Kiladjian, Jean‐Jacques

7018 Background: MF is a life-limiting malignancy characterized by marrow fibrosis, splenomegaly, and progressive cytopenias. JAK2 inhibitors can reduce spleen volume, which is considered a surrogate for disease response. For example, ≥10% SVR on ruxolitinib (RUX) is associated with improved OS among patients with platelet (PLT) counts ≥100×109/L. RUX cannot be administered at full dose in patients with lower PLTs, and it is not known whether the association between SVR and OS persists in such patients. PAC is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated SVR benefit vs BAT (including RUX) in PERSIST-2, which enrolled MF patients with PLTs ≤100×109/L. Here we present a retrospective landmark OS analysis of the relationship between SVR and OS on PERSIST-2. Methods: This analysis includes PERSIST-2 patients who were alive and on study at the start of the 12-week SVR window (study week 10) on PAC 200 mg BID or BAT. Spleen volume was assessed radiographically (MRI or CT). OS was evaluated among SVR responders vs non-responders within each treatment arm using different SVR thresholds (≥35%, ≥20%, ≥10%, > 0%) and a landmark analysis methodology. OS was compared using the log-rank test. Results: Among patients on PAC (n = 89), any SVR ( > 0%) at 12 weeks was significantly associated with improved survival (HR = 0.08 [95% CI: 0.01, 0.51], P = 0.0007). Among all SVR response thresholds, SVR ≥10% demonstrated the greatest separation in OS curves between responders vs. non-responders on PAC, with no deaths on study among 65 responders compared to 5 deaths among 24 non-responders (HR = 0.0 [95% CI: 0.0, 0.14], P < 0.0001). By contrast, SVR did not predict OS benefit on BAT (n = 84), including RUX (n = 39). For example, 11% (3/28) of patients on BAT who achieved SVR ≥10% died compared to a similar number (14%, 8/56) of non-responders (HR = 0.63 [95% CI: 0.17, 2.37], P = 0.49). Of the 28 patients on BAT who achieved SVR ≥10%, 23 (82%) were treated with RUX. Among these 23 patients, most patients were receiving low-dose RUX at the time of the landmark: 78% were on ≤10 mg BID and 43% were on £5 mg BID. By contrast, the median relative dose intensity on PAC was 100% (200 mg BID) through week 12 among both SVR ≥10% responders and non-responders. Conclusions: In MF patients with PLTs ≤100×109/L, achieving SVR on full-dose PAC was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on RUX, albeit at low doses. As PAC can be given at full dose regardless of PLT count, it is possible that PAC may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction. Clinical trial information: NCT02055781 .

7016 Background: Many patients (pts) with myelofibrosis (MF) experience anemia resulting from disease or JAK inhibitor therapy. The open-label, phase 2 ACE-536-MF-001 study (NCT03194542) evaluated the safety and efficacy of luspatercept (LUSPA) for the treatment of MF-related anemia. Methods: Eligible pts comprised 4 cohorts based on transfusion dependence (TD, defined as receiving 4–12 red blood cell [RBC] units/84 days [d] immediately up to cycle 1 d 1) and stable ruxolitinib (RUX) treatment; cohort 1: no TD, no RUX; cohort 2: TD, no RUX; cohort 3A: no TD, RUX; cohort 3B: TD, RUX. Pts received subcutaneous LUSPA 1.0 mg/kg (1.33 mg/kg for pts in cohort 3B expansion) with titration up to 1.75 mg/kg in 21-d cycles. Disease response was assessed at d 169 and treatment extended for pts showing clinical benefit; pts were followed for ≥ 3 years (y) post last dose. The primary endpoint was anemia response (defined as 84 consecutive d: ≥ 1.5 g/dL hemoglobin [Hgb] from baseline without transfusion [cohorts 1 and 3A] or RBC transfusion-free [cohorts 2 and 3B]); secondary endpoints included duration of response (DOR), transfusion frequency, change in Hgb level, and symptom response. Results: Of 95 pts in the ITT group, the most common reason for treatment discontinuation was lack of clinical benefit at d 169 (n = 28). Median (range) age was 71.0 (50–89) y. Most (54.7%) pts had primary MF, intermediate-risk 2 disease (75.8%), and > 2 y since initial diagnosis (74.7%). Median prior RUX therapy was 18.1 months (cohorts 3A/3B) and 84.7% of pts had baseline transfusion burden 6–12 units/84 d (cohorts 2/3B). Mean treatment duration was 42.8 weeks. Cohort 3B had the highest anemia response rate with 26.3% (95% CI, 13.4–43.1) of pts transfusion independent during the primary treatment period and 31.6% (95% CI, 17.5–48.7) transfusion independent during the entire treatment period; median (range) DOR was 448 d (85–1582). In cohort 3B: 19 (50.0%) pts had reduced transfusion burden by ≥ 50% during the primary treatment period; 8 (21.1%) pts achieved mean Hgb increase ≥ 1.5 g/dL from baseline throughout the entire treatment period and 6 (15.8%) achieved a mean ≥ 50% reduction in symptom score from baseline. Overall, 47.4% of pts had ≥ 1 treatment-related adverse event (TRAE), most frequently hypertension (17.9%, 5.3% grade ≥ 3); 3.2% of pts had a serious TRAE. One TRAE led to LUSPA discontinuation. Two (2.1%) pts had transformation to acute myeloid leukemia. Nine pts died on treatment from: post-procedural hemorrhage, pneumonia, intracranial hemorrhage, septic shock, ischemic stroke, multiple organ dysfunction syndrome, renal failure, pneumonitis, and myelofibrosis (n = 1 each); no deaths were considered related to the study drug. Conclusions: In pts with MF, the safety profile of LUSPA was consistent with previous studies and efficacy results showed promising improvements in anemia and transfusion burden in all cohorts. Clinical trial information: NCT03194542 .

AbstractBackgroundMyelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy.MethodsLongitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data.ResultsMomelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm.ConclusionsThese findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings.

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

Abstract Despite much of the past 2 years being engulfed by the devastating consequences of the SAR‐CoV‐2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show‐cased at the 15th Post‐American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th‐10th December 2020 and 7th‐10th October 2021, respectively. The inaugural Post‐ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Abstract Background: Splenomegaly is a marker of disease progression in MF; larger spleen size (SS) is correlated with poorer survival and debilitating MF symptoms. In a retrospective real-world study of 408 patients (pts) with MF treated with ruxolitinib (RUX), pts with SS ≥ 10 cm below the left costal margin (LCM) were significantly less likely to attain a spleen response than pts with SS &lt; 10 cm (Palandri 2017); this finding has not been reported in clinical trials of RUX. FEDR is a JAK2-selective inhibitor approved in the US, EU, Canada, and elsewhere as first-line (1L) MF treatment (Tx) and in pts previously treated with RUX. FEDR was evaluated as 1L MF Tx in the phase 3, placebo (PBO)-controlled JAKARTA trial, and in the phase 2, single-arm JAKARTA2 trial in pts previously treated with RUX. Pts allocated to FEDR 400 mg/day (d) in these trials reported substantial reductions from baseline (BL) in spleen volume and MF symptom severity after 6 FEDR Tx cycles. It is important to determine whether spleen volume and symptom improvements during FEDR Tx are influenced by degree of pre-Tx splenomegaly. Objective: Investigate the clinical efficacy of FEDR 400 mg/d in pts in JAKARTA & JAKARTA2 with large spleens at BL. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK-inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS &gt; 5 cm from LCM by palpation, platelets ≥ 50 ×10 9/L, and ECOG PS ≤ 2. These analyses include pts in each trial allocated to receive FEDR 400 mg/d in continuous 28d Tx cycles. Too few pts had BL SS &lt; 10 cm by palpation in JAKARTA (n = 21) and JAKARTA2 (n = 12) for meaningful comparison vs SS ≥ 10 cm. Thus, in these post hoc analyses we divided pts according to the median SS (mSS) at BL in each study , and assessed changes from BL in spleen volume and MFSAF total symptom score (TSS) at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Pts must have had spleen volume and/or TSS data at BL and EOC6. R esults: In JAKARTA, 96 pts were randomized to FEDR 400 mg/d; mSS at BL for all pts was 16 cm (range 5-40). Median (range) BL spleen volume was 1771 (316-3396) mL in the &lt; mSS cohort and 3329 (983-6430) mL in the ≥ mSS cohort; median TSS was 13.0 and 17.6, respectively. Spleen volume data were available at BL and EOC6 for 37 (82%) and 38 (75%) pts in the &lt; mSS and ≥ mSS cohorts, respectively. Median spleen volume reduction (SVR) at EOC6 was -38% [95%CI -43%, -31%] in the &lt; mSS group and -40% [-40%, -28%] in the ≥ mSS group (Figure). Changes in MF symptom scores at EOC6 were similar in the &lt; mSS (n = 37) and ≥ mSS (n = 34) cohorts, with median TSS reductions of -49% and -51%, respectively. For individual symptoms, median reductions in abdominal discomfort, bone/muscle pain, and early satiety were similar between BL SS cohorts, whereas changes were greater in the &lt; mSS group for pruritus and pain under ribs-left side, and greater in the ≥ mSS group for night sweats. In JAKARTA2, 97 pts received FEDR 400 mg/d (starting dose); BL mSS for all pts was 18 cm (range 5-36). Median (range) BL spleen volumes were 1937 (737-4305) and 4002 (1821-7815) mL for pts with &lt; mSS and ≥ mSS, respectively; and BL TSS was 17.2 (0.7-48.0) and 23.6 (1.0-44.0). Spleen volume and MFSAF TSS data were available at BL and EOC6 for 41 and 29 pts, respectively, in the &lt; mSS cohort, and for 41 and 22 pts in the ≥ mSS group. At EOC6, median SVR from BL was -35% [95%CI -40%, -29%] for pts with &lt; mSS at BL and -30% [-37%, -17%] for pts with ≥ mSS (Figure). Median TSS changes were -36% and -49% in the &lt; mSS and ≥ mSS cohorts, respectively; pts with ≥ mSS at BL had similar or greater reductions from BL in 5/6 MFSAF symptoms (all except pruritus) vs those with &lt; mSS. Conclusions: These analyses demonstrate that extent of splenomegaly at BL in JAKARTA and JAKARTA2 did not influence the likelihood of achieving improvements in spleen volume or MF symptom severity for pts receiving FEDR 400 mg/d as 1L MF Tx or as post-RUX salvage Tx. For pts who completed 6 FEDR Tx cycles, reductions in spleen volume and TSS at EOC6 in the ≥ mSS cohorts in both studies were similar to those in the &lt; mSS cohorts, even though BL spleen volumes and TSS were higher in the ≥ mSS groups. Figure 1 Figure 1. Disclosures Kiladjian: Incyte Corporation: 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: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Passamonti: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: 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. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees. Talpaz: Imago: Consultancy; Celgene: Consultancy; 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support . Cervantes: Bristol Myers Squibb: Consultancy, Honoraria. Harrison: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: 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; CTI BioPharma: 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; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: 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; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: 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; Abbvie: 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, Research Funding, Speakers Bureau. Mesa: AOP: Consultancy; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Samus: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Research Funding; CTI: Research Funding; Pharma: Consultancy; Promedior: Research Funding. Mascarenhas: Geron: Consultancy; Merus: Research Funding; Geron: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Galecto: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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; Forbius: Research Funding; Gilead: 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; 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; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek: Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Devos: Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Incyte: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb - Celegene: Consultancy; Novartis: Consultancy. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhang: Bristol Myers Squibb: Current Employment. Sy: Bristol Myers Squibb: Current Employment.