Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML

Abstract

Molecular failure in NPM1 mutated AML inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here we report an international multicentre cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66/79 (84%) and MRD negativity in 56/79 (71%). 18/79 (23%) patients required hospitalisation and no deaths were reported during treatment. 41 patients were bridged to allogeneic transplant with no further therapy and 25/41 were MRD negative assessed by RT-qPCR before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45% and in responding patients there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs. 91%, p<0.01), worse OS (HR 2.50, 95% CI 1.06-5.86, p=0.036) and EFS (HR 1.87, 95% CI 1.06-3.28, p=0.03). 18/35 non-transplanted patients became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1 mutated AML, either as a bridge to transplant or as definitive therapy.

Optimal Post-Remission Consolidation Therapy in Patients with AML

“…Multiple studies have concluded that pre-transplant positive MRD (assessed by multiparameter flow cytometry or RT-qPCR) is independently associated with a higher relapse incidence and lower survival [80][81][82][83][84]. There is a growing evidence that intervening MRD prior to haematological relapse may lead to better outcomes [37,39,[85][86][87][88]. Some studies have evaluated the treatment of molecular failure (monitored by RT-qPCR for fusion genes or NPM1) including some patients prior to allo-HSCT [85].…”

“…There is a growing evidence that intervening MRD prior to haematological relapse may lead to better outcomes [37,39,[85][86][87][88]. Some studies have evaluated the treatment of molecular failure (monitored by RT-qPCR for fusion genes or NPM1) including some patients prior to allo-HSCT [85].…”

“…Recent evidence proves that detectable MRD in NPM1 mut AML can be successfully cleared with venetoclax combined with low-intensity chemotherapy (AZA, decitabine, or LDAC) [37,87,88]. In recent Optimal Post-Remission Therapy in AML Acta Haematol 2024;147:148-159 DOI: 10.1159/000535457 reports, patients treated for MRD failure achieved MRD negativity rates of 71-92% [37,85,87], with venetoclax combinations being an interesting option as a bridge to allo-HSCT in molecular failure of NPM1 mut AML [85,87,88].…”