Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin’s lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG
Van der Werff Ten Bosch, J; Suciu, S; Thyss, Aet al.
[en] Between November 1990 and November 1996, EORTC Children Leukemia Group conducted a randomized trial in de novo acute lymphoblastic leukemia and lymphoblastic non-Hodgkin’s lymphoma patients using a Berlin–Frankfurt–Munster protocol to evaluate the monthly addition of intravenous 6-mercaptopurine (i.v. 6-MP) (1 g/m2) to conventional continuation therapy comprising per oral MTX weekly and 6-MP daily. Only during the first 18 months of the randomization period, 6-MP p.o. was interrupted for 1 week after each i.v. 6-MP. A total of 877
patients was randomized to either no i.v. 6-MP (Arm A) or additional i.v. 6-MP (Arm B). A total of 217 relapses (91 in Group A vs 128 in Group B) and 13 deaths in CR (5 vs 8) were reported; a total of 134 patients (55 vs 79) died. The median follow-up was 7.6 years. At 8 years, the disease-free survival rate was lower (P¼0.005) in Arm B (69.1% (s.e.¼2.2%)) than in Arm A (77.9% (s.e.¼2.0%)), and the hazard ratio was 1.45 (95% CI 1.12–1.89).
In conclusion, as delivered in this study, i.v. 6-MP was detrimental to event-free survival.
Disciplines :
Hematology Pediatrics Oncology
Author, co-author :
Van der Werff Ten Bosch, J
Suciu, S
Thyss, A
Bertrand, Y
Norton, L
Mazingue, F
Uyttebroeck, A
Robert, A
Boutard, P
Ferster, A
Plouvier, E
Maes, P
Munzer, M
Plantaz, D
DRESSE, Marie-Françoise ; Centre Hospitalier Universitaire de Liège - CHU > Service de pédiatrie (CHR)
Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin’s lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG
Pinkel D. Five-year follow-up of 'total therapy' of childhood lymphocytic leukemia. JAMA 1971; 216: 648-652.
Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 1998; 339: 605-615.
Riehm H, Feickert H, Lampert F. Cancer in children. Clinical Management. Berlin: Springer, 1986.
Zimm S, Collins JM, Riccardi R, O'Neill D, Narang PK, Chabner B et al. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 1983; 308: 1005-1009.
Estlin EJ, Lowis SP, Hall AG. Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia. Br J Haematol 2000; 110: 29-40.
Camitta B, Leventhal B, Lauer S, Shuster JJ, Adair S, Casper J et al. Intermediate-dose intravenous methotrexate and mercaptopurine therapy for non-T, non-B acute lymphocytic leukemia of childhood: a Pediatric Oncology Group study. J Clin Oncol 1989; 7: 1539-1544.
Camitta B, Mahoney D, Leventhal B, Lauer SJ, Shuster JJ, Adair S et al. Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study. J Clin Oncol 1994; 12: 1383-1389.
Jacqz-Aigrain E, Nafa S, Medard Y, Bessa E, Lescoeur B, Vilmer E. Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia. Eur J Clin Pharmacol 1997; 53: 71-74.
Covell DG, Narang PK, Poplack DG. Kinetic model for disposition of 6-mercaptopurine in monkey plasma and cerebrospinal fluid. Am J Physiol 1985; 248: R147-R156.
Zimm S, Ettinger L, Holcenberg J, Kasen B, Vietti T, Belasco J et al. Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Res 1985; 45: 1869-1873.
Adamson PC, Zimm S, Ragab AH, Steinberg SM, Balis F, Kamen BA et al. A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors. Cancer Chemother Pharmacol 1990; 26: 343-344.
Duval M, Suciu S, Lutz P, Benoit Y, Robert A, Thyss A et al. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood 2002; 99: 2734-2739.
Millot F, Suciu S, Philippe N, Benoit Y, Mazingue F, Uyttebroeck A et al. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organization for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol 2001; 19: 1935-1942.
Langermann H, Henze G, Wulf M, Rhiem H. Abschatzung der tumorzellmasse bei der akuten lymphoblastischen leukamie im kindesalter: prognotische bedeutung- und praktische anwendung. Klin Ped 1982; 194: 209-213.
Murphy S. Classification, staging and end results of treatment in childhood non-Hodgkin's lymphoma: dissimilarities from lymphomas in adults. Semin Oncol 1980; 7: 332-339.
Henze G, Fengler R, Hartmann R, Kornhuber B, Janka-Schaub G, Niethammer D et al. Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM group. Blood 1991; 78: 1166-1172.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33: 451-458.
Harris NL, Jaffe ES, Stein H, Banks PM, Chart JK, Cleary ML et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361-1392.
Linder J, Ye Y, Armitage JO, Weisenburger DD. Monoclonal antibodies marking B-cell non-Hodgkin's lymphoma in paraffin-embedded tissue. Mod Pathol 1988; 1: 29-34.
Group FMCS. Morphologic, immunologic, and cytogenetic (MIC) working classification of acute lymphoblastic leukemias. Report of the workshop held in Leuven, Belgium, April 22-23, 1985. First MIC Cooperative Study Group. Cancer Genet Cytogenet 1986; 23: 189-197.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-214.
Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. Blood 1994; 84: 3122-3133.
Vilmer E, Suciu S, Ferster A, Bertrand Y, Cave H, Thyss A et al. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. Leukemia 2000; 14: 2257-2266.
Buyse M, Staquet M, Sylvester R. Cancer Clinical Trials: Methods and Practice. Oxford, England: Oxford Medical Publication, 1984.
Cox D, Oakes D. Analysis of Survival Data. New York: Chapman & Hall, 1984.
Silverman LB, Declerck L, Gelber RD, Dalton VK, Asselin BL, Barr RD et al. Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 2000; 14: 2247-2256.
Bostrom B, Sensel M, Sather H, Gaynon P, La M, Johnston K et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 2003; 101: 3809-3817.
Mahoney Jr DH, Shuster JJ, Nitschke R, Lauer S, Steuber CP, Camitta B. Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 2000; 18: 1285-1294.
Kamps WA, Bokkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER et al. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia 2002; 16: 1099-1111.
Elion GB. The purine path to chemotherapy. Science 1989; 244: 41-47.
Schmiegelow K, Bjork OG, Glomstein A, Gustafsson G, Keiding N, Kristinsson J et al. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol 2003; 21: 1332-1339.
