6-MP based maintenance therapy of childhood ALL in Slovenia: a retrospective study from 1970 to 2004
Background: Maintenance therapy with 6-mercaptopurine (6-MP) as its major component has been one of the main reasons for the drastic increase in overall survival of paediatric acute lymphoblastic leukaemia (ALL) patients. In our cohort, consisting of patients receiving maintenance therapy for ALL and encompassing time period of three decades, we evaluated dosage, safety and efficiency of 6-MP in the treatment of childhood ALL according to treatment protocol, age and gender.
Methods: Slovenian paediatric ALL patients diagnosed and treated from 1970 to 2004 were identified through the national oncology patients` registry. Of 414 registered paediatric ALL patients, 320 received maintenance therapy for ALL and were included into the final study cohort. Information about age, gender, treatment protocol, 6-MP related toxic events and ALL relapse was extracted from patients` files. Differences in 6-MP dose reduction, 6-MP side effects and relapse according to gender, age and treatment protocol were statistically evaluated.
Results: After adjustment for gender and age incidence of 6-MP dose reduction (p<0.001) and bone marrow suppression (p = 0.019) was higher in recent treatment protocols, while relapse was more common in older protocols (p < 0.001). Younger patients had greater risk for sepsis/infection (p = 0.002), while greater age was a risk factor for osteonecrosis (p = 0.001). No statistically significant associations were found according to gender.
Conclusions: In the retrospective study, encompassing three decades of maintenance treatment of childhood ALL in Slovenia, recent protocols exhibited greater effectiveness and toxicity than older protocols.
Elert E. Living with leukaemia. Nature. 2013 Jun 27;498(7455):S2-3.
Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013 Jun 1;381(9881):1943-55.
Seibel NL. Treatment of acute lymphoblastic leukemia in children and adolescents: peaks and pitfalls. Hematology Am Soc Hematol Educ Program. 2008:374-80.
Jazbec JR, V. Karas-Kuzelicki, N. Leukemije otroške dobe. Zdravniški vestnik. 2008;77:5.
Landsburg DJ, Stadtmauer E, Loren A, Goldstein S, Frey N, Nasta SD, et al. Receipt of maintenance therapy is most predictive of survival in older acute lymphoblastic leukemia patients treated with intensive induction chemotherapy regimens. Am J Hematol. 2013 Aug;88(8):657-60.
Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012 May;87(5):472-8.
Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010 Feb;24(2):265-84.
Coulthard S, Hogarth L. The thiopurines: an update. Invest New Drugs. 2005 Dec;23(6):523-32.
Gehan EA, Freireich EJ. The 6-MP versus placebo clinical trial in acute leukemia. Clin Trials. 2011 Jun;8(3):288-97.
Bhatia S, Landier W, Shangguan M, Hageman L, Schaible AN, Carter AR, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group. J Clin Oncol. 2012 Jun 10;30(17):2094-101.
Karran P. Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br Med Bull. 2006;79-80:153-70.
Schmiegelow K, Al-Modhwahi I, Andersen MK, Behrendtz M, Forestier E, Hasle H, 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 Jun 11;113(24):6077-84.
Anžič J K-ZL. Akutna limfoblastna levkemija otrok. Zdravniški vestnik. 1995;64:673-6.
Mali P JJ. Preživetje otrok in mladostnikov z akutno limfoblastno levkemijo v Sloveniji v obdobju 1990-1999. Slov Pediatr. 2002;9:86-9.
Karas-Kuzelicki N, Jazbec J, Milek M, Mlinaric-Rascan I. Heterozygosity at the TPMT gene locus, augmented by mutated MTHFR gene, predisposes to 6-MP related toxicities in childhood ALL patients. Leukemia. 2009 May;23(5):971-4.
Carmichael M. Drug safety: double jeopardy. Nature. 2013 Jun 27;498(7455):S14-5.
Kadan-Lottick NS, Dinu I, Wasilewski-Masker K, Kaste S, Meacham LR, Mahajan A, et al. Osteonecrosis in adult survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2008 Jun 20;26(18):3038-45.
Relling MV, Yang W, Das S, Cook EH, Rosner GL, Neel M, et al. Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol. 2004 Oct 1;22(19):3930-6.
Sala A, Mattano LA, Jr., Barr RD. Osteonecrosis in children and adolescents with cancer - an adverse effect of systemic therapy. Eur J Cancer. 2007 Mar;43(4):683-9.
Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics. 2004 Jul;14(7):407-17.
Hale JP, Lilleyman JS. Importance of 6-mercaptopurine dose in lymphoblastic leukaemia. Arch Dis Child. 1991 Apr;66(4):462-6.
The Author transfers to the Publisher (Zdravniški vestnik/Slovenian Medical Journal) all economic copyrights following form Article 22 of the Slovene Copyright and Related Rights Act (ZASP), including the right of reproduction, the right of distribution, the rental right, the right of public performance, the right of public transmission, the right of public communication by means of phonograms and videograms, the right of public presentation, the right of broadcasting, the right of rebroadcasting, the right of secondary broadcasting, the right of communication to the public, the right of transformation, the right of audiovisual adaptation and all other rights of the author according to ZASP.
The aforementioned rights are transferred non-exclusively, for an unlimited number of editions, for the term of the statutory
The Author can make use of his work himself or transfer subjective rights to others only after 3 months from date of first publishing in the journal Zdravniški vestnik/Slovenian Medical Journal.
The Publisher (Zdravniški vestnik/Slovenian Medical Journal) has the right to transfer the rights, acquired parties without explicit consent of the Author.
The Author consents that the Article be published under the Creative Commons BY-NC 4.0 (attribution-non-commercial) or comparable licence.