EMATOLOGIA

MF is a clonal myeloproliferative neoplasm associated with splenomegaly, cytopenias and progressive bone marrow fibrosis (BMF) (Mughal. Int J Gen Med. 2014). Although RUX, a JAKi, is a standard therapy for patients with splenomegaly and/or symptoms, responses may be suboptimal/transient; and features, such as anemia, may worsen, presenting an unmet need in MF patients (Harrison. Cancer. 2024). PELA (DAK539), an investigational bromodomain and extra‑terminal inhibitor, modulates pro‑inflammatory and pro‑fibrotic pathways in MF pathogenesis (Rampal. Nat Med. 2025).

The MANIFEST study (NCT02158858) assessed PELA across various clinical settings; we report results from Arm 2, which evaluated PELA added to ongoing RUX in suboptimal responders.

Arm 2 enrolled adults with MF receiving RUX for ≥6 months at a stable dose for ≥8 weeks, with persistent splenomegaly or transfusion dependence. Patients were assigned to Cohort 2B (non-transfusion dependent [non‑TD]) or Cohort 2A (transfusion dependent [TD]). PELA 125 mg was administered orally once daily on Days 1–14 of 21‑day cycles; RUX was continued twice daily at pre‑study dose. Primary endpoints were spleen volume reduction ≥35% (SVR35) at Week 24 (W24) (Cohort 2B) and conversion from TD to transfusion independence (TI; Cohort 2A). Secondary and exploratory endpoints included total symptom score reduction ≥50% (TSS50), BMF, haemoglobin improvement and safety.

Eighty‑seven patients were treated (TD cohort = 59, non-TD cohort = 28). Median age was 69 years (41, 83); patients were Dynamic International Prognostic Scoring System category Intermediate-1 (8%), Intermediate-2 (63%) or high risk (29%). Pre-study RUX dose ranged 5–25 mg twice daily. Prior RUX median treatment duration was 30.2 months (3, 117), median spleen volume was 1860 cm³ (121, 7673), and median TSS was 19.7 (1, 61.6). W24 SVR35 was achieved in 15/83 (18.1%) evaluable patients, 9/55 (16.4%) TD patients and 6/28 (21.4%) non-TD patients. Overall SVR35 at any time was 28.8% and durable SVRs were observed with a median spleen response duration of 180.9 weeks (95% CL: 73.0, NE [not evaluable]). Among TD patients, TI was achieved by 12/46 (26.1%), with median time to TI being 12.4 weeks (0.1,45.1) and median TI duration being 68.0 weeks (95% CL: 34.7, NE). In non-TD patients, 6/28 (21.4%) achieved a hemoglobin response. W24 TSS50 was achieved by 32/85 (37.6%) evaluable patients, 21/58 (36.2%) TD patients and 11/27 (40.7%) non-TD patients; 47/82 (57%) evaluable patients had TSS50 at any time. W24 TSS mean absolute change (SD) was -7.39 (10.269). Among evaluable patients, BMF improved by ≥1 grade in 15/48 (31.3%) at W24 and 13/35 (37.1%) at W48. Most common grade ≥3 treatment‑emergent adverse events were thrombocytopenia (25.3%) and anemia (23%). No new safety signals were identified; overall safety profile was consistent with known PELA and RUX effects.

PELA added to RUX in MF patients with suboptimal response demonstrated meaningful clinical benefit, with improvements in SVR, TSS, haemoglobin, TD and BMF, alongside a generally manageable safety profile. These findings reinforce the therapeutic value of PELA+RUX across diverse MF settings including suboptimal responders to RUX.

Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm linked to dysregulated Janus kinase (JAK)-STAT signaling, characterized by splenomegaly, cytopenias, and substantial symptom burden (Mughal. Int J Gen Med. 2014). Monotherapy JAK inhibitors (JAKi), as current standard of care, offer inadequate durability of treatment response in a proportion of patients (Thaw. Curr Hematol Malig Rep. 2024). JAKi failure is associated with poor outcomes and reduced survival (Gill. Hematology Am Soc Hematol Educ Program. 2023), highlighting the unmet need for novel therapeutic approaches offering deep, durable responses, and potential to alter MF disease biology. Pelabresib (PELA), an oral, investigational, small molecule bromodomain and extra-terminal domain inhibitor, epigenetically modulates the dysregulated transcriptional and inflammatory pathways implicated in MF biology (Gomes & Harrison. Curr Hematol Malig Rep. 2023). In this study run by Marina Kremyanskaya et al. (Tisch Cancer Institute) arm 1 of the 4-arm, open-label, Phase 2 MANIFEST study (NCT02158858) investigated PELA monotherapy in primary or post-essential thrombocythemia/-polycythemia vera MF.

The aim of the study is to evaluate the safety, tolerability, and clinical activity of PELA monotherapy in JAKi-pretreated or JAKi-ineligible MF patients.

This study led by Moshe Talpaz et al. (University of Michigan) arm 1 patients were relapsed/refractory, intolerant, or ineligible for JAKi therapy and were assigned by transfusion dependence (TD) into cohorts 1A (TD) or 1B (non-TD). Patients received a starting dose of PELA 125 mg once daily for 14 days of every 21‑day cycle. Key inclusion criteria included dynamic international prognostic scoring system intermediate 2 (INT-2) or high-risk (HR), platelets ≥75×10⁹/L, blasts <10%, and ≥2 measurable MF symptoms using the Myelofibrosis Symptom Assessment Form v4.0; 1A required ≥6 red blood cell transfusions over the prior 12 wks; 1B required spleen volume ≥450 cm³. Primary endpoints were TD to transfusion independence (TI; no transfusion for ≥12 wks) (1A) and ≥35% spleen volume reduction (SVR35) at wk24 (1B). Secondary and exploratory endpoints included ≥50% symptom improvement (TSS50), bone marrow fibrosis (BMF) improvement, and safety.

A total of 100 patients (1A = 48, 1B = 52) were treated for a median duration of 46 wks (1, 364). Baseline characteristics showed a heavily pretreated, advanced MF population with substantial symptom and spleen burden: median age 71 years, 90% INT-2/HR, median spleen volume 1794 cm³ (281, 7371), median TSS 21 (1, 56), median hemoglobin 8.8 g/dL (6.1, 15.3). PELA demonstrated clinical activity in both cohorts with 26% (95% CI 13.5, 41.2; 11/43) TI in 1A and 19% (95% CI 9.6, 32.5; 10/52) SVR35 in 1B at wk24. Across both cohorts, TSS50 was 26% (24/94) at wk24, reflecting meaningful symptom improvement; mean absolute change was –8.92. Among evaluable patients, BMF improved by ≥1 grade in 18/54 (33.3%) at wk24 and 10/31 (32.3%) at wk48. Hemoglobin response was achieved in 24/52 (47.1%) patients in 1B. The safety profile was manageable; most common grade ≥3 treatment‑emergent adverse events were anemia (24.0%) and thrombocytopenia (16.0%).

PELA monotherapy demonstrated clinically meaningful single-agent activity and manageable safety profile in advanced MF patients, with improvements across MF hallmarks of splenomegaly, symptoms, anemia, and BMF. These results support the biological and clinical activity of PELA in this difficult-to-treat patient population and the continued development of PELA in MF.

Polycythaemia Vera (PV) is characterised by Janus Kinase/signal transducer and activator of transcription (JAK/STAT) activation, thrombotic and haemorrhagic events, sytemic symptoms, and risk of disease transformation. In high-risk patients with PV , the JAK inhibitor ruxolitinib normalises blood counts and improves symptoms. Here, in our study carried out by Tanveer Hamid,  we report a retrospective study on a cohort of high-risk PV patients treated with ruxolitinib,who exhibited intolerance or resistance to hydroxycarbamide. Outcomes of interest included change in haematocrit levels and subsequent phlebotomy requirements, documented spleen size and symptom burden , with reference to the MAJIC-PV Study. The aim of this study is to demonstrate replication of the findings of the MAJIC-PV study in a real world setting.

This is a single centre retrospective analysis of outcomes of PV patients who were intolerant or resistant to hydroxycarbamide (HC) and were initiated on treatment with ruxolitinib.Clinical response was assessed by evaluating full blood count (FBC) and haematocrit (HCT) levels,documenting venesection frequency prior to initiation of ruxolitinib therapy and at designated time points thereafter, documenting spleen size and defining symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).

A total of 12 patients with PV were followed in this analysis, all  JAK2V617F-positive, and identified as either resistant/intolerant to hydroxycarbamide. The age range was 48-81 years , with median age 72.5 years. There were 7 males and 5 females, and the duration of disease before initiation of ruxolitinib ranged from 2-216 months, median duration 77.5 months. Numbers of previous lines of therapy ranged from 1-2 , with a median of 1 previous therapy.n=4 (33%) were defined as HC intolerant, and n=8 (66%) defined as resistant. n=1 (8.33%) had a history of thrombosis,n=3 (25%) had a history of haemorrhage, and n=2 (16.6%) had diabetes, with n=7(58%) having hypertension.

Palpable spenomegaly was defined at baseline in n=4 (33%).Baseline FBC indices showed a median HCT of 0.473 (range 0.419-0.537). Looking at baseline venesection, 6months before initiation, n=9 , required venesection ranging from 1-7 episodes, with median 5 episodes. After 3 months of ruxolitinib, n=1 (1/12) required venesection - this was only 1 episode. At 6 months post initiation, n=5 had required a venesection, but the range was 1-2 episodes , with a median of 1 venesection in these 5 cases. Splenomegaly was no longer clinically apparent at the 3 month time point, and was subsequently maintained at T=6 months. MPN-SAF  scores at base line ranged from 0-11 with fatigue, pruritus, abdominal discomfort, night sweats and bone pain, being the most common symptoms. at T=3 months and at 6months, all symptoms had completely resolved except in n=2 patients with persisting fatigue. No deaths , thrombotic or haemorrhagic events, or infective issues/varicella zoster occurred. There were no discontinuations of ruxolitinib, and all n=12 remain on treatment.

Ruxolitinib is safe and well-tolerated in this cohort, with no discontinuations in therapy or infective complications. All patients with splenomegaly have had resolution on intitiation of ruxolitinib. There has been significant reduction in venesection requirements post initiation of therapy, and MPN-SAF scores demonstrate an improvement in well being with resolution of symptoms which has been  maintained. This real world data reflects the findings in the MAJIC-PV Study