High-dose methotrexate: the rationale...

To the Editor: With interest we read the recent Journal of Pediatric Hematology/ Oncology editorial by Dr Kamen on the ‘‘insecure rationale’’ for the use of high-dose methotrexate (HD-MTX) to treat children with osteosarcoma and acute lymphoblastic leukemia (ALL). Several points raised by Dr Kamen merit further clarification to be fully and accurately representative of the published literature. Dr Kamen aimed to discuss 2 recently published articles. The first article—an editorial by Dr Blay— focused on a publication that describes the treatment of patients with osteosarcoma without the use of HDMTX. The described study of Tunn and Reichardt, however, has several major limitations including a retrospective nonrandomized design and a relatively small number of patients. Although certainly of interest, the results, which describe long-term survival of patients with localized osteosarcoma of the extremity who have been treated without HD-MTX [actually without any methotrexate (MTX)] must be interpreted with caution; and further investigations are necessary to clarify whether HD-MTX is an essential component for the successful treatment of patients with osteosarcoma. A recently published editorial from Drs Jaffe and Gorlick provides an opinion that differs from Dr Kamen’s (ie, ‘‘HD-MTX in osteosarcoma: questions surcease—time for final acceptance’’); and their editorial may be helpful for readers who wish to consider the full spectrum of published opinions on this issue. The second paper that ‘‘caught Dr Kamen’s eye’’ was our recent paper reporting MTX pharmacogenomic studies conducted at St Jude Children’s Research Hospital. In particular, Dr Kamen was apparently intrigued by our comment concerning Supplementary Figure 6, that ‘‘MTX systemic exposure was not different among responder groups. ’’ MTX response was defined as the decrease in ALL (white blood cells) cells over 3 days after 1 initial dose of HD-MTX, and the magnitude of this response was not explained by MTXAUC alone. However, the response to MTX was highly associated with intracellular MTX polyglutamate (MTXPG) levels, and prior studies have clearly shown that the MTXPG levels are influenced by MTX dose and by MTX plasma concentrations. Of note, our more recent study was not designed to compare dosing or the importance of MTX systemic exposure, as all patients in this study received upfront HDMTX at the same intravenous dosage (ie, 1 g/m) and for each responder group there was up to 30% variation in MTXAUC. Our data indicate that at this dosage of HD-MTX, with tightly controlled hydration and urinary alkalization, and in this population of patients with all molecular subtypes of ALL, the relatively small variability in rate at which patients clear MTX from their blood does not influence their initial response to HD-MTX. This was not unanticipated. Concerning MTX usage in ALL, 3 issues need to be considered: first, MTX pharmacokinetics vary considerably in ALL patients, and higher plasma concentrations have been associated with better efficacy. Nevertheless, very high plasma MTX levels may be associated with increased toxicity, in particular if leukovorin rescue is not appropriately administered. Second, levels of MTXPGs (active metabolites) in ALL cells vary among patients and are influenced by the blood concentration of MTX and by the molecular subtype and lineage of the ALL cells. Finally, MTX pharmacodynamics defined as decrease in white blood cells has been shown to vary widely among patients with ALL, reflecting not only variability in treatment (eg, drug exposure), but also biology of the disease. We disagree with Dr Kamen on his assertion that there is an insecure rationale for HD-MTX, as we and others have clearly shown that HDMTX (1 g/m intravenous infusion) compared with low-dose MTX (180mg/m orally) achieves greater than 10-fold higher MTX steady state plasma concentrations, greater than 2fold higher intracellular MTXPG levels in the target ALL cells, and more effectively inhibits de novo purine synthesis and results in higher ALL blast clearance. Finally, and most importantly, MTX steady state plasma concentrations after HD-MTX treatment and the resulting intracellular MTXPG are related to disease-free survival in children with higher-risk ALL, and in the most recent study MTX in vivo response was related to disease-free survival in patients with low/standard risk and higher-risk ALL, after adjusting for other known risk factors. Indeed, many ascribe the improved treatment outcome in patients with T-lineage ALL or with E2A/PBX1 B-lineage ALL to the use of HD-MTX, as patients with T-lineage ALL require greater systemic exposure to MTX to achieve comparable levels of active MTXPG in their leukemia cells.