Physicians compliance during maintenance therapy in children with Down syndrome and acute lymphoblastic leukemia

Abstract

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have an inferior prognosis compared with non-DS ALL patients. We reviewed methotrexate (MTX)/mercaptopurine (6MP) maintenance therapy data for children with DS treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL92 or the NOPHO ALL2000 protocols between 1992 and 2007. The 5-year event-free survival probability (pEFS(5 yr)) for the 66 DS patients was inferior to the 2602 non-DS patients (0.50 ± 0.07 vs 0.77 ± 0.01 (P<0.001)). The 48 DS patients in first remission at the beginning of maintenance therapy had pEFS(10 yr) below that of the 522 non-DS control patients (pEFS(10 yr): 0.58 (95% confidence interval (CI) 0.43-0.77) vs 0.83 (95% CI 0.80-0.86), respectively (P<0.0001)). The DS patients received lower median doses of MTX (median: 11.8 vs 15.4 (P<0.0001)) and 6MP (median: 43.6 vs 59.4 (P<0.0001)). In Cox regression analysis, male gender, presence of DS and high median maintenance therapy white blood cell levels (mWBC) were associated with increased risk for relapse. DS-ALL patients with mWBC above or below 3.5 × 10(9)/l (protocol target) had pEFS(10 yr) of 0.31 and 0.72 (P=0.02), and the mWBC hazard ratio for DS-ALL patients was 2.0 (P<0.0005). We conclude that insufficient treatment intensity during maintenance therapy of DS-ALL patients may contribute to their poor prognosis.

Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

“…It cannot be ruled out that underreported treatment reduction of patients with DS-ALL contributes to the increased relapse risk. 48 This finding suggests that the currently accepted strategy of treatment reduction in DS-AML, which is characterized by a chemotherapy-sensitive phenotype, 49 is not applicable to DS-ALL. 47 The only exception may be DS-ALL patients with ETV6-RUNX1 or HeH, in which TRM outweighed the risk of relapse, for whom a 3-drug induction and a limited reinduction might be adequate.…”

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

“…Second relapses were the most common reason for treatment failure, indicating that patients with relapsed DS-ALL might have been treated with less intensive post-induction regimens to minimize the risk of treatment toxicity but subsequently failed to remain in long-term second remission. 36 In a study by Meyr et al, children with DS had worse outcome after relapse mainly because of increased toxicity rather than subsequent relapse, but if the relapse occurred after the year 2000 this difference was not maintained. 35 Adverse clinical factors, such as the time to relapse, age 37,38 and WBC 39 and cytogenetic risk factors, 17,18,20 are most likely surrogate markers for underlying submicroscopic genetic abnormalities.…”

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

“…Maintenance therapy seems to be important for most ALL subsets, including T-cell ALL21 and other patients with hyperleukocytosis at diagnosis,33 adolescents,34 and Down syndrome patients with ALL 35. Observational studies support that 6MP/MTX maintenance therapy is superior to other drug combinations,33 and that poor physician compliance or poor patient adherence significantly increase the risk of relapse 36–39.…”