Finally, Demonstrable Improvement in Remission Induction for Adult Acute Myelogenous Leukemia

By Jerome W. Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.

Synopsis: A multi-institutional study examined the addition of a purine analog, either cladribine or fludarabine, to the standard induction regimen ("7 & 3") in adult patients 60 years of age and younger with acute myelogenous leukemia, and found improved outcomes for those receiving cladribine. The added benefit from cladribine appears to be the result of a reduction in the incidence of resistant disease. The study arm containing cladribine, daunorubicin, and cytaribine yielded an overall survival at 3 years of 45% while conventional "7 & 3" therapy was only 33% at 3 years. Cladribine added to daunorubicin and cytarabine during remission induction improves leukemia control and patient survival for those 60 years of age and younger.

Source: Holowiecki J, et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: A multicenter, randomized phase III study. J Clin Oncol 2012;30:2441-2448.

This paper reports a three-arm study randomizing 652 previously untreated acute myelogenous leukemia (AML) patients to one of three arms: 1) conventional "7 & 3" with daunorubicin and cytarabine, 2) the same plus cladribine, or 3) the same plus fludarabine. There were no differences in known prognostic factors, including the distribution of favorable and unfavorable karyotypes, among those randomized. Overall survival at three years was 33% for group 1, 45% for group 2, and 36% for group 3. The addition of cladribine decreased leukemic resistance. Early mortality was similar for all three treatment arms studied. Cladribine can induce direct mitochondrial injury causing cell death, a molecular mechanism of action different from fludarabine. It appears to affect both proliferating and non-proliferating cell pools.

Commentary

Seven days of cytarabine and 3 days of daunorubicin became standard induction therapy for AML in the early 1980s.1,2 A series of studies exploring modifications, such as doubling the dose of cytarabine, extending its infusion to 10 days, or adding other drugs such as oral thioguanine, demonstrated no improvement in the rates of remission.3 Additional attempts to improve the standard of care included substituting other anthracyclines in place of daunorubicin or increasing its dose; these failed to substantially improve the outcomes. Genetic risk stratification has resulted in improved prediction of outcome results based on good risk and poor risk karyotypes.

Though "7 & 3" has been the "gold standard" AML induction treatment for decades, the data presented offer a cogent rationale to consider adding cladribine. It would appear, based on this credible multi-institutional study, that the addition of cladribine to ara-c and daunorubicin will result in an increase in survival of adults age 60 and younger when treated for acute myelogenous leukemia.

References

1. Yates JW, et al. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973;57:485-488.

2. Yates J, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: A CALGB study. Blood 1982;60:454-462.

3. Tefferi A, Letendre L. Going beyond 7 + 3 regimens in the treatment of adult acute myeloid leukemia. J Clin Oncol 2012;30:2425-2428.