Palmer, Jeanne

Abstract Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

Abstract TGFβ plays a pivotal role in the pathobiology of myelofibrosis (MF) by not only promoting bone marrow fibrosis (BMF) but also by enhancing the dormancy of normal but not MF hematopoietic stem cells (HSCs). TGFβ has also previously been reported to inhibit normal megakaryocyte (MK) production (Bruno et al Blood 1998). TGFβ1 promotes the synthesis of collagen by normal human mesenchymal stromal cells (MSCs). Treatment of MSCs with AVID200, a potent TGFβ1/3 protein trap, significantly decreased MSC proliferation, phosphorylation of SMAD2, and collagen expression. Robust expression of pSMAD2 was observed in the absence of exogenous TGFβ in normal donor or MF-MKs, Addition of AVID200 to MKs decreased pSMAD2 without affecting total SMAD2/3 and led to increased numbers of MKs. Treatment of MF MNCs with AVID200 also led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies. A phase 1b trial of AVID200 (NCT03895112) was performed and completed in INT-2/high risk MF patients resistant/intolerant to ruxolitinib (rux); baseline platelet count of ≥ 25 x 10 9/L, and grade 2/3 BMF. Subjects received AVID200 intravenously on Day 1 of a 21 day cycle. Response was assessed by IWG/ELN criteria after 6 cycles of AVID200. Subjects attaining at least a CI or SD with a decrease in BMF by ≥1 grade, continued AVID200. We previously presented the results of the dose escalation study (Mascarenhas ASH 2020) demonstrating that AVID200 was well tolerated without dose limiting toxicities at 3 tested dose levels (Lots A and B) in dose cohorts of 180 mg (A), 550 mg (A)/70 mg (B), and 180 mg (B). Here we report updated safety and efficacy results of the phase 1b dose expansion stage at the two highest doses tested (70 mg (B) and 180 mg (B). Twenty-two subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 in the dose escalation phase and 12 in the dose expansion phase [Table1]. Median time after rux discontinuation was 7.4 months (0.5-59.9). The most common mutations observed at baseline in this cohort included JAK2V617F (71%), TET2 (29%) ASXL1 (24%) and CALR (19%). (Fig 1) No DLTs were observed and Grade 3/4 AEs were observed in 16 (76.2%) subjects. Grade 3/4 non-hematologic AEs were observed in 8 (38.1%) subjects and included one subject in each case (epistaxis, mucositis, extraocular muscle paresis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, urinary tract infection, and syncope). Grade 3/4 hematologic AEs were anemia (6; 28.3%) and thrombocytopenia (2; 14.3%) [Table 2]. No fatal events were observed. The median number of cycles received was 5 (range 2 - 13) and 7 (33%) patients received more than 6 cycles. For dose levels 2-3 at cycle 7, a CI was attained in one subject at dose level 2 [anemia, spleen and TSS], 5 subjects had SD, 3 subjects had PD and two subjects with 10% and 15% blasts at screening developed MPN-BP while on study based on central review. Reasons for discontinuation by local PI included PD (n=8), lack of response (n=5), study completed (n=2), other (n=2), patient decision (n=1). Median % change in palpable spleen length was +10% (range -70% to +150%) and TSS change was -50% (-100% to +185.7%) The median platelet count at baseline was 114 x 10 9/L (range: 28-695) and 215 x 10 9/L (range: 66-263) after cycle 6 in 7 evaluable subjects (Fig 2A). Notably, 17 subjects had an increase in platelets from baseline during treatment and two subjects normalized their platelet counts. Maximum changes in platelets from baseline across all cycles was +63.8% [range -15.7%, +505.5%] (Fig 2B). Paired bone marrow biopsy pathology samples for 12 subjects were available for central review and showed no significant changes in BMF score or MK histo topography at end of treatment compared to baseline. All patients had elevated plasma levels of TGF β1, but not TGFβ2/β3 levels as detected by ELISA, which were dramatically reduced 21 days after the last dose of AVID200. AVID200 a TGFβ1/3 protein trap is well tolerated and clinical responses at cycle 7 of therapy in this advanced MF patient population were limited as judged by IWG/MRT response criteria. However, AVID200 therapy resulted in significant reduction in serum TGFβ levels and improvements in platelet counts indicating that TGF β1 plays a pivotal role in MF leading to thrombocytopenia which can be reversed with AVID200 therapy. We conclude that AVID200 may best be employed in combination therapy approaches in thrombocytopenic MF patients. Figure 1 Figure 1. Disclosures Mascarenhas: Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Forbius: Research Funding; Genentech/Roche: Consultancy, 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; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding. Palmer: PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte: Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding. Kuykendall: Celgene/BMS: Honoraria; Pharmaessentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Research Funding; Incyte: Consultancy; Abbvie: Honoraria; Blueprint: Honoraria. Mesa: Genentech: Research Funding; Promedior: Research Funding; Samus: Research Funding; Gilead: Research Funding; CTI: Research Funding; Abbvie: Research Funding; Sierra Oncology: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Pharma: Consultancy; CTI: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; AOP: Consultancy; La Jolla Pharma: Consultancy; Incyte Corporation: Consultancy, Research Funding. Rampal: Stemline: Consultancy, Research Funding; Memorial Sloan Kettering: Current Employment; BMS/Celgene: Consultancy; Abbvie: Consultancy; CTI: Consultancy; Novartis: Consultancy; Disc Medicine: Consultancy; Blueprint: Consultancy; Pharmaessentia: Consultancy; Incyte: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Kartos: Consultancy; Sierra Oncology: Consultancy. Gerds: PharmaEssentia Corporation: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Novartis: Consultancy. Yacoub: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Talpaz: Imago: Consultancy; Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support ; Celgene: Consultancy. Komrokji: Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau. Kremyanskaya: Astellas: Research Funding; Astex: Research Funding; Chimerix: Research Funding; Bristol Myers Squibb: Research Funding; Constellation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Hoffman: Kartos Therapeutics, Inc.: Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Novartis: Other: Data Safety Monitoring Board, Research Funding; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding. OffLabel Disclosure: AVID200 is a TGFb trap and is in clinical testing for fibrotic diseases. It does not have an approved indication at this time.

Abstract Introduction: Thrombocytopenia, a hallmark of cytopenic myelofibrosis (MF), is associated with poor survival and quality of life impairment. Patients with MF and moderate or severe thrombocytopenia (platelet counts <100x10 9/L, <50x10 9/L) tend to have high symptom burden as measured by the Total Symptom Score (TSS), driven largely by physical functioning symptoms (Mesa R et al, ASH 2021 abstract in submission). Pacritinib, an investigational JAK2/IRAK1 inhibitor, was studied in patients with platelet counts ≤100x10 9/L in the PERSIST-2 trial. Unlike the pivotal studies upon which available JAK1/2 inhibitors were approved that relied on a modified TSS version that excluded 'tiredness' from the response analysis, PERSIST-2 included 'tiredness' as part of TSS and found response rates of 25% for pacritinib vs. 14% for best available therapy (BAT), P=0.08. Here, we retrospectively analyzed TSS on PERSIST-2 using the modified scoring system. In addition, we evaluated the impact of pacritinib and BAT, including ruxolitinib, on MF symptoms including 'tiredness' and 'inactivity'. Methods: All PERSIST-2 patients in the intention-to-treat population randomized at least 22 weeks prior to the end of the study were included. PERSIST-2 randomized patients 1:1:1 to pacritinib 200mg BID, pacritinib 400mg daily, or BAT (including ruxolitinib). The modified TSS score was calculated as the sum of individual symptom scores for early satiety, abdominal discomfort, rib pain, night sweats, itching, and bone pain ('tiredness' and 'inactivity' were not included), and response was defined as a ≥50% reduction in score from baseline to week 24. Symptoms were categorized as physical function-related (tiredness, inactivity), spleen-related (satiety, abdominal discomfort, rib pain), or cytokine-related (sweats, itching, bone pain). The Wilcoxon Rank Sum test was used to compare differences in scores. Results: The analysis included 74 patients randomized to pacritinib 200mg BID and 72 to BAT; an additional 75 were randomized to pacritinib 400mg QD (dose no longer in development). At baseline, 39% had moderate and 46% had severe thrombocytopenia. Ruxolitinib was selected as BAT in 45% of patients with moderate and 38% with severe thrombocytopenia. The co-primary endpoint for the study - TSS response rate in pooled pacritinib arms versus BAT - showed a significant difference using the modified TSS: 30% vs. 14%, P=0.008. Similarly, the modified TSS response rate was higher for patients treated with pacritinib 200mg BID compared to BAT (35% vs. 14%, P=0.004, Figure 1a). Among patients on the BAT arm, modified TSS response rates were modestly higher for patients who received ruxolitinib prior to week 24 (19% [n=6/32]) compared to those who did not (10% [n=4/40]), though both were lower than response rates with pacritinib. Patients on the pacritinib 200mg BID arm experienced greater percentage reductions in individual myelofibrosis symptoms between baseline and week 24 compared to BAT, both in patients with moderate and severe thrombocytopenia (Figure 1b, 1c). For physical function symptoms, severity was reduced more on pacritinib 200mg BID compared to BAT by week 24 (median reduction in tiredness: 30% vs. 13%, P=0.0261; inactivity: 22% vs. 7%, P=0.099). Among patients with severe thrombocytopenia, symptom improvement was minimal on BAT (Figure 1b). Conclusion: The symptom benefit of pacritinib in patients with moderate and severe thrombocytopenia is demonstrated in the PERSIST-2 study. A significant reduction in symptoms was observed in patients treated with pacritinib 200mg BID, the dose being studied in an ongoing Phase 3 trial (PACIFICA), compared to BAT. Furthermore, the modified TSS response rate of 35% in patients treated with pacritinib 200mg BID is comparable to that reported for approved JAK1/2 inhibitors in patients with higher platelet counts, suggesting the potential for pacritinib to address the unmet need of patients with cytopenic myelofibrosis. Figure 1 Figure 1. Disclosures Palmer: CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Incyte: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding. Mesa: Incyte Corporation: Consultancy, Research Funding; Samus: Research Funding; Sierra Oncology: Consultancy, Research Funding; CTI: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Pharma: Consultancy; La Jolla Pharma: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; AOP: Consultancy. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Rampal: Sierra Oncology: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy; Stemline: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Kartos: Consultancy; Disc Medicine: Consultancy; Blueprint: Consultancy; Pharmaessentia: Consultancy; Incyte: Consultancy, Research Funding; Memorial Sloan Kettering: Current Employment; Abbvie: Consultancy; CTI: Consultancy. Buckley: CTI Biopharm: Current Employment. Roman-Torres: CTI Biopharm: Current Employment. Verstovsek: Protagonist Therapeutics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Ital Pharma: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Mascarenhas: Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding; Geron: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Galecto: Consultancy; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiladjian: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; AP Orphan: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Harrison: Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Speakers Bureau; Roche: 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; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: 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; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bose: Novartis: Honoraria; NS Pharma: Research Funding; Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Promedior: Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Astellas: Research Funding; BMS: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Craig: CTI BioPharma: Current Employment. Gerds: PharmaEssentia Corporation: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; Novartis: Consultancy.

Abstract Introduction: Historically, clinical outcome of patients with myelodysplastic syndrome (MDS), progressing on hypomethylating agents (HMA; azacitidine or decitabine) has been dismal with median overall survival (OS) of less than 6 months (Jabbour et al. Cancer 2010). With recent approval of venetoclax based combinations for acute myeloid leukemia (AML) and CPX-351 for AML with MDS related changes (primary or secondary), clinical outcome has improved in sub-set of high-risk patients compared to historical cohorts. Hence, we analyzed clinical outcome of MDS patients progressing on HMA, in the current era of novel therapies. Methods: We retrospectively analyzed clinical outcome of 43 MDS patients who progressed on HMA-based therapy and treated at the Mayo Clinic between February 2015 and February 2021. We describe clinical characteristics of these patients, therapies received after progressing on HMA-based therapy, duration of response attained after 1st line therapy post HMA-based therapy and OS from time of HMA failure till death or last follow up. We also performed Cox regression multivariate analysis for OS after progression on HMA-based therapy. Results: Baseline characteristics are summarized in Table 1.The median age of the patients were 69 years (range [R], 48-93). R-IPSS score in this cohort of patients was very low (2[5%]), low (5[12%]), intermediate (5 [12%]), high (11[26%]) and very high (20 [46.5%]). Forty-nine percent of patients had complex cytogenetics. Most commonly occurring mutations (≥ 5%) were TP53 (42%), splicing mutation (SRSF2/SF3B1/ or U2AF1) (16%), ASXL1 (12%), RUNX1 (7%), DNMT3A (5%) and IDH1/ or IDH2 (5%). The HMA-based therapy patients received were azacitidine (40%), decitabine (30%) and HMA plus venetoclax (30%). The median time to progression from time of initiation of HMA-based therapy was 5 months (R= 1-30). Sixty-three percent (n= 27) of patients progressed to AML after HMA-based therapy. The most common 1 st line therapies post HMA was venetoclax-based (12 [28%]), CPX-351 (12 [28%]), and allogeneic stem cell transplantation (SCT) (4 [9%]). Fifteen (45.5%) patients achieved CR/CRi, 17 (51.5%) patients progressed and 1 (3%) patient had stable disease. The percentage of patients received venetoclax with HMA, 1 st and 2 nd line therapy post HMA were 26%, 28% and 10%, respectively. Overall, 11 (25%) patients received SCT in this cohort of patients. The median duration of response after 1 st line therapy post HMA was not reached (NR; 66% progression free at 1 year) (Figure 1A). The median OS after HMA failure was 12.7 months (95% CI: 3.1-22.2) (Figure 1B). In the univariate analysis for OS after HMA failure, SCT at any time point (p = 0.01) and achieving CR/CRi after 1 st line therapy post HMA (p= <0.001) showed favorable significance for OS. Whereas, R-IPSS high/very high (p= 0.35), treatment with CPX-351 on AML progression (p=0.33), venetoclax-based therapy (p= 0.59) did not show statistical significance. Subsequently, in multivariate analysis, only achievement of CR/CRi after 1 st line therapy post HMA retained significance for favorable OS (HR: 0.19, 95% CI: 0.04-0.86, p= 0.03). Conclusions: To the best of our knowledge, this is the first report analyzing outcome of MDS patients progressing on HMA in the recent era. Acknowledging the limitations of retrospective analysis, our report suggests improved outcome of these high-risk patients compared to historical data. Utilizing venetoclax plus HMA combination earlier in patients with high-risk MDS as being evaluated in VERONA trial and consolidation therapy with SCT in eligible patients have potential to improve long term outcome of this group of high-risk patients. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Protagonist: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Foran: pfizer: Honoraria; takeda: Research Funding; trillium: Research Funding; boehringer ingelheim: Research Funding; syros: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; servier: Honoraria; bms: Honoraria; certara: Honoraria; abbvie: Research Funding; OncLive: Honoraria; gamida: Honoraria; taiho: Honoraria; novartis: Honoraria; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees.

Abstract Background :COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Among patients with hematologic malignancies, seroconversion rates also appear to be influenced by recent treatment and the type of treatment they have received. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. Current national guidelines recommend COVID-19 vaccination to be offered to CAR T recipients as early as three months thereafter. We retrospectively evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Methods:This retrospective study was conducted at three Mayo Clinic sites on NHL and MM patients that received CAR T infusions from Sept 2016 to June 2021. Baseline characteristics were ascertained from medical records. All NHL and MM patients who had received CAR T at any point and were alive at the time that the COVID-19 vaccine first became available were eligible for inclusion for antibody response evaluation. For antibody response to vaccination, antibody spike values > 0.80 U/mL were considered positive. Results: Out of 104 CAR T infusions, 73 patients are alive at the time of this submission. We have had 7 patients with known COVID-19 pre-CAR T and all 7 are currently alive (5 have antibody titers and 2 have not been tested yet). Nineteen patients developed known COVID infection post-CAR T (13 alive and 6 deceased). The mortality of COVID post-CAR T in our sample was 31.5%. Furthermore, of the 13 patients that survived COVID-19, they received CAR T an average of 416 days prior to COVID-19 infection (median = 337, range = 54 - 1406); the 6 patients who died from COVID-19 had received CAR T an average of 250 days prior to COVID-19 infection (median = 164, range = 7 - 846). All 6 deceased patients did not receive COVID-19 vaccination pre-CAR T. Out of 17 CAR T patients tested for antibody spike titers post COVID-19 vaccination, 76.4% were able to mount an antibody response. More patients with MM had a higher titer response to the vaccine (>250 U/mL) compared to the NHL counterparts (0.80-249 U/mL). All patients that received the vaccine, regardless of antibody response, were alive at the time of this submission. Conclusions:The majority of CAR T recipients with NHL and MM are able to mount an antibody response following COVID-19 vaccination in our relatively small sample. The frequency of seroconversion among CAR T recipients seems to be similar to patients with hematologic malignancy who had received a hematopoietic cell transplant reported elsewhere. These findings are limited by our small sample size and may be influenced by the timing of vaccination relative to CAR T. Furthermore, almost half of our patients received IVIG post CAR T which could potentially cause false positive antibody results as pooled immunoglobulin preparations may contain COVID-19 antibodies from vaccinated healthy donors. To better understand the characteristics of the immunologic response against SARS-CoV-2 in patients post-CAR T, larger multicenter studies exploring both humoral and cellular immunity will be needed. JEWN, MI and JM are co-first authors and PV, HM and AR are co-senior authors. Figure 1 Figure 1. Disclosures Munoz: Physicians' Education Resource: Honoraria; Seattle Genetics: Honoraria; Bayer: Research Funding; Gilead/Kite Pharma: Research Funding; Celgene: Research Funding; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa: Honoraria. Bergsagel: Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fonseca: Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy. Palmer: Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Incyte: Research Funding; PharmaEssentia: Research Funding. Dingli: Novartis: Research Funding; GSK: Consultancy; Apellis: Consultancy; Alexion: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Kapoor: Sanofi: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding; Oncopeptides: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Merck: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Bluebird Bio: Consultancy; Antengene: Consultancy, Honoraria; Sanofi: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Gamida Cell: Consultancy; Takeda: Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Vineti: Consultancy. Murthy: CRISPR Therapeutics: Research Funding.

Abstract Introduction: Allogeneic stem cell transplantation (allo-SCT) can be curative for patients with hematologic malignancies. Despite optimization of supportive measures, the risk of non-relapse mortality is a particularly important consideration in older individuals. Sarcopenia, defined as low skeletal muscle mass, has been shown to be associated with decreased overall survival in cancer patients and may identify individuals at higher risk of treatment-related complications. Methods: Using Mayo Clinic Arizona's hematopoietic stem cell transplantation database, patients aged 60 years or older who underwent allo-SCT between 2008 and 2018 were identified. Patients who underwent abdominal computed tomography (CT) at our institution within 90 days prior to their transplant date were included in the study. The skeletal muscle area (SMA) was obtained using a fully automated algorithm for segmenting abdominal CT images to quantify body composition based on a deep learning approach (Weston et al., Radiology, 2019). The skeletal muscle index (SMI) was then calculated using the SMA and the subject's height at the time the CT was obtained. Sarcopenia was defined based on previously described consensus (Cruz-Jentoft et al., Age Ageing, 2010; Magudia et al., Radiology, 2021). T-tests and Fisher's exact tests compared patient characteristics between groups, where appropriate. Kaplan-Meier methods were used to construct survival times. Log-rank tests compared survival distributions and Cox proportional hazards models estimated hazard ratios. Results: A total of 79 patients met inclusion criteria (Table 1). Of these, 50 (63%, n=50/79) had sarcopenia, and 29 (37%, n=29/79) had normal skeletal muscle mass. Among the sarcopenia group, 43 (86%, n=43/50) had SMI measurements. No differences were seen between groups in age at transplant, sex, Karnofsky performance scale, disease risk index, or conditioning regimen intent. There was no statistically significant difference in overall survival between those with sarcopenia and those with normal skeletal muscle mass (log-rank p=0.18). Median survival was 3.3 years (95% CI: 0.8, not estimable (NE)) for those with sarcopenia and 3.6 years (95% CI: 1.3, NE) for those with normal skeletal muscle mass. Given the infrequency of events, the upper bounds of the median survival confidence intervals were not estimable. The unadjusted hazard ratio (HR) for sarcopenia versus normal skeletal muscle mass was 1.65 (95% CI: 0.79, 3.47; p=0.18). Males had a higher mean SMI than females, as expected (50.4 versus 37.5, p<0.001; mean difference 13.0, 95% CI: 8.9, 17.1). Without considering sex, higher or lower SMI was not associated with survival time in a Cox model in those with sarcopenia (HR: 0.97, 95% CI: 0.92, 1.03; p=0.32). Sex alone was also not associated with any survival benefit among these 43 patients. After adjusting for the difference seen in SMI between sexes, on average, those with higher SMI were associated with a survival benefit (HR: 0.92, 95% CI: 0.84, 0.99; p=0.039). This amounts to roughly an 8% reduction in hazard rate as SMI increased. Conclusions: The presence of sarcopenia alone was not associated with overall survival in patients 60 years and older undergoing allo-SCT for hematologic malignancy. Rating sarcopenia severity using SMI may assist in identifying high risk individuals with sarcopenia as lower sarcopenia severity was associated with improved overall survival. Further studies are warranted to explore the possible impacts of interventions directed at improving skeletal muscle mass on transplant-related outcomes. Figure 1 Figure 1. Disclosures Gaulin: DeciBio: Honoraria; Olson Research Group: Honoraria. Jain: CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding.

SummaryRuxolitinib for steroid‐refractory acute graft‐versus‐host disease (SR‐aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib‐resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR‐aGVHD studies.

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.

e19023 Background: Acute GVHD (aGVHD) is a major cause of mortality and morbidity following stem cell transplantation (HCT). In effort to prognostic patients with aGVHD, the Mount Sinai Acute GVHD International Consortium (MAGIC) combined two biomarkers, ST2 and REG3α to generate an algorithm known as the Ann Arbor (AA) biomarker risk. This is now available as a commercial test to help predict risk for severe acute GVHD and non-relapse mortality when done at the onset of symptomatic aGVHD. Our institution began utilizing these lab values and here we report our “real world” experience. The primary aim was to correlate AA risk probabilities with recently defined endpoints including day 28 overall response rate (ORR) and 6 month freedom from treatment failure (6mFFTF) and overall survival (OS). Methods: 58 HCT patients who underwent HCT between October 2018 and November 2019 and had the biomarker assay at the onset of aGVHD were identified from the institutional database and clinical information about disease, transplant and outcomes was obtained from the medical records. Clinical staging of aGVHD was documented per standardized published guidelines. Day 28 ORR was defined as complete response by day 28. 6mFFTF was defined as a patient being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, and prior to the development of cGVHD. Results: When comparing low (n = 39), intermediate (n = 11), and high (n = 8) AA risk, there was no difference in age ( p =0.254), primary disease ( p =0.10), DRI ( p =0.994), donor source ( p =0.193), conditioning regimen intent ( p =0.537), GVHD prophylaxis ( p =0.351) ATG use ( p =0.06). Low AA risk was associated with lower grades of aGVHD at onset (grade I = 15%, grade II = 80%, grade III = 5%, grade IV = 0%), whereas high AA risk was associated with higher grades of aGVHD at onset (grade I = 0%, grade II = 50%, grade III = 25%, grade IV = 25%) ( p =0.009). For low, intermediate, and high AA risk the day 28 ORR was 69%, 45% and 29% ( p = 0.083); the 6mFFTF was 82%, 82%, and 25% ( p = 0.0001); 6 month OS was 92%, 100%, and 50% ( p = 0.0006) respectively. Conclusions: Our study shows a high correlation between AA risk and outcomes. High risk AA risk was associated with inferior outcomes This study was limited by the retrospective single institutional experience with relatively small numbers. However, our findings using the commercial assay mirror that seen with the MAGIC studies. Our “real world data” can serve as a foundation and continued validation for institutional implementation of AA risk stratification for aGVHD.