Greater reductions in driver mutation variant allele frequency (VAF) were observed with selinexor plus ruxolitinib, with VAF reductions of at least 20% achieved in 32.0% of patients compared with 23.9% with ruxolitinib alone. In addition, selinexor plus ruxolitinib reduced circulating peripheral blasts in patients with detectable blasts at baseline while maintaining zero circulating blasts in those without baseline blasts.²

The safety profile was consistent with previous experience of selinexor. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred more frequently with the combination (70.1% versus 50.0%),² with higher rates of hematologic toxicity, fatigue and nausea (data shown during webinar presentation). Grade ≥3 TEAEs leading to treatment discontinuation occurred in 14.5% and 8.6% of patients, respectively.²

Collectively, the SENTRY trial findings demonstrate that adding selinexor to frontline ruxolitinib significantly improves spleen responses while providing early evidence of disease modification and OS benefit, supporting continued evaluation of this combination in JAK inhibitor-naïve MF.

Summarizing the findings of the trial, Dr Harrison stated: “The benefits for selinexor and ruxolitinib in an upfront population with myelofibrosis were rapid, deep and sustained spleen volume from week 12 onwards, consistent across ruxolitinib dosing. Similar symptom benefit, but meaningful overall survival, which correlated with SVR35. There were also higher rates of VAF reduction. So that’s consistent with better overall survival due to spleen volume reduction and disease modification”

At Week 24, 44% of evaluable patients receiving monotherapy achieved a spleen volume reduction of at least 25% (SVR25), while 31% achieved SVR35. Symptom responses were also observed, with 37% of evaluable patients achieving at least a 50% reduction in total symptom score (TSS50). Among patients with anemia who had received at least 12 weeks of treatment, 58% achieved an anemia response, including 53% with a major response. VAF reductions from baseline were observed in 91% of patients, and exploratory analyses demonstrated reductions in mutant CALR CD34+ cells in most patients.³

The accompanying poster presented translational analyses from the ongoing INCA033989 program. Among 76 patients analyzed by next-generation sequencing, reductions in mutant CALR VAF were observed in 92% of patients, while single-cell sequencing demonstrated reductions in mutant CALR hematopoietic stem and progenitor cells in all patients achieving SVR25. Comparable spleen and anemia responses were observed irrespective of co-occurring somatic mutations, suggesting that clonal complexity did not appear to limit clinical response to INCA033989.⁴

Taken together, the clinical efficacy observed in the oral presentation and the molecular findings from the poster suggest that selective targeting of mutant CALR may provide clinically meaningful benefit while supporting further investigation of its potential disease-modifying activity in patients with CALR-mutated MF.

The primary endpoint of RBC transfusion independence for at least 12 consecutive weeks was achieved by 23.1% of patients receiving luspatercept compared with 13.3% receiving placebo (p=0.0674). During his presentation Dr Passamonti explained that the RBC transfusion independence rates in the placebo arm within the Asia-Pacific region (28.9% versus 23.9% with luspatercept) likely influenced the primary analysis because of regional differences in transfusion practice. A post hoc sensitivity analysis accounting for these regional differences favored luspatercept over placebo. In addition, secondary endpoints, including reductions in transfusion burden and improvements in hemoglobin, consistently favored luspatercept.⁶

The safety profile was consistent with previous studies. Serious TEAEs occurred in 44.0% of luspatercept-treated patients and 38.1% of patients in the placebo arm. After adjusting for exposure, serious TEAE incidence rates were similar between the treatment groups (exposure-adjusted incidence rate/100 patient-years [EAIR/100 PY] 64.3 versus 62.4).⁶

Taken together, these findings from the INDEPENDENCE trial support the continued evaluation of luspatercept as a strategy to reduce transfusion burden in patients with MF-associated anemia receiving JAK inhibitors.

Modified European LeukemiaNet (ELN) response rates were maintained throughout two years of continuous P1101 therapy and improved in patients who crossed over from anagrelide. At Month 24, responses were observed in 58.6% and 62.5% of patients in the early and delayed P1101 groups, respectively.⁸

Molecular responses also deepened with longer IFN exposure. At Month 24, partial molecular responses were observed in 34.7% of patients in the early P1101 group compared with 15.4% in the delayed P1101 group.⁸

Estimated progression-free survival (PFS) was higher in the early P1101 group. At 24 months, estimated PFS was 76.9% (95% CI: 66.4–84.4%) in the early P1101 group versus 43.1% (95% CI: 30.6–55.0%) in the delayed P1101 group.⁸

Safety findings during Year 2 were consistent with the established IFN profile. The incidence of new Grade ≥3 TEAEs declined in the second year of P1101 therapy (8.8% versus 23.1% in Year 1), while patients crossing over from anagrelide experienced no unexpected safety signals.⁸

These longer-term findings suggest that earlier initiation of ropeginterferon alfa-2b may result in deeper molecular responses and more durable disease control compared with delaying IFN therapy, while maintaining a predictable and manageable safety profile.

Bezuclastinib also produced marked reductions across multiple measures of disease burden. The median time to first response was 2 months, while the median duration of response had not been reached at the time of analysis. Across the ITT population, reductions of more than 50% were observed in bone marrow mast cell burden (89% of patients), serum tryptase (89% of patients), and KIT p.D816V VAF (91% of patients).¹¹

The safety findings were consistent with the established safety profile of bezuclastinib. Treatment-related AEs (TRAEs) occurred in 93% of patients, although the incidence of treatment-related serious AEs was low (6%). The most frequently occurring Grade ≥3 TRAEs were neutropenia (24%) and thrombocytopenia (14%). Dose reductions due to TRAEs occurred in 14.8% of patients, no treatment discontinuations due to TRAEs were reported, and there were no treatment-related deaths.¹¹

The primary results from the APEX study demonstrated that bezuclastinib was associated with objective clinical responses, reductions in markers of mast cell disease burden, and a manageable safety profile, supporting its continued evaluation in patients with AdvSM. ¹¹