CCG 1953: Acute Lymphoblastic Leukemia in Infants: Analysis of Prognostic Factors: A Report from the Children's Oncology Group.

Abstract

Background: Infant ALL has a poor therapeutic outcome. In contrast to other subtypes of ALL, infants have not benefited from risk-adapted therapy and intensification of therapy. This is the first cooperative group trial characterizing all infants at the molecular level for MLL/11q23 rearrangements for better stratification in future trials.Procedure: All infants enrolled on CCG 1953 were tested for MLL rearrangement by Southern Blot, and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or “other”) by reverse-transcriptase PCR.Results: 115 infants were enrolled (July 1996 to August 2000). Treatment for patients consisted of 4 courses of induction-consolidation-intensification followed by 3 cycles of intensified maintenance and 4 cycles of routine maintenance. Infants with 11q23/MLL abnormalities and a protocol-defined 5-6/6 related or unrelated donor identified within 4 months were assigned to BMT. Central nervous system prophylaxis consisted of triple intrathecal therapy during the first 10 weeks of therapy. Infants not undergoing BMT received additional CNS prophylaxis with very high dose methotrexate. Patients then received one year of intensified maintenance, followed by a year of standard maintenance. Overall event-free survival (EFS) was 41.7% (SD = 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL rearranged cases was 33.6%, and for MLL non-rearranged cases was 60.3% (p=.006). 5-year EFS for MLL/11q23 subgroups was as follows: t(4;11): 29.0%; t(11;19): 30.0%; t(9;11): 22.2%; and “other 11q23” 53.5% (p=.122). Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis for CD10 negativity, age less than 6 months, and MLL rearrangement, in that order. We did not observe a statistically significant difference in outcome between different MLL translocation partners, though we did observe a non-significant trend toward improved outcome in patients with “other” MLL translocation partners as compared to those with t(4;11), t(9;11) or t(11;19). Toxicity was the most frequent cause of death. Relapse as a first event in 1953 was later (median 295 days) compared to the predecessor1883 infant ALL trial (median 207 days).Conclusions: MLL/11q23 rearrangement, CD10 expression, and age are important prognostic factors in infant ALL, but individual molecular 11q23 translocation partners do not predict outcome. These results indicate that certain subgroups have an unusually poor outcome and are therefore candidates for novel therapeutic approaches in first remission. Given the high mortality, further dose intensification strategies are unlikely to result in better long-term survival.