Modest Spleen Shrinkage Plus Transfusion Freedom Predicts Longer Survival in Myelofibrosis Patients on Momelotinib

Myelofibrosis is one of the most unforgiving cancers of the blood and bone marrow, a disease in which scar tissue slowly strangles the body’s ability to make blood cells, forcing patients to depend on transfusions while their spleens swell to enormous sizes as they take over blood production. Now, new post hoc analyses from two pivotal phase 3 trials, SIMPLIFY-1 and MOMENTUM, suggest that when patients treated with the drug momelotinib achieve two things at once—freedom from red blood cell transfusions and a reduction in spleen volume—their overall survival improves dramatically. The findings, published in Annals of Hematology by an international team led by Francesca Palandri of the IRCCS Azienda Ospedaliero-Universitaria di Bologna, offer clinicians a clearer picture of which early treatment responses actually translate into longer lives.

The two endpoints at the heart of the analysis, spleen volume reduction (SVR) and transfusion independence (TI), have each been linked individually to improved survival in myelofibrosis before. What remained unclear, and what this study set out to resolve, is how the two responses behave when they occur together in the same patient. Spleen volume is typically measured by MRI or CT, with a reduction of at least 35 percent from baseline serving as the traditional regulatory benchmark for a clinically meaningful response. Transfusion independence, meanwhile, is defined as freedom from red blood cell transfusions over a specified period, reflecting restored or at least adequate natural blood cell production. Because myelofibrosis ravages the bone marrow, many patients require transfusions every few weeks, so breaking that dependency is one of the most tangible quality-of-life and survival milestones in the disease.

To interrogate the joint contribution of these endpoints, the researchers analyzed data from patients with primary myelofibrosis or myelofibrosis that had developed from polycythemia vera or essential thrombocythemia, all treated with momelotinib. The SIMPLIFY-1 trial enrolled patients who had never received a JAK inhibitor, while MOMENTUM enrolled patients whose disease had already been treated with another drug in that class, most commonly ruxolitinib. This distinction matters clinically, because JAK inhibitor–experienced patients represent a harder-to-treat population with fewer remaining options. In both trials, the researchers defined a dual response as the combination of transfusion independence with spleen volume reductions meeting one of four thresholds: at least 35, 25, 15, or 10 percent from baseline, all assessed at week 24 of treatment.

The results were strikingly consistent. Across every spleen volume reduction threshold examined, patients who achieved both transfusion independence and SVR at week 24 showed numerically longer overall survival than those who did not. In SIMPLIFY-1, the hazard ratios for death among dual responders ranged from 0.26 for the lowest threshold combination of at least 10 percent spleen reduction plus transfusion independence, with a 95 percent confidence interval of 0.16 to 0.43, up to 0.64 for the highest threshold of at least 35 percent plus transfusion independence, with a confidence interval of 0.38 to 1.10. A hazard ratio of 0.26 means dual responders at the lowest threshold faced roughly a quarter of the mortality risk of nonresponders during the observation period—a profound difference in a disease where median survival from diagnosis can be measured in just a few years.

The magnitude of the survival separation is perhaps best appreciated through the median overall survival figures. In SIMPLIFY-1, dual responders meeting the SVR10 plus TI criteria had a median overall survival of 120.8 months, compared with just 41.5 months for nonresponders—nearly a decade of additional survival. In MOMENTUM, the pattern held even in the more refractory, JAK inhibitor–pretreated population: dual responders showed hazard ratios of 0.33 for SVR10 plus TI (95 percent CI 0.17 to 0.65) and 0.32 for SVR35 plus TI (95 percent CI 0.11 to 0.88). Remarkably, median overall survival was not reached among dual responders in MOMENTUM for either threshold combination, while nonresponders had median survivals of 28.7 months for the SVR10 plus TI comparison and 32.0 months for the SVR35 plus TI comparison. For a population that has already failed a prior JAK inhibitor, survival curves that never reach a median during follow-up represent an exceptional outcome.

One of the most clinically important patterns in the data is that the separation of survival curves was most pronounced at the lowest spleen volume reduction thresholds of at least 10 and at least 15 percent. In other words, when a patient achieves or maintains transfusion independence on momelotinib, even a relatively modest shrinkage of the spleen appears sufficient to confer a survival advantage. This challenges the conventional wisdom that only the full 35 percent reduction—the standard endpoint used in drug approval trials—signals a meaningful survival benefit. The biological interpretation is that transfusion independence may serve as a proxy for the drug’s broader effect on the anemic, inflammatory milieu of myelofibrosis, so that once the transfusion need is controlled, smaller reductions in spleen size capture enough of the disease-modifying effect to matter for survival.

Momelotinib occupies a distinctive niche among JAK inhibitors precisely because of this anemia profile. Unlike other agents in its class, which can worsen anemia and thrombocytopenia—two of the most debilitating features of myelofibrosis—momelotinib additionally inhibits activin A receptor type 1, a signaling node that drives the iron-regulatory hormone hepcidin and contributes to the anemia of inflammation. That dual mechanism is thought to explain why momelotinib can improve or maintain hemoglobin levels while shrinking the spleen, making it particularly suited to the transfusion-dependent patient population that these analyses focus on. The new findings suggest that this anemia benefit is not merely a comfort measure; it may be a central component of the drug’s survival impact when paired with even modest spleen responses.

As with all post hoc analyses, important caveats apply. These were not pre-specified primary endpoints but retrospective subgroup comparisons within randomized trials, and patients who respond well to treatment early on may differ in other ways from those who do not, a phenomenon known as immortal time and confounding by indication. The authors note that the association between dual response and survival was consistent across both treatment-naive and JAK inhibitor–experienced populations, which strengthens the biological plausibility of the finding, but the analyses cannot definitively prove that the dual response itself causes the survival advantage. The work was sponsored by GSK, the manufacturer of momelotinib, and several authors are company employees, with the remaining academic investigators disclosing extensive consulting and advisory relationships with GSK and other pharmaceutical companies active in the myelofibrosis field.

Nevertheless, the practical implications for clinicians are considerable. Spleen volume and transfusion status are routinely assessed in myelofibrosis care, and the week 24 timepoint evaluated here falls early enough in the treatment course to inform real decisions about whether to continue, switch, or intensify therapy. If confirmed in prospective studies, the finding that a 10 to 15 percent spleen reduction combined with transfusion independence marks a survival advantage could reshape how physicians interpret early imaging results, sparing patients whose modest but genuine responses might otherwise be judged inadequate under the traditional 35 percent benchmark. It could also inform the design of future clinical trials, where dual response at lower SVR thresholds might serve as a more sensitive surrogate endpoint for survival.

For patients, the message is one of cautious hope. Myelofibrosis remains a formidable disease, and allogeneic stem cell transplantation—the only curative option—is available to only a minority due to age and comorbidities. But the growing arsenal of targeted therapies, and the accumulating evidence that meaningful responses can be recognized earlier and at lower thresholds than previously assumed, is steadily changing the prognosis. These analyses, presented in part at the 2025 annual meeting of the American Society of Hematology, add a crucial piece to that picture: in the era of momelotinib, the combination of a smaller spleen and a full blood count sustained without donor blood may be one of the strongest early signals that a patient is living longer with their disease.

Subject of Research: Association of dual transfusion independence and spleen volume reduction with overall survival in myelofibrosis patients treated with momelotinib

Article Title: Dual transfusion independence and spleen volume reduction are associated with overall survival in patients with myelofibrosis treated with momelotinib: post hoc analyses of SIMPLIFY-1 and MOMENTUM

Article References: Palandri, F., Schaap, N. P. M., Rey, J., von Bubnoff, N., Reiter, A., Hernández-Boluda, J. C., Devos, T., Psaila, B., McLornan, D. P., Ellis, C., Zhang, S., Kim, S., & Oh, S. T. (2026). Dual transfusion independence and spleen volume reduction are associated with overall survival in patients with myelofibrosis treated with momelotinib: post hoc analyses of SIMPLIFY-1 and MOMENTUM. Annals of Hematology. https://doi.org/10.1007/s00277-026-07299-0

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07299-0

Keywords: myelofibrosis, momelotinib, transfusion independence, spleen volume reduction, overall survival, JAK inhibitor, SIMPLIFY-1, MOMENTUM, hematology, clinical trials, anemia, Annals of Hematology