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Chronic Myeloid Leukemia, BCR/ABL Studies and Myelo-Proliferative Syndromes

Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML

Leukemia volume 19, pages 990–997 (2005)Cite this article

Abstract

A total of 24 patients (median age 58; range, 27–71 years) with chronic myeloid leukemia (CML) in first chronic (CP1) (n=14), second chronic (n=4), or accelerated phase (n=6) who were not candidates for conventional hematopoietic cell transplantation (HCT), received nonmyeloablative HCT from HLA-matched siblings a median of 28.5 (range, 11–271) months after diagnosis. They were conditioned with 2 Gy total body irradiation (TBI) alone (n=8) or combined with fludarabine, 90 mg/m2 (n=16). Postgrafting immunosuppression included cyclosporine and mycophenolate mofetil. All patients initially engrafted. However, 4 of 8 patients not given fludarabine experienced nonfatal rejection while all others had sustained engraftment. With a median follow-up of 36 (range, 4–49) months, 13 of 24 patients (54%) were alive and in complete remission. There were five (21%) deaths from nonrelapse mortality, one (4%) during the first 100 days after transplant. The proportions of grade II, III, and IV acute GVHD were 38, 4, and 8%, respectively. The 2-year estimate of chronic GVHD was 32%. The 2-year survival estimates for patients in CP1 (n=14) and beyond CP1 (n=10) were 70 and 56%, respectively. This study shows encouraging remission rates for patients with CML not eligible for conventional allografting.

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References

  1. Thomas ED, Clift RA, Fefer A, Appelbaum FR, Beatty P, Bensinger WI et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986; 104: 155–163.

    Article  CAS  PubMed  Google Scholar 

  2. Cross NCP, Feng L, Chase A, Bungey J, Hughes TP, Goldman JM . Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukemia patients after bone marrow transplantation. Blood 1993; 82: 1929–1936.

    CAS  PubMed  Google Scholar 

  3. Hughes TP, Kaeda J, Branford S, Rudzki 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: 1423–1432.

    Article  CAS  PubMed  Google Scholar 

  4. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300: 1068–1073.

    Article  CAS  PubMed  Google Scholar 

  5. Weiden PL, Flournoy N, Sanders JE, Sullivan KM, Thomas ED . Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc 1981; 13: 248–251.

    CAS  PubMed  Google Scholar 

  6. Dazzi F, Szydlo RM, Cross NC, Craddock C, Kaeda J, Kanfer E et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712–2716.

    CAS  PubMed  Google Scholar 

  7. Kolb HJ, Mittermüller J, Clemm CH, Holler G, Ledderose G, Brehm G et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.

    CAS  PubMed  Google Scholar 

  8. Collins RHJ, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.

    Article  PubMed  Google Scholar 

  9. Clift RA, Radich J, Appelbaum FR, Martin P, Flowers MED, Deeg HJ et al. Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia (Letter to Editor). Blood 1999; 94: 3960–3962.

    CAS  PubMed  Google Scholar 

  10. Clift RA, Buckner CD, Thomas ED, Bryant E, Anasetti C, Bensinger WI et al. Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood 1994; 84: 4368–4373.

    CAS  PubMed  Google Scholar 

  11. Radich JP, Gooley T, Bensinger W, Chauncey T, Clift R, Flowers M et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood 2003; 102: 31–35.

    Article  CAS  PubMed  Google Scholar 

  12. Appelbaum FR, Clift R, Radich J, Anasetti C, Buckner CD . Bone marrow transplantation for chronic myelogenous leukemia (Review). Semin Oncol 1995; 22: 405–411.

    CAS  PubMed  Google Scholar 

  13. 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 

  14. Clift RA, Appelbaum FR, Thomas ED . Treatment of chronic myeloid leukemia by marrow transplantation (Review). Blood 1993; 82: 1954–1956.

    CAS  PubMed  Google Scholar 

  15. Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating MJ, Gutterman JU . Hematologic remission and cytogenetic improvement induced by recombinant human interferon alphaA in chronic myelogenous leukemia. N Engl J Med 1986; 314: 1065–1069.

    Article  CAS  PubMed  Google Scholar 

  16. Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, et al., Europena Study Group on Interferon in Chronic Myeloid Leukemia, Italian Cooperative Study Group on CML, France IoC, German CML, UK Medical Research Council Working Party on CML, Spanish CML, Australian CML, Swedish CML. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders (Review). Blood 2001; 98: 3074–3081.

    Article  CAS  PubMed  Google Scholar 

  17. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  18. Sandmaier BM, McSweeney P, Yu C, Storb R . Nonmyeloablative transplants: preclinical and clinical results. Semin Oncol 2000; 27 (Suppl. 5): 78–81.

    CAS  PubMed  Google Scholar 

  19. Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.

    CAS  PubMed  Google Scholar 

  20. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  21. Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG et al. Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 2004; 104: 1550–1558.

    Article  CAS  PubMed  Google Scholar 

  22. Mickelson E, Smith A, McKinney S, Anderson G, Hansen JA . A comparative study of HLA-DRB1 typing by standard serology and hybridization of non-radioactive sequence-specific oligonucleotide probes to PCR-amplified DNA. Tissue Antigens 1993; 41: 86–93.

    Article  CAS  PubMed  Google Scholar 

  23. Petersdorf EW, Smith AG, Mickelson EM, Martin PJ, Hansen JA . Ten HLA-DR4 alleles defined by sequence polymorphisms within the DRB1 first domain. Immunogenetics 1991; 33: 267–275.

    Article  CAS  PubMed  Google Scholar 

  24. Saral R, Burns WH, Laskin OL, Santos GW, Lietman PS . Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med 1981; 305: 63–67.

    Article  CAS  PubMed  Google Scholar 

  25. Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR et al. Efficacy and safety of fluconazole for fungal infections after marrow transplant – a prospective, randomized, double-blind study. J Infect Dis 1995; 171: 1545–1552.

    Article  CAS  PubMed  Google Scholar 

  26. Boeckh M, Bowden RA, Goodrich JM, Pettinger M, Meyers JD . Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood 1992; 80: 1358–1364.

    CAS  PubMed  Google Scholar 

  27. Durnam DM, Anders KR, Fisher L, O'Quigley JO, Bryant EM, Thomas ED . Analysis of the origin of marrow cells in bone marrow transplant recipients using a Y-chromosome-specific in situ hybridization assay. Blood 1989; 74: 2220–2226.

    CAS  PubMed  Google Scholar 

  28. Ugozzoli L, Yam P, Petz LD, Ferrara GB, Champlin RE, Forman SJ et al. Amplification by the polymerase chain reaction of hypervariable regions of the human genome for evaluation of chimerism after bone marrow transplantation. Blood 1991; 77: 1607–1615.

    CAS  PubMed  Google Scholar 

  29. Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.

    CAS  PubMed  Google Scholar 

  30. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet 1998; 352: 1087–1092.

    Article  CAS  PubMed  Google Scholar 

  31. Passweg JR, Walker I, Sobocinski KA, Klein JP, Horowitz MM, Giralt SA, Chronic Leukemia Study Writing Committee of the International Bone Marrow Transplant Registry. Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants. Br J Haematol 2004; 125: 613–620.

    Article  PubMed  Google Scholar 

  32. Radich JP, Gehly G, Gooley T, Bryant E, Clift RA, Collins S et al. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995; 85: 2632–2638.

    CAS  PubMed  Google Scholar 

  33. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  34. Feinstein LC, Sandmaier BM, Hegenbart U, McSweeney PA, Maloney DG, Gooley TA et al. Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission. Br J Haematol 2003; 120: 281–288.

    Article  PubMed  Google Scholar 

  35. Gregoire V, Hittelman WN, Rosier JF, Milas L . Chemo-radiotherapy: radiosensitizing nucleoside analogues (Review). Oncol Rep 1999; 6: 949–957.

    CAS  PubMed  Google Scholar 

  36. Mattsson J, Uzunel M, Brune M, Hentschke P, Barkholt L, Stierner U et al. Mixed chimaerism is common at the time of acute graft-versus-host disease and disease response in patients receiving non-myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol 2001; 115: 935–944.

    Article  CAS  PubMed  Google Scholar 

  37. Uzunel M, Mattsson J, Brune M, Johansson JE, Aschan J, Ringden O . Kinetics of minimal residual disease and chimerism in patients with chronic myeloid leukemia after nonmyeloablative conditioning and allogeneic stem cell transplantation. Blood 2003; 101: 469–472.

    Article  CAS  PubMed  Google Scholar 

  38. Sloand E, Childs RW, Solomon S, Greene A, Young NS, Barrett AJ . The graft-versus-leukemia effect of nonmyeloablative stem cell allografts may not be sufficient to cure chronic myelogenous leukemia. Bone Marrow Transplant 2003; 32: 897–901.

    Article  CAS  PubMed  Google Scholar 

  39. Lange T, Deininger M, Brand R, Hegenbart U, Al-Ali H, Krahl R et al. BCR-ABL transcripts are early predictors for hematological relapse in chronic myeloid leukemia after hematopoietic cell transplantation with reduced intensity conditioning. Leukemia 2004; 18: 1468–1475.

    Article  CAS  PubMed  Google Scholar 

  40. Or R, Shapira MY, Resnick I, Amar A, Ackerstein A, Samuel S et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase (comment in: Blood 2003 Jun 15; 101(12): 5084; author reply 5084–5; PMID: 12788790). Blood 2003; 101: 441–445.

    Article  CAS  PubMed  Google Scholar 

  41. Das M, Saikia TK, Advani SH, Parikh PM, Tawde S . Use of a reduced-intensity conditioning regimen for allogeneic transplantation in patients with chronic myeloid leukemia. Bone Marrow Transplant 2003; 32: 125–129.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the physicians, nurses, and support staff of the collaborating centers for their dedicated patient care. We are also grateful to the study nurses Steve Minor, John Sedgwick, Mary Hinds, and the data coordinators Heather Hildebrant, Debbie Bassuk and Lucy Fetzko who made this analysis possible. We are grateful to Bonnie Larson and Helen Crawford for help with manuscript preparation. This work is supported in part by NIH Grants: CA78902, CA49605, CA18029, CA15704, Bethesda, MD, the European Leukemia Net, the Kompetenznetzwerk Akute und chronische Leukämien, and from a grant from Ministero dell'Istruzione, dell'Università, della Ricerca (MIUR), Italy. FR Kerbauy is supported by a grant from FAPESP/Brazil and an award from the Oncology Research Faculty Development Program from the Department of Health and Human Services, NIH, Bethesda, MD.

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Author notes

  1. D Niederwieser and B M Sandmaier: DN and BMS contributed equally to this paper.

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    F R Kerbauy, R Storb, T Gooley, J P Radich, D G Maloney, T R Chauncey & B M Sandmaier

  2. University of Washington, Seattle, WA, USA

    R Storb, T Gooley, J P Radich, D G Maloney, T R Chauncey & B M Sandmaier

  3. University of Leipzig, Leipzig, Germany

    U Hegenbart, H K Al-Ali & D Niederwieser

  4. Stanford University, Stanford, CA, USA

    J Shizuru & K G Blume

  5. Baylor University, Dallas, TX, USA

    E Agura

  6. University of Torino, Torino, Italy

    B Bruno

  7. University of Arizona, Tucson, AZ, USA

    E M Epner

  8. VA Medical Center, Seattle, WA, USA

    T R Chauncey

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Kerbauy, F., Storb, R., Hegenbart, U. et al. Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML. Leukemia 19, 990–997 (2005). https://doi.org/10.1038/sj.leu.2403730

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