Narrative review proposes phenotype-driven framework for managing myelofibrosis splenomegaly

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Frontiers in Medicine Published May 26, 2026 Medically reviewed May 26, 2026 Study authors: Yousef Al-Asa’d, Nabeel Qasem, Awni Alshurafa, Khalil Al-Farsi, Mohamed A. Yassin DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider a phenotype-driven framework for myelofibrosis splenomegaly management.

This narrative review focuses on the management of splenomegaly in patients with myelofibrosis. The scope encompasses a range of medications including ruxolitinib, fedratinib, pacritinib, momelotinib, pelabresib, navitoclax, and hydroxyurea. The authors aim to provide a structured approach to treatment selection based on patient phenotypes rather than relying on a single universal protocol.

The primary synthesized finding highlights that emerging combination strategies demonstrate superior reduction in spleen volume. Specifically, the combination of pelabresib plus ruxolitinib and navitoclax plus ruxolitinib are identified as showing this superior effect. The review also considers secondary outcomes such as symptom burden, portal hypertension, cytopenias, and spleen volume reduction.

Important limitations are noted regarding the available data. Specific adverse events, serious adverse events, discontinuations, tolerability, and sample sizes were not reported in the source document. Consequently, the certainty of the findings regarding safety profiles remains unclear based on this narrative synthesis alone.

The practice relevance of this review lies in its proposal of a practical phenotype-driven treatment framework. Clinicians should interpret these findings as a conceptual guide rather than definitive trial data. The absence of reported safety data means that caution is required when applying these combination strategies to individual patients.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Myelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, constitutional symptoms, cytopenias, and splenomegaly. Splenic enlargement, driven primarily by extramedullary hematopoiesis, represents a hallmark of MF and contributes substantially to symptom burden, portal hypertension, and worsening cytopenias through splenic sequestration. The identification of constitutive Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway activation as the central pathogenic mechanism in myeloproliferative neoplasms led to the development of JAK inhibitors, which have become the cornerstone of therapy for spleen volume reduction and symptom amelioration. Four JAK inhibitors—ruxolitinib, fedratinib, pacritinib, and momelotinib—are currently approved by regulatory agencies, each exhibiting distinct pharmacological profiles suited to different clinical phenotypes. Ruxolitinib remains the first-line standard for patients with adequate platelet counts, pacritinib is preferred in severe thrombocytopenia, and momelotinib is the agent of choice in anemia-dominant disease. Fedratinib serves as an effective second-line option following ruxolitinib failure. Emerging combination strategies, including pelabresib plus ruxolitinib and navitoclax plus ruxolitinib, have demonstrated superior spleen volume reduction in phase III trials and represent a promising therapeutic frontier. Conventional agents such as hydroxyurea and immunomodulatory drugs retain a role in select patients. Non-pharmacologic interventions—including splenectomy, splenic irradiation, partial splenic artery embolization, and radiofrequency ablation—remain valuable for patients refractory to or ineligible for medical therapy. This review provides a comprehensive and updated overview of the management of splenomegaly in MF, integrating all four approved JAK inhibitors, emerging combination therapies, peri-transplant considerations, and procedural approaches, and proposes a practical phenotype-driven treatment framework.