Flonoltinib and Selinexor Combinations Show Promise in Myelofibrosis Treatment
核心洞察
Flonoltinib (搜索) demonstrated significant spleen and symptom response in myelofibrosis (搜索) patients, suggesting it may be a new treatment option.
A phase 2 trial showed selinexor combined with ruxolitinib led to spleen length reduction and symptom alleviation in myelofibrosis (搜索) patients previously treated with ruxolitinib.
Navitoclax combined with ruxolitinib showed durable responses and potential disease modification in relapsed/refractory myelofibrosis (搜索), improving spleen volume and symptoms.
Myelofibrosis (搜索) (MF) treatment is evolving, with recent studies highlighting the potential of novel drug combinations to improve patient outcomes. Data presented at the 2024 ASH Annual Meeting and other venues showcase promising results for flonoltinib (搜索), selinexor, and navitoclax in treating this challenging condition.
Flonoltinib Monotherapy Shows Efficacy in Myelofibrosis
Flonoltinib (搜索) maleate (FM), a new generation JAK2 (搜索)/FLT3 (搜索) inhibitor, has demonstrated significant clinical benefits in patients with myelofibrosis (搜索). A first-in-human phase I/IIa study (NCT05153343) evaluated the safety and efficacy of FM in MF patients with intermediate-2 or high-risk disease. Unlike marketed JAK2 inhibitors, FM binds to both the pseudokinase (JH2) and kinase (JH1) domains of JAK2, exhibiting high selectivity for JAK2 and FLT3 over JAK1 and JAK3.
The study enrolled patients with primary MF, post-PV MF, or post-ET MF, who were at least medium-risk -1 to high-risk according to DIPSS criteria and had palpable splenomegaly. Patients received FM orally once daily for 14-day cycles. The primary endpoints were safety, tolerability, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic (PK) behavior. Secondary endpoints included a ≥35% reduction in spleen volume (SVR35) at week 24.
Results from 30 treated MF patients showed a maximum tolerated dose of 225 mg/day. At week 24, 77.3% (17/22) of patients who completed 12 cycles achieved SVR35. The best SVR35 rate was 83.3% (25/30), and the best TSS50 rate was 80.0% (24/30). Subgroup analysis indicated no significant difference in spleen response rates between patients previously exposed to JAK inhibitors and those who were JAK inhibitor-naive. The most common grade ≥3 hematological treatment-emergent adverse events (TEAEs) included anemia (48.4%) and thrombocytopenia (29.0%).
These findings suggest that FM may offer a new treatment option for myelofibrosis (搜索) patients, with a phase II trial currently underway.
Selinexor Plus Ruxolitinib Demonstrates Activity in Ruxolitinib-Pretreated Myelofibrosis
Preliminary findings from the phase 2 SENTRY trial (NCT04562389) indicate that selinexor (Xpovio) combined with ruxolitinib (Jakafi) is safe and effective in myelofibrosis (搜索) patients previously treated with ruxolitinib. The study enrolled 38 patients who received at least one dose of selinexor. At a 6-month analysis, 88% of patients experienced a reduction in spleen length, and 36% achieved a spleen response, defined as a reduction in spleen length of more than 50% per the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet response criteria.
Regarding symptom response, 86.67% of evaluable patients experienced alleviation of their symptoms, with 40.91% achieving a 50% reduction in total symptom score (TSS) or clinical-assessed symptom response. Four of nine transfusion-dependent patients achieved transfusion independence after treatment with the combination.
The most common any-grade adverse events (AEs) were anemia and nausea (both 36.8%), followed by vomiting (23.7%). The most frequent grade 3 or 4 AEs were anemia (18.4%) and thrombocytopenia (5.3%).
Minghui Duan, PhD, from Peking Union Medical College Hospital, noted that this combination may achieve similar therapeutic effects to selinexor monotherapy without requiring higher doses. Phase 3 of the SENTRY trial is currently enrolling patients with MF who are naive to JAK inhibitors.
Navitoclax and Ruxolitinib Show Potential in Relapsed/Refractory Myelofibrosis
Data from the phase 2 REFINE trial (NCT03222609) suggest that navitoclax (AbbVie (搜索)) in combination with ruxolitinib demonstrates durable responses and potential disease modification in relapsed/refractory (R/R) myelofibrosis (搜索) (MF). The open-label, multicenter trial evaluated navitoclax monotherapy versus navitoclax plus ruxolitinib in 125 patients with R/R MM. At the 21-month follow-up, the SVR35 rate was 23% at week 24 and 39% at any time on study (median duration of 11 months). The TSS50 rate was 24% at week 24 and 46% at any time on study. Bone marrow fibrosis (BMF) improved by ≥1 grade in 39% of patients receiving the combination treatment, and 23% of patients achieved an anemia response.
The most common adverse event was thrombocytopenia (86%), which was manageable with dose adjustments. These findings highlight the potential benefit of combining navitoclax with ruxolitinib for patients with R/R MF, offering potential disease modification alongside symptom and spleen volume reduction.
These studies collectively underscore the importance of continued research to optimize treatment strategies for myelofibrosis (搜索) and provide hope for improved outcomes for patients with this challenging condition.