The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

Abstract

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (X10 years) and 176 non-adolescents (o10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) o50 Â 10 9 /l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS 12y :0.71 vs 0.83, P ¼ 0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r S ¼ 0.36, P ¼ 0.02), which became nonsignificant for those who relapsed (r S ¼ 0.05, P ¼ 0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P ¼ 0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient ¼ 0.65, P ¼ 0.003) than for non-adolescents (coefficient ¼ 0.42, P ¼ 0.04). Adolescents had higher mean neutrophil counts (P ¼ 0.002) than nonadolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r S ¼ 0.38, P ¼ 0.02), which was not the case for those who developed a relapse (r S ¼ 0.15, P ¼ 0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Adult acute lymphoblastic leukaemia in Denmark. A national population‐based retrospective study on acute lymphoblastic leukaemia in Denmark 1998–2008

“…fewer Philadelphia chromosome positive patients and more high-hyperdiploid leukaemia); treatment protocol factors, including administration of hSCT; a lower TRM; and both patient and physician compliance to the protocol (Schmiegelow et al, 2010b). Due to the toxicities frequently experienced with ALL therapy when treating older patients, both our current paediatric and adult ALL2008 treatment protocol, and many others, have suggested a cut-off age of 40-45-years for protocol inclusion (Huguet et al, 2009;Storring et al, 2009;Tangen et al, 2010;Haiat et al, 2011).…”

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.…”

“…No study has explored the impact on relapse rates of various Ery-MTX polyglutamate chain lengths. At steady state, Ery-MTX PG is both interindividually and intraindividually related to the dose of oral MTX and may thus be used for monitoring treatment adherence 34,100…”

Duration of Adrenal Insufficiency During Treatment for Childhood Acute Lymphoblastic Leukemia

“…3,4 High-dose GC is extensively used in the treatment of acute lymphoblastic leukemia (ALL). 5,6 Children treated for ALL often experience severe and potentially lifethreatening infections. [7][8][9] However, what the clinical consequence of adrenal insufficiency in children treated for ALL with, among other drugs, high-dose GC therapy and the frequent infection rate they experience is still uncertain.…”