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© 1999 American Society for Clinical Oncology
Acute Lymphoblastic Leukemia in InfantsSt. Jude Children's Research Hospital, University of Tennessee, Memphis, TN PROGRESS IN THE TREATMENT of childhood acute lymphoblastic leukemia (ALL) has been remarkable, as demonstrated by the overall cure rates of nearly 80% now being attained in some clinical trials.1 Among the subgroups still resistant to therapy, infants may pose the most formidable challenge. With the exception of one small study, in which the 4-year event-free survival (EFS) was 54% ± 11% (SE),2 long-term outcomes in recent studies have not been encouraging.3-8 In this issue of the Journal of Clinical Oncology, the Children's Cancer Group (CCG) reports 4-year EFS rates of 33% ± 4.7% (SE) and 39% ± 4.2% in their CCG 107 and CCG 1883 studies.9 In the latter study, adequate control of CNS disease was achieved with use of intensive systemic and intrathecal treatment only; cranial irradiation was avoided altogether, even in infants with CNS leukemia at diagnosis. This result is important in view of the neuropsychologic deficits observed in patients treated with cranial irradiation,2 especially very young children.10 Indeed, infants treated on the CCG 107 study without cranial irradiation showed normal neuropsychologic development when tested at 5 years of age.11 Despite a 14.2% prevalence of CNS leukemia at diagnosis, the cumulative risk of isolated CNS relapse in the CCG 1883 trial was only 3% ± 2%. Investigators at St. Jude Children's Research Hospital also relied on early intensification of intrathecal treatment, in the context of effective systemic chemotherapy, to reduce the risk of CNS relapse and boost the overall EFS rate, among patients of all ages, including infants.12 Currently, both the St. Jude group and the Dutch Childhood Leukemia Study Group are testing the hypothesis that combined use of dexamethasone, intensive intrathecal treatment, and effective systemic chemotherapy can entirely eliminate the need for cranial irradiation in patients with ALL.13 Although this approach is likely to reduce the risk of neuropsychologic deficits, it may still produce unacceptable acute and late effects, warranting close monitoring of patients both during and after therapy. The prognosis for infants with ALL is determined by the presence or absence of certain presenting features. A very young age, high initial leukocyte count, lack of CD10 expression, myeloid-associated antigen expression, 11q23 translocations (or MLL rearrangements), and a poor early response to therapy predict an especially poor outcome.3-5,14-16 These high-risk factors are closely related to each other. However, in different multivariate analyses, an 11q23/MLL rearrangement and a poor early treatment response consistently emerged as the most important adverse prognostic indicators.5,17-20 In the 107 and 1883 trials, CCG investigators found that the t(4;11), which produces MLL-AF4 fusion, was the only translocation associated with a dismal outcome.9,21 However, cytogenetic data were available in only 94 (40%) of their 234 cases, and translocations other than the t(4;11) were found in only 12 cases. Altogether, 11q23 translocations, including the t(4;11), were found in 48% of the infant cases, in contrast to the 70% to 80% frequencies reported by others, using molecular techniques, with or without cytogenetics.5,15,17-20 Hence, additional study is needed to fully assess the prognostic impact of 11q23/MLL rearrangements not associated with the t(4;11) translocation. This task is well worth the effort, as many investigators would recommend allogeneic stem-cell transplantation for infants with any MLL rearrangement. Why do infants with ALL fare so poorly? Clearly, their adverse prognosis is not due solely to t(4;11)/MLL-AF4 fusion, as children 1 to 9 years old with this abnormality have a reasonably favorable outcome,22,23 a result recently confirmed in a European 11q23 workshop.24 This finding was recently extended to t(11;19)/MLL-ENL fusion, which predicted a significantly worse outcome in infants than in children 1 to 9 years of age.25 Thus, other factors must contribute to the generally poor treatment results obtained in infants. It may be important that the blast cells in infant ALL have a fetal origin, as demonstrated by the predominance of a fetal-type DJH joining sequence in the immunoglobulin gene,26 myeloperoxidase gene expression,27 in utero metastasis of leukemic cells in pairs of identical infant twins,28 and clonotypic gene fusion sequences in neonatal blood spots.29 The primitive nature of leukemic cells in infants may partly account for their greater resistance to therapy.30 Such blast cells grow well in stroma-supported culture in vitro, a finding that correlates with an increased risk of relapse.31 They also are resistant to cell death induced by growth factor deprivation,32 and they show greater resistance in vitro to prednisone, L-asparaginase, and teniposide than do leukemic cells from older children.33 Finally, studies of concordant leukemias in identical twins suggest that some cases of ALL arise in utero; the most aggressive forms present clinically during infancy, whereas the remainder appear sporadically throughout childhood.34-36 Can the treatment of infant ALL be improved? The increased in vitro sensitivity to cytarabine of leukemia blast cells from infants33 suggests that added clinical benefit might be obtained from chemotherapy regimens based on this agent. Investigators of the Dana-Farber Cancer Institute Consortium2 reported an improved outcome in infants treated with intensified therapy that included a course of high-dose cytarabine. In a Pediatric Oncology Group study featuring 1 year of intensified therapy that included high-dose cytarabine during the consolidation phase, the outcome was improved for infants with 11q23 translocations but not for those without this abnormality.37 The latter result suggests that prolonged chemotherapy similar to standard regimens in childhood ALL may be preferable for infants lacking 11q23 translocations. Perhaps most striking is the long-term EFS rate of nearly 50% among t(4;11)-positive adults treated in two German multicenter trials with a regimen containing high-dose cytarabine and mitoxantrone.38 Although high-dose cytarabine was also used in the CCG 1883 trial, the dosage was arbitrarily reduced by half in infants younger than 6 months of age, a group with a particularly high rate of relapse and hence requiring more intensive therapy. Although there is a general paucity of pharmacokinetic data in infants, limited studies indicate that the clearance of and systemic exposure to cytarabine are similar in infants and older children,39 which suggests that a reduction of cytarabine dosage may not be necessary for very young patients. Neonates may be an exception, although pharmacokinetic and pharmacodynamic studies are needed to explore this possibility. There is a paucity of data on allogeneic hematopoietic stem-cell transplantation in infants with ALL. Of the 12 infants undergoing this procedure in the CCG studies, only two survived; the others died of complications or relapsed ALL. The experience of the Fred Hutchinson Cancer Research Center is more encouraging, with seven of nine infants alive in remission for 2 to 11 years after allogeneic transplantation (J.E. Sanders, personal communication, December 1998). Clearly, additional studies of allogeneic stem-cell transplantation are needed for infants in first remission, especially those with a high risk of relapse. Because infant ALL accounts for only 2% to 5% of childhood ALL cases overall, national or international collaborative studies are needed to provide definitive answers and advance the cure rate. Current plans of the CCG and Pediatric Oncology Group include clinical trials testing the feasibility and efficacy of intensified chemotherapy, allogeneic stem-cell transplantation, and anti-CD19 immunotoxins. An international study involving 10 study groups and institutions in Europe and the United States will evaluate the efficacy of a "hybrid regimen" consisting of high-dose cytarabine and other agents effective against both acute lymphoid and acute myeloid leukemias. REFERENCES
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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