Abstract
This review charts the evolution of therapy for childhood acute lymphoblastic leukaemia (ALL) in the United Kingdom. The present chemotherapeutic regimen is the result of experience gained from carefully planned randomised cooperative studies carried out during the last two decades. In common with the experience of the West German and American groups, the best results have been in those treated with post remission intensification blocks. With current chemotherapy protocols, almost 70% of children with ALL in U.K. can be cured but there may be a medical cost of such a cure, in terms of both acute and long term toxicity. This was especially true when central nervous system (CNS) therapy with cranial irradiation was used. Therefore present regimens are examining chemotherapeutic options for CNS disease control and the efficacy of additional post remission intensification.
Failure of chemotherapy is most often seen in those children with a presenting white cell count of more than 50×109/l, very young children and/or the presence of certain chromosomal rearrangements (e.g. t4: 11, t9: 22). At present the optimum therapeutic option for such high risk patients and for the majority of those in second remission, is an allogenic bone marrow transplant if an HLA-matched sibling is available. Modern day therapy is both complicated and costly and will be beyond the resources available for most children with ALL in developing countries. A significant decrease in worldwide mortality due to ALL will only occur if either the disease can be prevented or a simpler cure devised.
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References
Mauer MA, Simone JV. The current status of the treatment of childhood acute lymphoblastic leukaemia.Cancer Treat Rev 1970; 73: 17–41.
Poplack DG, Reman G. Acute lymphoblastic leukaemia in childhood.Pediatr Clin North Am 1988; 35: 903–932.
Frei E, Sallan SE. Acute lymphoblastic leukaemia treatment.Cancer 1978; 42: 828–838.
Simone JV. Factors that influence haematological remission duration in acute lymphoblastic leukaemia.Br J Haematol 1976; 32: 465–472.
Frei E. Progress in treatment for the leukaemias and lymphomas.Cancer 1965; 18: 1580–1584.
Hardisty RM, Norman PM. Meningeal leukaemia.Arch Dis Child 1967; 42: 441–447.
Evans AE, Gilbert ES, Zandsitra R. Increasing incidence of central nervous system leukaemia in children.Cancer 1970; 26: 404–409.
Gribbon MA, Hardisty RM, Chessells JM. Long term control of central nervous system leukaemia.Arch Dis Child 1977; 52: 673–678.
Aur RJA, Simone JV, Husto HO et al. Central nervous system therapy and combination chemotherapy of childhood lymphoblastic leukaemia.Blood 1971; 37: 272–281.
Medical Research Council. Treatment of acute lymphoblastic leukaemia: Effect of prophylactic therapy against central nervous system leukaemia.Br Med J 1973; 2: 381–384.
Komp DM, Fernandez CH, Falletta JM et al. Central nervous system prophylaxis in acute lymphoblastic leukaemia.Cancer 1982; 50: 1031–1036.
Aur RJA, Simone JV, Verzosa MS et al. Childhood acute lymphoblastic leukaemia study VIII.Cancer 1978; 42: 2123–2134.
Medical Research Council. Effects of varying radiation schedule, cyclophosphamide treatment, and duration of treatment in acute lymphoblastic leukaemia.Br Med J 1978; 2: 787–791.
Medical Research Council. The treatment of acute lymphoblastic leukaemia (ALL) in childhood, UKALL III. The effect of added cytosine arabinsode and/or asparaginase, and comparison of continuous and discontinuous mercaptopurine in regimens for standard risk ALL.Med Pediatr Oncol 1982; 10: 501–510.
Medical Research Council. The treatment of acute lymphoblastic leukaemia in childhood, UKALL VII.Med Pediatr Oncol 1982; 10: 501–510.
Medical Research Council. UKALL trials 1972–1984. Improvement in treatment of children with acute lymphoblastic leukaemia.Lancet 1986; i: 408–411.
Medical Research Council. Medical Research Council leukaemia trial UKALL VII.Arch Dis Child 1985; 60: 1050–1054.
Sather M, Miller D, Nesbit M et al. Difference in prognosis for boys and girls with acute lymphoblastic leukaemia.Lancet 1981; i: 739–745.
Riehm H, Hadner M, Henze G et al. Acute lymphoblastic leukaemia: treatment result in 3 BFM studies (1970–81). In: Murphy SB, Gilbert J, eds.Leukaemia Research: Advances in Cell Biology and Treatment. New York: Elsevier Biomedical, 1983: 251–260.
Coccia PF. Development and preliminary findings of Children Cancer Study Group protocol (161, 162 and 163) for low, average and high risk acute lymphoblastic leukaemia in children In: Murphy SB, Gilbert J, eds.Leukaemia Research: Advances in Cell biology and Treatment. New York: Elsevier Biomedical, 1983: 241–250.
Eden OB, Lilleyman J, Shaw MP et al. Council Childhood leukaemia trial VIII compared with trial II–VII: Lessons for future management.Haematol and Blood Transfus 1987; 30: 448–455.
Eden OB, Lilleyman JS, Richards S et al. Results of MRC leukaemia trial UKALL VIII.Br J Haematol 1991; 78: 187–196.
Sallan SE, Gelber RC, Kimball V et al. More is better! Update of Dana-Farber Cancer Institute/Children's Hospital Childhood acute lymphoblastic leukaemia trials.Haematol Blood Transf 1990; 33: 459–466.
Pearson AD, Amineddine HA, Yule M et al. The influence of serum methotrexate concentration and drug dosage on outcome in childhood acute lymphoblastic leukaemia.Br J Cancer 1991; 64: 169–173.
Krahl R, Helbis W, Kubel M. Dose reduced induction therapy for acute leukaemia decreases both the complete remission and probability of leukaemia free survival.Folia Haematol Leipz 1990; 117: 783–786.
Shaw NJ, Chapman ME, Eden OB. Treatment ofPneumocystic carinii infection in leukaemia.Lancet 1987; ii: 518–519.
Darbyshire P, Eden OB, Jamieson B et al. Pneumonitis in lymphoblastic leukaemia of childhood.Europ J Paediatr Haematol Oncol 1985; 2: 141–147.
Sallan SE, Hitchcock-Bryan S, Gelber R et al. Influence of intensive asparaginase in the treatment of childhood non-T cell acute lymphoblastic leukaemia.Cancer Res 1983; 43: 5601–5607.
Eden OB, Shaw MP, Lilleyman JS, Richards S. Non-randomised study comparing toxicity ofEscherichia coli andErwinia asparaginase in children with leukaemia.Med Pediatr Oncol 1990; 18: 497–502.
Rivera GK, Mauer AM. Controversies in the management of childood acute lymphoblastic leukaemia: treatment intensification, CNS leukaemia and prognostic factors.Semin Haematol 1987; 24: 12–26.
Sallan SE, Vamitta BM, Cassady JR et al. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukaemia.Blood 1978; 51: 425–433.
Nesbit ME, Sather HN, Robinson LL et al. Randomised study of 3 years versus 5 years of chemotherapy in childhood acute lymphoblastic leukaemia.J Clin Oncol 1983; 1: 308–316.
Riehm H. Results and significance of six randomised trials in four consecutive ALL-BFM studies. In: Kobaysashi N, Akera T, Mizutani S, eds,Childhood Leukaemia: Present Problems and Future Prospects. London: Kluwer Academic Publishers, 1991: 135–148.
Henze G, Langermann HJ, Fengler R et al. Therapiestudie BFM 79/81 zur Behandlung der akuten lymphoblastichen Leukamie bie Kindern und Jungendichen: Intensivierte Reindutionstherapie fur Patientgruppen mit unterschiedlichem Rezidvrisiko.Klin Paediatr 1982; 194: 195–203.
Norton L, Simon R. The Norton-Simon hypothesis revisited.Cancer Treat Rep 1986; 70: 163–169.
Niemeyer CM, Hitchcock-Bryan S, Sallan SE. Comparative analysis of treatment programs for childhood acute lymphoblastic leukaemia.Semin Oncol 1985; 12: 122–130.
Lennard L, Lilleyman JS, Van-Loon J, Weinshilboum RM. Genetic variation in response to 6-mercptopurine for childhood acute lymphoblastic leukaemia.Lancet 1990; ii: 225–229.
Poplack DG, Balis FM, Zimm S. The pharmacology of orally administered chemotherapy. A reappraisal.Cancer 1986; 58: 473–480.
Balis FM, Savitch JL, Bleyer WA. Pharmacokinetics of oral methotrexate in children.Cancer Res 1983; 43: 2342–2345.
Chessells JM, Bailey CC, Richards S. MRC UKALL X. The UK protocol for childhood ALL: 1985–1990. The Medical Research Council Working Party on Childhood Leukaemia.Leukaemia 1992; 6 Suppl 2: S157-S161.
Steinherz PG, Gaynon P, Miller DR et al. Improved disease-free survival of children with acute lymphoblastic leukaemia at high risk for early relapse with the New York regimen-a new intensive therapy protocol: a report from the Children's Cancer Study Group.J Clin Oncol 1986; 4: 744–752.
Riehm H, Gadner H, Henze G et al. Results and significance of six randomized trial in four consecutive ALL-BFM studies.Haematol Blood Transf 1990; 33: 437–450.
Pinkel D. Lessons from 20 years of curative therapy of childhood acute leukaemia.Br J Cancer 1992; 65: 148–153.
Wheeler K, Leiper AD, Jannoun L et al. Medical cost of curing childhood acute lymphoblastic leukaemia.Br Med J 1988; 296: 162–166.
Lipshultz SE, Colan SD, Gelber RD et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukaemia in childhood.N Engl J Med 1991; 324: 808–815.
Eden OB. CNS minimal disease therapy in childhood leukaemia: the place for irradiation.Br J Cancer 1990; 62: 6–7.
Chessells JM, Cox TCS, Kendall B et al. Neurotoxicity in lymphoblastic leukaemia: comparison of oral and intramuscular methotrexate and two doses of radiation.Arch Dis Child 1990; 65: 416–422.
Nesbit ME, Robison LL, Littman PS et al. Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: a comparison of 1800 rad and 2400 rad.Lancet 1981; ii: 461–466.
Krance RA, Newman EM, Ravindranath Y et al. A pilot study of intermediate dose methotrexate and ara-c “spread out” or “up front” in continuation therapy for childhood non-T, non-B acute lymphoblastic leukaemia.Cancer 1991; 67: 550–556.
Littman P Coccia P, Bleyer WA et al. Central nervous system prophylaxis in children with low risk acute lymphoblastic leukaemia.Int J Radiat Oncol Biol Phys 1987; 13: 1443–1449.
Shalet SM, Price DA, Beardwill CG et al. Normal growth despite abnormalities of growth hormone secretion in children treated for acute leukaemia.J Pediatr 1979; 94: 719–722.
Slørdal L, Kolmannskog S, Moe PJ et al. High dose methotrexate (6–8 gm/m2) in childhood malignancies: clinical tolerability and pharmacokinetics.Pediatr Haematol Oncol 1987; 4: 33–42.
Starccski PJ, Lee PA, Blatt J et al. Comparable effects of 1800- and 2400- rad cranial irradiation height and weight in children treated for acute lymphoblastic leukaemia.Am J Dis Child 1987; 141: 550–552.
Radwanska U, Michalewska D, Armata J et al. Acute lymphoblastic leukaemia therapy in Poland.Folia Haematol Leipzig 198; 116: 199–210.
Young BD. Cytogenetic and molecular analysis of chromosome 11q23 abnormalities in leukaemia.Clin Haematol 1992; 5: 881–896.
Chessells JM. Leukaemia in the young child.Br J Cancer 1992; 66 (Suppl 18): S54-S57.
Djabali M, Selleri L, Parry P et al. A trithorax like gene is interrupted by chromosome 11 q 23 translocations in acute leukaemias.Nature Genet 1992; 2: 113–118.
Tkachuk DC, Kohler S, Cleary M. Involvement of a homolog of drosophila trithorax by 11q23 chromosomal translocations in acute leukaemias.Cell 1992; 71: 691–700.
Johnson FL, Rubin CM. Allogenic marrow transplantation in the treatment of infants with cancer.Br J Cancer 1992; 66 (suppl 18); S76-S79.
Rivera GK, Buchanan G, Boyett JM et al. Intensive retreatment of childhood acute lymphoblastic leukaemia in first bone marrow relapse: a pediatric oncology group study.N Engl J Med 1986; 315: 273–278.
Butturini A, Rivera GK, Bortin MM et al. Which treatment for childhood acute lymphoblastic leukaemia in second remission?Lancet 1986; i: 429–432.
Editorial. Treatment of childhood acute lymphoblastic leukaemia.Lancet 1988; i: 683–684.
Chessells J, Rogers DW, Leiper AD et al. Bone marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia.Lancet 1986; i: 1239–1241.
Eden OB, Stiller CA, Gerrard MP. Improved survival for childhood acute lymphoblastic leukaemia; possible effect of protocol compliance.Pediatr Hematol Oncol 1988; 5: 83–91.
Stiller CA, Draper GJ. Treatment centre size, entry to trials, and survival in acute lymphoblastic leukaemia.Arch Dis Child 1989; 64: 657–661.
Saha V, Eden T, Stiller CA et al. An audit of the activities of the pediatric oncology unit in Edinburgh, 1982–91.Scott Med J 1993; 38: 74–76.
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Saha, V., Eden, T. An odyssey in search of a cure: The evolution of treatment of childhood acute lymphoblastic leukemia in the United Kingdom. Indian J Pediatr 60, 525–538 (1993). https://doi.org/10.1007/BF02751430
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DOI: https://doi.org/10.1007/BF02751430