SEARCH:   Advanced

Blood, 11 June 2009, Vol. 113, No. 24, pp. 6041-6042. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Pulsipher, M. A. PubMed PubMed Citation Articles by Pulsipher, M. A. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this? Next Article  CLINICAL TRIALS Comment on Schmiegelow et al, page 6077 Maintenance loses its innocence Michael A. Pulsipher UNIVERSITY OF UTAH In this issue of Blood, Schmiegelow and colleagues on behalf of the Nordic Society for Paediatric Haematology and Oncology (NOPHO) present convincing evidence of a link between maintenance therapy with 6-mercaptopurine/methotrexate and the development of SMNs after treatment for pediatric ALL. Given the toxicities associated with pediatric acute lymphoblastic leukemia (ALL) induction, consolidation, and delayed intensification courses, arrival at the maintenance phase was once thought to be a time to celebrate and relax. Unfortunately, results of comparative studies of 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP) in maintenance initiated a decade ago took the shine off maintenance "relaxation," as up to 11% of children treated with 6-TG developed veno-occlusive disease. A higher percentage of children developed a syndrome of periportal fibrosis and portal hypertension.1,2 This left many groups with the seemingly more benign 6-MP at the core of their maintenance regimens. However, as Schmiegelow et al show, while use of 6-MP may avoid the early toxicities of its antimetabolite relative, because of the risk of late malignancies, its use in maintenance is not without consequences.3 View larger version (37K): [in this window] [in a new window]   Cumulative risk of a second malignant neoplasms (SMN) by risk group for patients not receiving a transplant in first remission (SR: standard risk 2.4% ± 0.7%; IR: intermediate risk 1.2% ± 0.7%; HR: higher risk 0.3% ± 0.3%; P = .007). See the complete figure in the article beginning on page 6077.   Earlier reports of second malignant neoplasms (SMNs) after pediatric ALL therapy rounded up the usual suspects of alkylating agents, topoisomerase II inhibitors (anthracyclines, etoposide), and irradiation.4,5 Many investigators subsequently modified their more intense, earlier phases of therapy to limit exposure to these higher-risk drugs and to radiation, with major progress occurring by eliminating cranial irradiation for a large percentage of children with ALL. Higher-risk disease regimens, however, still contain many of these agents, and have thus been associated with higher risks of second malignancies. With that in mind, this graph from the Schmiegelow paper jumps out at the reader (see figure). How is it that the cumulative risk of second cancers is 0.3% in high-risk patients and 8 times higher, or 2.4%, in standard-risk patients (P = .007)? Using several lines of evidence, the article makes a case against 6-MP. The authors first describe a tight association with the duration of 6-MP/methotrexate (MTX) maintenance and the development of SMNs. The longer duration of 6-MP/MTX maintenance (and thus higher risk) was built into the NOPHO treatment plan for lower-risk disease, hence potentially explaining the results in the graph. They go on to show that exposure levels of 6-MP matter: patients geno-/phenotyped for polymorphisms with low thiopurine methyltransferase activity (TPMT, methylates 6-MP, low TPMT activity increases cytotoxic 6-thioguanine nucleotides [6-TGN]) had higher risk of SMNs, and patients with wild-type TPMT with SMNs received 10% to 15% higher doses of 6-MP compared with those patients with normal TPMT function who did not get SMNs. Two further suggestive, but not definitive, points are made: (1) the onset of SMNs trended toward occurring earlier in patients with low compared with normal TPMT activity (P = .07) and (2) higher 6-TGN levels (the result of low TPMT activity) were noted in patients with SMNs compared with those without (P = .11). These observations add authoritative weight to a finding published a decade ago by the group at St Jude Children's Research Hospital. That finding stated that patients with low TPMT activity receiving 6-MP in combination with radiotherapy have increased risk of SMNs.6 The paper leaves many questions unanswered. Whether this association is caused by 6-MP therapy alone or whether high-dose MTX given along with 6-MP in maintenance contributes to the incidence of SMNs is unclear. Increased risk of SMNs in the NOPHO cohort is further associated with high hyperdiploidy, and the type of SMNs that occur differs from other reports, with a high incidence of tAML/MDS with aberrations of chromosomes 5 or 7. Although the authors speculate on reasons for these observations, the mechanisms behind these findings have yet to be elucidated. Finally, what other groups should do with the observations presented here is unclear. The NOPHO group initiated genotypic and phenotypic screening for low-activity TPMT polymorphisms in 2001, lowering 6-MP maintenance dosing from 75 to 50 mg/m2 when low TPMT activity patients are detected by their screen. It is too soon to know whether this intervention has decreased SMNs. The approaches of other groups vary in dosing levels and length of administration of 6-MP, and an association of SMNs with different dosing schemes has yet to be described. These questions aside, this work provides convincing evidence that high dose levels or poorly methylated 6-MP in the context of extended maintenance with methotrexate is associated with SMNs. It poses a challenge to either identify patients at increased risk, or identify methods of administration of 6-MP that minimize or eliminate risk of SMNs without sacrificing ALL treatment efficacy. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Vora A, Mitchell CD, Lennard L, et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukemia: a randomised trial. Lancet. 2006;368:1339–1348.[Medline] [Order article via Infotrieve] Broxson EH, Dole M, Wong R, et al. Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer. 2005;44:226–231.[CrossRef][Medline] [Order article via Infotrieve] Schmiegelow K, Al-Modhwahi I, Andersen MK, et al. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood. 2009;113:6077–6084.[Abstract/Free Full Text] Loning L, Zimmermann M, Reiter A, et al. Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood. 2000;95:2770–2775.[Abstract/Free Full Text] Hijiya N, Hudson MM, Lensing S, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007;297:1207–1215.[Abstract/Free Full Text] Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumors after radiotherapy and antimetabolites. Lancet. 1999;354:34–39.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Response: Could mutations in the hypoxanthine-guanine phosphoribosyl transferase gene induced by thiopurine therapy promote the development of second malignant neoplasms? Kjeld Schmiegelow, Ibrahim Al-Modhawi, Mette Klarskov Andersen, Mikael Berendtz, Erik Forestier, Henrik Hasle, Mats Heyman, Jon Kristinsson, Jacob Nersting, Randi Nygaard, Anne Louise Svendsen, Kim Vettenranta, and Richard Weinshilboum, the Nordic Society for Paediatric Haematology and Oncology Blood 2009 113: 6258-6259. [Full Text] [PDF] Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study Kjeld Schmiegelow, Ibrahim Al-Modhwahi, Mette Klarskov Andersen, Mikael Behrendtz, Erik Forestier, Henrik Hasle, Mats Heyman, Jon Kristinsson, Jacob Nersting, Randi Nygaard, Anne Louise Svendsen, Kim Vettenranta, and Richard Weinshilboum, for the Nordic Society for Paediatric Haematology and Oncology Blood 2009 113: 6077-6084. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Pulsipher, M. A. PubMed PubMed Citation Articles by Pulsipher, M. A. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020