Enhanced AML Remission With Cladribine Alternating Therapy

The combination of cladribine, low-dose cytarabine, and venetoclax alternating with azacitidine and venetoclax (AZA-VEN) achieved high rates of composite complete remission (CRc) and favorable overall survival (OS) in patients with acute myeloid leukemia (AML). Patients undergoing stem cell transplantation and of particular genomic backgrounds had significantly improved survival, highlighting the effectiveness of the regimen for diverse risk groups.

Alexandre Bazinet, MD, of the MD Anderson Cancer Center, and colleagues examined the efficacy of cladribine as an alternative to the hypomethylating agents and venetoclax (HMA-VEN) standard of care for patients with AML who are not eligible for intensive therapy. Their previous data showed promising 24-month OS and complete remission with CRc.¹ They aimed to extend the follow-up period and include a larger cohort for further analysis.

In a single-center, single-arm, prospective phase 2 clinical trial (NCT03586609), cladribine in combination with low-dose cytarabine and venetoclax (CLAD-LDAC-VEN) was investigated in an alternating schedule with azacytidine and venetoclax.² The trial included participants (n=141) with untreated non–acute promyelocytic leukemia AML who were at least 50 years old or younger than 50 and ineligible for standard induction chemotherapy.

Overall, the CRc for the CLAD-LDAC-VEN alternating with AZA-VEN was 86%, with a measurable esidual disease negativity of 76%. The 2-year OS was 61.6%, which was consistent with the smaller study,¹ and the 4-year OS was 52.3%. Event-free survival at two and four years was 54.5% and 50.3%, respectively. Patients receiving stem cell treatment (n=62) had significantly improved OS at two and four years compared with patients not receiving stem cell treatment (n=63) (P<.001).

In addition, the investigators created a predictive model to identify patient characteristics that determine OS. “We developed a risk score specific to this regimen using Cox regression and random force model to select prognostic variables,” Dr. Bazinet and colleagues explained. “This score effectively stratified patients into four different OS categories.” The top category, which had patients with NPM1 or DDX41 mutations, had a median OS of 60 months, whereas the worst category, which was composed of patients with a complex karyotype or a TP53 mutation, had a median OS of just seven months.

Bazinet further pointed out the improved outcomes of this regimen for intermediate groups. “Of note, patients with K or NRAS mutations treated with CLAD-LDAC-VEN showed an improved survival of 21 months, which compares favorably with historical data when these patients are treated with standard HMA-VEN where the expected survival is about 12 months,” they wrote.

References

1 Kadia TM, Reville PK, Wang X, et al. Phase II study of venetoclax added to cladribine plus low-dose cytarabine alternating with 5-azacitidine in older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2022;40(33):3848-3857. doi: 10.1200/JCO.21.02823

2 Bateller A, Kantarjian HM, Bazinet A, et al. Phase II study of cladribine with low dose cytarabine and venetoclax alternating with azacytidine and venetoclax for newly diagnosed acute myeloid leukemia. Abstract #56. Presented at the ASH Annual Meeting; December 7-10, 2024; San Diego, California.