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Allografting

Disease stage stratified effects of cell dose in unrelated BMT for hematological malignancies: a report from Japan marrow donor program

Bone Marrow Transplantation volume 46, pages 1192–1202 (2011)Cite this article

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Abstract

Cell dose is one of the major factors that can be manipulated in unrelated BMT. However, regarding disease-stage-stratified effects of cell dose, data are limited. We analyzed the registry data from 3559 patients with acute leukemia, CML and myelodysplastic syndrome who received T-cell replete unrelated BMT through the Japan Marrow Donor Program. Adjusted effects of cell dose were evaluated for various outcomes separately according to disease stages and children or adults. Acute GVHD and nonrelapse mortality were not affected by cell dose. Among children, a cell dose lower than 3.0 × 108/kg was associated with lower engraftment rates in advanced-stage diseases. Among adults, a cell dose of 3.4 × 108/kg or higher was associated with lower relapse rates and better survival rates only in early-stage diseases, whereas cell dose below 2.3 × 108/kg was associated with lower engraftment rates in advanced-stage diseases. In conclusion, effects of cell dose may differ among disease stages. A cell dose of 3.4 × 108/kg or higher is recommended only for adults with early-stage diseases. With the number of patients available for analysis in this study, we could not show any significant benefits associated with 4.6 × 108/kg or higher in children.

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References

  1. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE et al. Bone-marrow transplantation (first of two parts). N Engl J Med 1975; 292: 832–843.

    Article  CAS  PubMed  Google Scholar 

  2. Kernan NA, Bartsch G, Ash RC, Beatty PG, Champlin R, Filipovich A et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993; 328: 593–602.

    Article  CAS  PubMed  Google Scholar 

  3. Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N Engl J Med 1998; 339: 1177–1185.

    Article  CAS  PubMed  Google Scholar 

  4. Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood 2002; 99: 4200–4206.

    Article  CAS  PubMed  Google Scholar 

  5. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.

    Article  CAS  PubMed  Google Scholar 

  6. Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program. Blood 2000; 96: 4096–4102.

    CAS  PubMed  Google Scholar 

  7. Sierra J, Storer B, Hansen JA, Bjerke JW, Martin PJ, Petersdorf EW et al. Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA-matching, and marrow cell dose. Blood 1997; 89: 4226–4235.

    CAS  PubMed  Google Scholar 

  8. Dominietto A, Lamparelli T, Raiola AM, Van Lint MT, Gualandi F, Berisso G et al. Transplant-related mortality and long-term graft function are significantly influenced by cell dose in patients undergoing allogeneic marrow transplantation. Blood 2002; 100: 3930–3934.

    Article  CAS  PubMed  Google Scholar 

  9. Storb R, Prentice RL, Thomas ED . Marrow transplantation for treatment of aplastic anemia. An analysis of factors associated with graft rejection. N Engl J Med 1977; 296: 61–66.

    Article  CAS  PubMed  Google Scholar 

  10. Deeg HJ, Self S, Storb R, Doney K, Appelbaum FR, Witherspoon RP et al. Decreased incidence of marrow graft rejection in patients with severe aplastic anemia: changing impact of risk factors. Blood 1986; 68: 1363–1368.

    CAS  PubMed  Google Scholar 

  11. Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001; 98: 2043–2051.

    Article  CAS  PubMed  Google Scholar 

  12. Kimura F, Sato K, Kobayashi S, Ikeda T, Sao H, Okamoto S et al. Impact of AB0-blood group incompatibility on the outcome of recipients of bone marrow transplants from unrelated donors in the Japan Marrow Donor Program. Haematologica 2008; 93: 1686–1693.

    Article  PubMed  Google Scholar 

  13. Rocha V, Labopin M, Gluckman E, Powles R, Arcese W, Bacigalupo A et al. Relevance of bone marrow cell dose on allogeneic transplantation outcomes for patients with acute myeloid leukemia in first complete remission: results of a European survey. J Clin Oncol 2002; 20: 4324–4330.

    Article  PubMed  Google Scholar 

  14. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (eds). IARC: Lyon France, 2008.

    Google Scholar 

  15. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  16. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  17. Fine J, Gray R . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–497.

    Article  Google Scholar 

  18. Paulin T . Importance of bone marrow cell dose in bone marrow transplantation. Clin Transplant 1992; 6: 48–54.

    CAS  PubMed  Google Scholar 

  19. Byrne JL, Stainer C, Cull G, Haynes AP, Bessell EM, Hale G et al. The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia. Bone Marrow Transplant 2000; 25: 411–417.

    Article  CAS  PubMed  Google Scholar 

  20. Barrett AJ, Ringden O, Zhang MJ, Bashey A, Cahn JY, Cairo MS et al. Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia. Blood 2000; 95: 3323–3327.

    CAS  PubMed  Google Scholar 

  21. Han P, Story C, McDonald T, Mrozik K, Snell L . Immune escape mechanisms of childhood ALL and a potential countering role for DC-like leukemia cells. Cytotherapy 2002; 4: 165–175.

    Article  CAS  PubMed  Google Scholar 

  22. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 2002; 20: 405–412.

    Article  CAS  PubMed  Google Scholar 

  25. Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH . Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 1994; 330: 100–106.

    Article  CAS  PubMed  Google Scholar 

  26. Theilgaard-Monch K, Raaschou-Jensen K, Palm H, Schjodt K, Heilmann C, Vindelov L et al. Flow cytometric assessment of lymphocyte subsets, lymphoid progenitors, and hematopoietic stem cells in allogeneic stem cell grafts. Bone Marrow Transplant 2001; 28: 1073–1082.

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. Collins Jr RH, 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 

  29. Passweg JR, Stern M, Koehl U, Uharek L, Tichelli A . Use of natural killer cells in hematopoietic stem cell transplantation. Bone Marrow Transplant 2005; 35: 637–643.

    Article  CAS  PubMed  Google Scholar 

  30. Mavroudis D, Read E, Cottler-Fox M, Couriel D, Molldrem J, Carter C et al. CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies. Blood 1996; 88: 3223–3229.

    CAS  PubMed  Google Scholar 

  31. Bittencourt H, Rocha V, Chevret S, Socie G, Esperou H, Devergie A et al. Association of CD34 cell dose with hematopoietic recovery, infections, and other outcomes after HLA-identical sibling bone marrow transplantation. Blood 2002; 99: 2726–2733.

    Article  CAS  PubMed  Google Scholar 

  32. Dominietto A, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, Berisso G et al. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol 2001; 112: 219–227.

    Article  CAS  PubMed  Google Scholar 

  33. Shiobara S, Nakao S, Ueda M, Yamazaki H, Takahashi S, Asano S et al. Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation: indications and dose escalation. Ther Apher 2001; 5: 40–45.

    Article  CAS  PubMed  Google Scholar 

  34. Batinic D, Marusic M, Pavletic Z, Bogdanic V, Uzarevic B, Nemet D et al. Relationship between differing volumes of bone marrow aspirates and their cellular composition. Bone Marrow Transplant 1990; 6: 103–107.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Y Inamoto

  2. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    K Miyamura

  3. Department of Medicine, Keio University School of Medicine, Tokyo, Japan

    S Okamoto

  4. Hematology Division, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

    H Akiyama

  5. Department of Hematology, Meitetsu Hospital, Nagoya, Japan

    H Iida

  6. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    T Eto

  7. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan

    Y Morishima

  8. Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

    K Kawa

  9. Department of Pediatrics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

    A Kikuchi

  10. Department of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan

    Y Nagatoshi

  11. Department of Hematology and Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    J Tanaka

  12. Division of Hematology, Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan

    T Ashida

  13. Akita University Hospital, Clinical Oncology Center, Akita, Japan

    M Hirokawa

  14. Department of Pediatrics, Ibaragi Children's Hospital, Ibaragi, Japan

    M Tsuchida

  15. Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan

    S Mori

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Inamoto, Y., Miyamura, K., Okamoto, S. et al. Disease stage stratified effects of cell dose in unrelated BMT for hematological malignancies: a report from Japan marrow donor program. Bone Marrow Transplant 46, 1192–1202 (2011). https://doi.org/10.1038/bmt.2010.281

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