A Polish Adult Leukemia Group (PALG) Prospective International Randomized Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016) – Topline Results

Background: The combination of daunorubicin (DNR) for 3 days and cytarabine (Ara-C) for 7 days (DA) has been the backbone of induction chemotherapy (IC) in medically fit adults with acute myeloid leukemia (AML) for decades. Escalation of DNR to 90 mg/m² (DA-90) has shown benefit for selected patients when compared to DNR 45 mg/m². In two PALG randomized trials, the combination of cladribine and cytarabine using DNR 60 mg/m² (DAC) resulted in improved complete remission (CR) rate and overall survival (OS), compared with standard DA-60 induction. However, whether induction with DAC is superior to DA-90 was unknown.

Aims: PALG-AML1/2016 (NCT03257241) aimed to compare the efficacy and safety of induction DA-90 vs. DAC followed by intensive consolidation chemotherapy. The primary endpoint was CR and key secondary endpoints were CR without measurable residual disease (CR-MRD^-), event-free survival (EFS) and OS.

Patients and methods: In this phase 3 open-label randomized trial, patients (pts) with newly-diagnosed, untreated AML, ECOG performance status 0–2 and HCT-CI≤ 3 were randomized to DA-90 (n=220) or DAC (n=219) induction. Pts with persistent leukemia (>10% blasts) in non-aplastic bone marrow (BM) at day 14 received early second induction according to randomization arm (DA-45 and DAC, respectively). Patients who achieved a CR/CRi were offered either allogeneic stem-cell transplantation (alloSCT) or intermediate-dose cytarabine (IDAC) consolidation+/-autologous stem-cell transplantation (autoSCT) according to predefined risk group. Serial samples for multi-modality assessment of MRD were collected at multiple time points.

Results: Between 2017 and 2023, 439 pts, median age 47 (18-60) years were enrolled at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City and received the first IC. Median age was 46 years (18-60), 88% had de novo AML. Classification as favorable, intermediate-1, intermediate-2 and adverse risk (ELN 2010) was in 22.6%, 31.9%, 17.3% and 18.2% of pts, respectively. Karyotype was not available in 10% of pts. At baseline 364 pts had adequate samples for NGS evaluation and finally 377 pts were eligible for the reclassification of the genetic risk according to ELN2022. ELN 2022 classification as favorable, intermediate and adverse risk was in 28.6%, 19.4%, and 36.9% of pts, respectively. In 62 pts (14.1%) ELN 2022 risk was not available. There were no differences between DA-90 vs. DAC in age (46 [16-60] vs. 47 [19-60]; p=0.7), gender (males 43% vs. 44%; p=0.8), AML etiology (de novo [87% vs. 89%]; vs. secondary [13% vs. 11%] p=0.7) and both ELN 2010 as well as ELN 2022 genetic risk. There was a trend toward higher WBC count (11.5 G/L [2.98-293] vs. 7.02 G/L [2.28-498.6]; p=0.068) and higher baseline BM blast infiltration 60% [18-100] vs. 56% [18-100]; p=0.063) in the DAC arm.

After initial induction, marrow blast clearance (<10%) on day 14 was achieved in 341 pts (77.7%). Forty-five pts (10.3%) received early second induction per protocol. During induction, serious adverse events were experienced in 27.3% and 37.7% (p=0.02) of pts in the DA-90 and DAC arms, respectively. Early mortality 8 weeks after induction was comparable in both arms (5.9% vs. 7.3%; p=0.7). Eighty-one pts (36.2%) in DA-90 and 61 (30.4%) in DAC were referred for alloSCT (p=0.19).

The study was originally powered to include 582 pts to detect a 10% difference in CR/CRi, but was closed after recruitment of 75% subjects, on the recommendation of the Data Monitoring Committee, due COVID-19 pandemic-related slow accrual, increased availability of targeted therapies, and an unplanned analysis showing that the primary end-point could not be met.

The CR/CRi rates after 1 or 2 inductions were 78.1% and 76.1% in DA-90 and DAC, respectively (p=0.7). After a median follow-up time of 38.5 months, 3-year OS was 56% vs. 57% in DA-90 and DAC, respectively (HR 1.02; p=0.9). There was no significant difference in the probability of 3-year EFS, with 51% vs. 47% for DA-90 vs. DAC induction (HR 1.11; p=0.4).

Conclusions: In younger adults with AML, the addition of cladribine to standard DA-60 induction resulted in equivalent CR rates and survival compared to intensified induction with DA-90. Exploratory subgroup analyses and MRD assessments using flow cytometry and next-generation sequencing are forthcoming and will be presented at the meeting.