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Therapy

Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia

Leukemia volume 22, pages 1144–1153 (2008)Cite this article

Abstract

Until 1990, the survival of children with acute lymphoblastic leukaemia (ALL) in Russia was below 10%. To establish a protocol feasible under conditions there, ALL-MB 91 was designed to avoid prolonged bone marrow aplasia, thereby reducing needs for extensive supportive care, blood transfusions, long-lasting hospitalization and costs. High-dose therapies were avoided, anthracycline use was limited and CNS radiation therapy only foreseen in high-risk patients (about 30%). This was randomized against a modified BFM protocol. From 1995 to 2002, 834 patients of age up to 18 years were registered in 10 centres and 713 received after central randomization the allocated risk-stratified treatment. After a median follow-up of 7 years, the event-free survival (EFS) was 67±3% on ALL-MB 91 (N=358) vs 68±3% on ALL-BFM 90m (N=355). The overall survival (OS) was 71±3% vs 74±2%, respectively. Anaemia, thrombocytopenia, agranulocytosis >10 days and hospitalization (median 35 vs 68 days) were lower on ALL-MB 91 (P<0.01, N=197). While EFS and OS were similar with both protocols, ALL-MB 91 significantly incurred fewer toxicity and resource requirements and, therefore, has been increasingly used across Russia.

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References

  1. Alekseev N, Vorontsov I . Leukaemias in children. Leningrad 1988.

  2. Kisliak NS, Makhonova LA, Koshel’ IV, Kurmashov VI, Maiakova SA, Rumiantsev AG et al. Late (after 5-year remission) recurrences of acute leukemia in children (a cooperative study). Gematol Transfuziol 1989; 34: 8–12.

    CAS  PubMed  Google Scholar 

  3. Rumiantsev AG, Samochatova EV, Khamdan T . Treatment of acute lymphoblastic leukemia in children according to the Berlin-Frankfurt-Münster Program. Pediatriia 1991; 11: 58–63.

    Google Scholar 

  4. Rumiantsev AG, Samochatova EV, Maschan AA, Kryzhanovskii OI . Supportive care in the treatment of childhood acute lymphoblastic leukemia according to BFM programme. Pediatriia 1992; 2: 68–73.

    Google Scholar 

  5. Henze G, Langermann HJ, Brämswig J, Breu H, Gadner H, Schellong G et al. Ergebnisse der Studie BFM 76/79 zur Behandlung der akuten lymphoblastischen Leukämie bei Kindern und Jugendlichen. Klin Pädiatrie 1981; 193: 145–154.

    Article  CAS  Google Scholar 

  6. Riehm H, Gadner H, Henze G, Kornhuber B, Lampert F, Niethammer D et al. Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematol Blood Transfus 1990; 33: 439–458.

    CAS  PubMed  Google Scholar 

  7. Reiter A, Schrappe M, Ludwig WD, Lampert F, Harbott J, Henze G et al. Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 1992; 80: 2471–2478.

    CAS  PubMed  Google Scholar 

  8. 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.

    CAS  PubMed  Google Scholar 

  9. Veerman AJ, Hahlen K, Kamps WA, van Leeuwen EF, de Vaan GA, Vanwering ER et al. Dutch childhood leukemia study group: early results of study ALL VI (1984–1988). Haematol Blood Transfus 1990; 33: 473–477.

    CAS  PubMed  Google Scholar 

  10. Veermann A, Hählen K, Kamps W, van Leeuwen E, de Vaan G, Solbu G et al. High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia: Results of protocol ALL-VI from the Dutch Leukemia Study Group. J Clin Oncol 1996; 14: 911–918.

    Article  Google Scholar 

  11. Clavell LA, Gelber RD, Cohen HJ, Hitchcock-Bryan S, Cassady JR, Tarbell NJ et al. Four-agent induction and intensive asparaginase therapy for childhood acute lymphoblastic leukemia. N Engl J Med 1986; 315: 657–663.

    Article  CAS  PubMed  Google Scholar 

  12. Barr RD, DeVeber LL, Pai KM, Andrew M, Halton J, Cairney AE et al. Management of children with acute lymphoblastic leukemia by the Dana–Farber cancer institute protocols. Am J Pediatr Hem Onc 1992; 14: 136–139.

    Article  CAS  Google Scholar 

  13. Schorin MA, Blattner S, Gelber RD, Tarbell NJ, Donnelly M, Dalton V et al. Treatment of childhood acute lymphoblastic leukemia: results of Dana–Farber institute/children's hospital acute lymphoblastic leukemia consortium protocol 85-01. J Clin Oncol 1994; 12: 740–747.

    Article  CAS  PubMed  Google Scholar 

  14. Karachunskiy A, Stackelberg A, Miakova N . Comparative treatment results of childhood acute lymphoblastic leukemia according to protocols ALL-BFM 90 and ALL-MB 91. Pediatriia 1995; 2: 10–16.

    Google Scholar 

  15. von Stackelberg A, Karatchunsky A, Kudrjashova J, Miakova N, Belikova L, Rumiantzev A et al. Toxicity, supportive care and costs of two chemotherapy protocols for treatment of childhood all in Russia: BFM 90m and MB 91. Eur J Cancer 1999; 35: 1349–1355.

    Article  CAS  PubMed  Google Scholar 

  16. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9: 1783–1786.

    CAS  PubMed  Google Scholar 

  17. Uckun FM, Sensel MG, Sun L, Steinherz PG, Trigg ME, Heerema NA et al. Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 1998; 91: 735–746.

    CAS  PubMed  Google Scholar 

  18. Langermann HJ, Henze G, Wulf M, Riehm H . Estimation of tumor cell mass in childhood acute lymphoblastic leukemia: prognostic significance and practical application. Klin Pädiatr 1992; 194: 209–213.

    Article  Google Scholar 

  19. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al., Children's Cancer Group. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy. Blood 2000; 95: 3310–3322.

    CAS  PubMed  Google Scholar 

  21. Machin D, Gardner MJ . Calculating confidence intervals for survival time analyses. Br Med J 1988; 296: 1369–1371.

    Article  CAS  Google Scholar 

  22. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJW . Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006; 295: 1152–1160.

    Article  CAS  PubMed  Google Scholar 

  23. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  24. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  25. Kalbfleisch J, Prentice R . The Statistical Analysis of Failure Time Data. Wiley: New York (NY), 1980.

    Google Scholar 

  26. Gray B . cmprsk: subdistribution analysis of competing risks (resource on the Internet). R package version 2.1–7 [cited 2007 Oct 12]. Available from: http://www.r-project.org, http://biowww.dfci.harvard.edu/~gray.

  27. Gray RJ . A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  28. Harrell Jr FE and with contributions from many other users [resource on the Internet] Hmisc: Harrell miscellaneous (cited 2007 Oct 12). Available from: http://biostat.mc.vanderbilt.edu/s/Hmisc.

  29. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukaemia. J Clin Oncol 1996; 14: 18–24.

    Article  CAS  PubMed  Google Scholar 

  30. Jones B, Freeman AI, Shuster JJ, Jacquillat C, Weil M, Pochedly C et al. Lower incidence of meningeal leukemia when prednisolone is replaced by dexamethasone in the treatment of acute lymphoblastic leukemia. Med Pediatr Oncol 1991; 19: 269–275.

    Article  CAS  PubMed  Google Scholar 

  31. Balis FM, Lester CM, Chrousos GP, Heideman RL, Poplack DG . Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol 1987; 5: 202–207.

    Article  CAS  PubMed  Google Scholar 

  32. Balis FM, Poplack D . Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hemtol Oncol 1989; 11: 74–86.

    Article  CAS  Google Scholar 

  33. Nesbit M, Chard R, Evans A, Karon M, Hammond GD . Evaluation of intramuscular versus intravenous administration of L-asparaginase in childhood leukemia. Am J Pediatr Haematol Oncol 1979; 1: 9–13.

    CAS  Google Scholar 

  34. Kamps WA, Bökkerink JP, Hahlen K, Hermans J, Riehm H, Gadner H et al. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM 86 without cranial radiotherapy: results of DCLSG protocol ALL-7 (1988–1991). Blood 1999; 94: 1226–1236.

    CAS  PubMed  Google Scholar 

  35. Bleyer WA, Coccia PF, Sather HN, Level C, Lukens J, Niebrugge DJ et al. Reduction of central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol 1983; 1: 317–325.

    Article  CAS  PubMed  Google Scholar 

  36. Clarke M, Gaynon P, Hann I, Harrison G, Masera G, Peto R, et al., Childhood ALL Collaborative Group. CNS-directed therapy for childhood acute lymphoblastic leukemia: childhood ALL collaborative group overview of 43 randomized trials. J Clin Oncol 2003; 21: 1798–1809.

    Article  CAS  PubMed  Google Scholar 

  37. Chessells JM, Hall E, Prentice HG, Durrant J, Bailey CC, Richards SM . The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties. Leukemia 1998; 12: 463–473.

    Article  CAS  PubMed  Google Scholar 

  38. Rumiantsev AG, Samachatova EV, Karachunsky AI . Intensive chemotherapy of acute leukaemias (AL) in childhood with BFM protocols and Moscow experiences 1990–1992. First successes and failures. In: Büchner et al. (eds). Acute Leukemias IV. Prognostic Factors. Springer: Berlin, 1993, pp 344–346.

    Google Scholar 

  39. Samochatova EV, Aslanyan KS, Belikova L . The retrospective analysis of the treatment results of childhood acute lymphoblastic leukemia according to modified BFM protocol in the 9 Russian clinics (1991–1996). Pediatriia 1997; 4: 34–37.

    Google Scholar 

  40. Miakova NV, Aleinikova OV, Hartmann R, Rudneva AE, Trubina NM, Fechina LG et al. Treatment of acute lymphoblastic leukemia in children according to the ALL-BFM 90m protocol in the Russian Federation and the Republic of Belarus. Vopr Onkol 2002; 48: 347–351.

    CAS  PubMed  Google Scholar 

  41. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia 2000; 14: 2205–2222.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the Russian paediatric oncologists and laboratory co-workers from the participating centres involved, especially E Samochatova, S Plyasunova, M Dubrovina, T Nasedkina, K Kondratchik, G Novichkova, O Fuchs, E Rogacheva and D Lavruchin (all from Moscow); E Inushkina (Balashicha); O Chlebnikova, O Streneva (both from Ekaterinburg); O Plaksina (Nishni Novgorod); M Goroshkova, A Zemlyanskiy, E Shabashkewich (all from Nowokuznezk); L Chazaryan (Sochi) and G Pavlova (Cheboksari). We also thank all our German colleagues from the Charité—Universitätmedizin Berlin for their help in the education of Russian doctors and nurses, in particular, senior consultant Rüdiger Fengler, senior nurse Ina Arlt, and for help in statistics, Reinhard Hartmann. We also thank to Dr Martin Friedrichs, German Federal Foreign Office, and to all the members of the charity organization Kontakty-Kontakte e.V., Berlin, in particular project manager Eberhard Radczuweit, for continuous comprehensive support of our efforts to conduct this first multicentre trial in Russia. Meetings and travel expenditures of physicians, co-workers in the trial coordination center, technical equipment and drugs of this study were in part financed by the charity organization ‘Kontakty-Kontakte e.V.’, Berlin, Germany (http://www.kontakte-kontakty.de/).

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Author notes

  1. A Karachunskiy and R Herold: These authors contributed equally to this work.

Authors and Affiliations

  1. Russian Federal Clinical Research Centre for Paediatric Haematology, Oncology and Immunology, Moscow, Russia

    A Karachunskiy, N Miakova, L Bajdun, A Maschan, J Roumiantseva & A Rumjanzew

  2. Department of Paediatric Oncology/Haematology, Charité—Universitätsmedizin Berlin, Berlin, Germany

    R Herold, A von Stackelberg & G Henze

  3. Department of Paediatric Haematology, Morozov Children's Hospital, Moscow, Russia

    A Timakow & T Mahortih

  4. Paediatric Oncohaematological Centre, Regional Children's Hospital, Ekaterinburg, Russia

    L Fechina

  5. Department of Paediatric Haematology, Regional Children's Hospital, Nizhni Novgorod, Russia

    A Shamardina

  6. Department of Paediatric Oncology/Haematology, Regional Children's Hospital, Novokuznetsk, Russia

    S Dudkin

  7. Department of Paediatric Oncology/Haematology, Regional Children's Hospital, Sochi, Russia

    V Lebedev

  8. Department of Paediatric Oncology/Haematology, Regional Oncological Hospital, Balashiha, Russia

    S Varfolomeeva

  9. Department of Paediatric Oncology/Haematology, Regional Children's Hospital, Ulyanovsk, Russia

    V Timofeeva

  10. Department of Paediatric Oncology/Haematology, Regional Children's Hospital, Syktyvkar, Russia

    N Chipsanova

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  1. A Karachunskiy
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Correspondence to G Henze.

Additional information

This study has been presented in part at the annual meeting of the International Society of Paediatric Oncology (SIOP) 2005 in Vancouver.

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Karachunskiy, A., Herold, R., von Stackelberg, A. et al. Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia. Leukemia 22, 1144–1153 (2008). https://doi.org/10.1038/leu.2008.63

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