Komrokji, Rami S.

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 <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>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 (<4U RBC/8 wks). Arm A non-responders were offered cross-over to combined therapy. Results: Among 205 patients randomized, 14 were excluded from the primary analysis due to a 4 month interruption in drug supply. Among the 195 evaluable patients, 96 were assigned to Arm A and 99 to Arm B. Baseline characteristics were well balanced between arms with 85% of patients heavily TD, receiving a median of 4 units/8 weeks. Overall, 93% of patients received prior treatment with Epo and 18% azanucleosides. In an intent to treat analysis, 28/99 patients (28.3%) in Arm B achieved MER compared to 11/96 (11.5%) in Arm A (P=0.004). Among 136 patients who completed 16 weeks of study treatment, 28/72 (38.9%) and 10/64 (15.6%) achieved MER, respectively (P=0.004). Forty-four Arm A non-responders crossed over to combination-therapy with 11 patients (25%) experiencing a MER. Multivariable logistic regression analysis identified only treatment with LEN + EA as an independent covariate for erythroid response (P=0.01). Responses were durable with MER median duration of 23.8 months in Arm B compared to 13 months in Arm A. There was no significant difference in the frequency or distribution of >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.

Background: Heterozygous somatic mutations in the genes encoding RNA splicing factors SF3B1, U2AF1, SRSF2 or ZRSR2 induce aberrant splicing in cancer cells and are among the most common mutations in patients with MDS, AML or CMML. H3B-8800 is an orally available small molecule that binds to the SF3b complex and induces alternative splicing changes in cells. Because splicing factor mutant cells depend on residual wild-type function of splicing factors for survival, we hypothesized that H3B-8800 would induce preferential cell killing of mutant cells by further perturbing splicing to synthetic lethality. In pre-clinical models, H3B-8800 preferentially kills spliceosome mutant cells and induces antitumor activity in xenograft leukemia models with core spliceosome mutations (Seiler M et al Nature Medicine 2018). Therefore, we conducted a phase I clinical trial (NCT02841540) of H3B-8800 in patients with MDS, AML or CMML. Here we describe the safety profile and clinical outcomes of the dose escalation cohorts in this phase I trial. Methods: This phase I trial explored the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of H3B-8800 in patients with myeloid cancers. Dose escalation cohorts, employing a standard 3+3 design, examined 2 different once daily dosing regimens (schedule I: 5 days on/9 days off; schedule II: 21 days on/7 days off) in a 28-day cycle, with stratification based on lower-risk (LR) versus higher-risk (HR) myeloid neoplasms. Results: As of June 16th, 2019, 84 patients were enrolled at 24 centers in the US and Europe. Dose ranged from 1-40 mg among 65 patients on schedule I, while 19 patients were enrolled with dose ranging from 7-20 mg on schedule II. The patient population included AML (n=38), CMML (n=4), HR-MDS (n=20), LR-MDS (n=21) and 1 MDS with unknown risk level. Most patients (88%) had spliceosome mutations of interest. The most common mutations were in SRSF2 (p.P95H in 17, p.P95L in 9, p.P95_R102Del in 4), SF3B1 (p.K700E in 11, p.R625C in 4), and U2AF1 (p.Q157P in 6, p.S34F in 4). Patients remained on treatment from 7 to 819 days; 25 patients (30%) had time on treatment greater than 180 days, 20% more than 1 year and 2% over 2 years. The median therapy duration for LR-CMML/MDS, HR-CMML/MDS, and AML patients were 216, 62, and 47 days respectively. Most observed treatment related treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common treatment-related (as judged by the investigator, >10% frequency) TEAEs in the patients treated on schedule I were diarrhea (75%), nausea (37%), fatigue (28%) and vomiting (27%). The most common treatment-related TEAEs in the patients treated on schedule II were diarrhea (68%), vomiting (42%), QTc prolongation (21%), nausea (16%), and fatigue (16%). The most common dose limiting toxicity was prolongation of the QTcF interval >500 msec (n=2, 40 mg on schedule I and n=1, 20 mg on schedule II, all ≥Grade 3) and bradycardia without other arrhythmias (n=1, 14 mg on schedule II, ≥Grade 3). No ophthalmic AEs were observed; 1 patient (LR-MDS) experienced durable marrow aplasia. The maximum tolerated dose (MTD) has not been confirmed for either Schedule I or Schedule II. PK analysis indicates that H3B-8800 is rapidly absorbed and exhibits dose-proportional increase in plasma exposure. Consistent dose-dependent target engagement (i.e., alteration in mature mRNA transcripts) was observed in blood mononuclear cells from patients enrolled in the 2 mg up to 40 mg dose cohorts on both schedules. Despite this splicing modulation, no objective complete responses (CR) or partial responses (PR) meeting International Working Group criteria were observed. One patient with CMML had a durable platelet response that began in Cycle 1 and persisted through Cycle 13. Nine red blood cell (RBC) transfusion-dependent patients with MDS or CMML and 2 patients with AML did not require RBC transfusions for ≥8 weeks (up to 28 weeks) while on study. One platelet transfusion-dependent patient with LR-MDS did not require platelet transfusions for ≥8 weeks. Conclusion: Results from this first-in-human multicenter prospective clinical trial of a splicing modulator in myeloid neoplasms demonstrate dose-dependent target engagement and predictable PK profile of H3B-8800, and safety even with prolonged dosing. Although no objective CR or PR were achieved, decreased RBC or platelet transfusion requirements were observed in 12 (14%) of enrolled patients. Disclosures Steensma: H3 Biosciences: Other: Research funding to institution, not investigator.; Pfizer: Consultancy; Aprea: Research Funding; Stemline: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Astex: Consultancy; Onconova: Consultancy. Wermke:Novartis: Honoraria, Research Funding. Greenberg:Notable Labs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; H3 Biotech: Research Funding; Aprea: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: 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. Komrokji:Agios: Consultancy; JAZZ: Speakers Bureau; DSI: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; celgene: Consultancy; pfizer: Consultancy. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Brunner:Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Ades:Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Coombs:H3 Biomedicine: Research Funding. Foran:Agios: Honoraria, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Micol:AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy. Perez De Oteyza:Celgene: Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buonamici:H3 Biomedicine: Employment. Kim:H3 Biomedicine: Employment. Gourineni:H3 Biomedicine: Employment. Marino:H3 Biomedicine: Employment. Rioux:H3 Biomedicine: Employment. Schindler:H3 Biomedicine: Employment. Smith:H3 Biomedicine: Employment. Yao:H3 Biomedicine: Employment. Yuan:Eisai: Employment. Yu:H3 Biomedicine: Employment. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: H3B-8800 (experimental, unapproved)

Background: Myelofibrosis (MF) is associated with bone marrow fibrosis (BMF), splenomegaly, a high symptom burden, and poor prognosis; the JAK/STAT pathway is the central pathway implicated in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor and the only FDA-approved pharmacotherapy for treatment (Tx) of MF patients (pts), improves splenomegaly, but is unable to control all clinical manifestations of disease. Navitoclax is an orally bioavailable, novel small-molecule that targets and binds with high affinity to multiple antiapoptotic B-cell lymphoma 2 (BCL2) family proteins, including BCL-XL, BCL2, and BCL-W. Preclinical studies have demonstrated cytotoxic activity of navitoclax against myeloproliferative neoplasm-derived cell lines. Herein, the results of a phase 2 study (NCT03222609) evaluating the combination of navitoclax with ruxolitinib in pts with MF are reported. Methods: This phase 2 single-arm, multicenter, open-label study assessed the efficacy and safety of navitoclax combined with ruxolitinib in pts with MF. Eligible pts (≥18 yr, diagnosis of primary MF, post-essential thrombocythemia [PET]-MF, or post-polycythemia vera [PPV]-MF, ECOG 0-2, receiving at least 12 wk of continuous ruxolitinib therapy prior to study Tx initiation) received a starting dose of 50 mg navitoclax once-daily combined with the current stable dose of ruxolitinib (≥10 mg BID). Weekly intra-patient dose-escalation of navitoclax was allowed to a maximum daily dose of 300 mg based on tolerability and platelet count. Tx continued until the end of clinical benefit, unacceptable toxicity, or discontinuation. The primary efficacy endpoint was percentage reduction in splenic volume from baseline. Secondary endpoints included effect on total symptom score (TSS), overall response rate, rate of anemia response, improvement in BMF, and safety profile. Results: As of May 1, 2019, 34 pts (primary MF, n=16; PET-MF, n=5; PPV-MF, n=13) had received ≥1 dose of navitoclax in combination with ruxolitinib. Median age was 68 yr (range 42-86), 68% were male, and 9 pts (26%) had ≥3 prior lines of MF therapy. The median duration of prior ruxolitinib exposure was 745 days (range 134-4549). Of the 34 pts enrolled, 27 (79%) had JAK2 and 7 pts (21%) had CALR mutations. There were no pts enrolled with triple-negative MF. Of 33 pts with available baseline testing, 17 (52%) had high molecular risk, defined by mutations within ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1. The mean baseline platelet count was 231 x 109/L (range 99-706); mean baseline Hgb was 10.8 g/dL; 19 (56%) pts had elevated WBC at baseline (>1.5× ULN). Maximal navitoclax dose of 300 mg was achieved in 23 pts (68%). Of the 25 (74%) pts that enrolled on ruxolitinib doses >10 mg BID, 22 (88%) subsequently had the dose of ruxolitinib reduced to 10 mg BID. At the time of this analysis, 24 pts were evaluable for efficacy, with 20 pts completing ≥24 wk on study and 4 pts with Tx discontinuations prior to 24 wk. At wk 24, 7 of 24 pts (29%) achieved a spleen volume reduction of ≥35% (SVR35) from baseline by MRI as determined by prespecified central review; the median TSS was 7.4 (range 0-23), a 20% improvement from baseline. A SVR35 at any time on study was achieved in 10 pts (42%). Reductions in driver mutation allelic burden of >5% were observed in 10 (42%) pts; 6 pts (25%) had BMF improvement of ≥1 grade. One pt (4%) had an anemia response; the mean Hgb at wk 24 was slightly improved over baseline at 11.3 g/dL. Of the 19 pts with elevated baseline WBC, 16 (84%) reduced to within normal limits during Tx, with a median WBC reduction of 17.7 × 109/L. All pts experienced a Tx-emergent adverse event (TEAE); most common (≥20%) were thrombocytopenia (82%), diarrhea (62%), fatigue (53%), anemia (27%), nausea (27%), contusion (24%), and vomiting (21%). Grade ≥3 TEAEs occurred in 26 pts (77%); most common were thrombocytopenia (n=15, 44%; Grade 4 n=1, 3%) and anemia (n=8, 24%; no Grade 4). Five pts (15%) experienced serious AEs that resolved including anemia, upper abdominal pain, vomiting, chest pain, increased C-reactive protein, and abnormal liver function test (3% each). There were no significant episodes of bleeding and no TEAE-related deaths. Conclusions: Navitoclax in combination with ruxolitinib was well tolerated with clinically meaningful spleen responses, allelic burden reductions, TSS improvements, and encouraging improvements in BMF in pts with MF who have received prior Tx with ruxolitinib. Disclosures Harrison: CTI: Speakers Bureau; Promedior: Honoraria; Roche: Honoraria; Celgene: Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau. Garcia:Genentech: Research Funding; Abbvie: Research Funding. Mesa:CTI: Research Funding; Galena Biopharma: Consultancy; Samus: Research Funding; Genotech: Research Funding; AbbVie: Research Funding; NS Pharma: Research Funding; Baxalta: Consultancy; LaJolla: Consultancy; Shire: Honoraria; PharmaEssentia: Research Funding; Genentech: Consultancy; Celgene Corporation: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Promedior: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding; Gilead Sciences: Research Funding; Pfizer: Research Funding; Sierra Oncology: Consultancy. Somervaille:Novartis: Consultancy. Komrokji:pfizer: Consultancy; celgene: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Pemmaraju:sagerstrong: Research Funding; celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; samus: Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; incyte: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; affymetrix: Research Funding. Papadantonakis:Agios: Consultancy, Honoraria. Foran:Agios: Honoraria, Research Funding. O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Holes:AbbVie Inc: Employment, Other: Stock/stock options. Jia:AbbVie: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Hutti:AbbVie: Employment, Other: Stock/stock options.

Abstract Background: In 2 phase III studies comparing the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I [COMFORT-I]) or best available therapy (COMFORT-II), ruxolitinib treatment was associated with rapid and durable reductions in spleen volume, improved myelofibrosis (MF)-related symptoms and quality of life measures, and prolonged survival. However, the key measures of efficacy used in the COMFORT studies—magnetic resonance imaging/computed tomography (MRI/CT) to measure change in spleen volume and the modified Myelofibrosis Symptom Assessment Form v2.0 to assess change in MF-related symptoms—are not commonly used in clinical practice. Therefore, we analyzed the efficacy of ruxolitinib in COMFORT-I using practical, community-based measures of clinical benefit (spleen palpation and the Patient Global Impression of Change [PGIC] questionnaire). Methods: In COMFORT-I, patients (N = 309) with primary MF, post–polycythemia vera MF or post–essential thrombocythemia MF were randomized to receive ruxolitinib (n = 155) or placebo (n = 154). For this analysis, patients were divided into groups by degree of palpable spleen reduction and symptom improvement at week 12 as follows: patients with clinically relevant reductions in palpable spleen as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria (SPL), patients with “much improved” or “very much improved” symptoms as measured by the PGIC (PGIC), or patients who did not achieve SPL or PGIC (Neither). The Neither group encompassed patients with “minimally improved” symptoms with no worsening in palpable spleen or patients who achieved 10% reduction in palpable spleen with no worsening in symptoms (Minor), and patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (None). Nonevaluable patients (4/155 for ruxolitinib and 13/154 for placebo) were not included in the analysis. Additional measures of clinical benefit assessed at week 12 included changes in spleen volume and changes in white blood cell (WBC) count. Durability of all measures of clinical benefit with longer-term ruxolitinib therapy was also evaluated. Results: At week 12, the majority (91.4%) of patients randomized to ruxolitinib achieved some clinical benefit as measured by palpable spleen reduction and/or PGIC-assessed symptom improvement, vs 31.9% of those assigned to placebo (Figure 1). Benefits in palpable spleen length reduction and PGIC-assessed symptom improvement achieved at week 12 with ruxolitinib were sustained at week 24. Benefits in palpable spleen length reduction were sustained with longer-term ruxolitinib therapy (median follow-up: 149 weeks). At week 12, ruxolitinib treatment was associated with meaningful reductions in spleen volume by MRI or CT and WBC count in patients who achieved SPL and PGIC criteria, while worsening spleen volume and WBC count was observed with placebo (Figure 2); these effects were durable with longer-term therapy. Patients who achieved neither SPL nor PGIC criteria by week 12 (n = 47; 31.1%) achieved a clinically meaningful reduction in spleen volume by MRI or CT (mean change, −25.6%) and decreased WBC counts (mean change, −7.4%) at week 12 (Figure 2). Patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (n = 13; 8.6%) were generally older, more likely to have high-risk MF as assessed by the International Prognostic Scoring System, and had higher WBC counts, lower platelet counts, and worse fibrosis grade at baseline compared with those achieving defined palpable spleen length reduction and/or PGIC-assessed symptom improvement with ruxolitinib. Conclusions: Nearly all patients treated with ruxolitinib achieved some clinical benefit as assessed by practical measures of assessing efficacy (ie, palpable spleen reduction or PGIC-assessed symptom improvement) within 12 weeks of treatment initiation. Meaningful reductions in spleen volume and WBC count were observed in patients receiving ruxolitinib whether or not they achieved palpable spleen reduction by IWG-MRT/ELN consensus criteria or PGIC symptom improvement (“much improved” or “very much improved”) at week 12; these reductions were durable with long-term ruxolitinib therapy. Disclosures Miller: Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Komrokji:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:CTI: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Celgene: Research Funding. Sun:Incyte Corporation: Employment. Montgomery:Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of blood disorders defined by peripheral cytopenia(s), bone marrow failure, morphological dysplasia, and risk of progression. To understand the genetic, epigenetic and biological factors associated with the initiation and progression of MDS, NHLBI created the National MDS Study (NCT02775383). This is a prospective cohort study conducted at 92 community hospitals and 29 academic centers enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Eligible patients have yet to receive any therapy directed at their cytopenias. Previously untreated cytopenic participants underwent centralized histopathology and data review at the time of enrollment for assignment into distinct subcategories: MDS, MDS/MPN overlap, AML, and Other. Targeted exon sequencing of 96 genes was performed using marrow specimens from the first 300 consecutive individuals in the study. Here we report the genetic mutations for this cohort. Methods: NovaSeq 6000 was used for deep sequencing at a mean coverage of 1,286X and mean breadth (bases covered at ≥100X) of 99.8%. Reads were aligned against build GRCh38 using BWA-MEM, and VarScan2 was used to detect SNVs and INDELS. Variants were filtered for those with an allele base quality of >25 in combination with rule-based and manual review criteria. Subjects in the Other category without an identified malignancy were considered clonal cytopenias of undetermined significance (CCUS) when a mutation or a clonal cytogenetic change was present. Fisher's exact and Wilcoxon rank sum tests in combination with Bonferroni correction were applied to compare groups. Results : A total of 350 putative nonsynonymous pathogenic variants in 36 genes with an allele frequency of >.05 were identified across 150 patients (50%). At least one variant was noted in the following proportion of individuals: 61/72 (85%) with MDS, 13/13 (100%) with MDS/MPN, 15/17 (88%) with AML, and 61/198 (31%) in the Other category, of which 48 were CCUS and 13 were other cancers. Two CCUS patients only had a cytogenetic abnormality. Table 1 shows the distribution of variants in each subcategory of patients for the most commonly mutated genes in our cohort of 300 subjects. Mutations in these genes were enriched in specific groups: SF3B1, STAG2,TP53, and ASXL1 in MDS; TET2 in MDS/MPN; and IDH2 and TP53 in AML (one-sided p<0.0012). None were enriched in the Other group. Within the CCUS subset, 21 genes were mutated, with 37 of 50 (74%) patients having a mutation in TET2, ASXL1, SRSF2, SF3B1, or DNMT3A. The heatmap presented in Figure 1 summarizes variants by subject and allele frequency. Pair-wise comparisons of baseline characteristics of subjects between MDS, MDS/MPN, AML, or CCUS groups revealed no significant differences for age or sex. The CCUS group had significantly higher hemoglobins than the MDS group with median hemoglobin levels of 11.35 and 9.40 g/dL, respectively (p<0.0084). AML had significantly lower platelets compared to all other groups (median of 53 vs. > 110x109/L , respectively, p<0.0084). All groups significantly differed in their median ANC with AML having the lowest (0.8x109/L), followed by MDS (1.5x109/L), CCUS (2.45x109/L), and MDS/MPN overlap (5.95x109/L) (p<0.0084). There was no difference in the median number of variants per patient between groups or correlation with age (rs=0.11, p=0.18). The maximum variant allele frequency (maxVAF) per patient was highest in the MDS/MPN group (median = 0.42, range = 0.38-0.91) and lowest in the CCUS group (median = 0.37, range =0.06-0.98) with the MDS/MPN group having a significantly higher maxVAF compared to the MDS and the CCUS groups (p<0.0084). The proportions of subjects with mutations was similar for those who had abnormal (92% [34/37]) and normal (91% [80/88]) cytogenetics. Conclusions: Incorporation of gene-panel sequencing in the comprehensive evaluation of 300 adult cytopenic patients identified half of the cohort with potentially pathogenic variants. Ultimately, a diagnosis of CCUS was possible in 48 of 183 subjects (26%) not diagnosed with MDS, MDS/MPN overlap syndrome, AML, other cancers or clonal cytogenetics. This study continues to serially bank samples from patients with CCUS, in addition to MDS, MDS/MPN, and ICUS, with the goal to better understand the natural history of these diseases and their progression. Disclosures Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Al Baghdadi:Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Tracon: Equity Ownership; Epizyme: Equity Ownership; Bristol Myer Squibb: Consultancy, Honoraria; Sunesis: Equity Ownership; Portola: Equity Ownership; Heron therapeutics: Equity Ownership; Cardinal health: Consultancy, Honoraria; Bristol Myer Squibb: Equity Ownership; Celgene: Equity Ownership; Spectrum pharmaceutical: Equity Ownership; Astrazeneca: Equity Ownership; Seattle genetics: Equity Ownership; Roche: Consultancy, Honoraria. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Foran:Agios: Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Komrokji:DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy; Incyte: Consultancy; JAZZ: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Starczynowski:Kurome Therapeutics: Consultancy. 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.

Background: CMML is a heterogeneous disease with overlapping features of MDS and MPN. Several risk scores have been proposed in CMML, including CPSS (Such Blood 2013) that identifies 4 risk groups (low, intermediate-1 [int-1], int-2 and high risk) with median overall survival (OS) ranging from 12 months to > 5 years. HSCT is the only curative treatment in CMML, with an expected 20-40% post-transplantation OS. Current guidelines, common to MDS and CMML recommend rapidly transplanting higher-risk CMML and delaying transplant in lower-risk disease (de Witte Blood 2017). Retrospective transplant studies have shown better outcome in lower-risk CMML (Liu et al BBMT 2017). Whether this translates into a survival benefit compared to a delayed transplant strategy requires prospective studies. Multistate models based on retrospective data from transplant and non-transplant patients (pts) have addressed similar issues in MDS (Koreth JCO 2013, Della Porta Leukemia 2017). Through a large collaborative study, we address the question of optimal timing for HSCT in CMML patients through a similar large international collaborative study. Method: We retrospectively selected pts from 2 registries: International MDS/MPN Working Group (IWG cohort, Padron Blood Cancer J 2015) and EBMT with the following criteria: WHO-defined CMML, age ≤ 70y, ECOG 0-2, diagnosis after 2000, available CPSS at the time of diagnosis. Different states were considered in higher- (CPSS int-2 and high) and lower- risk (CPSS low/int-1) pts: diagnosis, AML transformation, transplantation and death. IWG data was used to estimate transition probabilities from diagnosis to AML, transplantation and death and from AML to transplantation and death. EBMT data was used for transplantation to death transitions (Figure 1). Results: 719 and 403 pts were identified in the IWG and EMBT registry, respectively (resp). Median age was 64 (range 16-70) in IWG and 58 (19-70) years in EBMT cohort. Patients were male in 69% and 67% of IWG and EBMT cohorts, respectively (resp). CPSS was low in 22% and 13%, int-1 in 31% and 31%, int-2 in 40% and 45% and high in 8% and 11% of the IWG and EBMT pts, resp. In the IWG cohort, the 1 year cumulative incidence of transformation into AML were 7.3% and 18.2% in lower and higher risk patients, resp. Among the 719 pts from IWG, 102 received HSCT. At the time of diagnosis the expected life time of higher risk (int-2 and high) patients was 25.2 months while it was 44.1 months in lower risk (int-1 and low) patients. Table 1 reports gain or loss in expected life time (until 60 months after diagnosis) for transplantation at different intervals from diagnosis (within 6, 12, 18 and 24 months) for patients who have survived and not transformed to AML until the prediction time point, taking into account CPSS at diagnosis. Expected life time is also given separately for higher risk pts after transformation into AML. There was a modest gain of life expectancy with transplantation in higher risk patients (CPSS int-2 and high) while it was not the case in lower risk patients. The survival gain in higher risk pts with HSCT rose from 1.11 at 6 months to 3.4 months at 24 months. There was also a survival benefit of HSCT in higher risk pts who were transformed to AML during their follow-up which was even higher in terms of gain of months: from 9.89 month if HSCT performed within 6 months to 14.25 months if performed within 18 months. Of note, the loss of survival in lower risk patients who underwent HSCT decreased over time: 11.1 months if HSCT is performed within 6 months and 3.7 months if HSCT is performed within 24 months, probably owing to transition to higher-risk CMML at this stage in some pts, a transition that could not be captured in the present dataset. Conclusion: For the first time, using a multistate model, we could provide evidence that the transplant benefit in CMML is restricted to higher-risk pts, in line with findings in MDS and current guidelines. More analyses will be performed to analyze other subgroups of patients, especially regarding their risk (other classification than CPSS, the role of somatic mutation…). More studies are needed to analyze the role of pre HSCT treatment and its potential impact on post-transplant outcome. Disclosures Robin: Novartis Neovii: Research Funding. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Kroeger:Riemser: Research Funding; Novartis: Honoraria, Research Funding; Medac: Honoraria; DKMS: Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi-Aventis: Honoraria. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Komrokji:Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. Killick:JAZZ: Honoraria; Celgene: Honoraria; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; ALEXION: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. 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. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: CMML is a myelodysplastic/myeloproliferative neoplasm with a median survival of 32 months and no therapies that improve its natural history. We have previously demonstrated that CMML bone marrow mononuclear cells (BMNCs) are hypersensitive to GM-CSF and that the GM-CSF axis is a viable therapeutic target (Padron et al., Blood 2013). Lenzilumab is a novel, humaneered IgG1κ monoclonal antibody, with high affinity for human GM-CSF that has activity in preclinical models of CMML. We report a Phase 1 clinical trial testing the safety and preliminary efficacy of this agent in CMML. METHODS: The study was approved by scientific and ethical review boards. This was a multicenter Phase 1 study designed to evaluate the safety and determine the recommended phase 2 dose of lenzilumab in subjects with CMML. Dose escalation proceeded using a standard 3+3 study design to determine the maximum tolerated dose (MTD). Three dose cohorts included 200 mg, 400 mg, and 600 mg, were given IV on day 1 and 15 of cycle 1 and then only on day 1 of subsequent 28-day cycles. Key inclusion criteria included a WHO-defined diagnosis of CMML and a platelet count greater than 20 x103 cells/dL. Response was evaluated utilizing the MDS/MPN International Working Group Criteria (Savona Blood 2015). Pharmacokinetic analysis and pharmacodynamics were evaluated by pSTAT5 by flow cytometry. RESULTS: Between July 2016 and June 2018, a total of 15 patients were enrolled. The median age at study entry was 74 years (range 52-85) and 80% were male. Nine patients were classified as CMML-0, 3 as CMML-1, and 3 as CMML-2. Seventy three percent of patients had normal cytogenetics or -Y. The most commonly mutated genes at screening included TET2 60%, ASXL1 53%, SRSF2 47%, and RAS pathway (i.e. NRAS or CBL) mutations 40%. Nine patients were previously treated with hypomethylating agents and/or experimental therapies, 3 were treated with hydroxyurea only, and 3 were untreated. The mean Hgb was 9.7g/dL (7.6-14g/dL), the mean platelet count was 147 x103 cells/dL (16-942 x103 cells/dL), and 66% of cases were MPN-CMML by the French-American-British classification at study entry. Three patients were enrolled at each dose level and an additional 6 patients were enrolled at 600mg as planned. Consistent with prior studies of lenzilumab, no dose limiting toxicities were identified and no treatment emergent grade 3 or 4 toxicities were reported. The mean duration on therapy was 221.8 days (14-787 days) and the majority of patients discontinued study drug because of disease progression or lack of response (69%). Five of 15 (33%) patients enrolled achieved clinical benefit by MDS/MPN IWG criteria with 3 platelet responses, 1 neutrophil response, and 1 spleen response. An additional patient had bone marrow myeloblast reduction from 6% to 1% which allowed that patient to undergo allogeneic stem cell transplantation. Clinical response was not statistically associated with somatic mutations or changes in pSTAT5 between screening and cycle 3. However, 3 of 4 patients with NRAS mutation achieved clinical benefit or had clinical meaningful bone marrow myeloblast reductions. CONCLUSION: Lenzilumab is well tolerated in patients with CMML, with no grade 3 or 4 treatment emergent adverse events or DLTs reported. Durable clinical benefit was achieved in 33% of patients and one patient was bridged to allogenic transplant, providing proof of concept that GM-CSF inhibition has activity in CMML. The favorable safety and activity profile of lenzilumab warrants future evaluation as part of a combination regimen targeted to specific subtypes more likely to respond, including patients with NRAS mutations. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Komrokji:celgene: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy. Lo:Humanigen: Employment. Durrant:Humanigen: Employment. Chappell:Humanigen: Employment. Ahmed:Humanigen: Employment. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

CMML is a lethal myeloid neoplasm with no therapies that improve its dismal prognosis. Inhibition of BET family members has been proposed as a therapeutic strategy based on preclinical data identifying BRD4 as a therapeutic target in acute myeloid leukemia. However, despite potent on-target transcriptional remodeling, early phase clinical trials have demonstrated only modest activity secondary to a variety of resistance mechanisms. In ovarian cancer BET inhibitor (BETi) treated cells, compensatory upregulation and addiction to pro-survival kinase networks have been observed. Given that over 50% of CMML cases have mutations upregulating kinase signaling, we hypothesized that BETi resistance is mediated by these networks in CMML and can be targeted therapeutically. We tested this hypothesis by performing a limited screen of kinase inhibitors alone and in combination with the IC20 of the BETi INCB54329 in 8 human leukemia cell lines. This screen revealed that the IC50 of the PIM inhibitor (PIMi) INCB53914 decreased after co-treatment with BETi in a majority of the leukemia cell lines tested. Synergy was validated chemically in U937, TF1 and SKM1 leukemia cells using other selective inhibitors of BET and PIM. We next assessed the activity of the BET-PIM combination in 14-day colony formation assays with 10 unique CMML bone marrow mononuclear cell (BM-MNCs) patient samples(Fig. 1A). These studies revealed that combination therapy significantly suppressed clonogenicity versus BMNCs treated with vehicle or single drug alone. Finally, this synergy was validated in vivo in 36 patient derived xenografts (PDX) from 3 CMML patients, as manifest by reduced leukemic burden/engraftment in CMML PDX treated with combination therapy(Fig. 1B). To explore the mechanism by which BETi and PIMi therapeutically synergize we treated U937 and SKM1 leukemia cells with INCB54329 and measured mRNA and protein levels for all PIM isoforms. Surprisingly, we identified that PIM1 was increased following treatment with INCB54329, other BETi, or a JQ1-derived PROTAC (Fig. 1C). PIM1 upregulation was also manifest in INCB54329 persistor U937 leukemia cells generated by daily BETi treatment for 6 weeks. Testing across a broader panel of leukemia cell lines revealed an inverse correlation between PIM1 induction and decrease in the IC50 of PIMi following BETi treatment, suggesting PIM1 upregulation confers sensitivity to combination therapy. Consistent with this, isogenic SKM1 leukemia cells engineered to overexpress PIM1 were resistant to INCB54329 and were more sensitive to INCB53914 versus controls cells. Recent studies have demonstrated that inhibitory miRNAs, especially those located near super-enhancers, are suppressed by BET inhibition. Given that several miRNAs are known to control PIM1 expression, we hypothesized that paradoxical PIM1 upregulation following BETi treatment was due to down-regulation of select miRNAs. To test this, we treated our leukemia cell models with broad inhibitors of miRNA activity (i.e., AGO and Dicer inhibitors) and observed a dose dependent increase in PIM1 levels similar to that seen with BET inhibition(Fig. 1Di). Further, integrating public H3K27 CHIP-seq and miRNA super enhancer datasets and using computational prediction algorithms, we identified 6 candidate miRNAs that could regulate PIM1 and were predicted to be controlled by BET inhibitors. Of these, only miR-33a levels were reduced in a dose dependent manner in SKM1 cells by BETi treatment(Fig. 1Dii). This was confirmed by genetically silencing all BET proteins, which suppressed miR-33a levels in SKM1 leukemia cells. Finally, miR-33a mimics (but not control miRNAs) abolished BETi-induced upregulation of PIM1(Fig. 1Diii). Collectively, these studies established BET and PIM inhibition as a novel and potent combination therapy for CMML that is mediated by miR-33a-dependent upregulation of PIM1(Fig. 1E). Disclosures Liu: Incyte Corporation: Employment. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Komrokji:Novartis: Speakers Bureau; JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy. Epling-Burnette:Incyte Corporation: Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Haura:Incyte Corporation: Research Funding. Reuther:Incyte Corporation: Research Funding. Koblish:Incyte Corporation: Employment.

Abstract CONTEXT AND OBJECTIVE: Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity included in the MDS/MPN overlap syndromes, with features of refractory anemia with ring sideroblasts (RARS) and thrombocytosis (platelet count ³ 450 x 10/L), recently renamed MDS/MPN with ring sideroblasts and thrombocytosis. Management of RARS-T is extrapolated from MDS and MPN treatment options namely for alleviating symptoms of anemia and, occasionally, for thrombocytosis. Individual case reports have suggested that lenalidomide may be effective in treating RARS-T. In non-del 5q, low-risk MDS, 25% of patients (pts) became red blood cell transfusion independent (RBC-TI). In the phase II study of lenalidomide in non-del 5q lower risk MDS, 35% of pts with RARS treated with lenalidomide achieved RBC-TI. The primary objective of this study is to evaluate a series of pts with RARS-T and compare hematological improvement (HI) responses among different treatment options. METHODS: This is a retrospective, single-center study. Patients with RARS-T were identified from the MDS Database at Moffitt Cancer Center. Samples for somatic mutation testing were obtained at time of referral. Descriptive statistics were used to describe baseline characteristics and response rates to treatment. The primary endpoint was HI using international working group criteria (IWG) 2006. The median overall survival (OS) was calculated from time of diagnosis. RESULTS: We identified 33 pts with RARS-T. The mean age was 67 years (38-80), 15 pts were male (45.5%), and majority were Caucasians (n=27, 82%). According to international prognostic scoring system (IPSS), 24 patients (73%) were low risk and 9 pts (27%) were int-1 risk. By revised IPSS, 11 pts (33%), 18 (55%), 3 (9%), and 1 (3%) were very low, low, intermediate, and high risk, respectively. The mean WBC was 7.7 (2.8-25.7), the mean Hemoglobin was 9.9 g/dl (7.3-12.4), and the mean platelet count was 682 (372-1644). Among 20 pts who had Next generation sequencing for somatic mutations at time of referral, 19 pts (95%) had SF3B1 mutation and 4 pts (20%) had JAK-2 V617 F mutation. The median OS was 90 mo (95% CI 47-134). For pts with JAK-2 V617F mutations, the median OS was 110 mo versus 74 mo for those with wild type (p=0.24). The rate of AML transformation was 3% (one patient only). Among the 33 pts, 8 pts had no treatment (observation only), 22 pts (67%) received erythroid stimulating agent (ESA) prior to any active therapy, 2 patients received lenalidomide with no prior ESA, and 1 pt ruxolitinib with no prior ESA. Twelve pts (36%) received lenalidomide (7 as first line active therapy after ESA and 2 without prior ESA exposure) and 13 pts (33%) received azacitidine (6 as first line active therapy after ESA). The HI rate for ESA was 36% (12/22) with a median duration of ESA treatment of 33mo. The HI rate for lenalidomide was 50% (6/12) with a median duration of lenalidomide treatment of 10.3mo. Among the 9 pts who received lenalidomide as first line active therapy (2 pts without prior ESA exposure) HI rate was 56%. The HI rate for azacitidine was 15% (2/13) with a median duration of azacitidine treatment of 6.3mo. CONCLUSIONS: Pts with RARS-T had favorable outcomes, with long overall survival and a low rate of AML transformation. Rates of hematological improvement with the use of azacitidine were lower than expected. Lenalidomide is an effective treatment option and should be considered when treating patients with RARS-T. Figure. Figure. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.