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Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT

Bone Marrow Transplantation volume 42, pages S40–S46 (2008)Cite this article

Abstract

Allogeneic haematopoietic SCT (HSCT) induces CRs in most patients with CML. With the excellent short-term treatment results induced by imatinib (IMA), attitudes have changed and only a minority of children are now transplanted upfront. This review addresses the role of IMA in children with CML, focusing on the starting dose of IMA, possible adverse effects, timing of HSCT in children, duration of IMA treatment and monitoring of treatment efficacy to unravel failure of early treatment of IMA as well as treatment of CML relapse after HSCT. As the paediatric experience with IMA is still very limited, many answers and algorithms are adapted from CML in adults. Basically, HSCT should be postponed to achieve an optimal tumour cell reduction by IMA treatment. Children with a low-risk EBMT score should undergo HSCT within 2 years after diagnosis to avoid prolonged exposure and unknown late effects of IMA. Without a perfectly HLA-matched donor, HSCT may be postponed until CML becomes refractory to IMA. As realized in the presently activated international trial CML-paed II, this approach represents a risk-adapted therapy with the benefit of being tailored to the needs and profile of an individual patient.

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References

  1. Geary CG . The story of chronic myeloid leukaemia. Br J Haematol 2000; 110: 2–11.

    Article  CAS  Google Scholar 

  2. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM et al. The biology of chronic myeloid leukemia. N Engl J Med 1999; 341: 164–172.

    Article  CAS  Google Scholar 

  3. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    Article  CAS  Google Scholar 

  4. Goldman J, Gordon M . Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter? Leuk Lymphoma 2006; 47: 1–7.

    Article  CAS  Google Scholar 

  5. Goldman JM, Daley GC . Chronic myeloid leukemia: a brief history. In: Melo JV, Goldman JM (eds). Myeloproliferative Disorders. Springer: New York, 2007, pp 10–13.

    Google Scholar 

  6. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists’ Collaborative Group. J Natl Cancer Inst 1997; 89: 1616–1620.

  7. Italian Cooperative Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330: 820–825.

  8. Druker BJ, Sawyers CL, Capdeville R, Ford JM, Baccarani M, Goldman JM . Chronic myelogenous leukemia. Hematology Am Soc Hematol Educ Program 2001, 87–112.

  9. Bennett C, Hsu K, Look AT . Myeloproliferative disorders. In: Nathan DC, Orkin SH, Ginsburg D, Look AT (eds). Nathan and Oski's Hematology of Infancy and Childhood. WB Saunders: Philadelphia, USA, 2003, pp 1188–1193.

    Google Scholar 

  10. Dow LW, Raimondi SC, Culbert SJ, Ochs J, Kennedy W, Pinkel DP . Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia. Cancer 1991; 68: 1678–1684.

    Article  CAS  Google Scholar 

  11. Millot F, Traore P, Guilhot J, Nelken B, Leblanc T, Leverger G et al. Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics 2005; 116: 140–143.

    Article  Google Scholar 

  12. Marin T, Butturini A, Kantarjian H, Sokal J, Mickey MR, Gale R . Survival of children with chronic myeloid leukemia. Am J Pediatr Hematol Oncol 1992; 14: 229–232.

    Article  CAS  Google Scholar 

  13. Suttorp M . Chronisch myeloproliferative Erkrankungen bei Kindern und Jugendlichen. Kinder Jugendmedizin 2004; 4: 25–30.

    Article  Google Scholar 

  14. Cwynarski K, Roberts IA, Iacobelli S, van Biezen A, Brand R, Devergie A et al. Stem cell transplantation for chronic myeloid leukemia in children. Blood 2003; 102: 1224–1231.

    Article  CAS  Google Scholar 

  15. Suttorp M, Harbott J, Lion T, Hochhaus A . Chronic myeloid leukemia in childhood [abstract]. Blood 1999; 94 (Suppl 1): 280b.

    Google Scholar 

  16. Millot F, Esperou H, Bordigoni P, Dalle JH, Michallet M, Michel G et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). Bone Marrow Transplant 2003; 32: 993–999.

    Article  CAS  Google Scholar 

  17. Barbany G, Hoglund M, Simonsson B . Complete molecular remission in chronic myelogenous leukemia after imatinib therapy. N Engl J Med 2002; 347: 539–540.

    Article  Google Scholar 

  18. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    Article  CAS  Google Scholar 

  19. Kantarjian HM, Cortes J, Guilhot F, Hochhaus A, Baccarani M, Lokey L et al. Diagnosis and management of chronic myeloid leukemia: a survey of American and European practice patterns. Cancer 2007; 109: 1365–1375.

    Article  CAS  Google Scholar 

  20. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for ‘harmonizing’ current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.

    Article  CAS  Google Scholar 

  21. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    Article  CAS  Google Scholar 

  22. Melo JV, Chuah C . Molecular basis of resistance to imatinib. Hematology Eur Hematol Assoc Edu Program 2006; 2: 86–92.

    Google Scholar 

  23. Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL et al. Dynamics of chronic myeloid leukaemia. Nature 2005; 435: 1267–1270.

    Article  CAS  Google Scholar 

  24. Pulsipher MA . Treatment of CML in pediatric patients: should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy? Pediatr Blood Cancer 2004; 43: 523–533.

    Article  Google Scholar 

  25. Champagne MA, Capdeville R, Krailo M, Qu W, Peng B, Rosamilia M et al. Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood 2004; 104: 2655–2660.

    Article  CAS  Google Scholar 

  26. Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, Békassy AN et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase, and in relapse after stem cell transplantation. Leukemia 2006; 20: 187–192.

    Article  CAS  Google Scholar 

  27. Kolb EA, Pan Q, Ladanyi M, Steinherz PG . Imatinib mesylate in Philadelphia chromosome-positive leukemia in childhood. Cancer 2003; 98: 2643–2650.

    Article  CAS  Google Scholar 

  28. Kovitz C, Kantarjian H, Garcia-Manero G, Abruzzo LV, Cortes J . Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood 2006; 108: 2811–2813.

    Article  CAS  Google Scholar 

  29. Jabbour E, Kantarjian HM, Abruzzo LV, O'Brien S, Garcia-Manero G, Verstovsek S et al. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2007; 110: 2991–2995.

    Article  CAS  Google Scholar 

  30. Deininger MW, Cortes J, Paquette R, Park B, Hochhaus A, Baccarani M et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007; 110: 1509–1519.

    Article  Google Scholar 

  31. Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12: 908–916.

    Article  Google Scholar 

  32. Atallah E, Kantarjian H, Cortes J . In reply to ‘Cardiotoxicity of the cancer therapeutic agent imatinib mesylate’. Nat Med 2007; 13: 14.

    Article  CAS  Google Scholar 

  33. Berman E, Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006; 354: 2006–2013.

    Article  CAS  Google Scholar 

  34. Dewar AL, Farrugia AN, Condina MR, Bik To L, Hughes TP, Vernon-Roberts B et al. Imatinib as a potential antiresorptive therapy for bone disease. Blood 2006; 107: 4334–4337.

    Article  CAS  Google Scholar 

  35. Dewar AL, Zannettino AC, Hughes TP, Lyons AB . Inhibition of c-fms by imatinib: expanding the spectrum of treatment. Cell Cycle 2005; 4: 851–853.

    Article  CAS  Google Scholar 

  36. Fitter S, Dewar AL, Kostakis P, To LB, Hughes TP, Roberts MM et al. Long-term imatinib therapy promotes bone formation in CML patients. Blood 2008; 111: 2538–2547.

    Article  CAS  Google Scholar 

  37. Ault P, Kantarjian H, O’Brian S, Faderl S, Beran M, Rios MB et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006; 24: 1204–1208.

    Article  CAS  Google Scholar 

  38. Weisdorf DJ, Anasetti C, Antin JH, Kernan NA, Kollman C, Snyder D et al. Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood 2002; 99: 1971–1977.

    Article  CAS  Google Scholar 

  39. Passweg JR, Walker I, Sobocinski KA, Klein JP, Horowitz MM, Giralt SA et al. Validation and extension of the EBMT risk score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplantation. Br J Haematol 2004; 125: 613–620.

    Article  Google Scholar 

  40. Suttorp M, Lion T, Creutzig U, Klingebiel T, Gadner H . Die Behandlung der chronisch myeloischen Leukämie bei Kindern und Jugendlichen—Konzept der mulizentrischen Pilotstudie CML-päd-. Klin Padiatr 1996; 208: 242–249.

    Article  CAS  Google Scholar 

  41. Suttorp M, Claviez A, Bader P et al. Allogeneic stem cell transplantation for treatment of chronic myeloid leukemia in pediatric patients: results of the prospective trial CML-paed I. J Clin Oncol (submitted).

  42. Gratwohl A, Schmid O, Baldomero H . Accreditation Committee of the European Group for Blood and Marrow Transplantation. Haematopoietic stem cell transplantation in Europe 2002. Changes in indication and impact of team density: a report of the EBMT activity survey. Bone Marrow Transplant 2004; 34: 855–875.

    Article  CAS  Google Scholar 

  43. Oehler VG, Gooley T, Snyder DS, Johnston L, Lin A, Cummings CC et al. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 2007; 109: 1782–1789.

    Article  CAS  Google Scholar 

  44. Goldman JM . How I treat chronic myeloid leukemia in the imatinib era. Blood 2007; 110: 2828–2837.

    Article  CAS  Google Scholar 

  45. McGlave PB, Shu XO, Wen W, Anasetti C, Nademanee A, Champlin R et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years’ experience of the national marrow donor program. Blood 2000; 95: 2219–2225.

    CAS  PubMed  Google Scholar 

  46. Goldman JM, Szydlo R, Horowitz MM, Gale RP, Ash RC, Atkinson K et al. Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 1993; 82: 2235–2238.

    CAS  PubMed  Google Scholar 

  47. Speiser DE, Hermans J, van Biezen A, Starobinski M, Jeannet M, Jacobsen N et al. Haploidentical family member transplants for patients with chronic myeloid leukaemia: a report of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1997; 19: 1197–1203.

    Article  CAS  Google Scholar 

  48. Hughes TP, Kaeda J, Branford S, Rudaki Z, Hochhaus A, Hensley ML et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1421–1430.

    Article  Google Scholar 

  49. Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O et al. Imatinib mesylate discontinuation in patients with chronic mylogenous leukemia in complete molecular remission for more than two years. Blood 2007; 109: 58–60.

    Article  CAS  Google Scholar 

  50. Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.

    Article  CAS  Google Scholar 

  51. O’Hare T, Eide CA, Deininger MWN . Bcr-Abl kinase domain mutations, drug resistance and the road to a cure of chronic myeloid leukemia. Blood 2007; 110: 2242–2249.

    Article  Google Scholar 

  52. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  53. Simula MP, Marktel S, Fozza C, Kaeda J, Szydlo RM, Nadal E et al. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia 2007; 21: 943–948.

    Article  CAS  Google Scholar 

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  1. Department of Paediatrics, University Hospital, Dresden, Germany

    M Suttorp

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Suttorp, M. Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant 42 (Suppl 2), S40–S46 (2008). https://doi.org/10.1038/bmt.2008.282

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