Outcome of Infants Less Than One Year of Age with Acute Lymphoblastic Leukemia Treated with the Interfant-99 Protocol.

Introduction

Acute lymphoblastic leukemia (ALL) in infants under 1 year of age is rare and has a poor outcome compared to ALL in older children. It is characterized by a high expression of MLL gene rearrangements, high tumor load and myeloid features. In 1999, a large collaborative international study, Interfant-99, was initiated with the aims to determine: (1) the outcome of a new treatment protocol including ALL and AML elements; (2) in a randomised way the value of a late intensification course with high dose araC and methotrexate; (3) which clinical and biological factors have independent prognostic value within infant ALL. Event-free survival (EFS) and overall survival (OS) were primary endpoints and analysed on an intention to treat basis.

Results

17 study groups representing >20 countries enrolled 482 patients leading to by far the largest trial ever reported in infant ALL. 79% of cases had an MLL rearrangement. Of these, 53% was t(4;11), 20% t(11;19), 11% t(9;11) and 16% had other MLL partner fusion genes.

Death in induction rate was 3.8% and 2.3% did not achieve CR at the end of induction, so CR rate was 94%. Death rate in CCR was 5.2%. Relapses occurred in 36% of cases and were mainly isolated bone marrow relapse. Median time from 1st CR to relapse was 8 months. The overall 4-year EFS is 47% and OS is 55%. This is at least comparable to the best historical controls and better than most of those of the participating study groups. Especially outcome of high-risk patients, defined by poor response to one week prednisone, had improved. The late intensification course with HD-araC and HD-MTX did not improve outcome.

Cox model showed that MLL rearrangement and age <6 months were strong independent prognostic factors for poor outcome. WBC > 300x10e9/L and poor prednisone response were also of independent prognostic value. The outcome was not depending on the type of MLL rearrangement.

Conclusions

Results of this first international treatment protocol for infant ALL are very satisfactory. Early bone marrow relapse remains the major cause of treatment failure indicating that early treatment intensification is necessary. The large international collaboration has enabled the start of studies to improve outcome for infant ALL. The new Interfant-06 study will stratify the patients based upon MLL status, age and WBC and will study the value of the use of two early "AML" courses in a randomised way.