Harrison, Claire

PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

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 < 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 > 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 < 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 < 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 < mSS and ≥ mSS cohorts, respectively. Median spleen volume reduction (SVR) at EOC6 was -38% [95%CI -43%, -31%] in the < mSS group and -40% [-40%, -28%] in the ≥ mSS group (Figure). Changes in MF symptom scores at EOC6 were similar in the < 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 < 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 < 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 < 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 < mSS at BL and -30% [-37%, -17%] for pts with ≥ mSS (Figure). Median TSS changes were -36% and -49% in the < 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 < 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 < 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.

Abstract Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis resulting from aberrant megakaryopoiesis and expression of pro-inflammatory cytokines. These processes, heavily influenced by bromodomain and extraterminal domain (BET) protein-mediated gene regulation, lead to myeloproliferation and cytopenias. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in the ongoing MANIFEST Phase 2 study (NCT02158858). Methods: In arm 1 of MANIFEST, pelabresib is administered as monotherapy to pts with MF who are intolerant/refractory to, or ineligible for RUX; in arm 2, as an 'add-on' to RUX in pts with MF who have suboptimal/lost response; and in arm 3 as combination therapy with RUX in JAKi treatment-naïve pts with MF. To evaluate the effects of pelabresib on BM biology, analyses were conducted using BM biopsy samples obtained pre-treatment and at 24 weeks post-treatment during the MANIFEST trial. Central pathology review of reticulin staining was conducted to evaluate BM fibrosis (BMF) grading and immunohistochemistry staining for changes in erythroids (ERY) and megakaryocytes (MK), respectively. Independent digital images of stained BM slides were also evaluated with a semi-quantitative cell-specific detection algorithm for reticulin density, percentage CD71+ ERY, mean number of CD61+ MK and mean distance between nuclei for CD61+ MK. Results: Exploratory analyses across the three treatment arms showed BM improvements after 24 weeks of treatment. Paired comparison by digital analysis of baseline and 24-week treatment BM biopsies from 29 pts showed reduction (range 67%-15.5%) in reticulin intersections per field in 45% (13/29) pts. Furthermore, digital analysis of CD71+ ERY and CD61+ MK from paired biopsies showed increased ERY progenitors in 50% (16/32) pts, decreased MK density in 57% (15/26) pts and decreased MK clustering in 46% (12/26) pts at 24 weeks. Decreased MK clustering correlated with decreased density of CD61+ MK in 75% pts (9/12). Correlative analysis between observed clinical responses and bone marrow improvements are ongoing and will be available for presentation at the conference. We previously reported (Talpaz M, et al. ASH 2020; Abstract 2163) that in pts with MF, pelabresib can reduce spleen volume, improve symptoms, improve bone marrow fibrosis, demonstrate increase in hemoglobin levels, and reduce transfusion burden. Updated 24-week data reflecting a higher number of evaluable pts and new long-term data at 48 weeks across the MANIFEST trial, will be presented. Conclusions: Treatment with pelabresib as monotherapy or in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in increased ERY progenitors, decreased MK density and reduction of BM fibrosis, as assessed by digital pathology. These data suggest possible disease-modifying potential for pelabresib by improving BM histology and function, leading to potential clinical benefits. Disclosures Verstovsek: Roche: Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Ital Pharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. 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. Mascarenhas: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: 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; Constellation: 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; Geron: Consultancy, Research Funding; Prelude: 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; Galecto: Consultancy; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Forbius: Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz: Celgene: Consultancy; Imago: Consultancy; Takeda: Other: Grant/research support ; 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. Mesa: La Jolla Pharma: Consultancy; Samus: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; CTI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AOP: Consultancy. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rampal: Incyte: Consultancy, Research Funding; Pharmaessentia: Consultancy; Blueprint: Consultancy; Disc Medicine: Consultancy; Stemline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Memorial Sloan Kettering: Current Employment; Kartos: 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. Taverna: Constellation Pharmaceuticals: Current Employment. Cui: Constellation Pharmaceuticals: Current Employment. Zavidij: Constellation Pharmaceuticals: Current Employment. Chen: Constellation Pharmaceuticals: Current Employment. Colak: Constellation Pharmaceuticals: Current Employment. Efuni: Constellation Pharmaceuticals: Current Employment. Keller: Constellation Pharmaceuticals: Current Employment. Trojer: Constellation Pharmaceuticals: Current Employment. Harrison: Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; 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; Geron: 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; Roche: 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; 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; AOP Orphan Pharmaceuticals: 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; Promedior: 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.

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 MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in polycythemia vera (PV) patients with resistance/intolerance to Hydroxycarbamide (HC). This analysis involved a primary comparison between the RUX and BAT arms for quality of life (QOL) durability over 60 months, with secondary comparisons of best QOL response within first year in complete hematologic responders (CR) vs a group of partial or no response (NR/PR). This is a unique analysis due to cross-over nature of prior studies. Patients were stratified by treatment arm with either RUX or BAT. QOL was assessed over 0-60 months using the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). MPN-SAF Total Symptom Score (TSS) was computed as the average of all completed items multiplied by 10 (scale 0-100, higher score represents higher symptom burden). Estimates of change from baseline and between arm differences in change by timepoint were made using a linear mixed model with compound symmetry covariance structure, which included covariates for categorical time point, treatment arm, and the interaction between time point and treatment arm. The difference between arms in proportion of patients with best post-baseline TSS response of 50% or greater was testing using a Chi-square test. In this study, 147 of the 190 trial patients had started treatment and completed at least their baseline assessment and were included in the analysis with 39 patients completing through 60 months. Groups were comprised of 76 patients in the RUX group (31 females, 45 males, mean age 64.2 [SD 11.4]) and 71 patients in the BAT group (29 females, 42 males, mean age 64.6 [SD 11.5]). Symptom scores at baseline were similar between arms, with MPN-SAF weight loss the only statistically significant difference (BAT 0.7 [SD 1.71] vs RUX 1.7 [SD 2.83], p=0.02). Significant, durable improvements in TSS were noted in RUX patients with symptom improvements lasting a mean of 52 months. BAT patients experienced a worsening of their symptom burden with improvements back to baseline notable at 56 months (Figure 1). MPN-SAF TSS there were significant differences between treatment arms in change from baseline to months 2-32, 44, and 48 (all p<0.05). In all months the trend was in the direction of larger improvement in the RUX arm, with the point estimate for difference ranging from 2.1 (at month 56) to 11.3 (at month 4) with most prominent changes occurring between months 2 and 32. Of the 80 patients with MPN-SAF TSS scores at baseline and at least one post-baseline timepoint, 13/41 (31.7%) BAT and 24/39 (61.5%) RUX patients had TSS reduction of 50% or greater in at least one time point, which was statistically significant (p=0.008). In regard to specific symptoms, there was a statistically significant between arm difference seen in over 5 timepoints for fatigue, early satiety, night-sweats, itching, bone pain, and weight loss. Comparing MPN-SAF TSS in Complete Response (CR n=51) vs Non-Responder/Partial Responders (NR/PR) (n=96) there was no difference at baseline in any of the measures at any time point. A possible limitation of this study is the potential for bias in which the patients who were lost to follow up could be different then the patients who remained in the study through all 60 months which would affect generalization, particularly at time points at the later years. The novel findings of this investigation demonstrate that Ruxolitinib ameliorates the PV symptom burden in patients resistant or intolerant to HC in a robust durable manner over at least four years, while patients receiving BAT have worsening of their symptom burden over this same time period. Figure 1 Figure 1. Disclosures Mead: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Yap: Celgene: Honoraria; Faron Pharmaceuticals: Honoraria. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Knapper: Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Drummond: Novartis: 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; CTI: Membership on an entity's Board of Directors or advisory committees. McMullin: Novartis: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Mesa: CTI: Research Funding; AOP: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Pharma: Consultancy; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding; Samus: Research Funding; Sierra Oncology: Consultancy, Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; La Jolla Pharma: Consultancy. Harrison: CTI BioPharma: 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; Shire: 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; Geron: 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; Constellation Pharmaceuticals: Research Funding; Galacteo: 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; Roche: 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; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: 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; Keros: 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.

Abstract The myeloproliferative neoplasms (MPN) polycythaemia vera (PV) and essential thrombocythaemia (ET) are associated with significant symptom burden with impaired quality of life (QoL). In the MAJIC study patients refractory/intolerant to hydroxycarbamide (HC), were randomised to treatment with ruxolitinib (Rux) or best available therapy (BAT). In this unique and comprehensive analysis we explore quality of life (QoL) outcomes in the MAJIC study using the MPN10 Self-Assessment Form (SAF) in particular using this unique dataset to explore for the first time differences between JAK2 ET vs PV, and JAK2 ET vs CALR ET at baseline and 12 months of therapy with Rux or BAT. Methods 306 patients were randomised, (190, PV and 116 ET arm) and followed for 5 years, no cross over was permitted. MPN10 SAF was assessed at baseline, 2, 4, 8 and 12 months in both arms. Equal variance two sample t-tests were used to test differences between diagnosis groups (JAK2 ET vs PV & JAK2 ET vs CALR ET) in baseline scores and 12-month change from baseline scores, here negative change from baseline indicates improvement. QoL data was also collected using MD Anderson Symptoms Inventory (MDASI) and 5 level EQ5D at the same time points as the MPN10 SAF. Results JAK2 ET vs PV 110 participants with JAK2 mutation were included in the analysis for JAK2 ET vs PV. 81 (74%) had PV and 29 (26%) had JAK2 ET; 44 patients (54.3%) with PV and 18 (62.1%) patients with ET were randomised to Rux, and 37 (45.6%) patients with PV and 11 (37.9%) with ET to BAT. Baseline mean total symptom score (TSS) was similar (JAK2 ET: 18.9. SD 18.4 and PV: 23.7, SD 17.81 (p=0.27). Mean for pruritus was 1.9 (SD 2.47) in JAK2 ET and 3.5 (SD 2.99) in PV (p=0.03). Other baseline scores were comparable: mean scores for fatigue was 3.3 (SD 3.07) for JAK2 ET vs 4.7 (SD 2.68) for PV, for early satiety was 2.6 (SD 2.78) for JAK2 ET vs 2.1 (SD 2.40) for PV, for abdominal discomfort 3.0 (SD 3.34) for JAK2 ET vs 2.0 (SD 2.78) for PV, for inactivity was 2.4 (SD 2.86) for JAK2 ET vs 3.2 (SD 2.72) for PV; for concentration problems was 2.2 (SD 2.51) for JAK2 ET vs 2.9 (SD 3.11) for PV, for night sweats was 1.6 (SD 2.20) for JAK2 ET vs 2.1 (SD 2.66) for PV, for bone pain was 1.8 (SD 2.97) for JAK2 ET vs 2.0 (SD 2.86) for PV, for fever was 0.5 (SD 1.46) for JAK2 ET vs 0.5 (SD 1.70) for PV and for weight loss was 0.3 (SD 0.73) for JAK2 ET vs 1.0 (SD 2.15) for PV (p>0.05 for all). Concerning change at 12 months, mean (SD) change in TSS was -0.5 (SD 10.86) for JAK2 ET (n=21) vs -0.8 (SD 13.32) for PV (n=66) (P=0.93). Mean for individual symptom scores at 12 months were also not significantly different between the two phenotypic disease group (P>0.05 for all parameters). (Fig 1, top panels). CALR vs JAK2 ET Exploring symptoms for CALR vs JAK2 ET: 45 patients were included; 9/16 (56.3%) CALR and 18/29 (62.1%) JAK2 patients were assigned to Rux (p=0.70). 10/16 (62.5%) CALR ET and 19/29 (65.5%) JAK2 ET. Baseline mean total symptom score (TSS) was similar (JAK2 ET: 18.9, SD 18.4 and CALR ET: 18.8, SD 16.99 (p=0. 0.98). All other baseline scores were comparable in this intolerant/ refractory population (p>0.05 for all. Concerning change at 12 months, mean (SD) change in TSS was -0.5 (SD 10.86) for JAK2 ET vs -2.8 (SD 9.96) for CALR ET (P=0.56). Mean for individual symptom scores at 12 months were also not significantly different between the two phenotypic disease group (P>0.05 for all parameters); the mean change in night sweats approached but did not reach significance similar (JAK2 ET: 0.2 (SD 1.89) and CALR ET: 1.8 (SD 3.07) (p=0. 0.06). (Fig 1, lower panels). Preliminary analysis of the MDASI and EQ5D-5L data at baseline and at 12 months shows similar results and will be presented. Conclusion This first analysis of its kind compared the symptom burden and other parameters of QoL of patients with PV and ET, resistant/intolerant to HC shows that with the exception of pruritus at baseline there were no substantial differences between JAK2 ET or PV. Equally changes in symptom burden across 12 months did not substantially differ between JAK2 ET or PV. A second analysis of JAK2 vs CALR ET also failed to show substantial differences. This data should be expanded in a larger cohort but supports a symptom continuum of JAK2 ET and PV and also JAK2 vs CALR ET. Figure 1 Figure 1. Disclosures Mead: Abbvie: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria. Knapper: Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Drummond: CTI: Membership on an entity's Board of Directors or advisory committees; BMS: 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. Mesa: Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Gilead: Research Funding; AOP: Consultancy; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy; La Jolla Pharma: Consultancy; Samus: Research Funding; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding; CTI: Research Funding. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. McMullin: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding. Harrison: CTI BioPharma: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Promedior: 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; Gilead Sciences: 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; BMS: 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; Janssen: 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; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Speakers Bureau; Geron: 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.

SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis.