ASH Annual Meeting

DaunorubicinATLANTA—The anthracycline daunorubicin may not be necessary in induction therapy of standard-risk children with acute lymphoblastic leukemia (ALL). A study presented here at the American Society of Hematology Annual Meeting suggests that these children may be able to achieve high survival rates without having to endure treatment-associated short- and long-term toxicities (Abstract 135). ALL is a curable disease for most children. The majority (55%) of cases of this heterogeneous disease are standard-risk ALL of B-cell lineage, and the best prognosis for an overall survival rate for this group of patients is about 90 percent. “These are exciting results using chemotherapy without daunorubicin in the initial treatment regimen for children with ALL,” said the moderator of a news briefing that featured the study, William Woods, MD, Hematology/Oncology Director and the Daniel P. Amos Children's Chair at Aflac Cancer Center and Blood Disorders Service at Children's Healthcare of Atlanta. “This is an important step toward front-line therapy with no anthracycline. The reduction in daunorubicin dose did not affect outcome, and the reduced treatment regimen may reduce long-term toxicity in these children.” Anthracyclines, introduced in the late 1970s, are “remarkable drugs,” said the lead author of the study, André Baruchel, MD, Head of the Department of Pediatric Hematology at Robert Debré University Hospital (Assistance Publique Hôpitaux de Paris) in Paris. “But they also have remarkable toxicity. There is an unclear benefit on efficacy with anthracyclines in ALL, and a clear risk of additive toxicity from myelosuppression and cardiac events. Very few randomized studies of anthracyclines in ALL have been conducted, and none since 1991. We asked the question do we really need this drug?” In order to assess the efficacy of ALL treatment without daunorubicin during induction therapy, Baruchel and colleagues from 20 centers across France and one center in Belgium initiated a multicenter Phase III clinical trial in which 1,128 pediatric patients with standard-risk B-cell ALL were randomized into two treatment arms, one containing daunorubicin, the other without the drug. The trial, which originally enrolled 1,201 children, spanned from December 2000 to June 2010, during which five-year event-free survival (EFS) and overall survival (OS) were assessed. At the 21-day mark, the 560 patients whose marrows contained less than 5% blasts (M1) were randomized to receive 40 mg/m2 of daunorubicin on days 22 and 29. Another 568 patients were randomized to receive no daunorubicin for the rest of induction. Patients received intensified treatment if they had M3 marrows at day 21 or minimal residual disease (MRD) of one percent or more at day 35. All patients received prednisone prephase, intrathecal methotrexate, dexamethasone, vincristine, and E coli asparaginase. Patients with day-21 M1 marrows also received a 12-week consolidation followed by two delayed intensifications. The first one included a total of 75 mg/m2 of doxorubicin; and the second did not contain anthracycline for the patients who had M1 marrow at day 21. Patients then went on maintenance therapy for two years. No patient received central nervous system irradiation. “Only the rare patients with D21 M3 marrow and/or a MRD level of at least one percent received an intensified treatment after complete remission with three block-consolidation, intensified interphase with six cycles of methotrexate at 5 g/m2 and a second delayed intensification,” Baruchel said. Equivalent Survival without Daunorubicin After a median follow-up of 69 months, the five-year event-free survival rate was 92.9 percent for patients treated with daunorubicin compared with 93.3 percent for those in the non-daunorubicin arm. Overall survival rates were 97.2 percent and 98.2 percent in the daunorubicin and non-daunorubicin arms, respectively. “More importantly for the real population of ALL patients, there were no differences between the two groups with regard to MRD levels, complete remission rates, or relapse incidence,” he said. “At day 21, most patients have very good molecular responses to induction without daunorubicin. This was a little surprising,” he added. “If we applied more sensitive testing, there may have been a difference. “Our study data have the potential to benefit children with ALL in two important ways. First, we now have strong evidence that reducing the amount of chemotherapy initially administered to these children—who constitute the majority of ALL patients—does not negatively affect their immediate outcome. Perhaps more importantly, we can anticipate that removing harmful chemotherapy from their treatment can help minimize their risk of experiencing heart damage later in life.” He added that even if patients are given an intermediate dose of daunorubicin (155 mg/m2), congestive heart failure may still appear many years after treatment. The bottom line, said Baruchel, is that “with longer follow-up, we may determine that daunorubicin is dispensable during induction in B-ALL of standard risk, at least for children who are good early responders to vincristine, dexamethasone, and asparaginase.” Previous Study Woods commented that he and his colleagues had done a study in the 1980s showing that standard-risk ALL patients do not need daunorubicin in the beginning of treatment. He noted that daunorubicin is given at the beginning of treatment when children are the most sick to reduce their chances of dying of infection. “Despite our study, many places continued to use anthracyclines in induction. Now we stratify patients by risk group and then hone our treatment. We still use daunorubicin in high-risk patients.” The Children's Oncology Group does not recommend the use of daunorubicin in standard-risk ALL patients, and also recommends a reduced dose of anthracyclines, Woods noted. “Below the threshold of 100 mg/m2 of daunorubicin, the probability of an early event is low. In the intermediate range of 155 mg/m2 of daunorubicin, patients will have events. So there probably is no safe dose of daunorubicin above 100 mg/m2.” Woods continued: “First we cured this cancer, and now that the cure rate is more than 80 percent, we have the luxury to cut back on treatment. We know that anthracyclines in small doses are still needed, particularly in consolidation. We hope to substitute other novel drugs, including those not yet invented, for anthracyclines.” ASH 2012 President Armand Keating, MD, Professor of Medicine at the University of Toronto, said that the expectation is that there will be more therapies like this in the years to come: “I think we were awed by the seriousness of these diseases and developed aggressive treatments. Now it's time to recalibrate… It will be interesting to document whether there is a reduction in heart complications and other long-term adverse events in these children.”

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