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Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies

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Abstract

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6–97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5–33.0%) and 16.9% (95% CI: 11.4–23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3–69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.

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References

  1. Takahashi S, Iseki T, Ooi J, Tomonari A, Takasugi K, Shimohakamada Y, Yamada T, Uchimaru K, Tojo A, Shirafuji N, Kodo H, Tani K, Takahashi T, Yamaguchi T, Asano S (2004) Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood 104(12):3813–3820

    Article  PubMed  CAS  Google Scholar 

  2. Takahashi S, Ooi J, Tomonari A, Konuma T, Tsukada N, Oiwa-Monna M, Fukuno K, Uchiyama M, Takasugi K, Iseki T, Tojo A, Yamaguchi T, Asano S (2007) Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood 109(3):1322–1330

    Article  PubMed  CAS  Google Scholar 

  3. Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, Sirvent A, Champlin RE, Chao N, Gee AP, Isola L, Laughlin MJ, Marks DI, Nabhan S, Ruggeri A, Soiffer R, Horowitz MM, Gluckman E, Wagner JE, Center for International Blood and Marrow Transplant Research; Acute Leukemia Working Party Eurocord (the European Group for Blood Marrow Transplantation); National Cord Blood Program of the New York Blood Center (2010) Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 11(7):653–60

    Article  PubMed  PubMed Central  Google Scholar 

  4. Terakura S, Atsuta Y, Tsukada N, Kobayashi T, Tanaka M, Kanda J, Najima Y, Fukuda T, Uchida N, Takahashi S, Nagamura-Inoue T, Morishima Y, Miyamura K, Japan Society for Hematopoietic Cell Transplantation (2016) Comparison of outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation and single-unit cord blood transplantation in adults with acute leukemia. Biol Blood Marrow Transplant 22(2):330–8

    Article  PubMed  Google Scholar 

  5. Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, Witherspoon R, Mielcarek M, Deeg JH, Sorror M, Dahlberg A, Sandmaier BM, Salit R, Petersdorf E, Appelbaum FR, Delaney C (2016) Cord-blood transplantation in patients with minimal residual disease. N Engl J Med 375(10):944–953

    Article  PubMed  PubMed Central  Google Scholar 

  6. Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, Kanamori H, Hidaka M, Sakura T, Onizuka M, Kobayashi N, Sawa M, Eto T, Matsuhashi Y, Kato K, Ichinohe T, Atsuta Y, Miyamura K, Donor/Source Working Group of the Japan Society for Hematopoietic Cell Transplantation (2016) Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol. 91(5):E284-92

    Article  PubMed  Google Scholar 

  7. Shouval R, Fein JA, Labopin M, Kröger N, Duarte RF, Bader P, Chabannon C, Kuball J, Basak GW, Dufour C, Galimard JE, Polge E, Lankester A, Montoto S, Snowden JA, Styczynski J, Yakoub-Agha I, Mohty M, Nagler A (2019) Outcomes of allogeneic haematopoietic stem cell transplantation from HLA-matched and alternative donors: a European Society for Blood and Marrow Transplantation registry retrospective analysis. Lancet Haematol 6(11):e573–e584

    Article  PubMed  Google Scholar 

  8. Miyao K, Terakura S, Kimura F, Konuma T, Miyamura K, Yanada M, Kako S, Morhishima S, Uchida N, Toya T, Ozawa Y, Fukuda T, Tanaka M, Sawa M, Takada S, Yoshida S, Kimura T, Ichinohe T, Atsuta Y, Kanda J, Donor/Source Working Group of the Japan Society for Hematopoietic Cell Transplantation (2020) Updated comparison of 7/8 hla allele-matched unrelated bone marrow transplantation and single-unit umbilical cord blood transplantation as alternative donors in adults with acute leukemia. Biol Blood Marrow Transplant 26(11):2105–14

    Article  PubMed  Google Scholar 

  9. Konuma T, Kanda J, Yamasaki S, Harada K, Shimomura Y, Terakura S, Mizuno S, Uchida N, Tanaka M, Doki N, Ozawa Y, Nakamae H, Sawa M, Matsuoka K, Morishige S, Maruyama Y, Ikegame K, Kimura T, Kanda Y, Ichinohe T, Atsuta Y, Yanada M (2021) Single cord blood transplantation versus unmanipulated haploidentical transplantation for adults with acute myeloid leukemia in complete remission. Transplant Cell Ther 27(4):334.e1-334.e11

    Article  CAS  Google Scholar 

  10. Konuma T, Ooi J, Uchida N, Ogawa H, Ohashi K, Kanamori H, Aotsuka N, Onishi Y, Yamaguchi H, Kozai Y, Nagamura-Inoue T, Kato K, Suzuki R, Atsuta Y, Kato S, Asano S, Takahashi S (2014) Granulocyte colony-stimulating factor combined regimen in cord blood transplantation for acute myeloid leukemia: a nationwide retrospective analysis in Japan. Haematologica 99(12):e264–e268

    Article  PubMed  PubMed Central  Google Scholar 

  11. Konuma T, Takahashi S, Uchida N, Kuwatsuka Y, Yamasaki S, Aoki J, Onishi Y, Aotsuka N, Ohashi K, Mori T, Masuko M, Nakamae H, Miyamura K, Kato K, Atsuta Y, Kato S, Asano S, Takami A, Miyazaki Y, Adult Myelodysplastic Syndrome and Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (2015) Effect of granulocyte colony-stimulating factor-combined conditioning in cord blood transplantation for myelodysplastic syndrome and secondary acute myeloid leukemia: a retrospective study in Japan. Biol Blood Marrow Transplant 21(9):1632–40

    Article  PubMed  CAS  Google Scholar 

  12. Arai Y, Takeda J, Aoki K, Kondo T, Takahashi S, Onishi Y, Ozawa Y, Aotsuka N, Kouzai Y, Nakamae H, Ota S, Nakaseko C, Yamaguchi H, Kato K, Atsuta Y, Takami A, AML and MDS Working Group of the Japan Society for Hematopoietic Cell Transplantation (2015) Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy. Blood. 126(3):415–22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Nagayama H, Nakayama K, Yasuo K, Tajika K, Dan K, Yamashita N, Asano S, Takahashi TA (1999) Immunological reconstitution after cord blood transplantation for an adult patient. Bone Marrow Transplant 24(2):211–213

    Article  PubMed  CAS  Google Scholar 

  14. Ooi J, Iseki T, Takahashi S, Tomonari A, Ishii K, Takasugi K, Shimohakamada Y, Ohno N, Uchimaru K, Nagamura F, Tojo A, Asano S (2003) Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 101(12):4711–4713

    Article  PubMed  CAS  Google Scholar 

  15. Ooi J, Iseki T, Takahashi S, Tomonari A, Takasugi K, Shimohakamada Y, Yamada T, Ishii K, Ohno N, Nagamura F, Uchimaru K, Tojo A, Asano S (2004) Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia. Blood 103(2):489–491

    Article  PubMed  CAS  Google Scholar 

  16. Ooi J, Iseki T, Takahashi S, Tomonari A, Takasugi K, Uchiyama M, Konuma T, Fukuno K, Soda Y, Ohno N, Nagamura F, Uchimaru K, Tojo A, Asano S (2005) Unrelated cord blood transplantation after myeloablative conditioning for adult patients with refractory anemia. Int J Hematol 81(5):424–427

    Article  PubMed  Google Scholar 

  17. Konuma T, Ooi J, Takahashi S, Tomonari A, Uchiyama M, Fukuno K, Tsukada N, Iseki T, Tojo A, Asano S (2006) Unrelated cord blood transplantation after myeloablative conditioning in patients with acute leukemia aged between 50 and 55 years. Bone Marrow Transplant 37(8):803–804

    Article  PubMed  CAS  Google Scholar 

  18. Ooi J, Takahashi S, Tomonari A, Tsukada N, Konuma T, Kato S, Kasahara S, Sato A, Monma F, Nagamura F, Iseki T, Tojo A, Asano S (2008) Unrelated cord blood transplantation after myeloablative conditioning in adults with acute myelogenous leukemia. Biol Blood Marrow Transplant 14(12):1341–1347

    Article  PubMed  CAS  Google Scholar 

  19. Sato A, Ooi J, Takahashi S, Tsukada N, Kato S, Kawakita T, Yagyu T, Nagamura F, Iseki T, Tojo A, Asano S (2011) Unrelated cord blood transplantation after myeloablative conditioning in adults with advanced myelodysplastic syndromes. Bone Marrow Transplant 46(2):257–261

    Article  PubMed  CAS  Google Scholar 

  20. Konuma T, Kato S, Ooi J, Oiwa-Monna M, Ebihara Y, Mochizuki S, Yuji K, Ohno N, Kawamata T, Jo N, Yokoyama K, Uchimaru K, Asano S, Tojo A, Takahashi S (2014) Single-unit cord blood transplantation after granulocyte colony-stimulating factor-combined myeloablative conditioning for myeloid malignancies not in remission. Biol Blood Marrow Transplant 20(3):396–401

    Article  PubMed  CAS  Google Scholar 

  21. Terakura S, Konuma T, Tanaka M, Ozawa Y, Onizuka M, Nanno S, Onishi Y, Aotsuka N, Kondo T, Kawakita T, Kato J, Kobayashi T, Nishida T, Yamaguchi T, Kuwatsuka Y, Takahashi S (2020) Randomised controlled trial of conditioning regimen for cord blood transplantation for adult myeloid malignancies comparing high-dose cytarabine/cyclophosphamide/total body irradiation with versus without G-CSF priming: G-CONCORD study protocol. BMJ Open. 10(12):e040467

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kai S, Wake A, Okada M, Kurata M, Atsuta Y, Ishikawa J, Nakamae H, Aotsuka N, Kasai M, Misawa M, Taniguchi S, Kato S (2013) Double-unit cord blood transplantation after myeloablative conditioning for patients with hematologic malignancies: a multicenter phase II study in Japan. Biol Blood Marrow Transplant 19(5):812–819

    Article  PubMed  Google Scholar 

  23. Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, Tojo A, Takahashi S (2017) Cryopreserved CD34+ cell dose, but not total nucleated cell dose, influences hematopoietic recovery and extensive chronic graft-versus-host disease after single-unit cord blood transplantation in adult patients. Biol Blood Marrow Transplant 23(7):1142–1150

    Article  PubMed  CAS  Google Scholar 

  24. Mizusawa M, Konuma T, Kato S, Isobe M, Shibata H, Suzuki M, Takahashi O, Oiwa-Monna M, Takahashi S, Tojo A (2020) Clinical outcomes of persistent colonization with multidrug-resistant Gram-negative rods in adult patients undergoing single cord blood transplantation. Int J Hematol 111(6):858–868

    Article  PubMed  CAS  Google Scholar 

  25. Sorror ML, Maris MB, Storb R et al (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106:2912–2919

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME et al (2014) Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 123:3664–3671

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825–828

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  29. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl 48:452–458

    Article  CAS  Google Scholar 

  30. Kanda Y, Sakamaki H, Sao H, Okamoto S, Kodera Y, Tanosaki R, Kasai M, Hiraoka A, Takahashi S, Miyawaki S, Kawase T, Morishima Y, Kato S, Japan Marrow Donor Program (2005) Effect of conditioning regimen on the outcome of bone marrow transplantation from an unrelated donor. Biol Blood Marrow Transplant 11(11):881–9

    Article  PubMed  CAS  Google Scholar 

  31. Riddell S, Appelbaum FR, Buckner CD, Stewart P, Clift R, Sanders J, Storb R, Sullivan K, Thomas ED (1988) High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia. J Clin Oncol 6(4):576–582

    Article  PubMed  CAS  Google Scholar 

  32. Barker JN, Kurtzberg J, Ballen K, Boo M, Brunstein C, Cutler C, Horwitz M, Milano F, Olson A, Spellman S, Wagner JE, Delaney C, Shpall E (2017) Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies. Biol Blood Marrow Transplant 23(6):882–896

    Article  PubMed  PubMed Central  Google Scholar 

  33. Takahashi S, Okamoto SI, Shirafuji N, Ikebuchi K, Tani K, Shimane M, Matsudaira T, Irie S, Tsuruta T, Matsuishi E et al (1994) Recombinant human glycosylated granulocyte colony-stimulating factor (rhG-CSF)-combined regimen for allogeneic bone marrow transplantation in refractory acute myeloid leukemia. Bone Marrow Transplant 13(3):239–245

    PubMed  CAS  Google Scholar 

  34. Takahashi S, Oshima Y, Okamoto S, Nishiwaki K, Nagayama H, Inoue T, Tojo A, Tani K, Asano S (1998) Recombinant human granulocyte colony-stimulating factor (G-CSF) combined conditioning regimen for allogeneic bone marrow transplantation (BMT) in standard-risk myeloid leukemia. Am J Hematol 57(4):303–308

    Article  PubMed  CAS  Google Scholar 

  35. Okamoto S, Takahashi S, Wakui M, Ishida A, Tanosaki R, Ikeda Y, Asano S (1999) Treatment of advanced myelodysplastic syndrome with a regimen including recombinant human granulocyte colony-stimulating factor preceding allogeneic bone marrow transplantation. Br J Haematol 104(3):569–573

    Article  PubMed  CAS  Google Scholar 

  36. Konuma T, Kato S, Ishii H, Oiwa-Monna M, Asano S, Tojo A, Takahashi S (2015) Long-term outcomes of granulocyte colony-stimulating factor-combined conditioning in allogeneic hematopoietic stem cell transplantation from HLA-identical family donors for myeloid malignancies. Leuk Res 39(6):625–631

    Article  PubMed  CAS  Google Scholar 

  37. Miyauchi J, Kelleher CA, Wang C, Minkin S, McCulloch EA (1989) Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 73(5):1272–1278

    Article  PubMed  CAS  Google Scholar 

  38. Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, Najima Y, Takagi S, Aoki Y, Wake A, Taniguchi S, Shultz LD, Ishikawa F (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28(3):275–280

    Article  PubMed  CAS  Google Scholar 

  39. Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens P, Boogaerts M, Dutch-Belgian Hemato-Oncology Cooperative Group; Swiss Group for Clinical Cancer Research (2003) Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 349(8):743–52

    Article  PubMed  Google Scholar 

  40. Konuma T, Kanda J, Inamoto Y, Hayashi H, Kobayashi S, Uchida N, Sugio Y, Tanaka M, Kobayashi H, Kouzai Y, Takahashi S, Eto T, Mukae J, Matsuhashi Y, Fukuda T, Takanashi M, Kanda Y, Atsuta Y, Kimura F (2020) Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017. Am J Hematol 95(4):343–353

    Article  PubMed  CAS  Google Scholar 

  41. Mardiney M 3rd, Malech HL (1996) Enhanced engraftment of hematopoietic progenitor cells in mice treated with granulocyte colony-stimulating factor before low-dose irradiation: implications for gene therapy. Blood 87(10):4049–4056

    PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank all of the physicians and staff at the hospital and the cord blood banks in Japan for their help in this study. We are also grateful to Prof. Shigetaka Asano for his contributions to the field and for his guidance in this study.

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T.K. conceived the project, designed the research, analyzed data, and wrote the paper. All the other authors participated in the treatment of the patients, and acquired the clinical data. All authors approved the final version.

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Correspondence to Takaaki Konuma.

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Konuma, T., Ooi, J., Nagayama, H. et al. Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies. Ann Hematol 101, 177–189 (2022). https://doi.org/10.1007/s00277-021-04676-9

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