Analysis of 500 Bone Marrow Transplants from Unrelated
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Bone Marrow Transplantation, (1999) 24, 995–1003 1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt Analysis of 500 bone marrow transplants from unrelated donors (UR-BMT) facilitated by the Japan Marrow Donor Program: confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia Y Kodera1, Y Morishima2, S Kato3, Y Akiyama4, H Sao5, T Matsuyama6, K Kawa7, H Sakamaki8, S Nakagawa9, N Hirabayashi10, H Dohi11, S Okamoto12, A Hiraoka13, H Gondo14, M Tsuchida15, HO16, M Harada17, S Asano18, T Juji19, T Sasazuki20 and F Takaku21 for the Japan Marrow Donor Program 1Department of Internal Medicine, Japanese Red Cross Nagoya First Hospital; 2Department of Hematology and Chemotherapy, Aichi Cancer Center; 3Department of Pediatrics, Tokai University Hospital; 4Department of Pediatrics, Kyoto University Hospital; 5Department of Internal Medicine, Meitetsu Hospital; 6Department of Pediatrics, Japanese Red Cross Nagoya First Hospital; 7Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health; 8Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital; 9Department of Internal Medicine, Hyogo Medical Center for Adults; 10Department of Internal Medicine, Nagoya Daini Red Cross Hospital; 11Department of Internal Medicine, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital; 12Department of Internal Medicine, School of Medicine, Keio University; 13Department of Internal Medicine, Center for Adult Disease, Osaka; 14First Department of Internal Medicine, Kyushu University Hospital; 15Department of Pediatrics, Ibaraki Children’s Hospital; 16Second Department of Internal Medicine, Chiba University School of Medicine; 17Second Department of Internal Medicine, Okayama University Hospital; 18Department of Internal Medicine, Institute of Medical Science, University of Tokyo; 19Japanese Red Cross Central Blood Center; 20Medical Institute of Bioregulation, Kyushu University; and 21Jichi Medical School, Japan Summary: (UR-BMT); Japan Marrow Donor Program (JMDP); acute GVHD; chronic GVHD; survival In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foun- dation under the auspices of the Ministry of Health and Allogeneic bone marrow transplantation (BMT) from HLA- Welfare in Japan. By December 1998, 122365 HLA-A,B identical sibling donors has been accepted as a cure- typed volunteer marrow donors and 7207 patients had oriented treatment for patients with hematological malig- been cumulatively registered in the JMDP. The results nancies,1–3 syndromes of marrow failure4–6 and certain her- of HLA-matching between donors and patients revealed editary disorders.7 It has been, nevertheless, a possible that 5684 out of 7207 (78.9%) patients could have at modality of treatment only for approximately one-third of least one HLA-A,B,DR serologically matched donor. the patients for whom BMT is the first choice of treatment Among these matched pairs, 1829 unrelated bone mar- because of the lack of HLA-matched related donors. To row transplants (UR-BMT) were performed. The initial provide the remaining patients with the chance of BMT, 500 UR-BMT transplanted from January 1993 to several investigators have explored the use of other sources October 1995 were analyzed as of July 1998. of marrow, including partially HLA-mismatched family Engraftment was achieved in 95% of cases. Probability members8,9 and unrelated donors who are phenotypically of the occurrence of grade III and IV acute GVHD was closely matched for HLA-A,B and DR antigens. The first 18.4%. The rate of disease-free survival (DFS) of the transplants involving unrelated donors were reported in the patients who had standard-risk leukemia and did not 10–14 15–29 = mid-1970s, followed by several other reports; then suffer from grade III or IV acute GVHD (n 154) was a large-scale study based on a publically established bone 60–71% and the rate of survival of patients with aplastic marrow donor bank was reported.30,31 Since the mid-1980s, anemia was 56%. It can be stated that UR-BMT is a Japanese hematologists as well as patients and their famil- modality of treatment which is as effective as related ies also started organizing a bone marrow donor bank. After BMT if the occurrence of grade III or IV acute GVHD successful experience with local marrow donor banks,32,33 is predicted and prevented. Keywords: bone marrow transplant from unrelated donor the Japan Marrow Donor Program (JMDP) was finally cre- ated at the end of 1991. In this report, we present the results of the initial 500 marrow transplants performed from unre- lated donors identified through JMDP between January Correspondence: Y Kodera, Department of Internal Medicine, Japanese 1993 and October 1995, and evaluated as of July 1998. Red Cross Nagoya First Hospital, 3-35, Michishita-cho, Nakamura-ku, Nagoya 453, Japan Received 21 September 1998; accepted 18 June 1999 UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 996 Materials and methods Table 1 Characteristics of 500 patients and corresponding donors JMDP Age (years) Patient Ͻ10 67 The JMDP was established in December 1991 with the 10–19 128 cooperation of the Japanese Red Cross and Japan Marrow 20–29 143 30–39 106 Donor Foundation under the auspices of the Japanese Min- 40–51 56 istry of Health and Welfare. Its principles and policies are Donor 20–29 151 basically similar to those of the marrow donor registries 30–39 195 in the United States and European countries.17,34,35 JMDP 40–50 154 involves 68 local blood centers for the HLA class I and II serological typing of volunteer donors and involves the cen- Sex (M/F) Patient 280/220 tral blood center for the accumulation of this HLA infor- Donor 298/202 mation for matching to registered patients and for HLA DNA typing among HLA serologically-matched pairs. Background disease of patients JMDP has also approved 129 units in 101 institutes experi- Malignant 435 enced in allogeneic BMT as transplant and harvest centers Chronic myelogenous leukemia 171 distributed throughout the country.36 Primary chronic phase 114 Secondary chronic phase 13 Third chronic phase 1 Donor recruitment and selection Accelerated phase 27 Blastic crisis 15 The recruitment of volunteer marrow donors was initiated Unknown 1 in January 1992, and by December 1998 the number of Acute lymphoblastic leukemia 126 1st remission 39 persons enquiring about marrow donation reached approxi- 2nd remission 32 mately 260000; among them 122365 persons were regis- Ͼ2nd remission, relapse, primary refractory 54 tered after confirmation of their willingness to donate fol- Unknown 1 lowed by HLA-A,B serological typing. HLA-DR Acute nonlymphocytic leukemia 99 serological typing had been also performed for 83.3% of 1st remission 29 2nd remission 27 these registered donors by December 1998. The matching Ͼ2nd remission, relapse, primary refractory 43 of donors and recipients was based on HLA-serotyping Myelodysplastic syndrome 33 according to the standard technique,37 and JMDP has Malignant lymphoma 6 approved 6/6 matched donors as suitable for the corre- Non-malignant 65 Aplastic anemia 48 sponding patients. Characteristics of the initial 500 donors Hereditary disorders 17 are shown in Table 1. Among 396 leukemia patients, Standard risk (AL: 1st CR; CML: 1st CP) 182 Patients High risk (other) 212 Unknown 2 From June 1992 to December 1998, 7207 patients were registered in the JMDP following the evaluation of unre- lated BMT indications according to the recipient criteria of JMDP by the Central Coordination Committee. The study procedures. The median length of follow-up was 3 years population is the initial 500 patients with malignant or non- and 7 months (range, 3 years and 2 months to 5 years and malignant disease who received marrow transplants at 103 5 months). The day of engraftment was defined as the first of 3 consecutive days on which the neutrophil count of 129 transplant centers approved by JMDP (appendix). 3 Patient characteristics are also summarized in Table 1. exceeded 500/mm . Thus, patients in whom engraftment Among the leukemia patients, those with acute leukemia in did not occur were designated graft rejection. Patients with initial engraftment in whom a severely hypocellular marrow first remission and those with chronic myelogenous leuke- 3 mia in primary chronic phase at the time of BMT were and/or an absolute neutrophil count of less than 500/mm designated as the standard-risk group and those in the other recurred were considered to have secondary graft failure. The diagnosis and the staging of acute and chronic GVHD situations were designated as the high-risk group. Patients 38,39 received a variety of preparative regimens, which are sum- were measured according to the standard criteria. The probability of disease-free survival, GVHD and relapse marized in Table 2. Methods of graft-versus-host disease 40 (GVHD) prophylaxis also varied, and are also listed in were calculated by Kaplan–Meier analysis. Table 2. Results Data collection and statistical analysis Identification of unrelated donors Among the 103 institutes where the 500 bone marrow trans- plants were performed, 15 (15%) undertook more than 10 By October 1995, 3509 registered patients were referred to procedures, 23 (22%) institutes performed five to nine pro- 68222 HLA-A, B, DR typed donor candidates. Then 8789 cedures, and the remaining 65 (63%) between one and four donor candidates (13% of the registered donor candidates) UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 997 Table 2 Preparative regimens and GVHD prophylaxis regimens received marrow with a one or two loci mismatch in the HVG direction, four received marrow with a one or two For 435 cases with malignancies loci mismatch in the GVH direction and 78 received mar- A With TBI 339 row with a one or two loci mismatch in both HVG and CY + CA 96 GVH directions.