The combination of ruxolitinib and the CDK4/6 inhibitor abemaciclib demonstrates safety and efficacy in previously treated myelofibrosis patients: Results of A phase I study Free

Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) are a standard of care for myelofibrosis (MF) patients with symptomatic splenomegaly and/or constitutional symptoms. However, JAK inhibitors often have a limited depth and duration of response. Thus, novel mechanism-based therapies are needed. JAK-STAT activating mutations, a hallmark of MF, promote G1/S-phase cell cycle transition via increased expression of CDC25A, Cyclin D and CDK6. Preclinical studies testing the combination of JAK inhibitors and CDK4/6 inhibitors (which are FDA-approved for breast cancer) in cell line and murine models of MF have demonstrated disease-directed biologic effects beyond those seen with JAK inhibition alone (Rampal et al. CCR 2021, Dutta et al. Cancer Res 2021). Based on these promising preclinical data, we hypothesized that the addition of the CDK4/6 inhibitor abemaciclib (ABE) to RUX in MF patients with persistent manifestation of disease despite RUX monotherapy is safe and will result in objective responses.

We conducted a phase I dose-escalation trial (NCT05714072) to evaluate the safety of combination therapy with RUX and ABE. Patients with MF treated with RUX for ≥12 weeks and an inadequate response to RUX, defined as either persistent radiographic splenomegaly (≥450 cm³) or MPN-SAF Total Symptom Score (TSS ≥5), platelets ≥75 × 10⁹/L and < 10% circulating or bone marrow blasts were eligible to enroll. Using a “3+3” design, three dose levels (DL) of ABE (50 mg, 100 mg, and 150 mg all BID) were combined with fixed doses of 10mg BID or 15mg BID of RUX. The primary endpoint was safety and identification of the recommended phase II dose of the combination. CTCAE v5.0 was used to grade adverse events (AEs). Dose-limiting toxicities (DLTs) were defined as grade ≥3 AEs during the first cycle of the combination treatment if deemed related to either study drug. Secondary endpoints included: spleen volume reduction by 25% (SVR25) and absolute MPN-SAF TSS change.

As of 6/30/2025, 9 pts were enrolled (3 pts per dose level). Median age at enrollment was 64 years [range:54-76], 66% were male. Prior treatments included RUX plus pelabresib/placebo (n=3), hypomethylating agents (n=2), hydroxyurea (n=2), stem cell transplant (n=1). 6 pts had a JAK2^V617F mutation and 3 pts a CALR mutation. Baseline disease characteristics of the cohort include (medians, with range): spleen volume 2303cm³ (531-3587cm³), MPN-SAF TSS 33 (14-47), WBC 26.5 K/uL (5-73 K/uL), peripheral blood blasts 4% (0-7%), LDH 943 U/L (202-2915 U/L). DIPSS scores were intermediate-1 (n=2) or intermediate-2/high (n=7). Median time on study was 8 cycles (range: 3 -14) with 6 patients still on treatment at data cut-off. No DLTs were observed. The most common AEs independent of attribution (all grade 1-2) were diarrhea (62.5%), anemia (75%), and thrombocytopenia (62.5%). Treatment-related AEs were largely grade 1-2, including diarrhea (62.5%), anemia (25%), and neutropenia (25%). Grade 3 events included anemia (n=2) and decreased neutrophil count (n=1). No AEs >grade 3 were observed and no patient discontinued treatment due to AEs. 3 patients discontinued study treatment due to investigator decision. At data cut-off, 6 of 8 treated pts were evaluable for spleen volume and symptom response. 5 of 6 evaluable patients (83%) achieved SVR25 and 3 of 6 patients (50%) achieved SVR35, with median SVR of -33% (-51.6% - +19.6%). Median change in absolute TSS was -9.5 (-13 - +4). Leukocytosis resolved in 4/6 evaluable patients by cycle 4 (C4); median baseline and C4 WBC 40.5 K/uL (20.8-73.29 K/uL) and 8.5 K/uL (3.9-22.5 K/uL), respectively. One patient achieved red blood cell transfusion independence. Serial driver mutation variant allele fraction (VAF) data was available from 3 patients (baseline versus cycle 13): VAF reductions were observed in two patients (JAK2: -25%, CALR: -20%), and one patient had a stable CALR VAF. Data on bone marrow fibrosis, cytokines and additional VAF data will be presented at the meeting.Conclusion: Combination therapy with RUX and the CDK 4/6 inhibitor ABE is safe and has encouraging objective evidence of efficacy among pts with advanced, previously treated MF, confirming preclinical hypotheses. These data nominate combined JAK and CDK4/6 inhibitor strategies for future investigation in JAK-STAT driven diseases. The combination of RUX and ABE will now advance to a phase II study in previously treated MF patients.