AUTHORS
Alex Bataller, MD, PhD, Rami Komrokji, MD2, Hannah Goulart, MD3, Najla Alali4, Alexandre Bazinet, MD, MSc5, Naval Daver, MD6, Courtney DiNardo, MD, MSCE7, David Sallman, MD8, Nicholas Short, MD9, Guillermo Montalban-Bravo, MD10, Elias Jabbour, MD11, Musa Yilmaz, MD12, Koichi Takahashi, MD,PhD13, Naveen Pemmaraju, MD14, Nitin Jain, MD15, Jayastu Senapati, MBBS, MD, DM16, Zhuoer Xie, MD,MS17, Onyee Chan, MD18, Eric Padron, MD19, Alison Walker, MD20, Kendra L. Sweet, MD, MS21, Samuel Benjamin Reynolds, MD22, Andrew Kuyknedall23, Yun Seongseok24, Rory Shallis, MD25, Ghayas C. Issa, MD26, Gautam Borthakur, MD27, Farhad Ravandi, MD28, Jeffrey Lancet, MD29, Guillermo Garcia-Manero, MD30, Hagop Kantarjian, MD31, Tapan Kadia I, MD32
AFFILIATIONS
1 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 Moffitt Cancer Center, Tampa, Florida, United States
3 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
4 Moffitt Cancer Center, Tampa, Florida, United States
5 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
6 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
7 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
8 Moffitt Cancer Center, Tampa, Florida, United States
9 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
10 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
11 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
12 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
13 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
14 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
15 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
16 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
17 Moffitt Cancer Center, Tampa, Florida, United States
18 Moffitt Cancer Center, Tampa, Florida, United States
19 Moffitt Cancer Center, Tampa, Florida, United States
20 Moffitt Cancer Center, Tampa, Florida, United States
21 Moffitt Cancer Center, Tampa, Florida, United States
22 Moffitt Cancer Center, Tampa, Florida, United States
23 Moffitt Cancer Center, Tampa, Florida, United States
24 Moffitt Cancer Center, Tampa, Florida, United States
25 Moffitt Cancer Center, Tampa, Florida, United States
26 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
27 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
28 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
29 Moffitt Cancer Center, Tampa, Florida, United States
30 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
31 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
32 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
ABSTRACT
Introduction: Venetoclax (VEN) combined with Azacitidine (AZA) is the standard of care for patients (pts) with newly diagnosed acute myeloid leukemia (AML) aged ≥75 yrs or deemed unfit for intensive chemotherapy. However, the median age at diagnosis of AML is 68 yrs and most patients are over the age of 60 yrs. For these patients, the standard of care remains intensive chemotherapy (7+3). A novel lower-intensity regimen leveraging the combination of VEN with cladribine (CLAD) and low dose araC (LDAC) has shown high rates of MRD negative response and excellent outcomes in patients aged ≥ 60 yrs and could be a more optimal standard of care for these patients.
Methods: We compared patients aged ≥ 60 yrs with newly diagnosed AML treated on a phase II study (NCT03586609) of CLAD + LDAC + VEN alternated with AZA + VEN with a cohort of patients aged ≥ 60 yrs treated in the frontline with 7+3. Age and ELN 2022 risk category were used for propensity score matching between both cohorts, after excluding patients with CBF rearrangement or WBC >50 x109/L. Due to differences in follow-up time, follow up was restricted in 7+3 cohort to the maximum follow-up of CLAD/LDAC/VEN.
Results: After matching, a total of 177 pts were included for each cohort: CLAD/LDAC/VEN (Cohort A) and 7+3 (Cohort B). 62% and 57% of patients were male in Cohort A and Cohort B, and the median age for each cohort was 68 yrs (range, 60-84) and 67 yrs (60-84), respectively (P=ns). 19% and 10% had secondary AML (P=0.01) and 14% and 10% had therapy related AML (P=ns) in each cohort, respectively. Patients had diploid or complex karyotype in 49% and 19% in Cohort A, compared to 49%, and 18% in Cohort B (P=ns for both). According to the ELN 2022 classification, 16%, 22% and 62% vs. 15%, 25%, and 60%, were classified as favorable, intermediate and adverse risk, in Cohorts A and B, respectively. TP53 was mutated in 19% of patients in each cohort. NRAS and KRAS mutations were present in 16% and 6% in Cohort A, compared with 7% and 4% in Cohort B, respectively (P=0.02 for NRAS, P=ns for KRAS). NPM1 mutation was present in 19% and 16% in Cohort A and B, respectively (P=ns). FLT3-ITD was present in 5 and 8% in Cohort A and B, respectively (P=ns).
The composite complete remission (CR) rate in Cohort A was 84% (148/177) pts, including 72% CR; compared with 82% (145/177) CRc and 55% (CR) in Cohort B (P=ns). After first cycle, 79% achieved CRc in Cohort A vs. 59% in Cohort B (P<0.001). The 4- and 8-week mortality was 1% and 3% for Cohort A compared with 5% and 7% for Cohort B, respectively. 47% and 36% proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) in first CR in Cohorts A and B, respectively (P=0.05).
The median follow-up was 31 and 73 months, respectively. The median OS was significantly longer in Cohort A vs. Cohort B (52 vs. 20 months, P=0.01). The median event-free survival (EFS) was 50 vs. 11 months, respectively (P<0.001). The 2-yr OS and EFS was 62% and 58% for Cohort A vs. 46% and 31% for Cohort B. Among responders, the 2-year cumulative incidence of death without relapse was 17% in both cohorts (P=0.83). The 2-year cumulative incidence of relapse (competing with death without relapse) was significantly lower in Cohort A compared Cohort B (18% vs. 50% P<0.001). The 2-yr OS was 88%, 70% and 51% for patients allocated in the favorable, intermediate and adverse ELN 2022 classification in Cohort A vs. 75%, 65%, and 31%, respectively in Cohort B (P-adj ns for favorable and intermediate ELN 2022 risk, P=0.04 for adverse ELN 2022 risk). Patients who went on to receive alloHSCT in CR1 in each cohort had a 2-yr OS after alloHSCT of 62% and 46%, respectively (P=0.013). The outcomes of patients with AML with N/KRASmutations in each cohort were: (Cohort A) CR rate 82%; 2-yr OS of 50% vs (Cohort B) CR 79% and 2-yr OS of 43%). In patients with TP53 mutations, the median OS and 2-yr OS were 7.2 months and 36% (Cohort A), and 13 months and 19% (Cohort B) (P=ns). In patients with myelodysplasia-related mutations, the median OS and 2-yr OS were 50 months and 59% (Cohort A), and 20 months and 45% (Cohort B) (P=0.09).
Conclusions: CLAD-LDAC-VEN alternating with AZA + VEN is a safe and effective frontline therapy for patients aged ≥ 60 years with newly diagnosed AML that compares favorably to 7+3, demonstrating higher rates of CRc and OS and lower rates of relapse in this retrospective analysis. Prospective studies are needed to confirm this benefit.
DISCLOSURES
Alex Bataller, MD, PhD: No relevant conflicts of interest to declare.