The combination of the nucleoside analog cytarabine (Cytosar-U) and the anthracycline daunorubicin (Daunoxome), the so-called “7 + 3” schedule, has been the standard of care for the treatment of acute myeloid leukemia (AML) for several years. Recent data suggest that better induction options exist, especially for younger patients, said Alan K. Burnett, MD, Head of Hematology, Department of Medical Genetics, Hematology and Pathology, Cardiff University, Heath Park, United Kingdom. He challenged the current 7 + 3 paradigm during the Ham-Wasserman Lecture delivered at ASH 2012.
Unresolved issues around the “conventional” approach include alternative anthracyclines or nucleoside analogs in induction, dose, and number of courses of consolidation, and which patients should receive an allograft in first remission.
Survival has improved in younger patients over the past 2 or 3 decades—although improvements in supportive care may be primarily responsible—but this improvement in survival may be limited to those with favorable-risk disease, Dr Burnett said. Little evidence of improved survival exists for older patients.
Molecular studies may help define the patients who are to receive an allogeneic transplant in first remission. “The ability to accurately monitor treatment by molecular or immunophenotypic techniques has the potential to enhance a personalized approach to treatment,” said Dr Burnett.
Because conventional chemotherapy has probably reached its potential, there is interest in novel treatments, particularly for older patients.
Higher Anthracycline Dose
Intensifying daunorubicin administration is an option that may improve overall remission rate and overall survival (OS), Dr Burnett pointed out.
In the E1900 trial, daunorubicin dosed at 90 mg/m2 in a 7 + 3 schedule for the first induction course resulted in a significantly higher overall remission rate, with more patients in complete remission after the first course, and a better OS rate compared with the 45-mg/m2 dose (23.7 vs 15.7 months, respectively). In 2 other studies, a similar approach improved the overall remission rate but not OS, except in patients aged 60 to 65 years.
Whether a higher daunorubicin dose should be the standard of care is not clear, noted Dr Burnett. Recent multigene mutation characterization may be useful in identifying those who benefit from the escalated dose.
Gemtuzumab ozogamicin (Mylotarg) is a monoclonal antibody to CD33 that is conjugated to the powerful intercalating agent calicheamicin. A single dose of gentuzumab ozogamicin (6 mg/m2) to augment daunorubicin and cytarabine failed to show benefit in clinical studies of patients with AML, with a concern about an excess of induction death in one trial (SWOG-106).
Three European randomized trials of nearly 3000 patients show a survival benefit when gentuzumab ozogamicin was given at lower daily dose levels (3 mg/m2) in combination with induction chemotherapy, with little increase in toxicity. These studies demonstrated improved survival in favorable and in intermediate-risk patients, but not in poor-risk patients.
Analogs in Induction
Novel nucleoside analogs under recent investigation include cladribine (Litak), fludarabine (Fludara), and clofarabine (Clolar).
Compared with cytarabine, cladribine significantly increased the proportion of patients who achieved complete remission with 1 course, but did not improve survival. In a more recent study, adding cladribine or fludarabine to 7 + 3 cytarabine was compared with 7 + 3 alone in a 3-arm study of patients aged <60 years. “The inclusion of cladribine, but not fludarabine, improved the remission rate and overall survival,” Dr Burnett said. “In a subgroup analysis, the addition of either nucleoside appeared to be beneficial in patients with an adverse karyotype.”
Adding fludarabine to induction therapy with cytarabine, granulocyte colony-stimulating factor, and idarubicin in younger patients reduced the rate of relapse significantly compared with daunorubicin or daunorubicin plus etoposide, but had no effect on remission rate or OS; however, this reduction in risk was offset by an increase in the rate of myelosuppression.
Clofarabine 20 mg/m2 in combination with daunorubicin did not improve response or OS in any risk group when compared with cytarabine plus daunorubicin in the United Kingdom NCRI AML16 trial.
Cytogenetics and Personalized Therapy
Determining which patients should undergo allogeneic transplantation may depend on predicting relapse using molecular studies, Dr Burnett claimed. Patients with a cKIT mutation have an increased risk of relapse. Biallelic CEBPα and NPM1 mutations without an FLT3 mutation have a favorable prognosis, similar to the core-binding factor leukemias, and therefore do not require a transplant.
Adverse cytogenetics include chromosomes 5 and 7 abnormalities, inv3, and complex and monosomal karyotypes, and predict rapid relapse. Allograft is recommended for such patients, but it only cures 30% to 40% of these patients, Dr Burnett cautioned.
Molecular data have emerged to estimate prognosis. An FLT3 mutation balances out the favorable effect of an NPM1 mutation, but “the impact of FLT3 mutations is complex and is influenced by the association with NPM1, whether it occurs alone and by the allelic ratio,” he said. “It is likely that the prognostic impact of each mutation will be modified by its association with other mutations.”
Dr Burnett added that the utility of allogeneic transplantation for FLT3 mutations has not been settled, “particularly when the allelic ratio and association (or not) with NPM1 is considered.”
FLT3 has been a target for the development of pharmaceuticals. Targeting FLT3 with quizartinib proved beneficial in patients with AML who have a mutation in FLT3 in an open-label study that was also reported at the meeting.