Analysis of 500 Bone Marrow Transplants from Unrelated

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 unrelated 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 unrelated 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 transplants 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. The median interval between initiation of CY 70 a donor search and marrow transplantation was 330 days + CY VP-16 23 (range 130 to 1077). For patients with chronic myelogenous CY + BU 43 CY + Tespamin 4 leukemia, the median interval was 406 days (range 130 to CY + L-PAM 8 1077), and for patients with other diseases it was 302 days CY + L-PAM + Tespamin 20 (range 150 to 1042). B With TLI 14 CY + BU 13 L-PAM + BU 1 Engraftment C Without radiation 82 Twenty-six of the 500 patients who died within 2 weeks BU + CY 52 after transplantation were not evaluated for engraftment. BU + CA + VP-16 2 Stable engraftment was achieved in 449 of 474 evaluable BU + CA + CY 10 BU + CY + L-PAM 3 cases (95%). Twenty-five of 474 patients suffered rejection BU + CY + Tespamin 1 or secondary graft failure. The rates of engraftment accord- BU + CY + VP-16 2 ing to the disease category were as follows: 123 of 126 CY + VP-16 + L-PAM 1 patients with acute lymphocytic leukemia (ALL) (98%), 97 + BU L-PAM 1 of 99 patients with acute non-lymphocytic leukemia GVHD prophylaxis (ANLL) (98%), 162 of 171 chronic myelogenous leukemia (CML) (95%), 33 of 33 myelodysplastic syndrome (MDS) CyA + MTX 425 FK-506 + MTX 11 (100%), six of six malignant lymphoma (100%), 41 of 48 FK-506 15 patients with aplastic anemia (84%), and 13 of 17 patients CyA + MTX + PSL 24 with hereditary disease (77%). Others 25

For 48 aplastic anemias GVHD TBI + CY 28 In 490 of 500 evaluable cases who survived more than 7 TBI + CY + VP-16 1 TBI + CY + CA 1 days after transplantation, the probability of having grade TLI + CY 12 II, III or IV acute GVHD was 40.1%, and that of grade III TAI + CY 2 or IV 18.4% (Figure 1). The respective occurrence of grade TAI + CY + BU 1 II, III, IV and grade III, IV acute GVHD for each decade + LFI CY 2 of patient age was as follows: 0–9 years old (n = 66): CY 1 23.4%, 12.5%; 10–19 years old (n = 123): 42.3%, 23.2%; For 17 hereditary diseases 20–29 years old (n = 141): 38.1%, 14.8%; 30–39 years old = = TBI + CY + BU 1 (n 105): 46.7%, 21.7%; and 40–51 years old (n 55): TBI + CY 1 48.0%, 18.4%. The probability of having either limited or TBI + CY + CA 1 extensive chronic GVHD among 343 patients who survived TBI + CY + VP-16 1 more than 100 days after transplantation was 44% (Figure + BU CY 10 2), among which the probability of having limited-type dis- BU + CY + VP-16 2 CY 1 ease was 21.7% and the probability of extensive-type 28.6%. Among the 500 cases, 86 cases were supplemented with ATG and 11 cases were marrow-grafted after T cell depletion. 100 90 80 a and 2395 patients (68% of the registered patients) were 70 matched to their respective HLA-A, B, and DR partners. 60 Thus, one patient could have 3.6 HLA-A, B, and DR- 50 b matched donor candidates. Among the above-mentioned 40

8789 donor candidates and 2395 patients with matched Probability (%) 30 c partners, 2953 donor candidates and 1456 patients 20 underwent HLA-DRB1 DNA typing to identify the ﬁnal 10 0 donors; subsequently, 500 unrelated BMT were performed. 02040608090 All 500 patients received marrow from a donor serologi- Days after bone marrow transplantation cally matched for HLA-A, B, DR antigens. Among the Figure 1 Cumulative incidence of grade I–IV: (a) grade II–IV (b) and patients whose HLA-DRB1 DNA typing results were grade III, IV (c) acute GVHD in 490 evaluable patients undergoing bone referred to those of donor candidates, 397 received marrow marrow transplantation from HLA-A, B, and DR serologically compatible from a donor matched for two of two DRB1 loci. Four unrelated volunteer donors. UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 998 100 100 90 80 70 80 a 60 b 50 60 40 c

Probability (%) 30 20 40 10 Probability (%) 0 0 500 1000 20 d Days after bone marrow transplantation

Figure 2 Cumulative incidence of chronic GVHD in 343 patients who 0 survived more than 100 days after bone marrow transplantation from 0 12345 HLA-A, B, and DR serologically compatible unrelated volunteer donors. Years after bone marrow transplantation Figure 4 Probability of disease-free survival among patients with acute myelogenous leukemia transplanted in first remission (n = 29): (a) second Survival of patients with leukemia remission (n = 27) (b) third or subsequent remission (n = 9) (c) and at the time of relapse (n = 33) (d) of the disease. The probability of disease-free survival (DFS) among patients with acute lymphocytic leukemia transplanted in first complete remission (1st CR), 2nd CR, 3rd or subsequent CR and non-CR was 56%, 33%, 22% and 12%, respectively (Figure 3). The probability of DFS among 100 patients with acute myelogenous leukemia transplanted in 1st CR, 2nd CR, 3rd or subsequent CR and non-CR was 71%, 55%, 43% and 12%, respectively (Figure 4). DFS for 80 chronic myelogenous leukemia transplanted in first chronic phase (CP), second CP, accelerated phase and blastic phase 60 was 45%, 36%, 41% and 10%, respectively (Figure 5). DFS a of 182 patients with standard-risk leukemia was then ana- 40 c lyzed according to the severity of acute GVHD. DFS of b patients who had grade 0–II acute GVHD was 60–71%, Probability (%) whereas that of patients with grade III or IV acute GVHD 20 was 6–17% (Figure 6), reflecting a statistically significant d Ͻ difference (P 0.0001). 0 0 12345 Years after bone marrow transplantation Patients with myelodysplastic syndrome Figure 5 Probability of disease-free survival among patients with The probability of DFS among 33 patients with myelo- chronic myelogenous leukemia transplanted in first chronic phase (n = = dysplastic syndrome varied from 50% to 10%, according 114): (a) in second chronic phase (n 14) (b) the accelerated phase (n = 27) (c) and blastic phase (n = 15) (d) of the disease. to the disease category and this is shown in Figure 7.

100 100

80 80 b a a 60 60 c b 40 40

c Probability (%) Probability (%) 20 d 20 d e

0 0 0 12345 0 12345 Years after bone marrow transplantation Years after bone marrow transplantation

Figure 3 Probability of disease-free survival among patients with acute Figure 6 Probability of disease-free survival among 182 patients with lymphoblastic leukemia transplanted in ﬁrst remission (n = 39): (a) second standard-risk leukemia without acute GVHD (n = 48) (a) with grade I (n remission (n = 32) (b) third or subsequent remission (n = 15) (c) and at = 57) (b) grade II (n = 49) (c) grade III (n = 13) (d) or grade IV (n = the time of relapse (n = 39) (d) of the disease. 17) (e) acute GVHD. UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 999 100 100

80 80

60 a 60 b 40 40 Probability (%) d 20 Probability (%) c 20 0 0 12345 0 Years after bone marrow transplantation 0 12345 Years after bone marrow transplantation Figure 7 Probability of disease-free survival among patients with myelodysplastic syndrome; patients with chronic myelomonocytic leukemia (n Figure 9 Probability of survival among 17 patients with hereditary = 4) (a) with refractory anemia (n = 9) (b) refractory anemia with excess disorders. blast (RAEB), (n = 7) (c) and with RAEB in transformation (n = 13) (d).

Table 3 Primary and secondary causes of death after transplantation Patients with aplastic anemia in 278 patients

Among 48 patients with aplastic anemia, the probability of Causes of death in 49 patients who died within overall survival was 56%. Survival of patients under 15 1 month after transplantation (%) years of age was 81% and that of patients aged 16 or over Sepsis 13 (18) was 32% (Figure 8). Hemorrhage 11 (15) Renal failure 8 (11) VOD 7 (10) Patients with hereditary disorders Hepatic failure 4 (6) Graft failure 6 (8) Probability of survival among 17 patients with hereditary GVHD 3 (4) disorders was 66%. These cases included a single case of IP 2 (3) adrenoleukodystrophy, Chediak–Higashi syndrome, Hur- Rejection 1 (1) ler’s disease, I-cell disease, metachromatic leukodystrophy, Relapse 2 (3) Other 14 (20) and pure red cell aplasia; two cases each of severe combined immunodeﬁciency syndrome and Wiskott–Aldrich Total 71 syndrome, three cases of metachromatic leukodystrophy, Causes of death in 229 patients who died at and four cases of familial hemophagocytic lympho- more than 1 month after transplantation (%) histiocytosis (Figure 9). GVHD 63 (19) Relapse 59 (18) Complications and causes of death IP 46 (14) Hemorrhage 23 (7) Among the 500 study patients, 278 of 497 reported cases Sepsis 25 (8) Renal failure 20 (6) (56.0%) died, and the primary and secondary causes of their Hepatic failure 17 (5) death are listed in Table 3. Forty-nine (17.6%) died within VOD 10 (3) Graft failure 7 (2) Rejection 5 (2) 100 Other 51 (16) a Total 326 80 % = percentage of total causes of death.

60 1 month after transplantation because of sepsis (18%), hemorrhage (15%), renal failure (11%) or other reasons. b 40 Two hundred and twenty-nine patients (82.3%) died more

Probability (%) than 1 month after transplantation because of GVHD 20 (19%), relapse of leukemia (18%), interstitial pneumonitis (14%) or other reasons.

0 0 12345 Years after bone marrow transplantation Performance status of surviving patients

Figure 8 Probability of survival among patients with aplastic anemia The latest performance status (Karnofsky score) was evalu- under 15 years of age (n = 21) (a) or over (n = 27) (b). ated. One-hundred and forty-two of 213 surviving cases UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 1000 (86%) had a performance score of 90 or 100, 12 (6%) had GVHD was higher in these study patients than in recipients a score of 80, 25 (8%) had a score between 20 and 70 of marrow from HLA-matched siblings; the probability of (Table 4). having grade II, III or IV acute GVHD was 40.1% and grade III or IV was 18.4%. These are significantly higher than the probabilities observed in HLA-matched sibling Discussion transplants among Japanese (grade II, III, IV GVHD: 15%; III, IV GVHD: 5%41), although they are still lower than in The JMDP’s experience since its establishment has indi- the previous report by Kernan et al30 (grade II, III, IV: cated that some people are, indeed, willing to donate their 64%; grade III, IV: 47%) and the reports by others17,18 in bone marrow in Japan, and that there is good cooperation which most of the recipients and donors were Caucasians. in this regard between medical and non-medical fields, and Chronic GVHD was observed in 136 of 343 evaluable cases good work is being done at many medical institutions.32,33,36 (44%) who survived more than 100 days. It was not sig- The results of allogeneic bone marrow transplantation nificantly higher than among Japanese patients who from HLA genotypically identical siblings, which started received the marrow from HLA identical siblings3 or that in 1974 in Japan, revealed that approximately 65% of reported by the NMDP.30 patients with leukemia at standard risk and 40% of patients Among 225 patients with acute leukemia, the probability at high risk could have prolonged leukemia-free sur- of disease-free survival was 56–71% for standard-risk vival.3,41 It was also revealed that the survival rate among patients and 12–55% for high-risk patients, virtually the patients with aplastic anemia is approximately 80%,6 same results as obtained from HLA-matched sibling BMT around 50% among patients with myelodysplastic syn- among Japanese.3,41 In acute leukemia, these equivalent drome3 and about 40%42 among patients with hereditary results as to the probability of disease-free survival of UR- disorders, when patients received HLA genotypically ident- BMT with respect to related BMT, despite the frequent ical grafts. These results, which are equivalent or slightly occurrence of severe acute GVHD, might come from the superior to those of previous reports,1,2,4,7,43 might be due low frequency of leukemia relapse after the UR-BMT over to the genetic homogeneity of Japanese people.41 On the that after related BMT (unpublished observation). Further other hand, some experiences of marrow transplantation study is required to confirm the low frequency of leukemia with related donors other than HLA genotypically identical relapse with UR-BMT. Nevertheless, this important issue siblings among Japanese9 resulted in a relatively low sur- may shed light on the mechanism of the so-called ‘GVL vival rate except in cases receiving a marrow graft from effect’. a HLA-phenotypically identical family member. For this On the other hand, among 179 patients with CML, the reason, the JMDP has provided only a donor whose HLA- probability of DFS was 45% for patients at standard risk, A, B, and DR antigens were serologically 6/6 matched to which was basically equivalent to that of patients at high the corresponding patient until the technologies assuring the risk transplanted from HLA-identical siblings among success of UR-BMT are established. Although the JMDP Japanese. This non-optimistic result seen in CML, did not restrict the diversity of the results of HLA-class II especially in the standard risk group, might be partially DNA typing for the final selection of donors, many trans- explained by the fact that most patients had to wait for an plant centers did not use donor candidates whose DRB1 unrelated marrow graft for more than 2 years from initial DNA typing was mismatched to the patients. The prob- diagnosis and also by the fact that they suffered from rela- ability of graft failure, which was evaluated by calculating tively severe acute GVHD more frequently than the average the probability of both initial myeloid engraftment and sec- (data not shown). ondary marrow failure, was 5%. This was higher than the When the probability of disease-free survival for those rate observed with HLA-matched sibling transplants3,6,41 patients with standard-risk leukemia (n = 182) was ana- and equivalent to the previous report of UR-BMT,30 and lyzed according to the severity of acute GVHD (with or this is associated with the background disease (higher rate without grade III or IV acute GVHD), the patient group with aplastic anemia and hereditary disease than with hem- without severe acute GVHD showed a 60–71% probability atological malignancies). The probability of having acute of DFS. This was equivalent to that of related BMT,41 sug- gesting that UR-BMT could be as effective as related BMT if severe acute GVHD is prevented. Grade III or IV acute Table 4 Performance status of 500 patients GVHD was particularly life-threatening among the patients in this study, whereas the survival rate of patients with less 100% 142 than grade II GVHD was equivalent to that of the patients 90% 46 who received an HLA-matched sibling transplant. There- 80% 12 70% 10 fore, development of methods to predict severity of acute 60% 2 GVHD and to control it is of primary importance for UR- 50% 4 BMT even among Japanese. 40% 0 Among 36 patients with aplastic anemia, the probability 30% 1 of overall survival was 56%, 81% for those under age 15 20% 1 Ͼ 10% 0 years of age and 32% for those 16 years of age. This is 0% 278 not surprising when one considers that most patients Unknown 4 already had a long history of transfusion by the time of transplantation. These results, which are superior to those UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 1001 of the previous report,30 might be due to the low rejection 7 Parkman R. The application of bone marrow transplantation rate among our cases. to the treatment of genetic disease. Science 1986; 232: Survival among 17 patients with hereditary disorders was 1373–1378. 66%, and among myelodysplastic syndrome 36%, also sug- 8 Hansen JA, Beatty PG, Anasetti C et al. Treatment of leuke- gesting that UR-BMT is an effective treatment for these mia by marrow transplantation from donors other than HLA genotypically identical siblings. In: Gale RP, Champlin RE disease categories. The causes of death among 278 patients (eds). Progress in Bone Marrow Transplantation. Alan R Liss: were analyzed, and an increased risk of death was indepen- New York, 1987, pp 667–676. dently associated with advanced disease at the time of BMT 9 Horibe K, Yoshida J, Oiwa K et al. Bone marrow transplan- and higher than grade III acute GVHD. Since the JMDP tation from related donors other than HLA identical siblings primarily accepted patients with a standard disease risk for in Japanese patients with hematological malignancies. Acta initiation of the donor search, advance of the disease is Haematol Jpn 1990; 53: 94–102. considered to be due to the length of wait for an appropriate 10 Horowitz SD, Groshong T, Bach FH, Hong R. Treatment of donor. This situation is now being remedied by the expan- severe combined immune deficiency with bone marrow from sion of the donor pool and a faster coordination system. an unrelated, mixed leukocyte culture nonreactive donor. Despite the increased risk of graft failure and severe Lancet 1975; 2: 431–433. 11 O’Reilly RJ, Dupont B, Pahwa S et al. Reconstitution in sev- acute GVHD, this study demonstrates that in a large patient ere combined immune deficiency by transplantation of marrow population transplantation of marrow from unrelated donors from an unrelated donor. New Engl J Med 1977; 297: can be an effective treatment for certain hematologic malig- 1311–1318. nancies, as well as marrow failure syndrome and certain 12 The Westminster Hospital Bone Marrow Transplant Team. hereditary disorders. Prophylactic and therapeutic maneu- Bone marrow transplant from an unrelated donor for chronic vers for GVHD, as well as more optimal approaches to granulomatous disease. Lancet 1977; 1: 210–213. the selection of unrelated donor44 are developing rapidly. 13 Speck B, Zwaan FE, van Rood JJ, Eernisse JG. Allogeneic Therefore, it is reasonable to expect further improvement in bone marrow transplantation in a patient with aplastic anemia the results of UR-BMT in the near future. 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Appendix raki Children’s Hospital; Jichi Medical School Hospital; Dokkyo University School of Medicine; Fukaya Red Cross Institutes participating in the 500 transplantations and har- Hospital; Saiseikai Maebashi Hospital; Gunma University, vest facilitated by the Japan Marrow Donor Program School of Medicine; Niigata University Medical Hospital; Niigata Cancer Center Hospital; Shinshu University School Hokkaido University School of Medicine; University Hos- of Medicine; Saku Central Hospital; Hamamatsu University pital, School of Medicine, Sapporo Medical University; School of Medicine; Hamamatsu Medical Center; Shizuoka Sapporo Hokuyu Hospital; Japanese Red Cross Asahikawa General Hospital; Shizuoka Children’s Hospital; Japanese Hospital; Hirosaki University School of Medicine; Tohoku Red Cross Nagoya First Hospital; Nagoya Daini Red Cross University School of Medicine; Yamagata University Hos- Hospital; Meitetsu Hospital; Nagoya University Hospital; pital; Akita University School of Medicine; Fukushima Nagoya Ekisaikai Hospital; Nagoya National Hospital; Medical College, National Cancer Center Hospital; The Aichi Medical School Hospital; Nagoya City University Institute of Medical Science, the University of Tokyo; Toho Hospital; Anjo Kousei Hospital; Fujita Health University University School of Medicine, Omori Hospital; Tokyo Hospital; Mie University Hospital; Kanazawa University Metropolitan Komagome Hospital, Nihon University School of Medicine; Kanazawa Medical University; Toy- School of Medicine, Itabashi Hospital; The Jikei University ama Prefectural Central Hospital; Fukui Medical School School of Medicine; School of Medicine, Keio University; Hospital; Shiga University of Medical Science; Center for Tokyo Medical College Hospital; Tokyo Medical and Den- Adult Disease, Osaka; Kinki University School of Medi- tal University Hospital, Faculty of Medicine; Yokohama cine; Osaka University School of Medicine; Osaka Medical City University Hospital; Kanagawa Children’s Medical Center and Research Institute for Maternal and Child Center; Kanagawa Cancer Center; Tokai University Hospi- Health; Matsushita Memorial Hospital; Hyogo College of tal; St Marianna University Hospital; Chiba University Medicine; Hyogo Medical Center for Adults; Kobe City School of Medicine; Chiba Cancer Center Hospital; Chiba General Hospital; Kobe University School of Medicine; Children’s Hospital; Matsudo Municipal Hospital, Kameda Kyoto University Hospital; Kyoto Prefectural University of General Hospital; Saitama Children’s Medical Center; Sait- Medicine; Social Insurance Kyoto Hospital; Tottori Pre- ama Cancer Center Hospital; Saitama Medical School; Iba- fectural Central Hospital; Tottori University Hospital; Hiro- UR-BMT facilitated by the Japan Marrow Donor Program Y Kodera et al 1003 shima Red Cross Hospital and Atomic-bomb Survivors Mary’s Hospital; Kokura Memorial Hospital; Saga Pre- Hospital; Yamaguchi University School of Medicine; fectural Hospital; Atomic Bomb Institute, Nagasaki Univer- Ehime Prefectural Central Hospital; Okayama National sity School of Medicine; Miyazaki Prefectural Hospital; Hospital; Kurashiki Central Hospital; Kyushu University Kumamoto National Hospital; Kumamoto University Hos- Hospital; Harasanshin General Hospital; Hamanomachi pital; Oita Medical University Hospital; Kagoshima Uni- General Hospital; National Kyushu Cancer Center; St. versity Hospital.