Phase II Study of Cladribine with Low Dose Cytarabine and Venetoclax Alternating with Azacytidine and Venetoclax for Newly Diagnosed Acute Myeloid Leukemia

Introduction: Venetoclax (VEN) combined with Azacytidine (AZA) or Low dose cytarabine (LDAC) is the standard of care for patients (pts) with newly diagnosed acute myeloid leukemia (AML) aged ≥ 75 yrs or not candidates to intensive treatment. However, some pts, including those with mutations in FLT3-ITD, N/KRASand TP53 do not appear to derive a survival benefit from the addition of VEN (median overall survival [mOS] 6-12 months). The addition of cladribine (CLAD) and LDAC with VEN has been shown to be highly effective in newly diagnosed AML. Here we report an expanded an updated cohort of patients with key subgroup analyses and long-term follow up.

Methods: Pts with newly diagnosed AML were enrolled in a prospective phase 2 clinical trial with CLAD (5mg/m2 days 1-5), LDAC (20mg SQ BID d 1-10) and VEN (400mg, d 1-21) induction therapy followed by a consolidation phase that alternates two courses of azacytidine (75mg/m2 d1-7) and VEN with two courses of CLAD (d 1-3), LDAC and VEN (same dose) (NCT03586609). Doses of VEN were modified with concomitant azoles and reduced days (7-14 d) during consolidation.

Results: From November 2018 to October 2023, 141 pts were enrolled in the study. The median age was 68 (range 47-84) and 58% were male. 53% had normal karyotype and 19% had complex karyotype. According to the ELN 2022 classification, 19%, 21% and 60% were classified as favorable, intermediate and adverse risk, respectively. DNMT3A (30%), NPM1 (23%) and TET2 (20%) were the most common mutations, and TP53 was mutated in 17% of patients. N/KRAS mutations and FLT3-ITD were present in 21% and 4%, respectively.

The composite complete remission (CR) rate was 85% (120/141 pts), with 73% achieving CR and 12% achieving CR with incomplete blood count recovery (CRi). The median cycles to first and best response was 1 (range, 1-3 and 1-7, respectively). Among pts with CR/CRi, 78% achieved negative measurable residual disease (MRD-) by flow cytometry. The 4- and 8-week mortality was 1 and 3%, respectively. The median time to absolute neutrophil count recovery (>1x10⁹/L) and platelet recovery (>100x10⁹/L) after first cycle was 26 and 24 days, respectively. The median number of cycles given was 2 (range 1-18). 62 patients (44%) proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.

The median follow-up was 28 months. The 2-yr OS and event-free survival (EFS) was 62% and 55%, respectively. The 2-yr OS was 84%, 67% and 51% for patients allocated in the favorable, intermediate and adverse ELN 2022 classification (P = .02, C index .59). Patients achieving MRD- had a better 2-yr OS (75%) compared to patients with positive MRD (32%, P < .001). There was not significant difference among pts with AML with or without N/KRAS mutations (CR rate of 83% for patients with N/KRAS mutations, 2-yr OS of 48% and 66% for patients with and without N/KRAS mutations, P = .1). The 2-yr OS was 85% for patients proceeding to HSCT, compared to 55% for those not receiving HSCT (P < .001), using a landmark analysis (landmark time 4.1 months).

In a multivariate analysis, a complex karyotype (HR 2.97, 95% CI 1.55-5.67, P < .001) and NPM1 mutation (HR 0.38, 95% CI 0.17-0.86, P = 0.02) were independent prognostic factors for OS. Using a survival random forest approach, we identified the most influential variables for OS to generate a predictive risk model for patients treated with this combination. Patients with NPM1 or DDX41 mutations were allocated in the very good risk group (n=43, MRD- 97%, mOS 60 months, 2-yr OS 85%). Patients without risk-defining genetic abnormalities were allocated in the good risk group (n=54, MRD- 84%, mOS 50 months, 2-yr OS 66%). Patients with N/KRAS without NPM1 mutation were allocated in the intermediate risk group (n=19, MRD- 56%, mOS 18 months, 2-yr OS 43%). Patients with complex karyotype or multihit TP53 mutation were allocated in the poor risk group (n=25, MRD- 56%, mOS 7 months, 2-yr OS 23%). This classification was able to properly stratify patients according to their survival, with a better performance than ELN 2022 (P < .001, C index .7).

Conclusions: CLAD-LDAC-VEN alternating with AZA + VEN produces an excellent rate of CR/CRi with high rates of MRD negativity , translating into favorable long term OS and EFS in patients aged ≥ 60 yrs or those unfit for intensive chemotherapy. Benefit was seen across most genomically defined subgroups, including those with RAS mutations, where an HMA-Ven alone approach is associated with a mOS of 12 months.