Revumenib Combination Shows Promise in Relapsed/Refractory AML with Specific Genetic Alterations
核心洞察
The phase 1/2 SAVE study evaluated an all-oral combination of revumenib, decitabine/cedazuridine, and venetoclax in relapsed/refractory AML (搜索) patients.
The overall response rate was 82%, with notable efficacy in patients harboring _KMT2Ar (搜索)_ (88%), _NPM1mt (搜索)_ (67%), and _NUP98r (搜索)_ (100%) genetic alterations.
A significant proportion of responders achieved minimal residual disease (MRD) negativity, particularly those with complete remission or complete remission with partial hematologic recovery.
An all-oral combination of revumenib (Revuforj) with decitabine/cedazuridine (ASTX727) and venetoclax (Venclexta) has demonstrated high remission rates in patients with relapsed/refractory acute myeloid leukemia (搜索) (AML (搜索)) harboring specific genetic alterations. These findings come from the phase 1/2 SAVE study (NCT05360160), presented at the 2024 ASH Annual Meeting by Dr. Ghayas C. Issa from The University of Texas MD Anderson Cancer Center.
The study showed particular benefit in patients with KMT2Ar (搜索), NPM1mt (搜索), and NUP98r (搜索) alterations. The overall response rate (ORR) among the 33 enrolled patients was 82%. Notably, the ORR was 88% in patients with KMT2Ar, 67% in those with NPM1mt, and 100% in patients with NUP98r.
Remission and MRD Negativity
Across all patients, 48% achieved complete remission (CR) or complete remission with partial hematologic recovery (CRh), while 39% achieved complete remission alone. Among the responders, 65% achieved minimal residual disease (MRD) negativity as assessed by multicolor flow cytometry (MFC). Specifically, 88% of patients achieving CR/CRh also reached MRD negativity.
Follow-up and Survival
With a median follow-up of 9.3 months (IQR, 7.6-12.5), the mutational landscape remained largely stable at progression, except for FLT3-ITD expansion and phenotype switch. The median time to first morphologic response was 28 days (range, 14-70), and bone marrow blasts were less than 5% at day 14 in 56% of patients.
The 6-month complete response duration (CRD) rate was 74% (95% CI, 44%-90%), and the median duration of response (DOR) was not reached. The 6-month overall survival (OS) rate was 68% (95% CI, 47%-80%), and the median OS was also not reached.
Safety Profile
The most common grade 3 or higher treatment-emergent adverse events (TEAEs) included febrile neutropenia (33%), lung infection (33%), elevated AST/ALT (18%), sepsis (18%), respiratory failure (18%), and decreased platelets (18%). QT prolongation (9%) and differentiation syndrome (3%) of grade 3 or higher were also observed, with Dr. Issa noting these were possibly related to revumenib.
Study Design and Rationale
The phase 1/2 study enrolled patients aged 12 years and older with relapsed/refractory AML (搜索) or myeloid mixed-lineage acute leukemia, harboring KMT2Ar (搜索), NPM1mt (搜索), or NUP98r (搜索) alterations. Patients had an ECOG score of 2 or lower and adequate organ function. The study utilized a 3+3 dose escalation design.
Patients received decitabine/cedazuridine (35 mg/100 mg orally per day on days 1-5), venetoclax (400 mg orally per day on days 1-14), and revumenib (113 mg or 163 mg orally every 12 hours) for days 1-28, along with posaconazole or voriconazole. Revumenib monotherapy was administered after HSCT for 1 year of maintenance. An amendment recommended holding revumenib after day 21 if bone marrow blasts were less than 5% at cycle 1, day 14. MRD was assessed with MFC at a sensitivity of 10-4.
The SAVE study aimed to improve response rates and decrease relapse risk in relapsed/refractory AML (搜索) by combining revumenib, ASTX727, and venetoclax. Hypomethylating agents plus venetoclax are standard for older or unfit AML patients, and oral ASTX727 has shown equivalent efficacy to intravenous decitabine. KMT2Ar (搜索) or NPM1mt (搜索) leukemias are prone to apoptosis via BCL2 inhibition, and BCL2 plus menin inhibition has shown potential to eradicate bulk and stem/progenitor cells in preclinical models.