Therapeutic effects of ruxolitinib in patients with myelofibrosis without clinically significant splenomegaly

To the editor:

Ruxolitinib is the first JAK inhibitor approved as therapy for high- and intermediate-risk myelofibrosis (MF). Two phase 3 trials have shown that ruxolitinib provides significant clinical benefit to patients with MF by reducing spleen size and ameliorating debilitating disease-related constitutional symptoms.^1,2  Patients participating in both studies were required to have clinically significant splenomegaly (at least 5 cm by palpation). Therapeutic benefit of ruxolitinib in patients without splenomegaly has never been documented. We recently reported long-term experience with ruxolitinib in 107 patients with advanced MF who participated in the phase 1-2 study at our center.³  Six patients from this study (Table 1) did not have palpable splenomegaly (4 had prior splenectomy). We describe their outcome in this letter.

Ruxolitinib improved disease-related symptoms in all patients within the first month of therapy. There was significant improvement in fatigue in all patients and resolution of drenching night sweats (2 patients), itching (2 patients), and bone pain and skin rash thought to be paraneoplastic (1 patient). Five patients had weight gain (up to 17%). Three of the splenectomized patients had abdominal pain and discomfort due to hepatomegaly. After 2 weeks of therapy, reduction of liver size could be appreciated that eventually decreased by 50%-68% (16 to 5 cm, 16 to 5 cm, and 14 to 7 cm, respectively). Time to best response varied from 3-24 months, a slower pace of reduction than reported for the response in splenomegaly.^1,2  Patients with marked leukocytosis and thrombocytosis normalized their blood counts. Treatment was well tolerated without drug interruptions due to toxicity. Adverse effects were limited to grade 3 myelosuppression (thrombocytopenia ×1, anemia ×2), requiring dose modification in 3 patients. No significant (grade 3 or 4) nonhematologic adverse events were observed. Median duration of therapy is 36 months (range 21-54+). Four patients discontinued ruxolitinib due to transformation to acute myeloid leukemia (AML; patient 1), disease progression (patient 4), or death due to other medical reasons (patients 2 and 3). Patient 1 had abnormal cytogenetics and 11% blasts in the bone marrow while starting therapy with ruxolitinib; he did not progress to AML for 2 years. Instead, he gained weight and improved his performance status, and is now in remission 30 months after induction chemotherapy and unrelated-donor hematopoietic stem cell transplantation. Two patients are continuing ruxolitinib after more than 54 and 45 months (patients 5 and 6, respectively). Particularly in patient 6 (who had very high WBC count and complex cytogenetics; very high-risk MF with expected average survival of only 9 months), an excellent disease control was observed.^1,3 

In this small cohort of patients, we could witness a positive effect of ruxolitinib on patient symptoms not related to reduction of spleen size. As the liver becomes the primary site of extramedullary hematopoiesis in patients after splenectomy it seems to respond to ruxolitinib in a similar way. Overall, treatment with ruxolitinib alleviates symptom burden and improves quality of life of patients with advanced MF without clinically significant splenomegaly.