5 months; P = 0.44; Figure 1A). TP53 variant allele frequency (VAF 〉 20% vs ≤ 20%) was not predictive of outcomes to HMA (7.8 vs 10.4 months, P = 0.36). However, TP53 MT patients who had clonal response to HMA (i.e. VAF 〈 5%; n=19 (27%)) had improved OS (14.5 vs 7.5 months; HR 0.33, 95% CI 0.18 to 0.59; P = 0.001; Figure 1B). In multivariable analysis incorporating age, revised international prognostic scoring system (IPSS-R) category, HSCT status, or type of HMA, TP53 clonal clearance remained an independent covariate for improved OS (HR 0.34, 95% CI 0.16 to 0.72; P = 0.005). Pts who underwent HSCT (n=13) had a trend for improved OS (14.5 months vs 7.9 months; P = 0.09). Notably in transplanted pts who had serial TP53 NGS (n=7), pts who achieved a VAF 〈 5% had significant improved OS (16.3 months vs 8.9 months; P=0.03). Compared to higher risk MDS/AML TP53 WT patients treated with HMA, there was no difference in CR (18% vs 14% (P = 0.64) or ORR rates (39% vs 40%). In contrast, TP53 MT patients had significantly inferior OS with HMA therapy (9.7 vs 15.4 months; HR 2.14, 95% CI 1.32. to 3.27; P = 0.001; Figure 1C). Conclusion In this large cohort of higher risk MDS and oligoblastic AML pts who received frontline HMA therapy, TP53 MT patients have significantly inferior OS with no significant differences in response rates or outcomes by HMA. TP53 MT patients who achieve maximum clonal suppression with HMA treatment (i.e. VAF 〈 5%) have improved OS as well as improved outcome with HSCT. Novel therapy targeting TP53 mutation is needed to improve outcomes. Figure 1. Figure 1. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.

Description: Introduction: Few treatment options are available to RBC transfusion-dependent pts with lower-risk MDS (LR-MDS) who are refractory/ineligible for erythropoiesis-stimulating agents (ESAs). Luspatercept is a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. In the phase 3, randomized, double-blind, placebo-controlled MEDALIST study (NCT02631070), luspatercept significantly reduced transfusion burden vs placebo. Longer-term efficacy analyses of the MEDALIST study (data cutoff Jan 7, 2019), including multiple responses, and safety are presented here. Methods: Eligible pts were ≥ 18 years of age with IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS (World Health Organization 2016 criteria); were refractory, intolerant, or unlikely to respond to ESAs (serum erythropoietin 〉 200 U/L); and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (1.0 mg/kg titrated up to 1.75 mg/kg, if needed) or placebo, subcutaneously every 3 weeks (wks). This analysis assessed the achievement and number of individual response periods of RBC transfusion independence (RBC-TI) ≥ 8 wks. Clinical benefit, defined as achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid (HI-E) response per International Working Group 2006 criteria, was also assessed, along with total duration of clinical benefit (time from achieving clinical benefit to discontinuation due to loss of benefit, adverse events [AEs], or other reasons). Longer-term efficacy and safety were also evaluated. Results: Pts were assessed for RBC transfusion burden/8 wks in the 16 wks before randomization: 66 pts received 2 to 〈 4 U RBCs (30.1% and 26.3% of pts receiving luspatercept and placebo, respectively), 64 received ≥ 4 to 〈 6 U (26.8% and 30.2%, respectively), and 99 received ≥ 6 U (43.1% and 43.4%, respectively); both arms had a median baseline burden of 5 RBC U/8 wks. Compared with our previous analysis and earlier data cutoff of May 8, 2018 (Fenaux P, et al. Blood. 2018;132:1), we now report that as of Jan 7, 2019, 72 (47.1%) pts treated with luspatercept and 12 (15.8%) treated with placebo achieved RBC-TI ≥ 8 wks. Analysis of multiple response periods of RBC-TI ≥ 8 wks in the luspatercept responders (i.e. initial RBC-TI ≥ 8 wks, followed by transfusion, followed by another period of RBC-TI ≥ 8 wks) demonstrated that 48 (66.7%) pts had ≥ 2 separate response periods, 22 (30.6%) had ≥ 3, 12 (16.7%) had ≥ 4 , and 7 (9.7%) had ≥ 5. Of the 12 pts achieving RBC-TI ≥ 8 wks with placebo, 4 (33.3%) had ≥ 2 responses; none had 〉 3. Overall, 48 (31.4%) pts receiving luspatercept and none receiving placebo remained on treatment as of the Jan 7, 2019 data cutoff. Median treatment duration was 50.9 (range 5.9-147.0) wks in pts receiving luspatercept vs 24.0 (range 7.4-103.0) wks in pts receiving placebo. Median duration of the longest period of RBC-TI ≥ 8 wks during Wks 1-48 was 30.6 (95% confidence interval [CI] 20.6-50.9) wks with luspatercept and 18.6 (95% CI 10.9-not evaluable) wks with placebo. Median total duration of clinical benefit was 83.6 and 26.8 wks for pts responding to luspatercept (n = 97) and placebo (n = 20), respectively. Of the 97 luspatercept-treated pts evaluable for clinical benefit, median duration of clinical benefit in pts with baseline transfusion burden of 4 to 〈 6 U/8 wks was 87.9 (range 13-125) wks, of 〈 4 U/8 wks was 84.7 (range 21-147) wks, and of ≥ 6 U/8 wks was 64.9 (range 8-122) wks. Twelve luspatercept-treated pts did not require a transfusion after the first dose of luspatercept up to Wk 48 or until time of analysis; as of Jan 7, 2019 data cutoff, 3 (25%) of those pts maintained response. AEs occurring more frequently with luspatercept vs placebo (fatigue, diarrhea, asthenia, dizziness) occurred early (Cycles 1-4), were mainly grade 1 or 2, decreased over time, and were not associated with a higher dose level. Progression to acute myeloid leukemia was similar in pts receiving luspatercept (n = 3 [2.0%]) and those receiving placebo (n = 1 [1.3%]). Conclusions: Most LR-MDS pts achieving RBC-TI and/or HI-E with luspatercept in the MEDALIST study had multiple responses with durable clinical benefit superior to that of pts receiving placebo, including those with a high baseline transfusion burden. AEs were mainly grade 1 or 2, decreased over time, and were not correlated with a higher dose level. Disclosures Fenaux: Aprea: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Mufti:Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Santini:Celgene Corporation: 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; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Finelli:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Komrokji:DSI: Consultancy; JAZZ: Consultancy; celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan:Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Ito:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Description: Background: Disease-specific measures of quality of life (QOL) can allow for improved assessment of disease-specific symptomatology and psychosocial factors. We recently reported on the development of the QUALMS, a 33-item QOL assessment tool for patients with myelodysplastic syndromes (MDS). We now report preliminary internal consistency and validity results from an international prospective study. Methods: From December of 2013 to July of 2014,an international cohort of MDS patients completed the QUALMS as well as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy Anemia Scale (FACT-An). Eligible patients were 18 or older, and had to have biopsy-proven MDS; those who had undergone stem cell transplantation were excluded. Baseline medical record review was performed at the time of enrollment to document key clinical and laboratory data, including bone marrow pathology and treatments; a second QUALMS administration and medical record review is planned for each patient to assess responsiveness. Participants were recruited from MDS centers across the United States, Canada and Italy. Individual QUALMS items were scored on a 5-point scale ranging from “Never” to “Always”. Overall mean score was calculated by transforming the raw mean to a 100 point scale, with higher scores indicating better MDS-related QOL. Baseline QUALMS scores were compared to clinical factors such as hemoglobin (Hg) and transfusion dependence as well as with scores on the other QOL scales. Preliminary exploratory factor analysis was also undertaken to identify candidate subscales. Results: As of this analysis, 201 patients had enrolled. The mean age was 71.7 years; there were 55% men, and the IPSS distribution was 44% LO, 43% INT-1, 10% INT-2, 1% HI and 2% unclassifiable. The majority of patients (53%) were receiving an erythropoiesis-stimulating agent, hypomethylating agent or lenalidomide, and 29% of the overall cohort was transfusion-dependent. The geographical distribution was as follows: 20% from the Dana-Farber Cancer Institute (Boston, MA); 9% from Columbia University (New York, NY); 15% from the Moffitt Cancer Center (Tampa, FL); 25% from the Odette Cancer Center (Toronto, Canada); and 31% from two GIMEMA hospitals (Rome and Sardegna, Italy). Scores on the QUALMS ranged from 19 to 78; the mean and median scores were 49.6 and 50.0 respectively. The measure had excellent internal consistency (α=.91), and was moderately correlated with the EORTC QLQ-C30: correlations (r’s) with the global health status scale, functional scales (i.e., physical, role, emotional, cognitive and social) as well as fatigue, nausea and pain scales ranged from 0.33 to 0.63 (all p’s

Description: Background: Luspatercept is a first-in-class erythroid maturation agent that binds TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. The phase 3 MEDALIST trial evaluated luspatercept in pts with RBC transfusion-dependent, IPSS-R-defined very low-, low-, and intermediate-risk MDS with ring sideroblasts (RS+) who were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents. This study explored associations of gene mutations, as analyzed by next-generation sequencing (NGS), with response to luspatercept, as well as dynamics of gene mutations on therapy in MEDALIST pts. Methods: DNA was isolated from bone marrow (BM) mononuclear cells from 222 of 229 pts enrolled in the study (148 luspatercept, 74 placebo) at screening and, when available, following treatment. NGS of 23 MDS-relevant genes was performed at screening and every 24 weeks; mean coverage was 1,000-fold and the variant allele frequency (VAF) cutoff was ≥ 1%. BM cell populations were analyzed by cytomorphology. Response criterion of RBC transfusion independence (RBC-TI) of ≥ 8 weeks within the first 24 weeks of treatment was used for correlative analyses. Results: Mutations in SF3B1 were found in 91.0% of pts analyzed at screening (median VAF 42%, range 6-71%), consistent with the study population being RS+. Overall, a median of 2 (range 0-5) of the 23 MDS-relevant genes analyzed were mutated per pt. In addition to SF3B1, the most frequently mutated genes were TET2 (41.9%), DNMT3A (18.9%), ASXL1 (13.1%), and SRSF2 (8.1%). Mutation profiles were similar to those found in previous studies of refractory anemia with RS (RARS; Malcovati L, et al. Blood. 2015;126:233-41) and balanced between luspatercept and placebo arms. Numbers of mutated genes at baseline were distributed similarly in luspatercept responders (R) and non-responders (NR) (Figure A), and comparable response rates were achieved irrespective of number of mutations, with response rates of 36.4%, 34.9%, 42.4%, and 33.3% for pts with 1 mutation, 2 mutations, 3 mutations, and 4 or 5 mutations in the 23 MDS-relevant genes analyzed, respectively. Response to luspatercept was independent of the presence of mutations in any of the genes analyzed individually (Figure B) or when grouped by functional categories (e.g. spliceosome, epigenetic regulation, transcription factor, etc.) (Figure C). Circos plots of co-occurring mutations showed similar mutation profiles in R and NR (Figure D). Response rates were also similar regardless of baseline SF3B1 allelic burden (R: 43%, NR: 42%; P = 0.11). At baseline, BM erythroid precursors were higher in R (R: 32.8%, NR: 26%; P = 0.008; while R and NR had similar levels of RS+ cells [R: 80%, NR: 84%; P = 0.25], Figure E), consistent with the postulated activity of luspatercept on the erythroid lineage. When comparing the frequency of mutation changes in luspatercept- vs placebo-treated pts at week 24 of the study, no statistically significant differences were observed in the frequency of newly acquired mutations (13/126 [10.3%] pts in luspatercept vs 8/64 [12.5%] pts in placebo, P = 0.63) or mutation losses (4/126 [3.2%] in luspatercept vs 5/64 [7.8%] in placebo, P = 0.17). Evaluation of changes in allele burden (median VAF at week 24 vs baseline) for mutations in genes associated with adverse prognosis (ASXL1, SRSF2, U2AF1, NRAS, IDH2, GATA2, TP53, RUNX1, and EZH2; Bejar R. Curr Opin Hematol. 2017;24:73-8) showed no change between luspatercept- or placebo-treated pts (1.01-fold, n = 58 and 0.95-fold, n = 19, respectively, P = 0.69). Conclusions: Pts enrolled in the MEDALIST study had mutations consistent with RS+, lower-risk MDS with a preponderance of SF3B1 mutations; genes associated with poor prognosis (and other genes) were balanced between study arms. RBC-TI responses with luspatercept were achieved regardless of SF3B1 allelic burden, number of baseline mutations, and presence of individual mutations, including adverse mutations, or co-mutations. Disclosures Platzbecker: Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dunshee:Celgene Corporation: Employment, Equity Ownership. Komrokji:DSI: Consultancy; pfizer: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Mufti:Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Garcia-Manero:Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Santini:Celgene Corporation: 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; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. See:Celgene Corporation: Other: Contractor. Tsai:Celgene Corporation: Employment. Risueño:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Named in Celgene patent filings related to predictive patient response biomarkers in hematological malignancies. Ma:Celgene Corporation: Employment, Equity Ownership. Schwickart:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Menezes:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.