Efficacy and Safety of Ruxolitinib for Treatment of Symptomatic Chronic Myelomonocytic Leukemia (CMML): Results of a Multicenter Phase II Clinical Trial

Abstract

Introduction CMML is a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with poor overall survival (OS). Like primary myelofibrosis, a large subset of CMML patients suffer from disease-related symptoms and splenomegaly that contribute to morbidity. 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 demonstrated activity in preclinical models and in a phase I/II clinical trial. The overall response rate in that trial was 38% by MDS/MPN IWG criteria and 43% of patients (pts) with baseline splenomegaly achieved a spleen response by palpation. However, that clinical trial did not systematically or objectively measure symptom burden or radiographic splenomegaly. Here, we report results of our second phase II clinical trial with ruxolitinib for treatment of CMML objectively measuring spleen responses and symptom improvement. Methods This was a phase II prospective multicenter study. Key eligibility criteria included confirmed diagnosis of CMML and having either symptomatic splenomegaly and/or a myeloproliferative neoplasms symptom assessment form (MPN-SAF) total score (TSS) >17, ANC ≥ 250/ul, and platelets ≥35,000 u/l. Ruxolitinib was administered at 20 mg po BID at the previously identified RP2D. Dose adjustments/holding occurred for both hematological and non-hematological parameters. The primary endpoint was clinical benefit or better response per International Working Group (IWG) criteria for MDS/MPNs and symptom improvement was assessed using the MPN-SAF TSS. Pts were treated at least for 16 weeks if no clear progression and those deriving a clinical benefit could continue on study. Serial blood counts, chemistry and bone marrow assessment were conducted to assure safety and assess efficacy. Spleen volume was measured by CT imaging and the percentage of spleen volume reduction (SVR) was captured. Daily measurements of the MPN-SAF were performed for up to 17 weeks while on study. Results A total of 29 pts were enrolled at 4 centers (Moffitt, John Hopkins, Cleveland Clinic and Dana Farber) between September 2019 and June 2022. The median age was 74 (63-87) years. The majority were white (93%) and male (62%) consistent with the known demographics of CMML. Most pts had CMML-0 (62%) and proliferative CMML (69%) by the French American British group criteria. Fifty nine percent were high risk by the Mayo Clinic CMML risk model. Two patients had prior hypomethylating agent treatment and two had prior hydroxyurea. The most common somatic mutations at baseline were TET2 (79%), SRSF2 (68%) and ASXL1(48%). NRAS (21%), CBL (37%), and JAK2 (21%) were seen at higher proportions than previously reported likely due to study inclusion criteria. The median duration of follow up was 16 months and at the data cut off 8 pts remains on treatment. The median duration on treatment was 4 mo (.5-23 mo). Treatment-related adverse events and reasons for discontinuation are similar to that reported in the initial phase 1/2 study. The overall response rate by MDS/MPN IWG criteria was 17%: 10% (3) partial response and 7% (2) marrow response; 69% (20) had stable disease and 14% (4) were not yet evaluable. In addition, a clinical benefit was achieved in 66% of pts (19/29). Among 20 pts evaluable for spleen response, 30% (6/20) achieved ≥ 35% SVR measured by CT scan and 10/20 (50%) had 10% or more SVR (Figure 1a). Fifty four percent of patients achieved MPN-SAF TSS >50% reduction at 60 days and all but four patients demonstrated an improvement in MPN-SAF TSS (Figure 1b). The estimated median overall survival was 24 months (95% CI 9-39). Conclusions Ruxoltinib demonstrated meaningful clinical activity in CMML patients with splenomegaly and/or high disease symptom burden. Two thirds of patients achieved clinical benefit, 33% had ≥ 35% SVR, and 54% had a reduction in TSS>50%. The overall survival compares favorably to historical data among higher risk CMML and the magnitude of symptomatic benefit is similar to that observed in primary myelofibrosis. Collectively, our data suggests that ruxolitinib is a viable therapeutic for patients with symptomatic CMML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal