In a phase II trial, treatment with the JAK2 inhibitor ruxolitinib resulted in clinical activity in two-thirds of patients with chronic myelomonocytic leukemia (CMML) with splenomegaly or an otherwise high disease symptom burden. The magnitude of symptomatic benefit was similar to that observed in primary myelofibrosis, for which this drug is approved.

“Our data suggest that ruxolitinib is a viable therapeutic for patients with symptomatic CMML,” said Eric ­Padron, MD, Associate Member in Malignant Hematology at Moffitt Cancer Center, Tampa, Florida, who presented the findings at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

Eric ­Padron, MD

As with primary myelofibrosis, a large subset of patients with CMML experience disease-related symptoms and splenomegaly. “We have demonstrated that CMML is molecularly characterized by hematopoietic stem and progenitor cell hypersensitivity to granulocyte-macrophage colony-stimulating factor [GM-CSF]. As the sentinel kinase required for GM-CSF signaling, JAK2 represents a rational therapeutic target in CMML, and pharmacologic inhibition has shown activity in preclinical models,” Dr. Padron said.

Earlier-phase studies have shown responses to the drug, but these studies did not objectively measure spleen response and symptom improvement. That was the intention of the current study.

The study enrolled 29 patients with symptomatic splenomegaly or myeloproliferative neoplasms with a Myeloproliferative Neoplasm–Symptom Assessment Form Total Symptom Score (MDS-SAF TSS) of at least 17. They were treated with ruxolitinib at 20 mg twice daily upfront or, for 7%, after therapy with hypomethylating agents. Patients had an absolute neutrophil count of at least 250/µL and a platelet count of at least 35,000/μL. All patients underwent computed tomography (CT) scans for spleen measurement at screening and at week 17 and had symptoms recorded during treatment using a validated instrument.

Outcomes With Ruxolitinib

The bone marrow response rate per the Myelodysplastic Syndrome/Myeloproliferative Neoplasm International Working Group criteria was 17%. This included partial responses in 10% and bone marrow responses in 7%; stable disease was achieved in 69% of patients; 14% of patients were not evaluable, Dr. Padron reported.

The median duration of response was 9.6 months, and seven patients have remained on study treatment for more than 12 months. Four patients discontinued treatment due to toxicity, primarily low platelet counts. One patient transitioned to bone marrow transplantation. There was no one genotype that responded better than others, he said.

Although the two patients with prior hypomethylating agents did not derive a benefit from the drug, Dr. Padron’s group has now treated 80 patients with CMML and has found response rates to be “similar” between patients with and without prior hypomethylating agents, he said. They also saw no hematologic responses on this study but have observed such responses in a phase I study, “some being quite striking—going from transfusion-dependent to -independent,” he added, though he cautioned that this is rare.

Of 20 patients objectively evaluated for splenomegaly (median spleen volume of 681 cm³ at baseline), 6 (33%) had a reduction in spleen volume of at least 35%, and 10 (50%) had a reduction of at least 10%. The median MPN-SAF TSS was 31 at baseline, and ruxolitinib resulted in a reduction of at least 50% in 54% of patients. All but four patients had some reduction in symptom score.

“I can tell you that for the patient who has been on the study the longest—33 months—the primary symptom was debilitating joint pain in the context of being ANA [antinuclear antibodies]-negative. He had a dramatic improvement in joint pain in his hands,” Dr. Padron noted.

CMML is a clinically heterogeneous malignancy, with reported survival ranging from 5 to 25 months. In this study, median overall survival was 24 months, “which compares favorably with historical data among higher-risk CMML,” Dr. Padron commented. “The magnitude of symptomatic benefit is similar to that observed in primary myelofibrosis.” 

Expert Point of View

Mrinal S. Patnaik, MBBS, Chair of the Acute Leukemia and Myeloid Neoplasms Group and Scientific Director of the Epigenetics Developmental Laboratory and the Epigenomics Program at the Mayo Clinic, Rochester, Minnesota, offered his thoughts on the phase II study findings of ruxolitinib’s efficacy in CMML.

He explained that CMML is a neoplasm that overlaps myelodysplastic syndrome and myeoloproliferative neoplasms, with proliferative and dysplastic subtypes. Although treatment with hypomethylating agents is the approach approved by the U.S. Food and Drug Administration, these drugs do not alter mutational allele burdens and have not clearly been shown to be effective in prospective clinical trials for proliferative subtypes. Patients with proliferative disease often develop splenomegaly and constitutional symptoms related to the same. Apart from hydroxyurea, there are limited management options for these symptoms, Dr. Patnaik noted.

“Biologically, given that CMML (especially RAS-mutant proliferative subtypes) has an inherent hypersensitivity to GM-CSF [granulocyte-macrophage colony-stimulating factor] and the fact that the JAK/STAT pathway is a major constituent of GM-CSF signaling, there is a clear rationale to test the safety and efficacy of JAK inhibitors for CMML,” he said.

“In this phase II study, Padron et al demonstrate a potential role, including safety data, for the JAK2 inhibitor ruxolitinib in managing splenomegaly and constitutional features in patients with CMML. This is an important and unmet area for these patients, and further randomized trials looking at spleen volume response and improvement in symptoms scores as primary endpoints are greatly encouraged,” he commented.

DISCLOSURE: Dr. Padron has received research funding from Incyte, BMS, Kura Oncology, and Syntrix Pharmaceuticals and has received honoraria from Blueprint, Taiho, and Stemline Therapeutics. Dr. Patnaik has received research funding from Stemline Therapeutics and Kura Oncology and has served on the advisory board for CTI Pharmaceuticals.

REFERENCE

1. Padron E, Tinsley-Vance SM, DeZern AE, et al: Efficacy and safety of ruxolitinib for treatment of symptomatic chronic myelomonocytic leukemia. 2022 ASH Annual Meeting and Exposition. Abstract 457. Presented December 11, 2022.