Hybrid Regimen Shows Promise for Infant ALL

ROTTERDAM, July 19 -- Infants with acute lymphoblastic leukemia (ALL) had improved event-free survival with a hybrid protocol that combined elements of acute myeloid leukemia (AML) therapy, investigators here found.

ALL in infants is rare and biologically different from ALL in older children, noted Rob Pieters, Ph.D., of Erasmus Medical Center-Sophia Children's Hospital, and international collaborators, in the July 21 issue of The Lancet.

The clinical course of infant ALL also differs substantially. Studies from various countries have shown a long-term event-free survival of 28% to 45% in infants compared with an event-free survival of about 80% in older children, the authors pointed out.

Of 482 infants who received the hybrid protocol, 58% were in complete remission at a median follow-up of more than three years, and four-year event-free survival was 47%, Overall survival was 55.3%,

But additional treatment with an intensified protocol during a randomized second phase of the study did not improve on the benefit achieved with the hybrid protocol.

"We believe that this hybrid treatment protocol will be used as the standard for continuing international collaborative studies that aim to further improve outcomes for acute lymphoblastic leukemia in infants," concluded Dr. Pieters.

Patients for the study came from 17 study groups in 22 countries. Eligibility criteria included age 365 days or younger, newly diagnosed ALL (except for patients with mature B phenotype), and no previous treatment for leukemia except emergency treatment. Patients were stratified into standard- and high-risk groups on the basis of their blast response to one week of daily systemic prednisone and one intrathecal dose of methotrexate.

Treatment began with a standard four-drug induction regimen for ALL plus low-dose cytarabine, which had demonstrated in vitro activity against infant lymphoblasts. Induction was followed by consolidation therapy for four weeks with standard agents and then seven weeks of re-induction therapy with an AML protocol. The first phase ended with an extended course of antimetabolites.

Patients who were alive and in complete remission after re-induction and were not undergoing stem-cell transplantation were eligible for a randomized trial of delayed intensified chemotherapy. Complete remission was defined by bone marrow testing that revealed fewer than 5% leukemic cells, hematopoiesis in regeneration, and no evidence of leukemic cells elsewhere.

Standard-risk patients were randomized to control or intensified therapy. Control therapy consisted of oral 6-MP, methotrexate, pulsed dexamethasone and vincristine, and intrathecal methotrexate with steroids. Intensified therapy consisted of an intensified version of the induction therapy (vincristine added), followed by a standard maintenance phase after two weeks of recovery.

High-risk control patients received standard maintenance intensified with pulses of cytarabine and etoposide. High-risk patients assigned to the study therapy received the intensified induction regimen followed by standard maintenance intensified with pulsed cytarabine and vincristine.

At the end of induction, 445 of 474 evaluable patients (94%) were in complete remission, comprising 312 standard-risk and 133 high-risk patients. Subsequently, 191 of the 445 patients were randomized to the delayed intensified phase of the study.

Four year disease-free survival did not differ between patients randomized to the control protocol (57%) or the experimental regimen (60.9%). Overall survival was 65.8% for the control group and 64.7% for the experimental group.

Age less than six months, white-cell count over 300x10?/L, and the presence of mixed-lineage leukemia gene rearrangement (regardless of the type of 11q23 rearrangement), were identified as unfavorable prognostic factors, with an event-free survival of 20% for a fifth of patients who had these three prognostic factors.

In a commentary, Josep-Maria Ribera, M.D., and Albert Oriol, M.D., of the Autonomous University of Barcelona in Spain, noted that the results were superior to historical outcomes achieved by the participating study groups. However, they cautioned that, encouraging results notwithstanding, new genome-based treatment strategies are needed for infants with ALL.