AUTHORS
Fieke W Hoff, MD, PhD, Ian Bouligny, M.D.2, Farhad Ravandi, MD3, Courtney DiNardo, MD, MSCE4, Naval Daver, MD5, Musa Yilmaz, MD6, Gautam Borthakur, MD7, Wei Ying Jen, BM BCh, FRCPath8, Jennifer Marvin-Peek, MD9, Guillermo Montalban-Bravo, MD10, Nicholas Short, MD11, Yesid Alvarado Valero, MD12, Nitin Jain, MD13, Naveen Pemmaraju, MD14, Jayastu Senapati, MBBS, MD, DM15, Danielle Hammond, MD16, Kelly Sharon Chien, MD17, Ghayas C. Issa, MD18, Hussein Ali Abbas, MD, PhD19, Koichi Takahashi, MD,PhD20, Elias Jabbour, MD21, Guillermo Garcia-Manero, MD22, Hagop Kantarjian, MD23, Tapan Kadia I, MD24
AFFILIATIONS
1 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
3 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
4 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
5 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
6 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
7 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
8 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
9 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
10 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
11 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
12 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
13 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
14 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
15 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
16 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
17 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
18 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
19 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
20 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
21 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
22 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
23 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
24 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
ABSTRACT
BACKGROUND: The BCL2 inhibitor venetoclax (VEN) has shown significant improvement in overall survival (OS) in combination with hypomethylating agents in older or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). To improve frontline therapy for younger and fit patients, we conducted a phase II study evaluating the addition of VEN to an intensive regimen of cladribine, idarubicin, and cytarabine (CLIA) in patients with ND AML and high-risk (HR) myelodysplastic syndromes (MDS). We herein report updated outcomes with an expanded cohort, longer follow-up, dosing optimization, and subgroup analyses (NCT02115295).
METHODS: Patients with ND AML or HR-MDS (≥ 10% blasts or IPSS ≥ 1.5), aged ≤ 65 years, and ECOG PS ≤ 2 were eligible. Treatment was cladribine (CLAD) 5 mg/m2 on D1-5, idarubicin (IDA) 10 mg/m2 on D1-3, cytarabine (ARA-C) 1.5 g/m2 on D1-5 and VEN 400 mg on D2-8 during induction. Consolidation (CONS) was CLAD 5 mg/m2 on D1-3, IDA 8 mg/m2 on D1-2, ARA-C 1 g/m2 on D1-3 and VEN 400 mg on D2-8. VEN was dose-adjusted for CYP3A inhibitors. Patients in remission could receive up to 5 cycles of CONS. A protocol amendment allowed omission of VEN after induction in patients who achieved complete remission (CR). G-CSF support was added to each cycle.
RESULTS: Between February 2019 and June 2026, a total of 133 patients (AML, n=123; MDS, n=10) were enrolled. The median age was 49 years (range, 18-64). The most frequent somatic mutations identified by NGS were NPM1 (30%), DNMT3A (30%), FLT3-ITD (18%), TET2 (15%), IDH2 (15%), PTPN11 (11%), and FLT3 D835 (11%). One patient had favorable cytogenetics, 49% had diploid karyotype, 29% had other intermediate-risk cytogenetics, and 20% had adverse or complex karyotype. According to the ELN 2022 criteria, 27% of patients were classified as favorable, 34% as intermediate and 39% as adverse-risk.
Patients received a median of 2 cycles (1-6) with remission achieved after a median of 1 cycle (1-2). Among AML patients, the composite complete remission (cCR; CR+CRi) rate was 95%, including 85% achieving CR. Among patients with cCR, 79% were MRD-negative by flow cytometry (FC) after induction; 15/20 evaluable MRD-positive patients converted to MRD-negative after one CONS cycle. Of the MDS patients, 9/10 (90%) achieved a cCR, including 7 (70%) with a CR. One patient achieved hematological improvement.
Among NPM1-mutated patients (n=37), 35 (95%) achieved CR, 1 CRi and 1 patient died during induction. After induction, 89% were MRD-negative by FC. High sensitivity NPM1 MRD testing by NGS (sensitivity 5x10-5) was prospectively performed in 9 patients; after induction, the median NPM1 MRD was 0.00014 (range, <0.0005-0.0149); 5 of 6 (83%) evaluable patients who had a repeat sample became MRD-undetectable after the first CONS. Three patients with NPM1-mutated AML relapsed, including 1 after SCT (NPM1 MRD status by NGS was unknown peri-treatment).
VEN was omitted during the first CONS in 15 (AML n=13, MDS n=2) patients with MRD-negative CR after induction. One patient relapsed after 1 CONS, 10 underwent SCT in CR1, and all are still alive. Median platelet and neutrophil recovery times were 25 and 27 days, respectively. One patient (WT1 co-mutation) relapsed before count recovery, 4 proceeded to SCT before platelet recovery, and one never recovered platelets >100x109/L. In 5 patients the ANC did not drop below 0.5x103/µL when VEN was omitted and G-CSF was administered.
At a data cut-off date of July 15, 2026, the median follow-up for the entire cohort was 3.4 years (IQR, 1.7-5.3). In AML, OS was 75%, and duration of response (DOR) was 86% at 3-years, respectively. Among MDS patients, OS was 86% at 3 years, while DOR remained 100% through 3 years. Overall, 72% of patients achieving cCR underwent SCT in CR1, with a median time from diagnosis to SCT of 119 (IQR, 99 to 152). In a landmark analysis, OS at 3 years was 84% with SCT in CR1 versus 63% without SCT (p=0.013).
DISCUSSION: CLIA-VEN was highly effective with cCR rates over 90% and durable remission in younger patients with ND AML and HR-MDS. Most patients achieved MRD negative by FC after induction, and low-level NPM1 MRD transcripts became undetectable (sensitivity <5x10-5) in 83% of evaluable patients after one consolidation cycle. Omission of VEN during consolidation in patients achieving MRD-negative CR appears feasible and is being evaluated further to reduce toxicity.
DISCLOSURES
Fieke W Hoff, MD, PhD: No relevant conflicts of interest to declare.