Gupta, Vikas

e19040 Background: Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis (MF) subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. This landmark analysis is based on post-baseline score changes from Weeks 21 (W21) to 24 and requires vastly different absolute TSS improvements for patients with very high or low baseline (BL) TSS to reach responder status. A phase 3 clinical study, SIMPLIFY-1, randomized 432 intermediate and high risk JAK inhibitor (JAKi) naive MF patients 1:1 to momelotinib (MMB) or ruxolitinib (RUX). Non-inferiority on the MPN-SAF TSS response rate endpoint at W24 was not met (MMB: 28% vs RUX: 42%); however, improvement in each of the 7 TSS items was similar for MMB vs RUX. To understand the discrepancy, we applied item analysis and mixed effect models for repeated measures (MMRM) to SIMPLIFY-1. Methods: Analyses were conducted in the intention-to-treat (ITT) population and in a symptomatic subset (selected as subjects with BL TSS ≥ 10). The distributions of TSS items were examined at BL and shift in scores at W24 (health state shifts) were assessed. GEE models were used to estimate item-level odds ratios using multiple predictive imputations for missing data. MMRM compared mean change in TSS from BL to W24 using data from all visits. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change. Results: BL scores across items were heterogenous in the MMB and RUX groups; the proportion of subjects with no or mild symptoms (0–3 on a 0-10 point scale) ranged from 44% (tiredness) to 81% (itching). Distributions of BL scores were different across arms with 6 out of 7 items in the MMB arm reporting more severe or very severe symptoms (scores of 7-10) at BL. Despite the imbalance in BL scores, item-level health state shifts showed similar improvements for MMB and RUX. Categorical responder analysis showed no significant differences on any items. Odds ratios for each between-group comparison ranged from 0.74 to 1.20. MMRM mean TSS change at W24 was 6.35 (MMB) vs 7.87 (RUX) in the ITT and 8.80 (MMB) vs 10.46 (RUX) in the symptomatic subset. Mean TSS were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset. The between-group difference was 1.52 (95% CI: (0.196, 2.847)) in the ITT and 1.67 (95% CI: -0.134, 3.468) in the symptomatic subset. Conclusions: Comparable item health state shifts at W24 and similar improvements in mean TSS as shown by MMRM, with a minimal between-group difference of 1.52 on the 70 point scale in context of an 8-point MCT suggest MMB provides clinically relevant and comparable symptom improvements to RUX; these analyses require further validation in independent data sets. Imbalance in BL symptom scores in MMB subjects may have contributed to the inability to demonstrate non-inferiority in TSS response rate at W24. Clinical trial information: NCT01969838.

7046 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 enrolled JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). S2 enrolled patients with MF with hematological toxicity during prior RUX therapy (n = 156) randomized 2:1 to open-label MMB or best available therapy (BAT; consisting of RUX in 88% of patients). In both trials, following the 24-week randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX/BAT could cross-over to MMB (RUX/BAT→MMB) for extended treatment (ET). Previously published data from the SIMPLIFY studies demonstrate robust overall survival (OS) for MMB-treated patients in S1 and S2 (median not reached and 34.3 months, respectively) with a maximum follow up of approximately 5 years and median of 2.9 years in S1 and 2.3 years in S2. Methods: OS data for patients receiving MMB in S1 and S2 are reported here for subgroups defined by Week 24 (W24) transfusion independence (TI) responders vs non-responders, and also other efficacy endpoints. Survival was estimated using KM analysis with descriptive log-rank tests for comparison applied (all p-values are descriptive). Results: As previously reported, W24 TI rates were higher in the MMB arms of S1 (67% vs 49%) and S2 (43% vs 21%). In S1, W24 TI responders in the MMB group show an OS advantage, with median OS not reached and 3-year survival of 80% (HR = 0.30; p = 0.0001) compared to MMB TI non-responders. Similarly in S2, W24 TI responders in the MMB group show a trend toward better OS compared to TI non-responders (HR = 0.57; p = 0.0652). The HRs in S1 for MMB responders vs non-responders for W24 SRR and TSS were 0.59 (p = 0.0904) and 0.65 (p = 0.1657), respectively. Alternative analyses using OS defined from W24 demonstrated consistent results. Conclusions: These new analyses suggest JAKi naïve patients receiving MMB who maintain or achieve TI at W24 have favorable OS compared to MMB TI non-responders, with a similar trend observed in S2. These findings are consistent with anemia and transfusion dependency being key predictors of shortened OS in MF and suggest that TI response at W24 may become a surrogate for clinical benefit, supporting the clinical relevance of MMB’s differentiated pro-erythropoietic ACVR1 inhibition. Clinical trial information: NCT01969838.

Background: The COVID pandemic has resulted in significant changes many aspects of daily living. To understand the impact that COVID-19 has had on the myeloproliferative neoplasm (MPN) patient population, we conducted an internet based survey. Methods: Survey: This survey was hosted Mayo Clinic's secured REDCap system for online surveys with a link to the survey alongside a brief description posted via the www.mpnqol.com website, as well as other MPN organizational partners. Survey responses were completely anonymous. Questions included MPN-Total symptom score (TSS), NCCN distress thermometer (NCCN-DT), questions regarding impact on medical care, and questions from CDC COVID-19 community survey question bank regarding the impact of social distancing as well as changes in health behaviors. Distress thermometer, MPN-TSS, and/or questions related to the impact of COVID-19 on MPN treatment were analyzed by: MPN diagnosis, among those with ET, PV, or MF diagnoses; medication status; stay at home order; community spread; and country. Associations were tested using Kruskal-Wallis or Wilcoxon rank sum tests (for continuous variables) or Fisher Exact tests (for categorical variables). Analysis: Results: Patient Demographics (Table 1): 1560 people responded to the survey, 1217 were eligible for analysis. Median age was 62 (range: 21-93), and 298 (24.6%) respondents were male. There were respondents from USA, Australia, Canada, Netherlands, Ireland, and UK. 233 patients (19.2%) have myelofibrosis, 419 (34.6%) polycythemia vera and 543 (44.8%) essential thrombocythemia. At the time of the COVID outbreak, 1026 (84.3%) were on MPN directed medical therapy, including ruxolitinib (15.3%), interferon (14.7%), hydroxyurea (42.7%) and ASA (47.7%). 165 (13.6%) respondents received COVID testing, of which 5 had positive tests. Impact on MPN Care (Table 2): We sought to understand how patient's clinical care changed. Over half respondents who spoke to their MPN doctor had a telemedicine visit after COVID19 (57.1%). 422 (36.5%) patients spaced out visits, of which 99 (22.7%) felt there were consequences. A change in therapy due to COVID-1 occurred in only 5.4% of patients. MPN Symptom Burden and QoL: Data captured on the NCCN-DT had a median of 4 (0-10). MPN-SAF-TSS composite score was collected in 1150 respondents, median score was 26 (0-90). These scores are higher than those previously reported. Pandemic Impact on Lifestyle (Table 1): 595 (49.5%) of patients report living in a community where there is significant COVID-19 spread. 946 (78.9%) reported that COVID-19 has impacted their day to day life. 198 (17.2%) of patients agreed, or strongly agreed that COVID had a significant impact on their finances. 799 (67.8%) had a stay at home order. Of those who quarantined (112), the median duration was 30d (1-120). The majority of people increased hand-washing, and cleaning habits. 954 (81.7%) respondents reported wearing masks in public. 908 (76.8%) reported increased stress from social distancing. The majority of respondents report using healthy coping habits, such as reaching out to friends/loved ones, breathing and relaxation, as well as healthy diet. Less than 15% of patients report unhealthy coping strategies, such as use of opioids, benzodiazepines, alcohol, or cannabis Factors associated with response: There were no differences in responses based on type of MPN. If a patient was on medication, they were more likely to have spoken to their provider (p<0.001). If there was a stay at home order in place, there was a higher MPN-TSS score (p<0.001). If the respondent lived in an area of high community spread, they had a higher NCCN-DT score (p<0.001). Patients in the USA had a higher NCCN-DT score (p=0.001), were more likely to stretch out the duration of time between visits (p<0.001) and less likely to have a telemedicine visit (p<0.001). Although fewer respondents in the USA thought COVID-19 was a serious disease (p=0.02), a higher percentage of respondents wore masks (p <0.001). Conclusions: In our survey of MPN patients, there were many changes noted in clinical care. The use of telemedicine was common, and at least a third had significant changes in their care. Most experienced increased stress, however, employed healthy coping strategies. Only a minority of patients had a COVID test, and only 5 were positive, further data will be needed to understand the impact of COVID infection. Figure 1 Disclosures Harrison: Roche: Honoraria; Incyte Corporation: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Honoraria; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Incyte Corporation: Honoraria; Roche Diagnostics: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; MustangBio: Honoraria; LFB Biotechnologies: Honoraria; Pacylex Pharmaceuticals: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gupta:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Pfizer: Consultancy. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Shimoda:Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company: Honoraria; Novartis: Honoraria, Research Funding; Shire plc: Honoraria; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Komatsu:AbbVie: Other: member of safety assessment committee in M13-834 clinical trial.; Otsuka Pharmaceutical Co., Ltd., Shire Japan KK, Novartis Pharma KK, PharmaEssentia Japan KK, Fuso Pharmaceutical Industries, Ltd., Fujifilm Wako Pure Chemical Corporation, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda Pharmaceutica: Research Funding; Meiji Seika Pharma Co., Ltd.: Patents & Royalties: PCT/JP2020/008434, Research Funding; PPMX: Consultancy, Research Funding; Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, AbbVie GK, Celgene KK, Novartis Pharma KK, Shire Japan KK, Japan Tobacco Inc: Consultancy; Takeda Pharmaceutical Co., Ltd, Novartis Pharma KK, Shire Japan KK: Speakers Bureau. Abello:Takeda: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Dr. Reddy's: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: 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; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: 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, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Mauro:Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Mesa:Samus Therapeutics: Research Funding; Novartis: Consultancy; Genentech: Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Research Funding; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Promedior: Research Funding.

Background Activating mutations in JAK2 are the molecular hallmark of PV. However, achieving molecular remission is not a validated endpoint in PV, as its correlation with patient-relevant endpoints, such as thrombotic events or disease progression, is not well established. The expression of MDM2, a negative regulator of wild-type p53, is significantly higher in CD34+ cells from patients with PV vs those from healthy controls. Therefore, MDM2 antagonists such as idasanutlin (idasa) may have selective and potentially disease-modifying effects in PV. This exploratory analysis reports baseline mutational profiling and serial measurements of JAK2 V617F variant allele frequency (VAF) from patients treated with idasa in the Phase II NP39761 study (NCT03287245). Methods Patients with PV, as defined by the 2016 World Health Organization criteria, were eligible for inclusion if their disease was HU resistant/intolerant according to European LeukemiaNet criteria and they were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV therapy with ruxolitinib and/or interferon was allowed. Idasa was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg, but dose increase (to 200 mg) or decrease (to 100 mg) was allowed per protocol-defined criteria. The primary efficacy endpoints were hematocrit control (HTC), defined as maintaining acceptable hematocrit levels with ≤ 1 phlebotomy between cycle 1, day 1 (C1D1) and wk 8 and no phlebotomy after wk 8, and complete hematologic remission (CHR), defined as HTC together with platelets < 400 × 109/L and white blood cell count < 109/L on the day of response assessment (or most recent test). JAK2 V617F VAF was analyzed at screening and at C3D28, C5D28 and wk 32. The JAK2 V617F VAF was determined using quantitative polymerase chain reaction. Baseline blood samples were sequenced using the Foundation Medicine FoundationOne Heme next-generation sequencing panel, which interrogates > 400 DNA-sequenced genes, to explore the genetic landscape of PV beyond JAK2 V617F. Results All 27 patients enrolled in the study harbored JAK2 V617F. Baseline and ≥ 1 later JAK2 VAF measurements were available in 23 patients, allowing for analysis. The median age was 56 y (range, 34-74), and 7 patients (26%) had been previously treated with ruxolitinib. Median treatment duration was 257 days (range, 5-677), and the median number of treatment cycles was 8 (range, 1-22). JAK2 V617F VAFs at baseline were highly variable, ranging from 7% to 96% (median, 66%). A reduction in JAK2 V617F VAF was observed as early as after 3 cycles (median reduction, 39%; n = 19) and was sustained in patients receiving treatment, with a median reduction of 58% at C5D28 (n = 17) and of 76% at wk 32 (n = 13). The median reductions in JAK2 V617F VAF were significantly higher for patients with CHR and HTC than in nonresponders on C3D28 (CHR, P < 0.01; HTC, P = 0.04) and C5D28 (CHR, P < 0.01; HTC, P = 0.03), with a similar trend also at wk 32 (CHR, P = 0.06; HTC, P = 0.19) (Figures). Baseline targeted sequencing (n = 16) identified several additional subclonal mutations. However, no TP53 mutations were detected. Variants in TET2 and ASXL1 were detected in 37% (6 of 16) and 20% (3 of 16) of patients, with VAFs of 2%-51% and 38%-50%, respectively. Notably, 68% of the patients had variants detected in 1 to 3 DNA repair genes, including ATM (VAF, 47%-52%), ATR (VAF, 49%), BRCA2 (VAF, 47%-51%), PARP1 (VAF, 52%), PARP3 (VAF, 48%), FANCM (VAF, 47%-50%), BLM (VAF, 48%) and MSH3 (VAF, 49%). In the absence of sequencing of patient-matched non-hematologic tissue and the VAFs being ≈50%, it is possible some of these variants are germline. Whether such variants predispose to PV is unknown. Conclusions Idasa has relevant clinical activity in patients with PV who are resistant to or intolerant of HU and showed rapid JAK2 V617F VAF reduction in a subset of patients as early as after 3 treatment cycles. The median JAK2 VAF reduction was significantly greater in patients who achieved CHR and HTC after 3 and 5 cycles of idasa treatment, suggesting that early molecular response was associated with higher likelihood of clinical response. Baseline mutations were seen in several genes commonly mutated in PV. A high frequency of variants in DNA repair genes has not previously been reported in PV and may contribute to genomic instability in this disease. Figure Disclosures Passamonti: Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau; Novartis: Speakers Bureau. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; AstraZeneca/MedImmune: Consultancy; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; Sierra Oncology: Research Funding. Gupta:Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Huw:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:Sierra Oncology: Consultancy; Incyte: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; AbbVie: Research Funding; Bristol Myers Squibb: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; Ardelyx: Current equity holder in publicly-traded company. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis resulting from aberrant megakaryopoeisis and expression of pro-inflammatory cytokines. These two processes, heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation, lead to myeloproliferation and cytopenias. CPI-0610 is a potent, selective and unique BET inhibitor under investigation in MF patients as monotherapy or in combination with ruxolitinib in the MANIFEST trial (NCT02158858). In ruxolitinib naïve and experienced MF patients, treatment with CPI-0610 monotherapy or in combination with ruxolitinib not only reduced spleen volume and symptoms, but also improved hemoglobin levels and overcame transfusion dependency in a subset of patients. To evaluate the effects of CPI-0610 on BM biology, correlative analyses were conducted using patient samples collected from the MANIFEST trial. Pre-treatment and post-treatment BM biopsy samples were available from 78 evaluable patients, with reticulin staining conducted and evaluated by local pathologists available for 34 pre-treatment and 24-week post-treatment pairs of BM biopsy samples. Improvement in reticulin staining of at least one grade was observed in 32% (11/34) of patients. Central pathology review of reticulin staining is ongoing and will be presented. Additional bone marrow biopsy pairs collected pre-treatment and 24-week post-treatment for exploratory histopathological assessments were available from a total of 23 unselected MANIFEST patients at the time of the abstract submission. To assess changes in erythroid and megakaryocytic lineages, H&E and immunohistochemistry (IHC) staining of CD71 and CD61 were conducted centrally. Semi-quantitative analysis revealed an overt increase in erythroid lineage formation in 61% (14/23) of patients. Patients with CD71 improvement in BM IHC generally showed a greater increase in median hemoglobin levels than those without improvement. Tight clusters of megakaryocytes (MK), characteristic in MF BM, were observed at baseline in all cases and were decreased/absent after treatment in 52% (12/23) patients. In addition, decreased MK number to <5/high powered field was also observed in 39% (9/23) of patients. Overall improvement in MK histotopography was observed in 65% of patients (15/23). Central histopathology review with IHC staining, including reticulin staining, will be conducted on additional samples and will be available for presentation at the conference. To further dissect the underlying mechanism of these relative improvements in bone marrow composition and histotopography induced by CPI-0610, CD34+ hematopoietic stem cells were isolated from peripheral blood collected from multiple MF patients at baseline to evaluate the impact of CPI-0610 on MK and erythroid differentiation in vitro. When CD34+ cells from MF patients were treated with CPI-0610 in erythroid differentiation conditions in the presence of SCF, IL3 and EPO, a dose-dependent increase in more mature erythroid cell populations was observed. However, under the same conditions, ruxolitinib suppressed erythroid differentiation, which is consistent with ruxolitinib inhibition of EPO signaling and the anemia caused by ruxolitinib treatment in MF patients. Suppressive effects of ruxolitinib on erythroid differentiation were partially rescued by CPI-0610 in a dose-dependent manner. CPI-0610 treatment of CD34+ cells from MF patients in MK differentiating conditions in the presence of SCF, IL6, IL9 and TPO resulted in a dose-dependent decrease in proliferation of CD34+ cells and an increase in the ratio of late MK (CD34-/CD41a+/CD42b+) and early MK (CD34+/CD41a+/CD42b+). This CPI-0610-induced dose-dependent maturation of aberrant immature MK cells may play a role in reducing MF disease manifestations. Molecular studies to further our understanding of the underlying mechanisms of CPI-0610 treatment are ongoing. Taken together, these paired BM biopsy and in vitro myeloid maturation results demonstrated an effect of CPI-0610 in promoting erythroid and MK differentiation. These results may partially explain CPI-0610's clinical effects in MF patients, including rising hemoglobin, reduced transfusion dependency and reduction in spleen volume and symptoms. Disclosures Mertz: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Keller:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Meyer:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zavidij:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cui:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Roche: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; PharmaEssentia: Research Funding; Incyte Corporation: Consultancy, Research Funding; ItalPharma: Research Funding; NS Pharma: Research Funding. Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:IMAGO: Consultancy; Takeda: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Harrison:Promedior: Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria. Mead:CTI: Consultancy; Gilead: Consultancy; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Abbvie: Consultancy. Mesa:Novartis: Consultancy; CTI BioPharma: Research Funding; Bristol Myers Squibb: Research Funding; Sierra Oncology: Consultancy; Genentech: Research Funding; Samus Therapeutics: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Incyte: Research Funding; Promedior: Research Funding; AbbVie: Research Funding. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Senderowicz:Constellation Pharmaceuticals: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Puma Biotechnology: Membership on an entity's Board of Directors or advisory committees. Colak:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Shao:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luptakova:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Humphrey:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wang:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Trojer:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Study Rationale: At present there are no effective therapies for patients with primary or secondary myelofibrosis (MF) after the failure of the JAK inhibitory class of therapies. Furthermore, patients with monocytosis, thrombocytopenia, accelerated phase, or high-risk genetic features fare poorly with JAK inhibitors (JAKi), as intolerance, resistance, and/or ineligibility often limit treatment options. Median overall survival in most studies post-JAKi demonstrate poor outcomes (14-28 months) among patients with MF. Consequently, there is a considerable need in identifying new therapeutic targets beyond JAK-STAT inhibition. One potential cancer target is CD123, aberrantly expressed on leukemia stem cells and aberrant/malignant microenvironmental plasmacytoid dendritic cells (pDC) in certain myeloid cancers including MF. Tagraxofusp (TAG), a CD123-targeted therapy FDA-approved for patients with blastic plasmacytoid dendritic cell neoplasm, a pDC-derived malignancy, has demonstrated preclinical proof-of-concept in MF. We now report the updated results of an ongoing study of TAG monotherapy in patients with relapsed/refractory MF, or who were unable to tolerate currently approved JAKi. (NCT02268253) Experimental Design: A multicenter Phase 1/2 trial with TAG administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1-3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8+) in stage 1, and 12 mcg/kg every 21 days (C1-4), 28 days (C5+) in the currently ongoing stage 2. Results: Thirty-five patients (pts) with a median age 69 years (range: 54-87) have been treated thus far: 26% had baseline monocytosis and 69% had baseline thrombocytopenia, which impacts optimal dosing of JAKi, including 37% with platelets <50x109/L including 7 pts with platelets ≤20; 75% had baseline palpable splenomegaly. Baseline genomic analysis in 35 pts revealed: JAK2 V617F (n=21); CALR (n=3); MPL (n=2); 7 of 21 pts who had comprehensive NGS, had an ASXL1 mutation. Most common treatment-related adverse events (incidence ≥15%) include hypoalbuminemia (23%), headache (17%), and elevated alanine aminotransferase (17%). Notably, capillary leak syndrome (CLS) was reported in 3 pts (1 was grade 4). Twenty-one pts (60%) achieved stable disease (SD) by IWG-MRT revised 2013 criteria, including 4 who had substantial clinical benefits; SD was noted in 7 of 9 (78%) with monocytosis, 7 of 13 (54%) with baseline platelets ≤50x109/L, including 3 of 7 (43%) with baseline platelets ≤20x109/L, and 2 of 3 (67%) pts with accelerated phase. At week 24, spleen responses by palpation were observed in 10 (45%), including 2 with >50% spleen reduction; 12 of 26 (46%) had symptom burden reduction, including 3 pts who met the IWG-MRT criteria. There have been three deaths, all deemed to be unrelated to study drug, occurring in cycles 1, 6, 13, respectively. The median overall survival of our cohort was 31 months (range: 0.6-42 months). Conclusions: Interim results demonstrate clinical efficacy and safety of TAG monotherapy in JAKi relapse/refractory/intolerant MF patients, including those associated with recognized poor-risk biological and clinical features, such as monocytosis. Some patients have experienced clinical benefit, including reduction in splenomegaly and improvement in quality of life and enrollment continues. Disclosures Pemmaraju: Celgene: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Blueprint Medicines: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Plexxikon: Research Funding; Cellectis: Research Funding; Incyte Corporation: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding. Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Honoraria, Research Funding. Ali:Incyte Corporation: Consultancy. Yacoub:Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company. Wang:PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Macrogenics: Consultancy; Astellas: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy. Lee:Roche Molecular Systems: Consultancy; Jazz: Consultancy; AstraZeneca: Consultancy; Helsinn: Other: Member -DSMB; BMS: Consultancy. Schiller:Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding. Brooks:Stemline: Current Employment. Rupprecht:Stemline: Current Employment. Talpaz:Takeda: Research Funding; IMAGO: Consultancy; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Mughal:Stemline: Current Employment. Verstovsek:PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI Biopharma Corp: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding.

Background PV is a clonal myeloid neoplasm characterized by activating mutations in JAK2 and increased red blood cell production. Reduction of thrombosis risk through lowering of hematocrit (Hct) and thus blood viscosity is critical, but management of constitutional symptoms is also important. HU is an effective and well-tolerated first-line treatment (tx) for PV, but pts who develop resistance to or intolerance of HU have limited tx options. A Phase I study of idasanutlin, an MDM2 antagonist leading to increased p53 activity, showed encouraging efficacy and potential disease-modifying effects via rapid reduction in JAK2 V617F variant allele frequency in 11 pts with PV. These results prompted the larger, international Phase II study of idasanutlin in HU-resistant/intolerant PV (NCT03287245); data from the initial phase of the study are reported here. Methods Pts meeting the 2016 WHO criteria for PV were eligible for inclusion if they had HU-resistant/intolerant disease according to the European LeukemiaNet (ELN) criteria and were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV tx with ruxolitinib (rux) or interferon was allowed. Idasanutlin was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg; increase to 200 mg was allowed for non-responders at cycle 3, day 28, and reduction to 100 mg was permitted for toxicity and for pts treated beyond cycle 12. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles. The primary endpoint (wk 32) was the composite response of Hct control (HTC) and spleen volume reduction > 35% by CT/MRI in pts with splenomegaly (> 450 cm3) and HTC alone in pts without splenomegaly. Key secondary endpoints included safety, complete hematologic response (CHR; defined as HTC and normalization of platelets/leukocytes) and ELN response. Results A total of 27 pts were included in this study and received tx with idasanutlin. Median age was 56 years (range, 34-74) and 16 pts (59.3%) were male (Table 1). All pts had JAK2 V617F mutation; 7 had previous exposure to rux. Median tx duration was 257 days (range, 5-677); the median number of treatment cycles was 8 (range, 1-23). Dose modifications occurred in 17 pts (63.0%; Table 2). A total of 3 serious AEs occurred: atrial flutter, atrial fibrillation and nausea/vomiting (n = 1 each). The serious cardiac AEs occurred in pts with pre-existing hypertension and a past incident of heart failure not symptomatic upon enrollment, respectively. No deaths, transformation to acute myeloid leukemia, progression to myelofibrosis or thrombotic events occurred during the study. AEs occurring in ≥ 15% of pts are listed in Table 3; gastrointestinal toxicity and fatigue were the most common events. The population for primary endpoint evaluation consisted of pts with response assessed at wk 32 (n = 16). One of 13 pts with baseline splenomegaly achieved a composite response (7.7%; Table 4). Nine of 16 pts (56.3%) among all evaluable pts achieved HTC: 6 of 11 rux-naive pts (54.5%) and 3 of 5 rux-exposed pts (60.0%). Eight of 13 pts (61.5%) among all pts had HTC duration ≥ 12 wk beyond wk 32: 5 of 9 rux-naive pts (55.6%) and 3 of 4 rux-exposed pts (75.0%). At wk 32, 8 of 16 pts (50.0%) achieved a CHR, with 6 of 13 (46.2%) having a CHR duration ≥ 12 wk beyond wk 32. Overall response rates per modified ELN response criteria in pts with baseline splenomegaly, pts without baseline splenomegaly and in all pts were 69.2% (9 of 13), 66.7% (2 of 3) and 68.8% (11 of 16), respectively; 9 of 15 pts (60%) among all pts had a response duration ≥ 12 wk beyond wk 32. Median (range) laboratory value changes at wk 32 were: platelets, −253 × 109/L (−2083 to +175) and leukocytes, −4.8 × 109/L (−25.3 to +3.4). At wk 32, 6 of 14 pts (42.9%) had a ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Conclusions Idasanutlin showed relevant clinical activity in pts with HU-resistant/intolerant PV and also in a subset of pts with prior rux tx. However, the low-grade gastrointestinal toxicity profile of idasanutlin was not effectively mitigated with antiemetic prophylaxis and led to frequent discontinuations. These results iterate the importance of tolerability of novel therapies administered over the long term for pts with PV. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Anders:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Burbury:Roche: Other: Support of parent study and funding of editorial support. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Imago Biosciences: Research Funding; Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gupta:Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kovic:Roche: Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: 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. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company.

Background: Primary and secondary [post-essential thrombocythemia (ET) or polycythemia vera (PV)] Myelofibrosis (MF) are clonal hematopoietic neoplasms marked by constitutive JAK-STAT activation, bone marrow fibrosis, cytopenias, and constitutional symptom burden. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option in this disease. Median overall survival (OS) after JAK inhibitor (JAKi) discontinuation is poor, ranging from 6-24 months (Harrision et al. Ann Hematol. 2020). Haploidentical (Haplo)-HCT with post-transplant cyclophosphamide (PTCy) has improved donor availability, but data on post-HCT outcomes in MF remain scarce. Herein, we describe clinical outcomes of patients (pts) with MF who underwent haplo-HCT with PTCy. Methods: We conducted a multi-institutional study where we retrospectively reviewed charts to obtain pt, disease, and treatment characteristics of MF pts who underwent haplo-HCT from 2000 to 2019. Graft-versus-host-disease (GVHD), relapse, and non-relapse mortality (NRM) were described as cumulative incidences. OS and relapse free survival (RFS) were estimated using the Kaplan-Meier method. Univariate analyses were conducted with Cox or Fine and Gray regression. Results: Fifty-eight adult pts from 11 centers underwent haplo-HCT and were included in the analysis. Pt, disease, and HCT characteristics are listed in Table 1. Thirty-four (59%) pts were over 60 years of age at the time of HCT. Of the 53 pts in whom driver mutation data was available, JAK2 was reported in 34 (64%), CALR in 10 (19%), MPL in 4 (8%), and 5 (9%) were triple-negative. Twenty-two (38%) pts had HCT-CI ≥ 3. Median CD34+ cell dose was 6.81 (range: 2.3-28.6) x 106/kg. All pts received PTCy as a part of GVHD prophylaxis regimen. Median follow-up in this study was 28 (range: 3.3-75.7) months. Neutrophil and platelet engraftment was reported in 53 (91%) and 47 (81%) pts at a median time of 20 (range: 14-70) and 31 (range: 15-225) days, respectively. Five pts (9%) had graft failure. The cumulative incidences of all-grade acute and chronic GVHD were in 44% (95% CI: 31-56%) at 6 months and 31% (95% CI: 18-44%) at 2 years. Grade 3-4 acute GVHD was seen in 5 (9%) pts. Post-HCT relapse/disease persistence occurred in 12 (21%) pts with a median of 416 (range: 28-917) days. The 2-year estimates of OS, RFS, relapse and NRM were 69% (95% CI: 55-80%), 52% (95% CI: 37-65%), 21% (95% CI: 11-34%) and 27% (95% CI: 16-39%) respectively (Fig 1). On univariate analyses (Table 2), older age (HR 2.17, P=.012) and a higher HCT-CI (HR 1.4, P<.001) was associated with higher NRM. Higher HCT-CI was also associated with higher all-cause mortality (HR 1.38, P=.003). Bone marrow as a graft source was associated with a higher risk of relapse (HR 5.04, P<0.001, Fig 2), but did not significantly affect OS (HR 0.78, 95% CI: 0.18-3.46), RFS (HR 1.89, 95% CI: 0.71-5.02) or NRM (HR 0.58, 95% CI: 0.09-3.84). JAKi use prior to HCT, spleen size or type of driver mutation did not significantly affect outcomes. Conclusions: Based on this study, we conclude that haplo-HCT with PTCy is a valid option in pts with MF. The graft failure rates appear to be similar to those reported with sibling and unrelated donors. Older age, higher HCT-CI and bone marrow as graft source were associated with inferior outcomes. JAKi use prior to HCT or type of driver mutation did not significantly affect outcomes. Disclosures Grunwald: Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Merck: Consultancy; Agios: Consultancy; Janssen: Research Funding; Cardinal Health: Consultancy; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Forma Therapeutics: Research Funding; Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Merck: Research Funding; Astellas: Consultancy; Genentech/Roche: Research Funding; Premier: Consultancy; Premier: Consultancy; Astellas: Consultancy; Premier: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Trovagene: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Astellas: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding. Dholaria:J&J: Research Funding; Takeda: Research Funding; Angiocrine: Research Funding; bms: Research Funding; Poseida: Research Funding. Abedin:Jazz Pharmaceuticals: Honoraria; Agios: Honoraria; Helsinn Healthcare: Honoraria; Pfizer: Research Funding; Helsinn Healthcare: Research Funding; Actinium Pharmaceuticals: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. DeZern:MEI: Consultancy; Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy. Gerds:Sierra Oncology: Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Apexx Oncology: Consultancy; Roche/Genentech: Research Funding; Imago Biosciences: Research Funding; Gilead Sciences: Research Funding. Jain:Bristol Myer Squibb: Other: for advisory board participation; Takeda: Consultancy, Honoraria; CareDx: Other: Advisory Board.

Abstract Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1− myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation–based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

Abstract Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.