Children with Down Syndrome (DS) and NCI Standard Risk (SR) Acute Lymphoblastic Leukemia (ALL) Have a Superior Five-Year Event-Free Survival (EFS) When Treated with Escalating Intravenous Methotrexate on the Children's Cancer Group (CCG) Study 1991

Abstract 497

DS is associated with a high incidence of ALL that is linked to unique biological and clinical features. In some studies these children have had an inferior outcome and have demonstrated unusual sensitivity to the side effects of chemotherapy, particularly methotrexate (MTX). CCG-1991 aimed to: 1) determine in a randomized fashion the benefit of double delayed intensification (DI) over single DI in a modified BFM therapy that uses dexamethasone as the sole corticosteroid and 2) compare the outcome of treatment that included escalating-dose intravenous (IV) MTX without leucovorin, and vincristine, to one that contains oral (PO) MTX, mercaptopurine, vincristine and dexamethasone during the interim maintenance phases (IM) of therapy. Patients received a 3-drug induction with vincristine, pegylated asparaginase, dexamethasone, and intrathecal cytarabine and MTX. This was followed by consolidation, delayed intensification, interim maintenance, and maintenance phases of therapy. Slow early responders by bone marrow morphology (Day 7/14 M3-M3, or M3-M2; or M2 at Day 28 Induction) and patients with unfavorable cytogenetics [(t(9;22)(q34;q11), (4;11)(q21;q23), balanced t(1;19)(q23;p13) or hypodiploidy with < 45 chromosomes] were non-randomly assigned to a COG augmented BFM therapy regimen (N Engl J Med 1998; 338:1663). Rapid early responders with no unfavorable cytogenetics or CNS leukemia were randomized in a 2 × 2 factorial design to one of the 4 regimens -Table 1. Three thousand fifty four children with NCI SR ALL were enrolled on CCG-1991; 2078 non-T ALL eligible patients were randomized. A total of 108 patients with DS were enrolled, 77 patients were randomized to one of the 4 regimens; 45 patients were randomized to the arms containing PO MTX during IM (OS+OD), and 32 to the ones containing IV MTX (IS+ID) during IM. IV methotrexate, as given in this study, was generally well tolerated, but the mean total dose was lower in patients with DS. There was no increased hepatic toxicity, seizures or leukoencephalopathy in patients with DS during IM on either the IV or PO MTX arms, as compared to those without DS. Similarly, the incidence of systemic infections was not higher in patients with DS. The incidence of mucositis, however, was increased in patients with DS as compared with patients without DS, particularly in those who received IV MTX. Five-year EFS and overall survival (OS) for patients with DS randomized to the IV MTX and PO MTX arms are listed in Table 2. The overall 5-year EFS and OS of randomized patients with DS are 90.1% ± 4.9% and 94.8% ± 3.7% respectively. We conclude that patients with DS and SR-ALL without adverse features can be cured with COG BFM-modified therapy with escalating-dose IV MTX without leucovorin rescue during the interim phases of therapy.