Ruxolitinib Discontinuation Syndrome in a Patient with Primary Myelofibrosis

A 62-year-old man with JAK2V617F-positive primary myelofibrosis was initiated on ruxolitinib therapy following progressive splenomegaly and significant constitutional symptoms affecting quality of life. Given his preserved platelet count, ruxolitinib was initiated at 20 mg twice daily, with rapid symptomatic improvement and a reduction in spleen size by > 50%. Over the next 18 months, the patient maintained clinical benefit, including improved appetite and resolution of night sweats.

 After 20 months of therapy, the patient developed progressive thrombocytopenia (platelets < 80 × 10⁹/L) and anemia, prompting a dose reduction of ruxolitinib to 10 mg twice daily. Despite this adjustment, the patient’s thrombocytopenia worsened, and ruxolitinib was discontinued without any further dose reductions due to concern for bleeding risk. Within 5 days of cessation, the patient presented to the emergency department with fever, acute respiratory distress, hypotension, and worsening splenomegaly. CT imaging revealed bilateral pulmonary infiltrates consistent with acute respiratory distress syndrome (ARDS), and labs showed elevated inflammatory markers and leukocytosis.

The clinical picture was consistent with ruxolitinib discontinuation syndrome, a cytokine rebound phenomenon characterized by systemic inflammation, splenic re-expansion, and multi-organ dysfunction. The patient required intensive care unit admission and vasopressor support. Corticosteroids were initiated empirically, and ruxolitinib was cautiously restarted at 5 mg twice daily. Within 72 hours, the patient’s respiratory status improved, and vasopressors were weaned. After a nearly 2-week hospitalization, the patient was discharged to a rehabilitation facility with plans to follow up in the outpatient setting with his oncologist for further adjustments to ruxolitinib or to consider alternative therapies.

Discontinuing or Transitioning Between JAK Inhibitors

“Ruxolitinib withdrawal syndrome,” or “ruxolitinib discontinuation syndrome,” is characterized by sudden worsening of disease symptoms, rapid rebound splenomegaly, and worsening of cytopenias.¹ Ruxolitinib discontinuation syndrome typically occurs within 21 days of therapy cessation without clear correlation to the prescribed dose.^1-3 Occasionally, ruxolitinib discontinuation may be associated with severe symptoms including hemodynamic instability, shock, or ARDS. In rare cases, ruxolitinib discontinuation syndrome has been fatal.^2-6 This patient case underscores the potential serious complications of abrupt ruxolitinib discontinuation.

There are no standard guidelines for the prevention and management of ruxolitinib discontinuation syndrome. However, current literature suggests that tapering ruxolitinib over 1–2 weeks, with or without corticosteroid prophylaxis, may mitigate the risk of discontinuation syndrome.^1,7,9 When transitioning from one JAK inhibitor to another, transition strategies include (1) tapering off one medication completely before initiating another, (2) tapering off one medication while simultaneously gradually up-titrating another, or (3) transitioning immediately from one JAK inhibitor to another without a taper or washout period.^7,9

Several studies have demonstrated the safety and efficacy of patients with myelofibrosis who were transitioned directly from one JAK inhibitor to another. A retrospective analysis from the prospective SIMPLIFY-1 trial evaluated the safety of transitioning directly from ruxolitinib to momelotinib in 197 patients. In this study, immediate transition from ruxolitinib to momelotinib was not associated with signs or symptoms of ruxolitinib discontinuation syndrome, and control of spleen volume was maintained in this patient cohort.¹⁰

Transition strategies between different JAK inhibitors should consider medication-specific pharmacokinetics such as half-life and JAK1 activity as well as patient-specific risk factors such as splenomegaly, symptom and disease burden, and thrombocytopenia.^7,9 Patients should be educated on the signs and symptoms of ruxolitinib discontinuation syndrome (e.g., fever, rebound splenomegaly, respiratory distress, low blood pressure, etc.) as well as on the importance of discussing any dose reductions or discontinuations with their medical team. Practical tips on how to avoid missing prescribed doses of JAK inhibitor therapy and to ensure continued access to the medication from the patient's dispensing pharmacy are additional helpful components of comprehensive patient education. Clinicians should maintain a high level of suspicion for ruxolitinib discontinuation syndrome and establish institutional protocols for safe discontinuation and transition between JAK inhibitors.

Conclusions

Management of JAK inhibitor discontinuation—particularly ruxolitinib—requires careful planning to prevent discontinuation syndrome, a potentially life-threatening rebound phenomenon associated with sudden onset of constitutional symptoms, accelerated splenomegaly, and worsening cytopenias. Best practice includes tapering the dose over 1–2 weeks (or longer depending on the current dose and disease burden). Prophylactic corticosteroids during tapering or for up to several weeks post-discontinuation may further reduce the risk of discontinuation syndrome. When transitioning to alternative JAK inhibitors, clinicians may choose between sequential discontinuation and initiation, overlapping therapies, or direct switching—guided by pharmacokinetics and JAK1 activity as well as patient-specific factors. Several studies have demonstrated the safety of immediate transition from one JAK inhibitor to another, without a taper or washout period. In emergent discontinuation scenarios, early recognition of discontinuation syndrome and prompt reinitiation of JAK inhibition alongside supportive care and corticosteroids is key. Practitioners should develop institutional standards to guide JAK inhibitor tapering and/or transitions to optimize outcomes.

References

1. Ruxolitinib (Jakafi). Package insert. Incyte; 2021.
2. Palandri F, Palumbo GA, Elli EM, et al. Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis. Blood Cancer J. 2021;11(14):1–9. doi:10.1038/s41408-020-00392-1.
3. Houthuys JF, Wilmer AP, Peetermans M, Meersseman P, Devos T. Severe ARDS due to Ruxolitinib discontinuation syndrome: case presentation and literature review. Heliyon. 2022;8(12):e11782. doi:10.1016/j.heliyon.2022.e11782.
4. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86(12):1188–1191. doi:10.4065/mcp.2011.0518.
5. Coltro G, Mannelli F, Guglielmelli P, et al. A life-threatening ruxolitinib discontinuation syndrome. Am J Hematol. 2017;92(8):833-838. doi:10.1002/ajh.24794.
6. Barbui T, Vannucchi AM, Alvarez-Larran A, et al. High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib. Leukemia. 2021;35(2):485–493. doi:10.1038/s41375-020-01084-6.
7. O’Sullivan J, Omerdeen I, Psaila B. When, which and how to switch: Navigating JAK inhibitors in myelofibrosis. Br J Haematol. 2024 Nov 27. doi:10.1111/bjh.19929.
8. Arnall J, Elmes J, Yogarajah U, Meek B, Moore DC. Managing and mitigating discontinuation syndrome with ruxolitinib and other novel JAK inhibitors for myelofibrosis. J Hematol Oncol Pharm. 2025;15(1):36–41.

9. Mesa R, Verstovsek S, Platzbecker U, et al. Clinical outcomes of patients with myelofibrosis after immediate transition to momelotinib from ruxolitinib. 2023;109(2):676-681. doi: 10.3324/haematol.2023.283106.