Background: Acute lymphoblastic leukemia (ALL) in infants represent 2.5% to 5% of all childhood ALL, and has an inferior therapeutic outcome compared to that of older children. Among several risk factors, rearrangement in MLL gene is most closely associated with this poor outcome. This is the first series of cooperative group trials stratifying ALL in infants with MLL gene status.

Procedure: Infants with ALL, age less than 12 months, were registered on two consecutive multi-center trials designated MLL96 and MLL98. All the patients were tested for MLL gene rearrangements by Southern Blot analysis and/or fluorescence in situ hybridization. According to the MLL gene status, patients with rearranged MLL gene were allocated to intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT), and those with germline MLL were treated with standard chemotherapy alone (total treatment duration was 83–85 weeks). In MLL98 study, treatment intensification and early use of HSCT were introduced compared to MLL96 study.

Results: A total of 101 infants were enrolled between December 1995 and December 2002. Seventy-nine had rearranged MLL and 22 had germline MLL. Event-free survival (EFS) of all 101 infants with ALL was 52.0% at 5 years; 5-year EFS for MLL rearranged cases was 39.7%, and for MLL germline cases was 95.5% (p<0.001). Among the MLL rearranged patients, 3-year EFS improved from 34.0% in MLL96 trial (N=41) to 43.6% in MLL98 trial (N=38). Although their were no secondary malignancies among the whole enrolled patients, physical growth impairments was observed in MLL rearranged patients, while no significant late effects were observed in MLL germline patients.

Conclusions: Risk stratification with MLL gene status was successful for infants with ALL. Excellent results were obtained for the germline MLL group using chemotherapy alone, and early introduction of allogeneic HSCT in first remission seemed effective for the MLL rearranged group. However, use of HSCT with less toxic conditioning regimens or development of effective chemotherapy including molecular target therapy are needed for MLL rearranged patients in order to avoid severe late effects for infants.

Disclosures: Japan Leukemia Research Fund; Japan Children’s Cancer Association; Grant-in-Aid for Cancer Research from the Ministry of Health and Labor of Japan.

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