PRIMARY BLASTS FROM INFANTS WITH ACUTE LYMPHOBLASTIC-LEUKEMIA CAUSE OVERT LEUKEMIA IN SCID MICE

The establishment of an in vivo animal model system for infant acute l ymphoblastic leukemia (ALL) would allow the testing of new agents agai nst primary leukemic cells from infant ALL patients. We have demonstra ted previously that growth of B-lineage leukemic cells in mice with se vere combined immunodeficiency (SCID) was a significant prognostic fac tor for children with high risk ALL. We now have examined the signific ance of this prognostic variable for 13 infants with newly diagnosed A LL treated at participating institutions of the Children's Cancer Grou p (CCG). Chromosomal translocations were detected in 10/12 evaluated c ases, including five with t(4;11), one each with t(7;9) and t(7;11), t (1;19), and t(9;22), and two with t(11;19). Twelve of the thirteen inf ants with ALL achieved remissions following induction chemotherapy. Pr imary leukemic cells from 8 of the 13 infants caused overt leukemia in SCID mice. Among these 8 SCID+ infants, 7 were CD10(-) and seven had cytogenetic or molecular evidence of an 11q23 rearrangement. Six of th e 8 SCID+ infants have relapsed only 2 remain in remission following c hemotherapy or bone marrow transplant. However, among the 5 SCID- infa nts there were also two relapses. These data are suggestive of a poore r outcome for SCID+ infants, but larger numbers of patients must be an alyzed to assess their statistical significance. In summary, we have e stablished a SCID mouse model for human infant ALL that will be useful for 1) predicting short-term and long-term outcome of patients, 2) te sting pharmacokinetics, efficacy, and toxicity of new agents, and 3) e lucidating the in vivo mechanisms of chemotherapeutic drug resistance in infant ALL.