Abstract
Abstract Background: Current therapeutic strategies for Myelodysplastic/Myeloproliferative Neoplasms overlap syndromes (MDS/MPN) remain suboptimal. Selinexor, an innovative oral selective inhibitor of exportin 1, presents a promising mechanism-based therapeutic approach. Both preclinical and clinical evidence suggest synergistic antileukemic effects when selinexor used in conjunction with hypomethylating agents or JAK inhibitors.
Patients and Methods: A prospective exploratory single arm trial was conducted to evaluate the efficacy and safety of the selinexor in combination with either azacitidine or ruxolitinib in patients with MDS/MPN. Treatment was tailored based on the predominant clinical features: of the patients those exhibiting myelodysplastic syndrome (MDS)-dominant characteristics received, selinexor in combination with azacitidine, whereas those with myeloproliferative neoplasm (MPN)-dominant characteristics were administered selinexor alongside ruxolitinib. The primary endpoint was the overall response rate (ORR) at six months, evaluated according to the 2015 International Working Group (IWG) criteria for MDS/MPN. Safety, progression and survival were secondary endpoints. This trial was registered at Clinicaltrials.gov as NCT06664970.
Results: A cohort of 20 patients was enrolled in the study, containing 4 individuals exhibiting MDS-dominant characteristics and 16 individuals with MPN-dominant phenotypes. The median age of patients with MDS-dominant phenotypes was 66 years, with one female participant (25%), whereas the median age for those with MPN-dominant phenotypes was 62.5 years, including six female participants (37.5%). The ORR at six months for the entire cohort was 60.0% (12 out of 20 patients). Among the MDS-dominant group (N=4), the ORR was 75% (3 out of 4 patients). Clinical benefits (CBs) observed in this subgroup included improvements in total symptom score (TSS) (25%, 1 out of 4), erythroid response (25%, 1 out of 4), platelet response (25%, 1 out of 4), and neutrophil response (25%, 1 out of 4). In the MPN-dominant group (N=16), the ORR was 56.3% (9 out of 16 patients), with partial responses noted in 12.5% (2 out of 16) and partial marrow responses in 18.8% (3 out of 16). CBs in this group included spleen response (31.3%, 5 out of 16), TSS improvement (12.5%, 2 out of 16), erythroid response (12.5%, 2 out of 16), and platelet response (6.3%, 1 out of 16). Adverse events (AEs) were reported in 14 patients (70.0%), predominantly transient and not necessitating modifications to treatment; however, three patients (15.0%) experienced grade ≥3 AEs, with two fatalities (10.0%) attributed to these events. Across the entire cohort, with a median follow-up duration of 6 months (range: 3-9 months), two patients (10.0%) died and one patient (5.0%) transformed to acute myeloid leukemia.
Conclusion: The combination of selinexor with azacitidine or ruxolitinib showed good efficacy and safety in MDS/MPN patients.
Key word: Myelodysplastic/Myeloproliferative Neoplasms; Selinexor; Azacitidine; Ruxolitinib; Efficacy
