Selinexor Plus Ruxolitinib Decreases Spleen Volume in Myelofibrosis

Haris Ali, MD

Significant reduction in spleen volume, total symptom score and hemoglobin stabilization was achieved with the combination of selinexor (Xpovio) and ruxolitinib (Jakafi) in an open-label dose-escalation/dose-expansion, phase 1 study of patients with treatment-naïve myelofibrosis that was presented during the 2022 ASH Annual Meeting.¹

Adverse events (AEs) were generally manageable with the combination, with no clinically relevant grade 3/4 AEs and no bleeding, serious infections, or clinical sequalae.

With once weekly oral selinexor at either 40 mg or 60 mg plus ruxolitinib at 15/20 mg twice daily given in 28-day cycles, “all patients had a reduction in spleen volume on the treatment,” said presenting author Haris Ali, MD, of City of Hope Medical Center in Duarte, California.

Eleven of 12 (92%) efficacy-evaluable patients achieved a spleen volume reduction (SVR) of 35% or greater (SVR35) at week 24 of treatment, which was a key secondary endpoint of the study. At 24 weeks, 4 of 6 (67%) achieved a reduction in the TSS of 50% or greater (TSS50).1 No patient had an increase in spleen volume from baseline. The median change in spleen volume was –45% at week 12 and –49% at week 24.

Responses were also noted in those who received low doses of ruxolitinib (5 mg twice daily).

“These data demonstrate that the combination of selinexor and ruxolitinib has the potential to be a novel first-line treatment for myelofibrosis patients,” Ali said.

In the primary analysis population, the rate of SVR35 at week 24 was 69% (n = 11/16) and the rate of TSS50 was 33% (n = 4/12). The primary analysis population consisted of patients who had available baseline assessment and were treated until 12 or 24 weeks or discontinued before these timepoints. Patients with missing data at each timepoint were considered nonresponders.

Overall, 13 of 23 (56.5%) transfusion-independent patients who had at least 8 weeks of treatment had less than 2-g/dL decreases in hemoglobin (Hb) level, including 9 of 11 (81.8%) with a baseline Hb less than 10 g/dL. When broken down by selinexor dosage, all 4 transfusion-independent patients with a baseline Hb less than or equal to 10 g/dL who were treated with 40 mg once weekly and 5 of 7 (71.4%) treated with 60 mg had a less than 2-g/dL decrease in Hb level.

Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with approved indications in multiple myeloma and diffuse large B-cell lymphoma. XPO1 is a RAN-dependent nuclear export factor that facilitates the nonredundant nuclear to cytoplasmic transport of many cargo proteins and protein-RNA complexes, which includes tumor suppressors proteins and oncogene RNAs, Ali said.

RAN and XP01, key proteins of nucleocytoplasmic transport, are important for the survival and proliferation of cellular myelofibrosis models with aberrant activation of JAK/STAT signaling1, Ali said in providing the rationale for studying this combination.

Previously on this study, the authors reported results from week 12 treatment, at which time 75% of evaluable patients achieved an SVR35.2

As of Oct 21, 2022, 24 patients have been dosed: 40 mg of selinexor (n = 11) and 60 mg (n = 13) weekly in combination with ruxolitinib at 15/20 mg twice daily as per standard of care. One patient received 20 mg of selinexor for 3 cycles, then switched to 60 mg and was included in the 40-mg group for the purpose of this analysis. For prophylaxis of nausea, all patients received a 5-HT3 antagonist prior to each selinexor dose and then as needed.

Eleven of the 24 (45.8%) patients had primary myelofibrosis, 6 (25.0%) had post-essential thrombocythemia myelofibrosis, and 7 (29.2%) had post-polycythemia vera myelofibrosis. At baseline, 1 patient had packed red blood cell transfusion–dependent anemia. Dynamic International Prognostic Scoring System (DIPSS) risk category was intermediate-1 in 7 (29%) patients, intermediate-2 in 11 (45.8%), and high risk in 6 (25.0%).

The safety population included all patients who received at least 1 dose of selinexor (n = 24). There were no dose-limiting toxicities observed at either selinexor dose level. The most common treatment-emergent AEs were nausea (75%), anemia (62.5%), fatigue (58.3%), and thrombocytopenia (54.2%), the majority of which were grades 1/2. The most common reported grade 3/4 treatment-emergent AEs were anemia (37.5%) and thrombocytopenia (20.8%), both of which were reversible.

Eligible patients had a spleen volume of 450 cm³ orlarger by imaging; were intermediate-1 with symptoms, intermediate-2, or high-risk on the DIPSS; had an ECOG performance status of 0 to 2, and a platelet count of at least 100 x 10⁹/L.

Ten patients in the study discontinued treatment with selinexor plus ruxolitinib, two patients had progressive disease, one patient transformed to acute myelogenous leukemia, 2 discontinued due to treatment-related adverse events, another 2 patients underwent transplant, 1 patient withdrew from the study, there was 1 unrelated death, and 1 withdrawal due to physician decision.

Enrollment has been completed in the dose-expansion phase of the study.

_References

_{1. Ali H, Maher K, Kishtagari A, et al. A phase 1, open-label, dose-escalation study of Selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 1734.}

_{2. Ali H, Kishtagari A, Maher KR, et al. A phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis. J Clin Oncol. 2022;40(16): 7060.}