Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 3 appraisals
Blood advances
Phase 1b study of ABBV-744, a novel, selective BET inhibitor, as monotherapy for patients with myelofibrosis
Janus kinase inhibitors (JAKi) are standard of care for patients with myelofibrosis (MF) but can be associated with treatment-limiting cytopenias and do not modify underlying disease. Novel treatments targeting other clinically relevant pathways are needed. Inhibitors of bromodomain (BD) and extraterminal domain (BET) proteins are a promising class of drugs that have demonstrated the ability to modulate key pathways involved in inflammation, fibrosis, and apoptosis. ABBV-744 is a novel small molecule that targets the BDII of BET proteins and has previously been shown to be well tolerated when administered daily at doses of 120 and 180 mg to patients with acute myeloid leukemia. We report the outcomes of a multicenter, open-label phase 1b study of ABBV-744 in patients with MF who received ≥1 previous lines of therapy, including a JAKi. The primary objective was safety, including dose-limiting toxicities (DLTs). Secondary end points included a reduction in spleen volume of ≥35% (SVR35), ≥50% reduction in total symptom score (TSS50), objective response rate, and pharmacokinetics. All 21 patients experienced at least 1 treatment-emergent adverse event, and 11 patients experienced a DLT. The most common events leading to DLTs were thrombocytopenia (33%) and anemia (24%). SVR35 was attained in 24% of patients at week 12 and 33% at week 24. TSS50 was reported for 29% of patients at 12 weeks and 19% at week 24. These outcomes are noteworthy in this heavily pretreated population considering the advanced disease state and limited treatment options for this patient population. This trial was registered at www.clinicaltrials.gov as NCT04454658.
27 May 2026
Read appraisal →Blood advances
Selinexor plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: a multicenter, open-label, phase 1 study
The phase 1 portion of SENTRY/XPORT-MF-034 (NCT04562389) evaluated the exportin 1 inhibitor selinexor (40 mg/60 mg once weekly) plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (n = 24). Primary end points were maximum tolerated selinexor dose, recommended clinical trial dose, and safety. No dose-limiting toxicities were reported. Common adverse events were nausea, fatigue, anemia, thrombocytopenia, constipation, vomiting, and headache. Nausea was transient, mainly grade 1, and managed by prophylactic antiemetics. Four deaths occurred, all unrelated to study treatment. Selinexor 60 mg in combination with ruxolitinib was identified as the recommended phase 3 dose based on safety, efficacy, and exposure-response analyses. Overall safety profiles and grades of clinically significant adverse events were similar and generally manageable regardless of selinexor dose. A greater proportion of patients achieved spleen volume reduction of ≥35% (SVR35) and total symptom score reduction of ≥50% (TSS50) at week 24 in the selinexor 60-mg group (79% and 58%) than the 40-mg group (38% and 25%). Among evaluable patients who received suboptimal ruxolitinib ≤5 mg twice daily in the selinexor 60-mg group, SVR35 was observed in 100% (6/6) and TSS50 in 75% (3/4) of patients. The trial was registered at ClinicalTrials.gov as NCT04562389.
26 May 2026
Read appraisal →Blood advances
Phase 2 study of the lysine-specific demethylase 1 inhibitor bomedemstat for essential thrombocythemia
Novel treatments that can improve outcomes of essential thrombocythemia (ET) are needed. In a phase 2 trial, participants with ET who required cytoreduction and had inadequate response to, or were intolerant of, ≥1 standard therapy received bomedemstat at a starting dose of 0.6 mg/kg per day, titrated to achieve a target platelet count (200 × 109/L to 400 × 109/L). Primary end points were safety and response, defined as a platelet count of ≤400 × 109/L without new thromboembolic events. Of 73 who received bomedemstat, at 24 weeks, 49 of 64 evaluable participants (77%) achieved a response. Durable reductions in platelet count (≤400 × 109/L for ≥12 weeks) were observed in 52 of 72 participants (72%). Durable reduction in white blood cell count (<10 × 109/L for ≥12 weeks) was observed in 61 of 72 participants (85%); of 10 participants with elevated white blood cell count at baseline, 9 had normal white blood cell count (<10 × 109/L) at week 24. Hemoglobin levels remained stable. After 24 weeks of treatment, a decrease in variant allele frequency of CALR, JAK2, or MPL was observed in 39 of 46 (85%) evaluable participants. By week 24, 2 of 73 participants (3%) had experienced ≥1 thrombotic event, and 15 of 73 (21%) experienced ≥1 hemorrhagic event. During overall treatment period, grade 3 or 4 adverse events (AEs) occurred in 34 of 73 participants (47%). AEs led to temporary treatment interruption in 29 participants (40%) and permanent discontinuation in 11 (15%). No participants died due to AEs. Bomedemstat had clinically relevant activity and manageable safety in participants with ET. This trial was registered at www.clinicaltrials.gov as #NCT04254978.
26 May 2026
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