Induction Anthracycline Skipped in Pediatric Leukemia Regimen



ATLANTA – Children with standard-risk B-lineage acute lymphoblastic leukemia can be safely spared from at least some of the toxicity associated with anthracyclines, the results of a randomized clinical trial suggest.

The 5-year overall survival rate among children with B-cell lineage acute lymphoblastic leukemia (ALL) treated without daunorubicin in the induction regimen was 98%, compared with 97.3% of those who received the anthracycline, Dr. Andre Baruchel reported at the annual meeting of the American Society of Hematology.

Event-free survival rates 5 years after randomization were also virtually identical, at 92.8% without daunorubicin and 92.6% with daunorubicin, said Dr. Baruchel, head of the pediatric hematology department at Robert Debré University Hospital (Assistance Publique Hôpitaux) in Paris.

"There was no difference in terms of complete remission rate, MRD [minimal residual disease] levels, event-free survival, overall survival, [and] cumulative incidence of relapse, secondary malignancy. Whatever the criteria you choose for trying to capture any difference between receiving or not receiving daunorubicin in these patients, you cannot find it," he said.

By cutting daunorubicin out of the induction phase, the investigators were able to reduce the total cumulative dose from 155 mg/m2 to 75 mg/m2.

Children with standard-risk B-cell lineage ALL comprise about 55%-60% of all cases, and generally have the best prognosis with modern chemotherapy, with overall survival rates hovering around 90%.

Anthracyclines were introduced in the late 1970s, and have become a mainstay for ALL therapy in both children and adults, but the evidence for including them in induction regimens has been weak, Dr. Baruchel said. He noted that a recent Cochrane Review of randomized studies of anthracyclines in leukemia found only three studies with sufficiently robust evidence, and none had been performed within the last 20 years.

Furthermore, anthracycline use varies with different protocols and risk groups, making it difficult to get a clear picture of their efficacy up front in ALL. What is clear, however, is that anthracyclines carry significant risk of both myelosuppression and cardiotoxicity, Dr. Baruchel said.

Hold the Daunorubicin?

To see whether they could safely eliminate daunorubicin from the induction regimen, the authors looked at 1,195 patients with standard-risk B-cell lineage ALL treated in the FRALLE 2000-A trial. The children, who ranged from 1 to 9 years in age, were treated with an induction regimen of prednisone prephase plus intrathecal methotrexate, dexamethasone 6 mg/m2 per day, vincristine, and L-asparaginase 6000 IU/m2 for nine infusions. Children were assessed for blood response on day 8, with a good response defined as less than 1000 blasts/mm3, and for an M1 bone marrow response on day 21 (less than 5% blasts).

In all, 94.7% of patients had a day 21 bone marrow morphology response, and 1,128 of these children were then randomized to either daunorubicin 40 mg/m2 on day 22 and day 29 (560 patients) or no daunorubicin (568).

The children were also assessed on day 35 for an end-of-induction response with bone marrow morphology and DNA-based polymerase chain reaction for MRD. The 61 patients who were not randomized because of inadequate bone marrow morphology received two infusions of daunorubicin.

Patients in the randomized phase went on to a 12-week-consolidation phase with vincristine, dexamethasone, mercaptopurine, and oral methotrexate. Consolidation was followed by a first delayed intensification phase, up to a total cumulative dose of daunorubicin of 75 mg/m2, interphase therapy, second delayed intensification, and a 24-month maintenance phase. Details of the regimen can be found in the abstract.

A molecular analysis showed that there was no difference in minimal residual disease measured at either 10-2 or 10-3 thresholds. Dr. Baruchel commented that there could possibly be a difference detected with more sensitive thresholds.

Similar Results in 1980s

Dr. William G. Woods, director of hematology/oncology at the Aflac Cancer Center and Blood Disorders Service at Children’s Healthcare of Atlanta, commented that similar trials were conducted in the United States in the late 1980s in standard-risk ALL, which showed that it was possible to safely eliminate daunorubicin from induction regimens.

Dr. Woods was not involved in the study, but moderated the briefing at which the data were presented.

Dr. Baruchel and Dr. Woods declared that they have no relevant conflicts of interest.

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