Venetoclax Plus Decitabine for Young Adults with Newly Diagnosed ELN Adverse-Risk Acute Myeloid Leukemia: Updated Results of a Phase 2 Trial

Background: The young adults with newly diagnosed (ND) ELN adverse-risk acute myeloid leukemia (AML) fit for intensive chemotherapy (IC) have low complete remission (CR) rate and dismal outcomes compared with AML in favorable- and intermediate-risk categories. Venetoclax (VEN) combination with hypomethylating agents is a new standard of care for older and unfit AML patients (pts) and has been demonstrated to improve composite complete remission and overall survival (OS). We previously reported that VEN plus decitabine (DEC) as frontline treatment for young pts with ND ELN adverse-risk AML and demonstrated promising efficacy and safety at median follow-up of 2.7months in a phase 2 trial (Chen et al, ASH 2021). Here we present an updated analysis of efficacy and safety results in the ongoing study.

Methods: This multicenter, single-arm, phase 2 trial (NCT04752527) enrolled young pts (aged between 18 and 59) with ND AML, who met the adverse risk group according to 2017 ELN risk stratification screened by fast next-generation sequencing (NGS), multiplex RT-PCR and fluorescence in situ hybridization (FISH) within 72 hours, and were eligible for standard induction chemotherapy. The study design was previously reported (Chen et al, ASH 2021). The primary outcome was composite complete remission (CRc: CR plus CR with incomplete blood count recovery [CRi] and morphologic leukemia free state [MLFS]). Secondary outcomes were OS, event-free survival (EFS) and safety. The data cut-off date was July 31, 2022.

Results: Between February 12, 2021 and July 31, 2022, 286 patients aged between 18 and 59 with ND AML underwent screening. 78 pts were classified as ELN adverse-risk category by fast NGS (within 72 hours) together with multiplex RT-PCR and FISH and 42 pts were enrolled, comprising 26 males and 16 females. Median age was 39 years (range, 19-58) (Table 1).

As of the cut-off date, 40 pts completed the first cycle of VEN+DEC and 37 pts completed two courses. In cycle 1, 31 (77.5% [95% CI, 61-89]) pts achieved CRc, 8 (20% [95% CI, 10-36]) pts had partial remission and 1 (2.5% [95% CI, 0-15]) had no response. 24 (77.4% [95% CI, 58-90]) of 31 pts achieving CRc had measurable residual disease (MRD) negativity assessed by multiparameter flow cytometry (MFC) with a sensitivity of 10^-3-10^-4(0.1%-0.01%).

Pts with RUNX1 and FLT3-ITD mutations had higher CRc rates of 83.3% and 80%, respectively. Pts harboring TP53 and ASXL1 mutations achieved encouraging CRc rates of 62.5% and 75%, respectively. The CRc rates in pts with 11q23/KMT2A rearrangements and complex karyotype were 66.7% and 88.9%, respectively.

The CRc and MRD negativity were achieved in 91.9% (34/37, 95% CI, 77-98) and 82.3% (28/34, 95% CI, 65-93) of the pts after the second course of treatment. 31 (73.8%) of 42 pts received allogeneic hematopoietic stem cell transplantation (HSCT), among them 26 patients achieved complete remission before HSCT, 3 received HSCT after morphologic relapse and 2 with salvaged HSCT.

At median follow-up of 10.2 months (range, 0.8-17), the median OS and EFS were not reached (Figure1a, b). Estimated 12-months OS was 92.9% (95% CI, 79-98) and EFS was 71.4% (95% CI, 55-84). Among enrolled pts achieving CRc in cycle 1, median time to blood cell count recovery for absolute neutrophil count (ANC) ≥1000 cells per μL was 30 days (range, 16-NR), and for platelet count ≥50 000 platelets per μL was 20 days (range, 0-NR).

Among 40 pts evaluable for safety analysis, the most common non-hematological adverse events were infections with grade 3 or worse neutropenia in 18 (45%) pts and febrile neutropenia in 11 (27.5%) pts. Notable serious adverse events were pneumonia in 5 (12.5%) pts and sepsis in 1 (2.5%). Mortality rates of 30-day and 60-day were 0%.

Conclusions: VEN plus DEC was an effective, lower-intensity regimen that was well tolerated for young adults with ND ELN adverse-risk AML, producing high rates of CR and encouraging EFS and OS.

No relevant conflicts of interest to declare.