Paper Details

ABSTRACT

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are rare overlap syndromes characterized by concurrent dysplastic and proliferative features, a high risk of leukemic transformation, and limited approved therapies. DNA methyltransferase inhibitors (DNMTi) yield a moderate response rate, and dysregulated JAK/STAT inflammatory signaling contributes to disease biology, providing a rationale for combining DNMTi and JAK inhibition. The MDS/MPN IWG launched ABNLMARRO, a platform for testing novel combinations in these syndromes (PMID: 36153475). Arm A of ABNLMARRO-001 evaluates the first all-oral doublet of ASTX727 (DNMTi) plus itacitinib (a selective JAK1 inhibitor).

Methods: ABNLMARRO-001 (AM-001; NCT04061421) is an open-label, multicenter, phase 1b/2 study for MDS/MPN overlap syndromes. Arm A of ABNLMARRO-001 combined ASTX727 (fixed-dose oral decitabine 35 mg/cedazuridine 100 mg, days 1-5) with itacitinib 300 mg daily in 28-day cycles. The RP2D was defined in a phase 1b run-in, and 20 additional patients received >=1 dose (safety/efficacy population).  Twenty-seven patients received ≥1 dose (safety/efficacy population): 7 in phase 1b (4 treatment-naïve, 3 relapsed/refractory) and 20 treatment-naïve patients in phase 2. Responses were assessed at Cycle 3 Day 1 and Cycle 7 Day 1 using modified 2015 MDS/MPN IWG criteria (PMID: 25624319). Adverse events (AEs) were graded by CTCAE v5.0. The ORR (complete remission, optimal or partial marrow response, or partial remission) is reported with exact (Clopper-Pearson) 95% CIs. Overall survival (OS), defined as time from first study treatment to death from any cause, was estimated by Kaplan-Meier.

Results: Median age was 72.0 years (Q1-Q3 64.5-75.5); 18 (66.7%) were male. WHO subtypes were MDS/MPN-unclassifiable (n=11, 40.7%), CMML (n=10, 37.0%), MDS/MPN-RS-T (n=4, 14.8%), and atypical CML (n=2, 7.4%). Median cycles received was 5 (range 1-16). Toxicity: Grade >3 hematologic AEs were frequent - thrombocytopenia (n=16, 59.3%), leukopenia/neutropenia (n=15, 55.6%), and anemia (n=8, 29.6%). Febrile neutropenia occurred in 11.1% (n=3). Clinically significant bleeding was noted on this background of severe myelosuppression, including grade >3 epistaxis in 3 (11.1%) and one fatal intracranial hemorrhage (3.7%). Three deaths (11.1%) occurred during treatment from intracranial hemorrhage, cardiac failure with underlying atrial fibrillation, and respiratory failure (1 each).  Best overall response (N=27): ORR was 15/27 = 55.6% (95% CI 35.3-74.5), and the complete remission + optimal-marrow-response rate was 11/27 = 40.7% (95% CI 22.4-61.2). Among 25 evaluable patients, best responses were complete remission (2), optimal marrow response (9), partial remission (2), partial marrow response (2), stable disease (7), and progressive disease (3); 6 patients (22.2%; 95% CI 8.6-42.3) were bridged to allogeneic HSCT. At the time of the data cut (15 June 2026), median OS had not been reached (Kaplan-Meier survival of 66.7%, 51.1-87.0%, at 18 months), with a median follow-up of 22.9 months.

Conclusions: This first all-oral DNMTi (ASTX727) plus selective JAK1 inhibitor (itacitinib) doublet was active in MDS/MPN, with an ORR of 55.6%, CR/optimal marrow of 40.7%, and 22% bridged to allogeneic HSCT, with median overall survival not reached with a median follow-up of 22.9 months. While patient populations differ, the activity seen with this all-oral regimen was consistent with a retrospective analysis of ASCERTAIN patients with CMML (PMID: 40524338) and a prospective study of ruxolitinib-azacitidine in all MDS/MPN (PMID: 42304430). Similarly, this doublet was well tolerated but did lead to some marrow suppression in select patients. DNMTi sequencing or dose modification with hematopoietic support may be central to mitigating myelosuppression in future MDS/MPN doublets. ABNLMARRO continues to explore ruxolitinib and ASTX727 in an all-oral combination, as JAKi + DNMTi therapy appears effective in MDS/MPN.  A larger study in that cohort will help ascertain whether the combination offers greater promise in these diseases than a single-agent DNMTi.