Background The requirements with respect to HLA compatibilityand the relative importance of matching for individual classI and class II HLA alleles in the transplantation of hematopoieticstem cells from unrelated donors have not yet been established.
Methods We performed retrospective DNA typing of alleles at11 polymorphic loci of HLA genes in 440 recipients of hematopoieticstem cells from unrelated donors who were serologically identicalwith their respective recipients for HLA-A, B, and DR antigens.Of these recipients, 80 percent had leukemia; the rest had lymphoma,marrow failure, or a congenital disorder.
Results Multivariate analysis showed that incompatibility forHLA-A alleles and incompatibility for HLA-C alleles were independentrisk factors for severe acute graft-versus-host disease (GVHD)(HLA-A, P=0.006; HLA-C, P=0.001). Mismatching of HLA-A, butnot of HLA-C, alleles was an independent risk factor for death(P<0.001). Mismatching of HLA-C alleles was a significantrisk factor for relapse of leukemia (P=0.035). HLA-B disparitywas a significant risk factor for both GVHD and death in theunivariate analysis, but not in the multivariate analysis. Disparitiesin class II HLA alleles of the DRB1, DQA1, DQB1, DPA1, and DPB1loci were not identified as significant risk factors for acuteGVHD or death in the multivariate analysis.
Conclusions Genomic typing of class I HLA alleles adds substantiallyto the success of transplantation of hematopoietic stem cellsfrom unrelated donors, even if the donors are serologicallyidentical to their recipients with respect to HLA-A, B, andDR antigens.
Patients with malignant hematologic diseases, various formsof marrow failure, and certain congenital disorders can be successfullytreated with transplantation of hematopoietic stem cells fromHLA-identical siblings.1,2,3,4,5,6,7 However, only 30 percentof patients for whom such treatment is the first choice havean HLA-matched donor within their immediate families. In studiesin the United States of transplantation of marrow from unrelateddonors, a single mismatch for HLA-A or B (class I HLA antigens)or HLA-DR (a class II HLA antigen), determined by serologictyping, increased the risk of acute graft-versus-host disease(GVHD) and decreased overall survival.8,9,10 Thus, in Japan,Europe,11 and the United States,12,13 transplantation of cellsfrom unrelated donors is usually performed with donor–recipientpairs that are serologically identical for HLA-A, B, and DRantigens.
The multigene HLA family has at least 12 polymorphic loci: HLA-A,B, C, DRA1, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1.There is strong linkage disequilibrium among the alleles ofHLA loci. DNA-amplification methods for typing class I and IIHLA alleles have substantiated the extensive polymorphism ofthe HLA system,14 initially documented in serologic studies,and have defined alleles that cannot be identified serologically.15,16,17,18,19,20,21,22,23,24Using these molecular techniques, several groups found thatmatching of DRB1 and DQB1 alleles, but not DPB1 alleles, decreasedthe risk of acute GVHD and improved survival after the transplantationof hematopoietic stem cells from unrelated donors who were serologicallymatched with the recipients for HLA-A, B, and DR antigens.25,26,27,28,29The influence of class I HLA alleles was not evaluated in theseinvestigations.
In the present study of stem-cell transplantation in Japan,we performed retrospective DNA typing at 11 polymorphic HLAloci, including class I HLA alleles, in 440 cases of transplantationfrom unrelated donors who were serologically identical to therecipients with respect to HLA-A, B, and DR antigens. The resultsshowed that genomic matching of class I HLA alleles is an importantfactor in the clinical outcome of hematopoietic stem-cell transplantation.
Methods
HLA Typing
Serologic Assays
Serologic typing for HLA-A, B, and DR was performed with useof the standard two-stage complement-dependent test of microtoxicity.30
DNA Amplification
Alleles at the HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1,DPA1, and DPB1 loci were identified with the use of the polymerasechain reaction (PCR) with sequence-specific oligonucleotideprobes,15,16,17,18,19,20 PCR restriction-fragment–lengthpolymorphisms,21,22 PCR single-strand conformation polymorphisms,19,23or PCR sequence-specific primers.24 To verify the reliabilityof the DNA-based results, we performed HLA genotyping of eachsample in two to four laboratories, and resolved by consensusany discrepancies. These HLA-typing results were included inthe statistical analyses.
Patients
A total of 440 donor–recipient pairs who were matchedserologically for HLA-A, B, and DR antigens participated inthis study. Four patients who survived fewer than 10 days aftertransplantation were excluded from the analysis of acute GVHD.The characteristics of the 440 donor–recipient pairs aresummarized in Table 1.
Table 1. Base-Line Characteristics of the Donors and Recipients.
HLA Typing of Patients and Donors
The patients were divided into four groups on the basis of thecompleteness of HLA genotyping (Table 1). Alleles at 11 polymorphicloci, HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1,and DPB1, were investigated for 363 donor–recipient pairs.HLA-C typing of 84 of the 363 pairs by means of PCR amplificationof DNA with the sequence-specific primer could not be achieved.Accordingly, the first 363 pairs were divided into group 1 (279pairs with HLA-C typing) and group 2 (84 pairs without HLA-Ctyping). From the analysis of this first set (groups 1 and 2),it was apparent that matching for alleles at HLA-DRB3, DRB4,DRB5, DQA1, DPA1, and DPB1 did not affect the risk of GVHD orsurvival; therefore, alleles at HLA-A, B, C, DRB1, and DQB1were examined in the remaining 77 donor–recipient pairs.Information on HLA-C was obtained for 63 pairs but not for theother 14 pairs; thus, group 3 consisted of 63 pairs with HLA-Ctyping and group 4 of 14 pairs without HLA-C typing.
There were no significant differences among these groups inthe base-line characteristics of the donor–recipient pairs(Table 1). Therefore, all the pairs were included in the univariateanalysis of the effect of allele matching at the HLA-A, B, DRB1,and DQB1 loci. Groups 1 and 2 were included in the univariateanalysis of the effect of allele matching at the HLA-DRB3, DRB4,DRB5, DQA1, DPA1, and DPB1 loci, and groups 1 and 3 were includedin the univariate analysis of the effect of allele matchingat the HLA-C locus and in the multivariate analysis.
Definition of HLA Mismatching
For each donor–recipient pair we determined whether themismatch was one in which the recipient's alleles were not sharedby the donor (defined as the GVHD vector) or the donor's alleleswere not shared by the recipient (defined as the rejection vector).In the analysis of factors contributing to acute GVHD, the GVHD-vectormismatch was used. In the analyses of factors contributing torelapse or death, the mismatch was defined as that of eitherthe GVHD vector or the rejection vector.
Evaluation of GVHD
Occurrences of acute GVHD were graded according to establishedcriteria.31,32 The grades were 0, I, II, III and IV, accordingto the severity of GVHD in the skin, liver, and gastrointestinaltract.
Statistical Analysis
The estimated probability of the development of grade III orIV acute GVHD, the survival rate, and the relapse rate werecalculated by the Kaplan–Meier method.33 The Mantel–Coxtest was used to test the equality of cumulative curves forthe incidence of grade III or IV GVHD, survival curves, andrelapse curves.34 The Cox proportional-hazards model35 was usedfor multivariate adjustment of various covariates and for quantifyingthe relations among acute GVHD, death, relapse, and a groupof explanatory variables (sex [donor–recipient pair],age of the recipient, age of the donor, diagnosis, leukemiarisk group, and treatment) (Table 1). Selection of the factorswith an important effect on the rates of acute GVHD, relapse,and survival was based on a forward stepwise procedure.36 Pvalues of 0.05 or less were considered to indicate statisticalsignificance. All statistical analyses were performed with BMDPstatistical software (programs 1L, 2L, and 4F).36
Results
Compatibility of HLA Alleles
Among the 440 donor–recipient pairs that were serologicallymatched for HLA-A, B, and DR antigens, matching with respectto HLA-A, B, DRB1, and DQB1 alleles was found by DNA typingin 73 percent, 84 percent, 82 percent, and 80 percent of thepairs, respectively (Table 2). Of these 440 serologically matchedpairs, 241 (55 percent) had identical HLA-A, B, and DRB1 alleles.We did not assess matching of HLA-C, DQ, and DP by serologicmethods, but we noted in DNA typing that more than 69 percentof the pairs were compatible for alleles at the HLA-C, DQA1,and DQB1 loci. In contrast, fewer than 50 percent of the pairswere compatible with respect to DPA1 and DPB1 alleles.
Table 2. Extent of Matching of HLA Alleles among Donor–Recipient Pairs.
Acute GVHD
The incidence of acute GVHD of grade III or IV in our studywas 18 percent (80 of 436 donor–recipient pairs). In theunivariate analysis, no statistically significant associationswere observed between the development of grade III or IV acuteGVHD and sex (P=0.89), the age of the recipient at the timeof transplantation (P=0.84), or the severity of disease (P=0.28).
The occurrence of grade III or IV acute GVHD was significantlyassociated with disparity in HLA-A, B and C alleles. For HLA-Aalleles, the estimated cumulative rate of grade III or IV acuteGVHD was 15 percent of the recipients in matched pairs, as comparedwith 31 percent of mismatched pairs (P<0.001) (Figure 1A).The corresponding rates for HLA-B were 17 percent and 31 percent(P=0.006), and for HLA-C, 13 percent and 32 percent (P<0.001)(Figure 1B and Figure 1C). In contrast, matching of DRB1, DQA1,and DQB1 alleles had no significant effect on the occurrenceof severe acute GVHD. For DRB1 alleles the rates were 17 percentfor matched pairs and 27 percent for mismatched pairs (P=0.058);the rates for DQA1 were 17 percent and 28 percent (P=0.14);and for DQB1 they were 18 percent and 22 percent (P=0.46). Theprobability that grade III or IV acute GVHD would develop inthe recipients in DPA1- and DPB1-matched pairs (19 percent and18 percent, respectively) and mismatched pairs (18 percent and19 percent, respectively) were almost the same. The probabilityof grade III or IV acute GVHD among the 160 patients who receivedhematopoietic stem cells from unrelated donors with whom theywere fully matched for HLA-A, B, C, and DRB1 at the alleliclevel was 11 percent, whereas in a previous study of 120 patientsreceiving transplants from genotypically identical siblings(matched for HLA-A, B, and DR) it was 6 percent.37
Figure 1. Kaplan–Meier Curves for the Cumulative Probability of Grade III or IV Acute GVHD.
The incidence of GVHD in patients who received transplants matched for the HLA-A, B, or C allele was compared with that in patients who received HLA-A–, B–, or C–mismatched transplants. Results from 436 patients who survived more than 10 days were analyzed. Of these 436 patients, HLA-C alleles were typed for 338. Numbers of patients with GVHD and total numbers for the subgroups are shown in parentheses. Tick marks indicate the patients who died without grade III or IV acute GVHD.
Multivariate analysis revealed that mismatches of the HLA-Aallele and the HLA-C allele were significant risk factors forthe development of grade III or IV acute GVHD (Table 3). Multivariateestimates of the odds ratios for grade III or IV acute GVHDin pairs matched for the HLA-A alleles or HLA-C alleles were0.48 (P=0.006) and 0.42 (P=0.001), respectively, as comparedwith those with mismatches (Table 3). Matching of the HLA-Ballele was not a significant factor in the development of acuteGVHD (P=0.22). When the HLA-A,C–matched donor–recipientpairs were evaluated for the occurrence of grade III or IV acuteGVHD, the probability of its occurrence in 8 pairs mismatchedat HLA-B (25 percent) was higher than that in 178 pairs matchedat HLA-B (11 percent), although the difference was not statisticallysignificant (P=0.18).
Table 3. Factors Affecting the Incidence of Grade III or IV Acute GVHD, Mortality, and Relapse in Recipients of Transplants from Unrelated Donors Who Were Serologically Matched for HLA-A, B, and DR.
The probability that the recipient in a pair mismatched at theHLA-A, B, or C locus would have grade III or IV acute GVHD was20 percent when there was one mismatch and 43 percent when therewere two or more mismatches, as compared with 11 percent whenthere were no mismatches (P<0.001).
Survival
As shown in Figure 2A, matching of the HLA-A allele was associatedwith increased survival (survival rate at one year, 63 percentamong matched and 38 percent among mismatched recipients; P<0.001).There was a weak association between HLA-B matching and an increasedrate of survival (survival rate at one year, 58 percent amongmatched and 44 percent among mismatched pairs; P=0.039) (Figure 2B).Even in HLA-A–matched pairs, HLA-B matching was associatedwith an increased rate of survival among recipients (survivalrate at one year, 65 percent among matched and 49 percent amongmismatched pairs; P=0.045) (Figure 2D). Surprisingly, HLA-Cmatching was not associated with increased survival (survivalrate at one year, 57 percent among matched and 53 percent amongmismatched pairs; P=0.69), even though mismatching at HLA-Cwas found to be an important risk factor for acute GVHD (Figure 2C).Survival rates at one year among recipients matched forthe HLA-DRB1, DQA1, and DQB1 alleles were 59 percent, 58 percent,and 59 percent, respectively, as compared with 45 percent, 41percent, and 42 percent among mismatched recipients (P=0.023,P=0.077, and P=0.016, respectively).
Figure 2. Kaplan–Meier Curves for the Probability of Survival.
The survival of patients who received transplants matched for the HLA-A, B, or C allele was compared with that of patients who received HLA-A–, B–, or C–mismatched transplants (Panels A, B, and C). Survival was also compared between HLA-A–matched patients who received HLA-B–matched transplants and HLA-A–matched patients who received HLA-B–mismatched transplants (Panel D) and between HLA-A,B–matched patients who received HLA-DRB1– or DQB1–matched transplants and HLA-A,B–matched patients who received HLA-DRB1– or DQB1–mismatched transplants (Panels E and F). Numbers of patients who died and total numbers for the subgroups are shown in parentheses. Tick marks indicate the patients who were alive at the time of last contact.
To test whether the effects of class II HLA matching on survivalare due to linkage disequilibrium within the HLA system, weanalyzed the effect of matching for class II HLA alleles onthe survival rate in the 276 patients matched with their donorsfor both the HLA-A and the HLA-B allele. In this group, matchingor mismatching of the HLA-DRB1, DQA1, or DQB1 alleles had noinfluence on survival (P=0.44, P=0.35, and P=0.080, respectively)(Figure 2E and Figure 2F). The survival curves for patientsmatched for HLA-DPA1 and DPB1 alleles among 203 patients whowere also matched for HLA-A, B, DRB1, DRB3, DRB4, and DRB5 allelesdid not differ significantly (survival rates at one year, 55percent and 57 percent, respectively) from the survival curvesof DPA1- and DPB1-mismatched patients (survival rates at oneyear, 57 percent and 55 percent, respectively). The survivalrate at one year among the 157 patients who received hematopoieticstem cells from unrelated donors fully matched at HLA-A, B,C, and DRB1 alleles was 65 percent.
Survival was also related to the recipient's age (survival ratesat one year, 62 percent for recipients younger than 18 years,58 percent for recipients 18 to 35 years old, and 41 percentfor those older than 35 years; P=0.003) and to the leukemiarisk group (survival at one year, 65 percent for those at standardrisk and 46 percent for those at high risk; P<0.001), butit was not associated with sex (P=0.85).
Multivariate analysis identified four factors — namely,HLA-A matching, the recipient's age, the leukemia risk group,and diagnosis — as important independent factors affectingmortality among patients receiving hematopoietic stem cellsfrom unrelated donors. Multivariate estimates of the odds ratiosfor death in recipients with an HLA-A–allele match, anage greater than 40 years, a high risk of leukemia, and a diagnosisof acute myeloid leukemia were 0.45 (P<0.001), 2.33 (P<0.001),1.69 (P<0.001), and 0.63 (P=0.042), respectively, as comparedwith recipients without these factors (Table 3).
Relapse of Leukemia
By univariate analysis, the rate of relapse of leukemia in theHLA-C–matched group was higher than that in the HLA-C–mismatchedgroup, although this difference did not reach statistical significance(relapse rate at one year, 23 percent for the matched groupand 12 percent for the mismatched group; P=0.060) (Figure 3).Matches for HLA-A, B (Figure 3), DRB1, DQA1, DQB1, DPA1, orDPB1 (data not shown) had no influence on the rate of leukemicrelapse. Multivariate estimates of the odds ratios for relapseassociated with a high risk of leukemia and an HLA-C match were3.23 (P<0.001) and 2.22 (P=0.035), respectively (Table 3),suggesting that HLA-C matching is a risk factor for leukemicrelapse. The relapse rate at one year for the 141 patients whoreceived hematopoietic stem cells from an unrelated donor whowas fully matched at the allelic level for HLA-A, B, C, andDRB1 was 20 percent.
Figure 3. Kaplan–Meier Curves for the Probability of Relapse of Leukemia.
The rate of relapse of leukemia in patients matched for the HLA-A, B, or C allele was compared with that in patients mismatched for HLA-A, B, or C. Among 384 patients with malignant hematologic diseases, relapse data were available for 367. Of these 367 patients, HLA-C alleles were typed for 289. Numbers of patients who had relapses and total numbers for the subgroups are shown in parentheses. Tick marks indicate the patients who were alive at the time of last contact or who died without relapse.
Discussion
Our results show that mismatches with respect to HLA-A and HLA-Calleles between the donor and recipient of hematopoietic stemcells are strong risk factors for the development of grade IIIor IV acute GVHD in the recipient. By contrast, incompatibilitiesfor class II HLA alleles did not have a critical effect on therisk of acute GVHD. Previous investigations demonstrated thatmatching of the HLA-DRB1 and DQB1 alleles affects the developmentof acute GVHD,27,28 but the effects of matching of the HLA-A,B, and C alleles were not examined in those studies. Therefore,it is possible that the finding of an association between anincreased risk of GVHD and mismatches of alleles at the DRB1and DQB1 loci actually reflected class I HLA disparities, becauseof the strong linkage disequilibrium between class I and classII HLA alleles. Alternatively, it is possible that the rolesof the individual HLA loci in hematopoietic stem-cell transplantationdiffer according to ethnic background. Mismatching at the HLA-Alocus was observed most frequently for A2 among our Japanesedonor–recipient pairs (96 of 190 Japanese patients [51percent]) whereas in most whites the HLA-A2 allele is A*0201.38Thus, mismatching for HLA-A2 alleles may be less frequent inwhite than in Japanese populations.
Previous studies demonstrated that the occurrence of GVHD correlateswith a decreased risk of relapse of leukemia after hematopoieticstem-cell transplantation, probably because of T cells or naturalkiller cells in the graft that are cytotoxic to leukemic cells(a graft-versus-leukemia mechanism).39,40,41 The associationwe observed between matching of the HLA-C allele and an increasedrisk of leukemic relapse suggests that the use of stem cellsthat are mismatched at the HLA-C locus can avert relapse, possiblyby inducing a graft-versus-leukemia reaction. Studies of killer-cellinhibitory receptors on natural killer cells and some CD8+ cytotoxicT lymphocytes have shown that specific recognition of HLA-Cmolecules on target cells by these inhibitory receptors inhibitsthe lytic activity of the natural killer cells and cytotoxicT cells.42,43,44 Therefore, in principle, a mismatch at HLA-Cwould allow engrafted natural killer cells and cytotoxic T cellsto lyse the recipient's leukemic cells without the usual inhibition.
The overall rate of survival was significantly affected by HLA-Amismatching, which agrees with our finding that HLA-A mismatchingis a strong risk factor for acute GVHD. By contrast, the overallsurvival rate was not affected by HLA-C incompatibility, eventhough HLA-C disparity is a strong risk factor for grades IIIand IV acute GVHD. This discrepancy may be due to the protectionfrom leukemic relapse that is apparently provided by an HLA-Cmismatch.
In a univariate analysis, there was a significant differencein the frequency of acute GVHD between HLA-B–matched andHLA-B–mismatched pairs (P=0.006) and a lower rate of survivalamong HLA-B–mismatched patients, even in the HLA-A–matchedgroup (P=0.045). However, in a multivariate analysis we didnot find that mismatching for HLA-B alleles was a significantrisk factor for acute GVHD and death from any cause. This differencemay reflect the relatively small number of allele mismatchesat the HLA-B locus, as compared with those at the HLA-A andC loci. For this reason, we believe that HLA-B disparity shouldnot be disregarded as a factor affecting both the risk of GVHDand overall survival.
As for the HLA-DRB1 and DQB1 loci, we found a slightly lowerrate of survival in the mismatched group than in the matchedgroup when results in HLA-A–matched and HLA-B–matchedpatients were evaluated, but the difference did not reach statisticalsignificance. Further investigation is needed to determine theeffect of the matching of HLA-DRB1 and DQB1 alleles on survival.
It is very difficult to match HLA-DP alleles together with HLA-Aand B alleles because of the lack of strong linkage disequilibriumbetween these alleles. Therefore, it is fortunate that disparityof HLA-DP had no important effects on the clinical outcome ofrecipients of hematopoietic stem cells from unrelated donors.
In conclusion, our new, clinically relevant observations arethat HLA-A and C disparities at the allelic level are importantrisk factors for severe acute GVHD; that HLA-A disparity isan important risk factor for death from all causes; that HLA-Cmatching at the allelic level is a risk factor for relapse ofleukemia; and that HLA-B matching at the allelic level is alsoprobably a risk factor both for severe acute GVHD and for deathfrom all causes.
Supported by research funds for bone marrow transplantationfrom the Ministry of Health and Welfare of Japan.
* Other participants in the Japan Marrow Donor Program are listedin the Appendix.
Source Information
From the Department of Genetics, Medical Institute of Bioregulation (T.S., N. Kamikawaji), and the Department of Medical Informatics, Faculty of Medicine (N. Kinukawa), Kyushu University, Fukuoka; the Japanese Red Cross Central Blood Center, Tokyo (T.J., T.A.); the Department of Hematology and Chemotherapy, Aichi Cancer Center Hospital, Nagoya (Y.M.); the Department of Surgery, Sakura National Hospital, Chiba (H.K.); the Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Kanagawa (H.I.); the Department of Microbiology and Immunology, Showa University School of Medicine, Tokyo (T.Y.); the Department of Tissue Physiology, Division of Adult Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo (A.K.); the Department of Internal Medicine, Japanese Red Cross Nagoya First Hospital, Nagoya (Y.K.); and Jichi Medical School, Tochigi (F.T.) — all in Japan. Other authors were Yoshiaki Nose, M.D., Ph.D. (Department of Medical Informatics, Faculty of Medicine, Kyushu University), Takashi Ono, M.D. (Department of Genetics, Medical Institute of Bioregulation, Kyushu University), Takeo Sakamaki, M.D., Ph.D. (Division of Clinical Research, Sakura National Hospital), Shunichi Kato, M.D., Ph.D. (Department of Pediatrics, Tokai University School of Medicine), Yuichi Akiyama, M.D. (Department of Pediatrics, Kyoto University School of Medicine, Kyoto), Shinichiro Okamoto, M.D., Ph.D. (Department of Medicine, Keio University School of Medicine, Tokyo), Hiroo Dohy, M.D., Ph.D. (Department of Medicine, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima), Mine Harada, M.D., Ph.D. (Second Department of Internal Medicine, Okayama University School of Medicine, Okayama), and Shigetaka Asano, M.D., Ph.D. (Institute of Medical Science, Tokyo University, Tokyo).
Address reprint requests to Dr. Sasazuki at the Department of Genetics, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
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Appendix
The following centers and investigators, all in Japan, participatedin the study: Kyushu University — S. Yasunaga, S. Yoshitake,T. Koyanagi; Tokyo Medical and Dental University — Y.Date; Japanese Red Cross Central Blood Center — Y. Ishikawa,K. Sawanaka, K. Kashiwase, A. Ogawa; Tokai University Schoolof Medicine — T. Naruse, H. Ando, Y. Matsuzawa; ChugaiDiagnostics Science — K. Matsubara, A. Kobayashi; Transplantationcenters — Hokkaido University Hospital, Sapporo UniversityHospital, Sapporo Hokuyu Hospital, Japanese Red Cross AsahikawaHospital, Hirosaki University Hospital, Tohoku University Hospital,Yamagata University Hospital, Akita University Hospital, FukushimaMedical College, National Cancer Center Central Hospital, Instituteof Medical Science at the University of Tokyo, Toho UniversityHospital, Omori Hospital, Tokyo Metropolitan Komagome Hospital,Nihon University Hospital, Itabashi Hospital, Jikei UniversityHospital, Keio University Hospital, Tokyo Medical College Hospital,Tokyo Medical and Dental University Hospital Faculty of Medicine,Yokohama City University Hospital, Kanagawa Children's MedicalCenter, Kanagawa Cancer Center, Tokai University Hospital, St.Marianna University Hospital, Chiba Children's Hospital, MatsudoMunicipal Hospital, Kameda General Hospital, Saitama Children'sMedical Center, Saitama Cancer Center Hospital, Saitama MedicalSchool Hospital, Ibaraki Children's Hospital, Jichi MedicalSchool Hospital, Dokkyo University Hospital, Fukaya Red CrossHospital, Saiseikai Maebashi Hospital, Gunma University Schoolof Medicine, Niigata University Hospital, Niigata Cancer CenterHospital, Shinshu University Hospital, Saku Central Hospital,Hamamatsu University Hospital, Hamamatsu Medical Center, ShizuokaGeneral Hospital, Shizuoka Children's Hospital, Japanese RedCross Nagoya First Hospital, Nagoya Daini Red Cross Hospital,Meitetsu Hospital, Nagoya University Hospital, Nagoya EkisaikaiHospital, National Nagoya Hospital, Aichi Medical School Hospital,Nagoya City University Hospital, Showa Hospital, Anjo KouseiHospital, Fujita Health University Hospital, Mie UniversityHospital, Kanazawa University Hospital, Kanazawa Medical UniversityHospital, Toyama Prefectural Central Hospital, Fukui MedicalSchool Hospital, Shiga University of Medical Science, Centerfor Adult Disease in Osaka, Kinki University Hospital, OsakaUniversity Hospital, Osaka Medical Center and Research Institutefor Maternal and Child Health, Matsushita Memorial Hospital,Hyogo College of Medicine Hospital, Hyogo Medical Center forAdults, Kobe City General Hospital, Kobe University Hospital,Kyoto University Hospital, Kyoto Prefectural University of MedicineHospital, Social Insurance Kyoto Hospital, Tottori PrefecturalCentral Hospital, Tottori University Hospital, Hiroshima RedCross Hospital and Atomic-Bomb Survivors Hospital, YamaguchiUniversity Hospital, Ehime Prefectural Central Hospital, OkayamaNational Hospital, Kurashiki Central Hospital, Kyushu UniversityHospital, Harasanshin General Hospital, Hamanomachi GeneralHospital, National Kyushu Cancer Center, St. Mary's Hospital,Kokura Memorial Hospital, Saga Prefectural Hospital, NagasakiUniversity Hospital, Miyazaki Prefectural Hospital, KumamotoNational Hospital, Kumamoto University Hospital, Oita MedicalUniversity Hospital, and Kagoshima University Hospital.
Hematopoietic Stem-Cell Transplantation for Acute Leukemia
Eiermann T. H., van Bekkum D. W., Vriesendorp H. M., Machida U., Kami M., Hirai H., Bolan C. D., Leitman S. F., Sasazuki T., Juji T., Kodera Y., Aversa F., Martelli M. F., Reisner Y.
Extract |
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N Engl J Med 1999;
340:809-812, Mar 11, 1999.
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A correction has been published: N Engl J Med 1999;340(5):402.
