Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone deacetylase inhibitors (HDACi) down-regulate JAK2 via interference with chaperone function. Pracinostat, a pan-HDACi, has modest single-agent activity in myelofibrosis. We conducted a single-institution, phase 2, investigator-initiated trial of ruxolitinib plus pracinostat (begun after 12 weeks of ruxolitinib) in 25 patients with myelofibrosis, of whom 20 received both agents. Sixteen (80%) patients had objective responses (all "clinical improvement"). The rate of spleen response (by palpation) was 74%, and that of symptom response 80%. Most responses occurred prior to pracinostat initiation. Three patients experienced improvement in bone marrow fibrosis, and one a near-complete molecular response after two years on study treatment. All patients discontinued pracinostat and are currently off-study. Pracinostat interruptions and dose reductions were frequent, often due to worsening anemia. These findings do not support continued development of pracinostat in myelofibrosis.

Myeloproliferative neoplasms (MPNs) are clonal disorders divided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) or Ph chromosome-negative MPNs. Co-occurrence of these disease entities is very rare and typically involves presence of common p190 or p210 BCR/ABL fusion transcript (responsible for CML) along with JAK2^V617F mutation (most common driver mutation in Ph-negative MPNs). Because of the rarity of such cases, it is not clear if the outcomes are any different in these patients. In this article, we report a unique patient with polycythemia vera driven by a rare complex in-frame deletion-insertion mutation in JAK2 exon 12, and CML driven by uncommon p210 e14a3 (b3a3) BCR/ABL fusion transcript. We describe clinical and laboratory features, bone marrow pathology, treatment, and overall outcome.

Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and is a frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb <10 g/dl on every determination for 12 w or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on it for ≥6 months with a stable dose for the preceding ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, or an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must be on-study for ≥12 w (84 d) to be response-evaluable. Results A total of 56 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty four pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Seventeen TD and 17 non-TD pts received sotatercept alone for a median of 11 (3-73) cycles. Sixteen pts received 0.75 mg/kg and 18, 1 mg/kg. Eight of 27 (30%) evaluable pts responded. Of these, 5 were anemia responses; 3 TD pts achieved TI. Six responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 19 (1-22) days and median duration of response (DOR), 23.3 (3.9-68.4) months. Seven pts (21%) were on-study for <84 d and hence not response-evaluable: 2 because of stem cell transplant (SCT), 2 due to logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Two pts continue on study. Reasons for d/c include lack or loss of response (14), progressive MF (6), SCT (4), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. Median rux dose at study entry was 10 (5-25) mg bid. Median number of cycles was 25 (2-49). Six of 19 (32%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (6-147) days and median DOR, 18.2 (3.7-56.8) months. Two pts (10%) were on-study for <84 d and hence not response-evaluable, 1 due to SCT and 1 due to loss of insurance. Two pts remain on study. Reasons for d/c include lack or loss of response (8), SCT (4), progressive MF (3), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 w because of early d/c from the study. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement for ≥12 w. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was <11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7) and limb (bone/muscle/joint) or back pain (n=2). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 30% when used alone and 32% when used in conjunction with a stable dose of rux. All responses in the rux cohort occurred in non-TD pts. The trial (NCT01712308) has been closed to new pt enrollment. Figure 1 Figure 1. Disclosures Bose: Sierra Oncology: Honoraria; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Promedior: Research Funding. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; DAVA Oncology: Consultancy; Celgene Corporation: Consultancy; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kadia: BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Novartis: Consultancy; AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Jazz: Consultancy; Liberum: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other. Andreeff: Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy; Syndax: Consultancy; ONO Pharmaceuticals: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Medicxi: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Aptose: Consultancy; Breast Cancer Research Foundation: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Senti-Bio: Consultancy. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Janssen: Honoraria; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Borthakur: Ryvu: Research Funding; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding. Huynh-Lu: Incyte Corporation: Speakers Bureau. Nguyen-Cao: Incyte Corporation: Speakers Bureau. Kantarjian: AbbVie: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Precision Biosciences: Honoraria; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Research Funding; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding. Verstovsek: NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Gilead: Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Sotatercept is an activin receptor ligand trap. This trial evaluates sotatercept for the treatment of anemia in patients with MPN-associated myelofibrosis.

New automated hematology analyzers have led to the availability of novel hematological parameters, including the immature platelet fraction (IPF) and the immature reticulocyte fraction (IRF), both of potential interest in patients with myeloproliferative neoplasms (MPNs). We performed a prospective analysis of 217 patients with MPN, including 32 (15%) with essential thrombocythemia (ET), 43 (20%) with polycythemia vera (PV), and 142 (65%) with myelofibrosis (MF); the IPF and IRF were measured by the Sysmex XN analyzer. As compared to patients with ET, both a higher IPF and IRF were observed among patients with PV and MF. Factors associated with high IPF among patients with PV/ET were male sex, thrombocytopenia, and diagnosis of PV; among patients with MF, they were elevated peripheral blasts, low platelet count, JAK2 V617F mutation, and previous therapy. Factors associated with high IRF among patients with PV/ET were low hemoglobin, high reticulocyte count, and PV diagnosis; among patients with MF, they were peripheral blasts and elevated reticulocytes. The IPF and IRF represent novel parameters in patients with MPN with potential relevant clinical implications. Comparison with healthy subjects and those with secondary polycythemia is needed to confirm our preliminary findings.

Background:Anemia is common in myelofibrosis (MF) and current treatments are unsatisfactory. Anemia is not improved, and often initially worsened by ruxolitinib (rux), the only approved treatment for MF. Sotatercept is a first‐in‐class, activin receptor IIA (ActRIIA) “ligand trap” that sequesters ligands that bind to the ActRIIA, some of which inhibit terminal erythropoiesis.Aims:To evaluate the efficacy and safety of sotatercept in anemic subjects with MF, alone and with rux.Methods:This ongoing, single‐institution, investigator‐initiated, phase 2, open‐label trial (ClinicalTrials.gov Identifier: NCT01712308) enrolls adults with primary MF or MF arising from polycythemia vera or essential thrombocythemia with anemia with or without RBC transfusion‐dependence (per International Working Group for Myelofibrosis Research and Treatment criteria). Sotatercept is given subcutaneously every 3 weeks. Subjects on the sotatercept‐only arm receive 0.75 or 1 mg/kg. Subjects on a stable dose (for ≥8 weeks) of rux receive 0.75 mg/kg of sotatercept and must have been on rux for ≥6 months. Responses include increases in hemoglobin (Hgb) of ≥1.5 g/dL (for ≥12 weeks) from baseline in anemia‐only subjects (without transfusions) and RBC transfusion independence in RBC transfusion‐dependent subjects. Subjects had to be on treatment for ≥84 days to be evaluable.Results:Of 48 subjects enrolled, 6 never began sotatercept and 1 received 0.3 mg/kg/dose; these subjects are not considered further. Of the remainder, 26 subjects received sotatercept only (12 received 0.75 mg/kg and 14, 1 mg/kg) and 15, sotatercept and rux. Baseline variables are displayed in the Table.Seven of 20 (35%) evaluable subjects in the sotatercept‐only cohort responded; 4 of 10 anemia‐only subjects and 3 of 10 RBC‐transfusion‐dependent subjects. Two other subjects who achieved ≥1.5 g/dL Hgb increases from baseline discontinued early for other reasons. Of 13 evaluable subjects receiving sotatercept and rux, 3 (23%) responded (all anemia‐only subjects). An additional subject had a 1.5 g/dL Hgb increase from baseline that was not sustained for ≥84 days due to the need for a rux dose increase from 10 to 15 mg twice daily. The median numbers of cycles of sotatercept were 5 (range, 1–53) and 10 (range, 2–26), and median times on study were 4 (range, 1–39+) and 7 (range, 2–31+) months, respectively, in the sotatercept‐only and sotatercept plus rux cohorts. Median time to response in the monotherapy cohort was 21 (range, 7–22) days and median duration of response was 12 (range, 4–39+) months. In the combination cohort, the 3 responses began at 7, 14 and 140 days, and are ongoing at 17+, 18+ and 30+ months. Several subjects in both cohorts required sotatercept to be held for Hgb ≥11.5 g/dL and resumed when Hgb <11 g/dL.Eight subjects remain on study, 4 in each cohort, including 2 responders in the sotatercept‐only cohort and 3 in the combination cohort. Reasons for discontinuation (n = 33) include no or loss of benefit (11), censoring because of a transplant (6), MF progression (7), patient choice (3), inability to comply with study requirements (2), hypertension (1), leukemic transformation (1), loss of health insurance (1) and unrelated medical problems (1).Sotatercept was well tolerated. Most adverse events (AEs) were grades 1 or 2. Grade 3 myalgias/arthralgias occurred in 2 subjects (5%). Grade 3 hypertension occurred in 6 subjects (15%) and grade 2 in 2 (5%). These were not associated with high Hgb values. No grade 4 AEs occurred.Summary/Conclusion:Sotatercept improves anemia of MF, both when given alone and in subjects receiving rux.image