Palbociclib combined with venetoclax and azacitidine in NUP98-rearranged pediatric AML: A multicenter phase II trial demonstrating durable remission and survival benefit

Abstract Background NUP98-rearranged AML has a dismal prognosis with a 2-year OS of less than 35% with current therapies. The combination of hypomethylating agents and BCL-2 inhibitors venetoclax shows promise in some AML patients, and CDK6 inhibitor palbociclib has demonstrated potential anti-leukemia activity in preclinical models. Thus, a multi-center, phase 2 cohort study was conducted to evaluate the efficacy and safety of this combination therapy (palbociclib, venetoclax and azacitidine, VAP) in these patients. Methods This multi-center, single-arm, phase 2 cohort study was conducted across 34 hospitals of China. Eligible patients were aged 0 to 18 years with newly diagnosed NUP98- rearranged AML after induction chemotherapy, or those with refractory or relapsed AML with NUP98 fusions. Patients received azacitidine 75mg/m2 via subcutaneous injection on day 1-7, palbociclib 50mg/m2 via oral administration on day 8-28, and venetoclax 50mg/m2 on day 1, 100mg/m2 on day 2, and 200mg/m2 on day 3-28 via oral administration (VAP regimen). The primary endpoint was the composite of complete remission (CR) and complete remission with incomplete hematologic recovery (CRi), as defined by the International Working Group (IWG) criteria. The secondary endpoints included the overall response rate, minimal residual disease (MRD) status, relapse rate, 2-year overall survival (OS), 2-year event-free survival (EFS), duration of response, and safety. The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2300074396) and conducted in accordance with Good Clinical Practice guidelines. Findings From December 2022 to March 2024, nine patients were enrolled, including six (66.7%) patients with NUP98-NSD1 fusions, two (22.2%) patients with NUP98-KDM5A fusions, and one (11.1%) patient with NUP98-TOP1 fusion. Six patients achieved CR with MRD negativity. All patients with NUP98-NSD1 fusions demonstrated complete molecular remission eventually, while those with NUP98-KDM5A or NUP98-TOP1 fusions had persistent positivity. The median OS and EFS were 21 months and 13 months, respectively. The 2-year OS and EFS rates were 88.9% and 77.8%. Treatment-related adverse events were uncommon, including cytopenia, febrile neutropenia, tumor lysis syndrome and pneumonia. No treatment-related deaths were reported. Conclusion The combination of palbociclib, venetoclax and azacitidine is a safe and effective treatment for pediatric patients with NUP98-rearranged AML. It achieved high rates of durable remission at morphological, immunophenotypic, and molecular levels, offering promising long-term survival outcomes. This regimen could become a new standard of care for this high-risk subgroup, potentially redefining frontline therapy, although larger studies with longer follow-up are needed to confirm these findings.