For myelofibrosis, the treatment landscape is poised for change as new targets have emerged, and treatments are evolving beyond the standard Janus kinase (JAK) inhibitors. Novel therapies are being paired with the commonly used JAK inhibitor ruxolitinib, as reflected by a wealth of studies presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition. Here is a sampling of highlights.
96-Week Update of Phase III MANIFEST-2
The 96-week data for the phase III MANIFEST-2 trial of pelabresib combined with ruxolitinib have bolstered previous findings for the benefit of the combination of single-agent ruxolitinib as front-line therapy for myelofibrosis (MF).1 The results were presented by Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York.
“By addressing the underlying disease pathology, dual inhibition of both downstream JAK signaling and BET-mediated gene expression offers a paradigm shift in first-line therapy that may change the disease trajectory for patients with JAK inhibitor–naive myelofibrosis,” Dr. Rampal said. He added that the initial Week 24 data were informative, “but if we’re going to give patients combination therapy we need to see enduring durability of response,” and the updated Week 96 data provided that.
The global, randomized phase III MANIFEST-2 trial enrolled 430 patients with MF who had not received a JAK inhibitor. Patients were treated with pelabresib, an oral small molecule inhibitor of BET proteins, plus ruxolitinib or ruxolitinib alone. BET proteins target inflammatory pathways involved in MF. Both BET and JAK/STAT signaling pathways drive MF progression; their dual inhibition is believed to achieve deeper responses and potentially modify disease in JAK inhibitor–naive patients.
The study met its primary endpoint, showing a statistically significant improvement in spleen volume reduction (SVR) ≥ 35% (SVR35) response at Week 24 with the combination vs ruxolitinib. The median follow-up of 115 weeks, which yielded the Week 96 results presented at ASH 2025, constitutes the longest follow-up to date of a randomized combination trial in JAK inhibitor–naive patients with myelofibrosis, Dr. Rampal indicated.
At 96 weeks, key observations for pelabresib plus ruxolitinib vs ruxolitinib alone included:
- Deep and durable spleen volume reduction in evaluable patients: SVR35 was 91.5% vs 57.5%, with this response sustained in more patients on the combination.
- Sustained improvements in MF symptoms and anemia. An improvement of ≥ 50% in total symptom score (TSS; TSS50) was reported by 9% more patients on the combination than on ruxolitinib alone (37% vs 28%, respectively).
- Improvements at the bone marrow level, including bone marrow fibrosis, reduced megakaryocyte density, and recovery of CD71-positive erythrocyte progenitor cells. More than half (52.5%) of evaluable patients on the combination demonstrated an improvement in fibrosis of at least one grade, vs 27.5% with ruxolitinib alone.
- Reduction in the variant allele frequency (VAF) of driver mutations.
- Fewer progression-free survival events (progressive splenomegaly or leukemic transformation) with pelabresib plus ruxolitinib: 10.3% vs 15.7%, representing a 25% reduction in risk.
The safety profile of the combination was overall comparable to ruxolitinib alone, with numerically fewer deaths and progression events with the combination. At 96 weeks tolerability was comparable, including the occurrence of grade ≥ 3 events. Anemia was less common and thrombocytopenia more common with the combination.
Cases of leukemia transformation remained stable with the combination since the Week 48 data cutoff. In the placebo plus ruxolitinib arm, these increased from 0.9% at Week 48 to 3.7% at Week 96. Total cases of accelerated phase at Week 96 were 2.3% with the combination and 1.9% with placebo plus ruxolitinib; blast phase cases totaled 5.1% and 3.7%, respectively. The early imbalance in cases of leukemic transformation was in line with the previously observed frequency in myelofibrosis, Dr. Rampal noted.
“Collectively, we believe these data credential a novel therapeutic approach to myelofibrosis,” Dr. Rampal said, adding in the discussion session that “there are patients who do fantastically well with ruxolitinib alone, who have enduring responses for years, but we have to put effort into identifying patients who need a combination approach such as this one.”
Phase II RESTORE Trial
Elritercept given with ruxolitinib to patients with poor-prognosis MF showed “robust efficacy” in terms of multiple outcomes in the phase II RESTORE trial, said Ciro R. Rinaldi, MD, PhD, FRCPath, of United Lincolnshire Hospitals NHS Trust and University of Lincoln, in England.2
At the recommended phase II dose (3.75 mg/kg every 4 weeks), elritercept plus ruxolitinib reduced the need for red blood cell transfusion, increased levels of hemoglobin and platelets, and further reduced spleen volume and symptoms in patients with intermediate-2 or high-risk disease.
Dr. Rinaldi described the rationale for elritercept, noting the prevalence and challenge of treating anemia in MF. “JAK inhibitors such as ruxolitinib are effective in reducing spleen size and symptom burden but unfortunately are also associated with anemia and thrombocytopenia and this can limit their use, lead to suboptimal dosing and reduced clinical benefit. There is a need for therapies to rebalance the bone marrow structure and microenvironment and help hematopoiesis, in addition to reducing spleen size and symptoms.
“Elritercept was designed for that purpose,” he said. Elritercept is a modified activin receptor type IIA/IgG1 fusion protein. It selectively binds and potently blocks downstream signaling of the TGF-β superfamily ligands activin A and B and GDF8 and 11.
The drug was evaluated in a phase II study of 38 patients with primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF with anemia. All had severe anemia, and at least 60% were transfusion-dependent. Risk classifications by the Dynamic International Prognostic Scoring System (DIPSS) were intermediate-2 or high in about 90% of patients.
The key findings were these:
- At Week 36: 45% achieved red blood cell transfusion independence for ≥ 12 weeks and 39% achieved this for ≥ 16 weeks.
- At Week 36: 65% achieved ≥ 50% reduction in red blood cell transfusion.
- At Week 24: In non–transfusion-dependent patients, 36% and 50% achieved mean hemoglobin increases of ≥ 1.5 and ≥ 1.0 g/dL, respectively, over any 12-week period.
- In patients with baseline spleen volume ≥ 450 cm3, 21% achieved maximum spleen volume reduction (SVR) ≥ 25%; 8% achieved maximum SVR35.
- 90% of patients achieved a reduction in TSS during the study; for 48% this was a ≥ 50% reduction (TSS50).
- Changes in JAK2 V617F VAF were observed following treatment in several patients.
- Overall, elritercept was well tolerated when given with ruxolitinib.
“These findings support elritercept as a differentiated therapy in the treatment of patients with anemia and myelofibrosis, whether it is due to underlying disease, treatment with ruxolitinib, or both,” Dr. Rinaldi said.
Real-World Study of Ruxolitinib
A real-world study of ruxolitinib has provided reassurance that patients with MF can be treated long-term with this JAK inhibitor—including those with anemia and/or transfusion with appropriate dose-optimizing strategies, according to Prithviraj Bose, MD, of The University of Texas MD Anderson Cancer Center.3Most patients were not requiring transfusions at the time they initiated ruxolitinib. Those who were receiving transfusions often saw this need decline following ruxolitinib treatment. Nearly half became transfusion-free after 1 year of follow-up, he reported.
“This was pleasantly surprising,” Dr. Bose said in an interview with The ASCO Post.“We have the notion that ruxolitinib worsens anemia or at least does not improve it, but here in this real-world study, among the minority of patients who were transfusion-dependent going into the study, we saw many become transfusion-independent. That was very interesting.” He added “This may be happening because, with ruxolitinib, the spleen shrinks so well that in some patients their anemia improves.”
Ruxolitinib is approved for the treatment of intermediate- or high-risk MF. The poster presented at ASH examined the real-world duration of ruxolitinib treatment in a large cohort, based on a retrospective analysis using Medicare claims data. Dr. Bose and his team identified 2,268 adults with at least two claims for MF from January 2016 to December 2023 and at least one claim for ruxolitinib from January 2017 to December 2021; patients with a diagnosis of anemia, and those receiving transfusion, were identified. In this cohort, 96% were aged ≥ 65 years and therefore considered intermediate- to high-risk; approximately one-fifth had some comorbidity.
Median time from MF diagnosis to ruxolitinib treatment was 4.5 months, median duration of treatment was 3.1 years, and median follow-up was almost 4 years. Most patients (69%) starting the drug were treatment-naive. “This was good to see, because we know that if you start treatment early, you have a survival advantage,” Dr. Bose said.
The mean daily ruxolitinib dose was 23 mg at initiation and 21 mg at the last recorded dose; 91% had a dose change during follow-up (mean, −4.2 mg); 49% had a dose reduction and 41% had a dose increase. Among the 384 who required transfusion prior to index, 70% received transfusions during months 0–3, dropping to 52% during months 10–12 postindex. Overall, 36% of patients remained on ruxolitinib at the end of follow-up. After ruxolitinib discontinuation, 25% received another MF treatment, mostly hydroxyurea (11%), fedratinib (8%), and pacritinib (5%).
Agent Targets CALR Mutation
Phase I data presented at ASH suggest that INCA033989, a first-in-class antibody targeting mutant calreticulin (CALR), has activity in patients with myeloproliferative neoplasms whose disease has limited treatment options.4
A full report on the study of INCA033989 is on page 30. Notably, the findings offer “compelling proof-of-concept” for a differentiated, targeted treatment approach in MF, said lead author John O. Mascarenhas, MD, of the Icahn School of Medicine at Mt. Sinai, New York.
Stem Cell Transplant Still the Curative Approach
Stem cell transplant (SCT) remains the preferred curative approach for eligible patients with MF at higher risk. In a prospective study that compared outcomes between intermediate-2 and high-risk patients undergoing SCT or continuing on ruxolitinib, the SCT arm showed significantly improved event-free survival, with benefits consistent across age and DIPSS risk groups.5 Overall survival at 3 years was comparable and high in both arms, exceeding 80%, and SCT was associated with its well-known morbidities. However, nonrelapse mortality with transplant was 7%, reported Nico Gagelmann, MD, of University Medical Center, Hamburg-Eppendorf in Germany.
As Dr. Gagelmann noted, “Myelofibrosis patients with disease-related symptoms, or those who clearly fall outside the low-risk category, are candidates for JAK inhibition, investigational therapy, or transplantation. Ruxolitinib has been central to this… Its impact has been consistent and clinically meaningful and has reshaped patients’ lives. We see parallel improvement in spleen volume, response and symptom burden, and these benefits translate into survival with optimal dosing and sustained therapy being critical for maximizing outcomes.
“But these advantages and advances are not absolute. Ruxolitinib does not eliminate the disease completely, responses are not universal or indefinitely durable, and high-risk biologic features continue to drive poor outcomes, which is why, despite the progress enabled by JAK inhibitors, allogeneic transplantation remains the only curative treatment option for myelofibrosis and is still a critical component of management for appropriate candidates,” he continued.
Especially for patients with intermediate-2 and high-risk disease, SCT has yielded a meaningful long-term survival advantage over conventional management in both clinical trials and clinical experience. This has spurred an increase in transplant volume globally, “but this has been based on retrospective studies in the pre-JAK inhibitor era,” Dr. Gagelmann indicated. “Some other retrospective decision models have also questioned the benefit of transplantation in ruxolitinib-pretreated patients.”
To address these issues and determine if SCT is still superior, the investigators designed an open-label two-arm multicenter phase II trial to compare the efficacy of allogeneic SCT in patients with a suitable donor (HLA-identical sibling or 10/10 unrelated matched donor) to outcomes in patients lacking a donor. Patients undergoing SCT received 3 months of pretransplant ruxolitinib induction while the nontransplant patients received continuous ruxolitinib. The primary endpoint was event-free survival at 3 years, defined as survival without relapse, disease progression, death, or change in therapy. The full analysis population included 71 patients from 14 German centers, of whom 57 underwent SCT and 14 received continuous ruxolitinib.
Key outcomes for SCT vs continuous ruxolitinib at 3 years were:
- Improvement in event-free survival: median not reached vs 18 months (hazard ratio = 0.16; P < .001); rates were 75% vs 44%.
- Comparable overall survival: 84% vs 83%.
- Relapse rate: 18% vs 56% (P = .02).
- Nonrelapse mortality: 7% vs 0%; P = .04.
- Acute graft-vs-host disease with SCT: 27% grades 2 to 4; 7% grades 3 to 4.
- Chronic graft-vs-host disease with SCT: 63% all grades; 32% moderate to severe.
- SCT was associated with a steadily improving quality of life over time; continuous ruxolitinib followed a more intermittent course.
Dr. Gagelmann added, “Subgroup analysis confirmed consistent benefits of transplantation across relevant subgroups, such as age, disease type, risk and risk groups.” He pointed out that as expected, nonrelapse mortality was higher in the SCT arm, “but in absolute terms was relatively low, just 7%, and in addition disease-related mortality was lower in the transplant arm, being 9% compared to 17% in the ruxolitinib arm.” Noting that graft-vs-host disease continues to be an issue with SCT, he said, “Strategies are needed to mitigate transplant-related morbidity and mortality.”
DISCLOSURES: Dr. Rampal had disclosures for AbbVie, Blueprint Medicines, Bristol Myers Squibb/Celgene, CTI/Sobi, CTI BioPharma Corp, Cogent, Jubilant, Protagonist, Galecto, Geron, GSK, Incyte, Kartos, Karyopharm, Novartis, MorphoSys, Pfizer, PharmaEssentia, Promedio, Servier, Sierra Oncology, Stemline Therapeutics, Roche, Zentalis, and Sumitomo. Dr. Rinaldi had disclosures for MSD, GSK, and Novartis. Dr. Bose had personal financial disclosures for Incyte, BMS, Sobi, GSK, Novartis, AbbVie, Takeda, Merck, RayThera, Disc, Ionis, Sumitomo, Karyopharm, Geron, Pharma-
Essentia, Cogent, Blueprint, Morphic, Jubilant, and Deciphera. Dr. Mascarenhas had personal disclosures for Incyte, Novartis, BMS, Geron, Karyopharm, AbbVie, Sobi, MorphoSys, Roche, Merck, Keros, Disc, PharmaEssentia, Italfarmaco Spa, Sumitomo, GSK, Galecto, Pfizer, and Blueprint Medicines. Dr.Gagelmann had no disclosures.
REFERENCES
1. Rampal R, et al. Phase III MANIFEST-2 study. 2025 ASH Annual Meeting & Exposition (2025 ASH). Abstract 910. Presented December 8, 2025.
2. Rinaldi CR, et al. Updated results from the phase 2 RESTORE trial. 2025 ASH. Abstract 909. Presented December 8, 2026.
3. Bose P, et al. An analysis of the Medicare fee-for-service claims database. 2025 ASH. Abstract 6391. Presented December 8. 2025.
4. Mascarenhas JO, et al. Preliminary results from dose escalation of two global Phase 1 studies. 2025 ASH. Abstract 484. Presented December 8, 2025.
5. Gagelmann N, et al. The German MPN Study Group. Abstract 911. 2025 ASH. Presented December 8, 2025.
