Newer Strategies Aim to Improve Long-Term Remission Rates in AML

SEATTLE--While about 65% of adults with newly diagnosed, acutemyelogenous leukemia (AML) are able to achieve complete remissionof their disease, this remission is often short-lived when conventionalpostremission regimens are used. However, new approaches to postremissiontherapy are proving beneficial to patients, Robert J. Mayer, MD,said at a symposium held in conjunction with the American Societyof Hematology's 37th Annual Meeting.

These approaches include high-dose cytarabine (ara-C) as postremissionchemotherapy, and cytogenetic analysis to "risk adapt"postremission therapy to an individual patient's cancer karyotype.

Dr. Mayer, professor of medicine, Harvard Medical School, andclinical director, Department of Medicine, Dana-Farber CancerInstitute, presented data from a study conducted by CALGB (Cancerand Leukemia Group B), involving 693 AML patients in completeremission following induction therapy with standard-dose cytarabineand daunorubicin (Cerubidine).

Patients then were randomized to receive four cycles of cytarabinein one of three dosage schedules: high dose (3g/m², twicedaily, on days 1, 3, and 5); intermediate dose (400 mg/m²/day× 5 days); or low dose (100 mg/m²/day × 5 days).This regimen was followed by four cycles of monthly maintenancetreatment with cytarabine and daunorubicin, after which all treatmentwas discontinued.

Four-year disease-free survival rates showed significant advantagesfor patients who received the high-dose cytara-bine consolidationregimen--43% of the high-dose patients achieved continuous completeremission (CCR) vs 31% and 23% for the intermediate- and low-dosegroups, respectively. (Dr. Mayer added that these results werefor patients younger than age 60; for those older than 60, theCCR rates were 16% or less for each of the three dosage groups.)

An analysis of pretreatment cytogenetic status showed an evenmore striking effect of high-dose cytarabine, Dr. Mayer said.

Patients were divided into three prognostic groups according toleukemia karyotype: favorable [t(8;21) or inv(16)]; intermediate[t(15;17) or normal]; and unfavorable (other karyotypes).

The higher postremission doses of cytarabine strikingly prolongedremission in the favorable subset, improved remission outcomein the intermediate group, and had little or no effect on theunfavorable group.

In a related study of 276 patients randomly selected from theCALGB trial, the presence or absence of c-ras mutations was alsofound to be a valuable prognostic factor for the effectivenessof postremission, high-dose cytarabine therapy, Dr. Mayer said.

In this study, presented at the ASH meeting (abstract 2380), patientswhose leukemia was ras-mutation positive had 4-year survival ratesin complete remission of 0% for low-dose cytarabine, 50% for intermediate-dosecytarabine, and 67% for high-dose cytarabine.

For ras-negative leukemias, on the other hand, there was far lessof an effect: 21% for low-dose, 34% for intermediate-dose, and36% for high-dose cytarabine therapy.

Dr. Mayer said that these study results bring the postremission,high-dose chemotherapy approach "roughly into the same ballpark"as allogeneic and autologous bone marrow transplantation, in termsof long-term remission rates for the treatment of certain cytogeneticsubgroups of AML.

Risk Adaptation

"One could argue," Dr. Mayer said, "that therapyplanning should be based on risk adaptation. The lesson from anumber of clinical trials is that the results of a regimen maybe as dependent on the treated population as on the administeredagent. You need to know the cytogenetic and clinical risk factorsto identify patients with different long-term prognoses in orderto individualize their therapy."

A number of questions remain regarding the postremission, high-dosechemotherapy approach. For example, Dr. Mayer said, if postremissioncytarabine is more effective than conventional cytotherapy, whyis that not the case for remission induction?

There are data from Australia, he noted, comparing high-dose cytarabineduring induction with conventional cytara-bine treatment. Thestudy results suggest that even though remission rates were similarwith the two induction regimens, the patients who were inducedwith high-dose cytarabine had a longer duration of remission.

Other questions still to be resolved by comparative trials includea determination of the optimal dosage schedule of cytarabine;whether additional chemotherapeutic drugs, such as etoposide (VePesid),might make the high-dose cytarabine therapy even more effective;whether toxicity from drug-induced myelosuppression can be decreasedwith, for example, hematopoietic growth factors; and whether theprobability of neurotoxicity of the high-dose regimen in olderpatients can be reduced.

Finally, Dr. Mayer emphasized that even the more successful, high-dosechemotherapeutic approach has its limitations, and further developmentof other types of therapy, utilizing other aspects of cell biology,is needed.