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DOI: 10.1055/s-0029-1239529
© Georg Thieme Verlag KG Stuttgart · New York
Allogeneic Stem Cell Transplantation for Pediatric and Adolescent Patients with CML: Results from the Prospective Trial CML-paed I
Allogene Stammzelltransplantation bei Kindern und Jugendlichen mit CML: Ergebnisse der prospektiven Therapiestudie CML-paed IPublikationsverlauf
Publikationsdatum:
04. November 2009 (online)
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Abstract
Purpose: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea±interferon.
Patients and Methods: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis.
Results: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen – total body irradiation or busulfan – exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87±11% if grafted from a sibling (n=41), 52±9% from matched UD (MUD, n=71), and 45±16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74±9%), compared to 7–12 months (n=52; 62±15%), and >12 months (n=43; 62±17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20±12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT.
Conclusion: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.
Zusammenfassung
Hintergrund: Die allogene Stammzelltransplantation (SZT) ist kurativ für Patienten mit CML, einer im Kindesalter seltenen Leukämie. Wir evaluierten prospektiv den Effekt einer frühzeitigen SZT nach standardisierter Vorbehandlung mit Hydroxyurea±Interferon bei pädiatrischer CML.
Patienten und Methoden: Zwischen 1995 und 2004 wurden 200 Kinder und Jugendliche (medianes Alter: 12,4 Jahre) eingeschlossen: Bei HLA-kompatiblem verwandtem Spender (MRD) wurde die SZT binnen 6 Monaten angestrebt; bei unverwandten Spendern (UD) binnen 12 Monaten.
Ergebnisse: 176 Patienten wurden transplantiert; mit einem MRD im Median nach 4 Monaten und mit einem UD binnen 11 Monaten nach Diagnose. Bei SZT befanden sich 158 Patienten in chronischer Phase (CP1/CP2), 9 in Akzeleration und 9 in Blastenkrise. Die Konditionierung – Ganzkörperbestrahlung oder Busulfan-basiert – hatte keinen Einfluss auf die Überlebenswahrscheinlichkeit. Diese betrug nach 5 Jahren mit einem Geschwisterspender (n=41) 87±11%, mit MUD (n=71) 52±9% und mit nicht HLA-kompatiblem Spender (MMD, n=55) 45±16%. Patienten in CP1 mit SZT binnen 6 Monaten zeigten trendmäßig eine höhere Überlebenswahrscheinlichkeit (n=49; 74±9%) als jene, die nach 7–12 Monaten (n=52; 62±15%) oder >12 Monaten (n=43; 62±17%) transplantiert wurden (p=0,157). Die Rezidivwahrscheinlichkeit nach 5 Jahren betrug 20±12%. UD und MMD waren mit höherer Transplantat-gegen-Wirt-Erkrankung und therapiebedingter Mortalität assoziiert.
Schlußfolgerung: Diese Daten der ersten prospektiven Studie zur CML im Kindes- und Jugendalter können zur Entscheidungsfindung herangezogen werden, wenn die Risiken einer SZT gegen die zunehmend eingesetzte Primärtherapie mit Imatinib abzuwägen sind.
Key words
Chronic myeloid leukemia - children - adolescents - stem cell transplantation
Schlüsselwörter
Chronisch myeloische Leukämie - Kinder - Adoleszente - Stammzelltransplantation
References
-
1 Altman AJ. Chronic leukemias of childhood. In: Pizzo PA et al., Hrsg.
Principles and practice of pediatric oncology . Lippincott-Raven, New York 1997: S483-S497 - 2 Bacher U. et al . Clonal aberrations in philadelphia chromosome negative hematopoiesis in patients with chronic myeloid leukemia treated with imatinib or interferon alpha. Leukemia. 2005; 19 460-463
- 3 Barbany G. et al . Complete molecular remission in chronic myelogenous leukemia after imatinib therapy. N Engl J Med. 2002; 347 539-540
-
4 Bennett C. et al .Myeloproliferative disorders. In: Nathan DC et al., EDS.
Nathan and Oski's hematology of infancy and childhood . W. B. Saunders, Philadelphia 2003: 1188-1193 - 5 Berger U. et al . Gender aspects in chronic myeloid leukemia: long-term results from randomized studies. Leukemia. 2005; 19 984-989
- 6 Berman E. et al . Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006; 354 2006-2013
- 7 Champagne MA. 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
- 8 Champlin RE. et al . Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation IBMTR histocompatibility and stem cell sources working committee and the European group for blood and marrow transplantation (EBMT). Blood. 2000; 95 3702-3709
- 9 Clift RA. et al . Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood. 1994; 84 2036-2043
- 10 Clift RA. et al . Marrow transplantation for CML: The seattle experience. Bone Marrow Transplant. 1996; 17 ((Suppl 3)) 5-6
- 11 Creutzig U. et al . Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials. Leukemia. 2005; 19 2030-2042
- 12 Cwynarski K. et al . Stem cell transplantation for chronic myeloid leukemia in children. Blood. 2003; 102 1224-1231
- 13 Davies SM. et al . Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors. Am J Med. 2001; 110 339-346
- 14 Devergie A. et al . Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: A randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: A report from the French Society of Bone Marrow Graft (SFGM). Blood. 1995; 85 2263-2268
- 15 Dewar AL. et al . Inhibition of C-FMS by imatinib: Expanding the spectrum of treatment. Cell Cycle. 2005; 4 851-853
- 16 Dini G. et al . Unrelated-donor bone marrow transplantation for philadelphia chromosome-positive chronic myelogenous leukemia in children: Experience of eight european Countries. The EBMT Paediatric Diseases Working Party. Bone Marrow Transplant. 1996; 18 ((Suppl 2)) 80-85
- 17 Dow LW. et al . Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia. Cancer. 1991; 68 1678-1684
- 18 Druker BJ. et al . Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355 2408-2417
- 19 Fabarius A. et al . Induction of centrosome and chromosome aberrations by imatinib in vitro. Leukemia. 2005; 19 1573-1578
- 20 Faderl S. et al . The biology of chronic myeloid leukemia. N Engl J Med. 1999; 341 164-172
- 21 Fitter S. et al . Long-term imatinib therapy promotes bone formation in CML patients. Blood. 2008; 111 2538-2547
- 22 Giralt S. et al . Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: An analysis from the international bone marrow transplant registry. Blood. 2000; 95 410-415
-
23 Goldman JM. Chronic Myeloid Leukaemia. In JA Whittaker and JA Holmes, eds.
Leukemia and Related Disorders . London, Blackwell Science 1998: 252-269 - 24 Gratwohl A. et al . Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: Transplant activity, long-term data and current results. An analysis by the chronic leukemia working party of the european group for blood and marrow transplantation (EBMT). Haematologica. 2006; 91 513-521
- 25 Hansen JA. et al . Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998; 338 962-968
- 26 Hansen JA. et al . The role of HLA matching in hematopoietic cell transplantation. Rev Immunogenet. 1999; 1 359-373
- 27 Hehlmann R. et al . Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure. Blood. 1999; 94 3668-3677
- 28 Horowitz MM. et al . Allogeneic bone marrow transplantation for CML: A report from the international bone marrow transplant registry. Bone Marrow Transplant. 1996; 17 ((Suppl 3)) 7-9
- 29 Hughes T. 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
- 30 Kerkela R. et al . Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006; 12 908-916
- 31 Lahaye T. et al . Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: A 4.5-year follow-up. Cancer. 2005; 103 1659-1669
- 32 Marin T. et al . Survival of children with chronic myeloid leukemia. Am J Pediatr Hematol Oncol. 1992; 14 229-232
- 33 McGlave PB. et al . Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years’ experience of the national marrow donor program. Blood. 2000; 95 2219-2225
- 34 Melo JV. et al . Resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Lett. 2007; 249 121-132
- 35 Millot F. 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
- 36 Millot F. 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
- 37 Millot F. et al . Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics. 2005; 116 140-143
- 38 Nguyen L. et al . I. V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant. 2004; 33 979-987
- 39 Olavarria E. et al . Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood. 2001; 97 1560-1565
- 40 Schrappe M. 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-Munster. Leukemia. 2000; 14 2205-2222
- 41 Speiser DE. et al . Haploidentical family member transplants for patients with chronic myeloid leukaemia: A report of the Chronic Leukaemia Working Party of off European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 1997; 19 1197-1203
- 42 Stone RM. Optimizing treatment of chronic myeloid leukemia: A rational approach. Oncologist. 2004; 9 259-270
-
43 Suttorp M. Chronisch Myeloproliferative Erkrankungen. In: Gadner H et al., Hrsg.
Pädiatrische Hämatologie und Onkologie . Springer, Heidleberg 2005: S724-S731 - 44 Suttorp M. Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant. 2008; 42 (Suppl 2) S40-S46
- 45 Suttorp M. et al . Chronic Myeloid Leukemia (CML) in Childhood – Results of the Multicenter Trial CML-paed. Blood. 2004; 104 178a
- 46 Suttorp M. et al . Treatment of chronic myeloid leukemia in children and adolescents – concept of the multicenter pilot study CML-ped. Klin Padiatr. 1996; 208 242-249
- 47 van Rhee F. et al . Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: A report from the chronic leukemia working party of the european group for blood an marrow transplantation. Bone Marrow Transplant. 1997; 20 553-560
- 48 Weisdorf DJ. et al . Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood. 2002; 99 1971-1977
- 49 Yakoub-Agha I. et al . Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: A prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006; 24 5695-5702
Correspondence
Prof. Dr. Meinolf Suttorp
Klinik für Kinder- und Jugendmedizin, Bereich Pädiatrische
Hämatologie und Onkologie, Universitätsklinikum Carl Gustav Carus
Fetscherstraße 74
01307 Dresden
Germany
Telefon: +49/351/458 3522
Fax: +49/351/458 5864
eMail: meinolf.suttorp@uniklinikum-dresden.de