57

KA Sobocinski3, MM Nlr~rowitz~,AA Rimm3, MM Bortin’

Summary

- Use of allogeneic bone marrow transplants continues to increase. During the Xi-year period between 1955 and 1990, more than 33 000 patients received allogeneic bone marrow transplants; more than 4% of these were performed during the 3 years 1988-1990. Tzmsplwi!te arc effective therapy for leukemia and other henztologic diseases. It is widely considered that transplants are the treatment of choice for aplastic anemia and chronic mye~agenous feukemia. those who fail conventional therapy for acute leukt;mia and a variety of genetic, metabolic and immune deficiency disorders. Successful a~~~i~a~ion of bone marrow ~ransplan~atjon is limited by complications such as graft failure, graft rers@s host Gsease GVWD and interstitial pneumonia and, until recentiy, the requirement for an HLA-identical sibling donor. In the past few years. an increasing number of transplants were performed usin,0 unrelated or HLA-partially matched related donors with ZGWGSuccess. Development of post-transplant complications can often be predicted by risk factor assessment. In this report. citrrent data from the IBMTR are summarized and several risk factors affecting outcome identified.

Introduction The fnternational Bone Marrow Transplant Registry flBMTR) is a voluntary working group of 219 transplant teams thar contribute detaited data on their consecutive allogeneic bone marrow transplants to a centralized Statistical Center.

These: data are analyzed to determine results of bone marrow transplants for various disorders and to identify patient, disease and treatment factors associated with successful outcome. ~n~t~all~ estabiished in 1969, its participants include approximately 70% of all active transplant centers.

58

In addition to analyses of outcome, the IBMTR conducts periodic surveys to assess worldwide use of allogeneic and syngeneic bone marrow transplants covering the period 1955-1990 16-81. The first successful allogeneic bone marrow transplants were performed to treat p~rn~y immune deficiency diseases in the late 1960s. Utilization of bone marrow transplants increased gradually during the 1970s and increased dramatically during the 1980s (fig 1). There were approximately 33 000 allogeneic bone marrow transplants between 1955 and 1990, and more than half of them have been performed since 1987. Diffusion of bone marrow transplant technology is also reflected by an increase in the number of centers performing transplants: 55 in 1977 verws 342 in 1990. Over 60% of currently active programs began after 1980. Prior to 1980, most transplants were for nonmalignant disease, Between 1988 and 1990, 73% were for leukemia, 10% for other malignant diseases, 8% for severe aplastic anemia and related disorders, 3% for immune deficiencies, 2% for thalassemia major and 4% for genetic, metabolic, and other rare diseases (fig 2).

Cumuiallve Numberof Patients

1984

1986

198%

ISCN

Year

Fig 1. Annual and cumulative numbers and percentages of patients receiving allogeneic or syngeneic bone marrow trans.. plants, 1981-1990.

Selection of donors The immunologic barrier between donor and recipient in allogeneic bone marrow transplants is bidirectional. As in solid organ transplants, immune competent recipient cells can recognize disparate histocompatibility antigens on donor cells and reject the graft. In addition, donor T-lymphocytes m the transplanted bone marrow can recognize disparate host histocompatibiiity antigens and initiate graft-verscrs-host disease (GVHD). TO minimize both rejection and GVHD, most transplants use sibling donors matched for the major histocompatibility genes as determined by serologic typing for HLA-A, -B, and -DR antigens. These alleles are inherited in a Mendelian codominant manner. Given curt-rent family size in Europe and North America, only about 35% of otherwise eligible transplant candidates will have an HI-A-identical sibling donor [23]. Alternative donors for persons without an HL~-identical sibling include unrelated donors and partially HLAmatched related donors.

Fig 2. Diseases for which allogeneic bone marrow transplants were performed. 1988-1990.

In 1991, the IBMTR analyzed results of 406 transplants using related donors other than HLA-identical siblings (alternative related donors) and compared these results to 3648 concurrent HLA-identical sibiing transplants (table I) [t 3. Alternative related donor transplants were as-

&mar-recipient Hi&disparity Phenotypic identify

disparate

%I=36

ZB=239

&rcome

RR

P

Graft failure* Acute GVHD Ch&c GVHfl

2.6 1.0 1.4

NS NS MS

2-L& disparate

I-LOCUS

.-

n=59

RR

P

RR

2.0 1.2 1.3

9 0.009 NS NS

1.3 3.1 0.9

ll=&? P

RR

P

< 0.001

5.9

4 0.0001

L2.4

< 0.0001 98% of patients with leukemia in this study received totai body radiation

LO-

and gastrointestinal tract involvement. Chronic GVHD usually occurs later and is characterized by skin changes similar to scleroderma, sicca syndrome. maloabsorption and features of autoimmuni!y. In an IBMTR study of 2 036 recipients of HLA-identical sibling transplants for leukemia or aplastic anemia, the probabiIity of grade II-IV acute GVHD was 44% in patients receiving methotrexate or cyclosporine. to prevent GVHD and 65% in patients not receiving any GVHD prophylaxis (P c 0.01) [ 131. Other risk factors for acute GVHD identified in this study include: alloitnmune female donors for male recipients, not older age, trimethoprim-sulfamethoxa~ole given and lower pre-transplant performance status. When all adverse risk factors were present, the cumulative probability of acute GVHD was 87%. If none were present, the risk was 166. An I~~TR analysis of 2 534 recipients of HLA-identical sibling transplants surviving at least 90 days post-transplant showed that prior actue GVHD was the most important risk factor for chronic GVHD 121. Three-year probabilities of chronic GVHD were 28, 49, 59, 80 and 85% for patients with grades 0, I, II, III, and IV acute GVHD, respectively (P c 0.0001) (fig 3). Among 217 patients without prior acute GVHD (tlr MN> chronic GVHD), recipient age > 20 years, use of non-T-cell depleted bone marrow and alloimmune female donors for male recipients predicted a high risk of chronic GVHD. These risk factors are similar to those for actue GVHD, suggesting a similar pathogcnesis.

OS-

0

6

Fig 3. Pr~)habiiity prior acute GVHD transplan!.

13 Months

18 24 postha;rsplant

30

36

of chronic GVHD according to severity of among patients surviving 3 YOdays post-

Graft-versus-leukemia

(GVL) reactions

Although it is often assumed that the antileukemia effect of bone marrow transplants is from highdose chemotherapy and/or radiation in the preparative regimens, both animal and experimental data support a role for the donor bone marrow in preventing post-transplant relapse. A 1990 IBMTR analysis studied possible immune-mediated antileukemia effects in 2254 persons receivmarrow sibling bone HLA-identical ing transplants for “early leukemia” (first remission of acute leukemia and chronic myelogenous leukemia in first chronic phase) [ 181. Four groups were investigated: I) recipients of non-T-cell depleted altografts without GVWD; 2) recipients of non-T-cell depleted allografts with GVHD; 31

62

recipients of T-cell depleted allogtafts; and 4) recipients of genetically identical twin transplants (fig 4). Decreased relapse was observed in recipients of non-T-cell depleted allografts with acute {relative risk (RR) 0.68, P = 0.031, chronic (RR 0.43, P = Q.01) and both acute and chronic GVHD (RR 0.33, P = ~.~~~I~ compared to recipients of non-T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. In acute lymphoblastic leukemia, acute GVHD was more strongly associated with anmyelogenous in acute tileukemia activity; leukemia and chronic myelogenous leukemia, chronic GVHD was more strongly associated. Patients with acute myelogenous leukemia receiving identical twin transplants had an increased probability of relapse (RR 2.58, P = 0.008) compared to allograft recipients without GVHD. These data support an antileukemia effect of allogenic transplants independent of GVHD. Patients with chronic mvelogen~ns leukemia receiving T-cell deplete; transpiants, with or without GVHD, had higher probabilities of relapse (RR 6.91 and 4.45, respectively; P = O.QOO1) than recipients of non-T-cell depleted allografts without GVHD. These data suggest that T-cell depletion alters the antileukemia effect of transplants in chronic myelogenous leukemia by a mechanism(s) separate from GVHD. in acute leukemia, the risks of relapse with T-cell depletion were similar to non-T-cell depleted transplants without GVHD, suggesting that increased relapse in this settin,- is due to decreased GVHDassociated antileukemia activity.

Outcome of allogeneic bone marrow transplants The most common indications for bone marrow transplant are aplastic anemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic mye~ogenous leukemia; these account for more than 80% of ail allogeneic transplants (fig 2). Outcome of transplants for these diseases is briefly outlined below. Aplnstic

anemia

Bone marrow transplant from an HLA-identical sibling is the treatment of choice for patients with anemia. In an analysis of severe aplastic 595 ~ansplants for aplastic anemia performed between 1985 and 1990 and reported to the I~MTR, the overall probability (-+95% confidence interval) of survival at 5 years was 64 Lt:4%. The probability of survival was significantly higher in younger than in older patients (fig 5). Major causes of death in this group are shown in figure 6. The effects of pre-transplant conditioning and GVHD prophylaxis were examined in another study of 595 transplants performed between 1980-1987. None of the 3 conditioning regimens (cyclopho~~hamide alone, cyclophosphamide plus limited field radiation and cyclophosphamide plus total body radzatiun) was associated with superior

NOGVHD M=433) 5mmlty(N=m)

,.A=---

CQVHDonly-iN=127)

d

4 AQVHD + COVHD (N=435)

0

12

24

36

43

80

73

Fig 4. Ac~ri~l probability of relapse after HLA-identical bone marrow transplants for early leukemia nccording to lype of graft and developmelt of GVHD. sibling

Fig 5. Actuarial prohhility of survival af~cr HLA-identical sibling bone marrow transplants for severe aplastic anemia according to recipient age. i985-199~.

63

P c 0.0001

Fig 6. Primary causes of death after HLA-identical sibling bone marrow transplants for severe aplastic anemia, 1985 1990.

long-term survival. Of the 3 GVHD prophylaxis regimes studied (methotrexate, cyclosporine, and methotrexate plus cyclosporine), cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69 + 5%) versU.s methotrexate only (56 f 7% P < 0.003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (F c 0.0002) and chronic GVHD (P < 0.005) [14]. Acute myelogenous

0

12 Monlhs

Fig 7. Actuarial probability of relapse after HLA-identical sibling bone marrow transplants for acute myelogenous leukemia according to remission state at transplant, 1985-1990.

leukemia

Comprehensive data for I 776 recipients of HLAidentical sibling transplants for acute myelogenous leukemia between 1985-1990 were reported to the IBMTR. The i-year probability of relapse after 1122 tra~~splants in first complete remission was 28 f 8%; after 230 in second or subsequent remission, the probability was 40 -i- 10%; and, after 424 transplants in relapse or partial remission, it was 59 2 7% (fig 7). Corresponding probabilities of leukemia-free survival were 51 f 4%, 21 + 7% and 21 It 5%. respectively (fig 8). Whether all patients with acute myelogenous leukemia achieving first remission should receive a bone marrow transplant is controversial. Reported s-years probabilities of leukemia-free survival with chemotherapy range from 20-50%; probabilities with transpIants are between 3560%. comparison of chemo~erapy and transplant results is further complicated by differences in patients receiving chemotherapy versus transplants and by the fact that transplant series exclude patients who relapse too soon to allow transplant in first remission. Some centers recom-

Advance6

(t&=424)

1

0

12

24 Monthhs

66

46

Fig 8. Actuarial probability of leukemia-free survival after HLA-identical sibling bone marrow transplants for acute myelngenous leukemia according to remission state al transplant, 1985-1990.

mend transplants only for patients with prognostic features associated with high relapse risk if treated with chemotherapy. To evaluate this strategy, the IBMTR anaIyzed data for 704 recipients of HLA-identical sibling transplants for acute myelogenous leukemia in first remission 1211. Younger age and lower leukocyte levels at diagnosis were associated with higher leukemia-

64 free survival. These prognosXic variables are similar to those reported to affect outcome after chemotherapy. These findings suggest that a strategy of treatment assignment based on risk factor analysis is unlikely to resolve the controversy of transplant \$~rs chemotherapy for acute myelogenous leukemia in first remission. About 20-4OQ of children and adults with acute myelogenous leukemia never achieve remission,

eve11 with

intensive

induction

1.07

P < 0.0001 OS-

Advanced (N=284) Intermediate (N=600)

chemotherapy.

die of resistant leukemia, usually within 6 months. Recently, the IBMTR completed a study of 88 patients with acute myelogenous leukemia who failed to attain a remission despite intensive induction chemotherapy. They received HLA-identical sibling bone marrow trnnsplants between 1982-1989. The 2-year probability of leukemia-free survival was 23 + 8% and of relapse was 58 t 13%. These data suggest that bone marrow transplants should be considered for patients failing !G achieve remission with chemotherapy 151. Most

EarIy (N=514)

0.0

G

12

34 Ycnths

36

48

Fig 9. Actuarial probability ol’ relapse afkr HLA-identical sibling bone marrow transplants for acute lymphoblastic icukcmin according IO remission state ni transplant, 1985-1990.

P < 0.0061

Comprehensive data for 1398 HLA-identical sibling bone marrow transplants between 1985 and 1990 for acute lymphoblastic leukemia (ALL) were reported to the IBMTR. The 5-year actuarial probabilities of relapse were 27 f 5% for 5 14 patients’ transplants in first complete remission, 49 f 6% for 600 transplants during the second or subsequent remission, and 59 + 8% for 284 transplants with more advanced leukemia (fig 3). Corresponding probabilities of leukemia-free survival at 5 years were 50 + 5%, 33 + 5% and 18 f 5% respectively ffig IO). Remission status at transplant is the most important predictor of outcome in ALL. The IBMTR analyzed data for 690 patients with acute lymphoblastic leukemia who had undergone transplants in first and second remission (table IV) to identify other prognostic factors for reiapse and leukemia-free survival 14, 201. Variables associated with increased probability of relapse were similar for first and second remission transplants and include GVHD prophylaxis without methotrexate and the absence of GVHD. In first remission transplants, leukocyte counts 2 50 x IO’/1 at diagnosis were also associated with increased risk of relapse. In second remission transplants, relapse while receiving chemotherapy was associated with incr’zased posttransplant relapse. In first remission adults, non-

0.8

3

0.6-

% 5r .C x

Advanceil (N=284)

C.5

0.0

1 0

12

I

I

I

24 Months

36

48

Fig

10. Actuarial probability ol’ Icuhemin-l’rcc survival :ICIW HLA-identical sbiling bone marrow transplants for acute lynrpboblastic leukemia according to remission state a transplant, 1985-1990.

T-cell phenotype, male to female donor-recipient sex-match and GVHD wzre associated with decreased leukemia-free survival. Inclusion of corticosteroids in the regimen to prevent GVHD was associated with a higher probability of leukemia-free survival.

65

Table IV. Variables associatedwith outcome of bone marrow t~nsp~a~~tion FOF acute ~y~ph~~asti~leukemia fAtI_+). First CR * Outcome variable

Second CR

RR”*

F

RR**

P

Cyclosporine or

5.2

< ~.~~~~

3.I

f o.oifDI

T-cell depletion No acute or chronic >sox log/l On chemotherapy

3.1 2.5

NA

cO.0~ < 0.03 NA

2.0 NS 3.3

< 0.002 NS c: oltoo2

2.8 I .9 2.2

< 0,004 c 0.002 < 0.002

NS NS NS

NS NS NS

Favorable

Unfovoroble

Relupse

GVHD prophylaxis GVHD Leukocytes at Dx Relapse occurred

Methotrexate Acute and& chronic

C 50:: log/l Off chemotherapy

T~~U~l~~~i~~.~~~lU~~

CVHD prophylaxis GVHD Sex match

With steroids No acute or chronic M+M,F-+F, F-+M

Without steroids Acute and/or chronic M-+F

Immune phenotype Patient age Relapse occurred

T-ceil

Not T-celi

I.7

ol’ rclap~ alicr HLA-identical sibling bone mitrrow transplants for chronic myelogenous leukemia according KP = chronic phase;

to disease phase at AP = accelerated phase;

transplant

BP = blast

phase), 1985- 1990.

P < O.oool

0

12

24 Months

36

45

Fig 12. Actuarial probability ot’ leukemia-free survival i.ltc‘r HLA-ide~~icai sibling bone marrow transplants for chronic myelogenous leukemia according to disease phase at transplant (CP = chronic phase; AP = accelerated phase; BP = blast phase),

1985-1990.

phase, 36 + 9% for those in accelerated phase, and 77 + 15% for those in blast phase (fig 11). Probabilities of leukemia-free survival were.45 + 4% in chronic phase, 32 rt 6% in accelerated phase, and 9 E!Z 6% in blast phase (fig 12). A 1988 IBMTR report analyzed data on 405 patients with chronic myelogenous leukemia transplanted in chronicphase [ 151. Two variables were associated with leukemia-free survival: age and acute GVHD. Younger patients and those without acute GVHD had superior outcomes. Variables correlated with leukemia relapse were T-cell depletion and chronic GVHD. T-cell depletion markedly increased relapse risk; this effect was only partially explained by decreased GVHD. The effect of T-cell depletion and the high relapse rate observed after transplants from identical twins (fig 4), suggest that immune-mediated antileukemia effects of allogeneic transplants are important in preventing relapse after bone marrow tra~lsplants for chronic myeloge~ous leukemia.

We thank S Nell and D’Etta Wz’aoch K&er for help with data analysis, and D Jacobsen for typing the manuscript. This study was supported by Public Health Service Grant POI-CA-40053 from the National Cancer 1ns:itute and the National Institute of Allergy and Inectious Diseases of the US Department of Health and Human Services and by grants from the Alpha Therapeutic Corporation; Armour Pharmaceutical Company: Lynde and Harry Bradley Foundation; B~stol-Myers; Burroughs-Wellcome Company; Charles E Culpeper Foundation; Eleanor Naylor Dana Charitable Trust; Eppley Foundation for R.esearch; Hoechst-Roussel Pharmaceuticals; Immunex Corporation; Kettering Family Foundation; Robert J and Helen C Kleberg Foundation; Eli Lilly and Company; Ambrose Monell Foundation; Samuel Roberts Noble Foundation: Ortho Biotech Corporation; John Oster Family Foundation; Jane and Lloyd Pettit Foundation; RGK Foundation; Roerig Division of Pfizer Pharmaceuticals; Sandoz Research Institute; Stackner Family Foundation; Starr Foundation; Joan and Jack Stein Charities; Swiss Cancer League; and Wyeth-Ayerst Research. This 109th report from the International Bone Marrow Transplant Registry was prepared for the members of the Advisory Committee: RP Gale, University of California, Los Angeles, CA, USA, Chairman: RC Ash, Medical College of Wisconsin, Milwaukee, WI, USA; K Atkinstin. St Vincent’s Hospital, Sydney, Australia; FH Bach, University of Minnesata, Minneapolis, MN, USA; AJ Barrett, The Royal Postgraduate Medical School, London, UK: DW van Bekkum, Radiobiological Institute TNO, Rijswijk, The Netherlands; JC Biggs, St

67 Vincent’s Hospital, Sydney, Australia; KG Blume, Stanford University Hospital, Stanford, CA, USA; R Champlin, Anderson Cancer Center, Houston, TX, USA, KA Dicke, University of Nebraska Medical Center, Omaha, NE, USA; G Ehninger, Med Univepitaetsklinik, Tubingeu, Germany: A Fischer, HBpital Necker EnfantsMalades, Paris, France; SJ Forman, City of Hope National Medical Center, Duarte, CA, USA; J Gajewski, University of California, Los Angeles, CA, USA; E Gehan, Anderson Cancer Center, Houston, TX, USA, E Gluckman Hopital Saint-Louis, Paris, France; JM Goldman, Hammersmith Hospital, London, UK, RA Good, All Children’s Hospital, St Petersburg, FL, USA, W Helbig, Karl Marx Universitiit, Leipzig, Germany; PJ Henslee-Downey, University of Kentucky, Lexington, KY, USA; RH Herzig, University of Louisville, Louisville, KY USA; W Hinterberger, Med UnivKlinik, Vienna, Austria; R Hong, University of Wisconsin, Madison, WI, USA; N Jacobsen MD, Rigshopitalet, Copenhagen, Denmark; JH Kersey, University of Minnesota, Minneapolis, MN, USA; HJ Kolb, Universitl Muenchen, Munich, Germany; B Kubanek, Universit~t Ulm, Ulm/Donau, Germany; A Marmont, Ospedale San Martino, Genoa, Italy; T Masaoka Center for Adult Diseases, Osaka, Japan; HA Messner, Princess Margaret Hospital, Toronto, Ontario, Canada: RJ O’Reilly, Memorial Sloan-Kettering Cancer Institute, New York, NY, USA; R Pasquini. Hospital de Clinicas, Curitiba, Parana, Brazil; G Phillips, University of British Columbia, V~couv~, BC, Canada; R Potvles. Royal Marsden Hospital, Sutton, Surrey, UK, HG prentice, Royal Free Hospital, London, UK; J Reiffers, Groupe Hospitalier du Haut Leveque, Pessac, France: AA Rimm, Medical College of Wisconsin, Milwauk:-.*,WI. USA; 0 Ringddn. Huddinge University Hospital, Huddinge, Sweden, J Ritz, Dana Farber Cancer Institute, Boston, MA, USA: JJ van Rood, University Hospital, Leiden, The Netherlands; C Rozman, Universidad de Barcelona, Barcelona, Spain; UW Schaefer, University of Essen, Essen, Germany; B Speck, Kantonsspital Basel. Basel, Switzerland; S Tura, S Orsola University Hospital, Bologna, Italy; RS Weiner, University of Florida, Gainesville, FL, USA, J Wingard, Johns Hopkins Oncology Center, Baltimore, MD, USA; FE Zwaan, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia. The following institutions ,voluntarily contributed the data that made these studies possible: British Hospital of Buenos Aires, Buenos Aires, Argentina; Navy Hospital Pedro Mallo, Buenos Aires, ~gentina; Institute of Medical Science, Adelaide, Australia; Royal Brisbane Hospital, Brisbane, Australia; Royal Alexandra Hospital For Children, Camperdown, Australia; Royal Prince Alfred Hospital, Camperdown, Australia; St Vincent’s Hospital, Darlinghurst, Australia; Royal Hobart Hospital, Hob.art, Australia; Royal Children’s Hospital, Parkville, Australia; Royal Melbourne Hospital, Parkville, Australia; Royal Perth Hospital, Perth, Australia; Alfred Hospital, Prahran, Australia; Prince of Wales Children’s Hospital, Randwick, Australia; Royal North Shore

Hospital, St. Leonards, Australia; Royal Holbart Hospital, Tasmania. Australia; Westmead Centq westmead, Australia; Queen Elizabeth Hospital, Woodville, Australia; Med Univ-Klinik, Vienna, Austria; Cliniques Univ Saint-Luc, Brussels, Belgium; University Hospital Antwerp, Edegem, Belgium; University Ziekenhujs Gasthuisberg, Leuven, Belgium; Instituto Nac;ionai de Cancer, Rio de Janeiro, Brazil; Hospital de Clinjcq Curitiba, Brazil; Instituto do Caroaco INCOR, Sao Paula, Brazil; Tom Baker Cancer ~entre~oothills Hospital, Calgary, Alberta, Canada; McMaster University, Hamilton, Ontario, Canada; Montreal Children’s Hospital, Montreal, Quebec, Canada; Royal Victoria Hospital, Montreal, Quebec, Canada; Princess Margaret Hospital, Toronto, Ontario, Canada; British Columbia’s Children’s Hospital, Vancouver, BC, Canada; Vancouver General Hospital, Vancouver, BC, Canada; Hospital Militar, Santiago, Chile; Beijing Medical University, Beijing, China: North Tai Ping Road Hospital, Beijing, China; Lanzhou General Hospital. Lanzhou, China: Institute de Hematologia E Immunologia, Havana, Cuba; Institute for Hematology and Blood Transfusion, Prague, Czechoslov~ia; Rigshospitalet, Copenhagen, Denmark University of Helsinki, Helsinki, Finland; Turku University, Turku, Finland; Angers University, Angers, France; Centre Regional de Transfusion Sanguine, Besanqon, France: Universitaire de Caen, Caen, France; Hiipital A Michallon, Grenoble, France; Centre Hospitalier Regional de Lille, Lille, France; Hopi&l Debrousse, Lyon, France; Hrjpital Edouard Herriot, Lyon, France; Institut J Paoli I, Calmettes, Marseille, France; Hopital des Enfants Malades, .Paris, France; Hopital Robert Debre, Paris, France; HBpital Saint-Antoine, Paris, France; HBpital Saint-Louis, Paris, France; Hotel Dieu de Paris, Paris, France; Groupe Hospitalier du Haut Leveque, Pessac, France; H&pita1 Jean Bernard, Poitiers, France; H&pita1 Nord. St Etienne, France; H3pital Purpan, Toulouse, France; hopital Regional de Toulouse, Toulouse, France; Hopital Paul-Brouss:, Viiiejuif, France; Universitatsklinikum Rudolf Virhoiv, Berlin, Germany; Medizinische Hochschule Hannover, Hannover, Germany; Christian-4lbre=hts-Universitat, Kiel, Germany; Karl Marx Universitat, Leipzig. Germany; ~niversitats ~nderkl~nik, Munich, Gerry: Universitat Muenchen, Munich. Germany; Medizinische Universitatsklinik, Tubingen, Germany; Universitat Ulm, UlmlDonau, Germany; National Institute of Haematology, Budapest, Hungary; Semmelweis University, Budapest, Hungary; Tata Memorial Hospital, Bombay. India, St. James’s Hospital, Dublin, Ireland; Hadassah University Hospi~l, JeNSakIII, Israel; S Orsola University Hospital, Bologna, Italy; Spedali Civili, Brescia. Italy; Ospedale San Martino, Genoa, Italy: University of Milan, Milan, Italy; Ospedale Civile, Pesaro, Italy; Hospital of Pescara, Pescara, Italy; Ospedale S Camille. Rome, Italy; University degli Studi, La Sapienza. Rome, Italy; University of Rome, Rome, Italy; Tokai University School of Medicine, Kanagawa, Japan; Kanazawa University School of Medicine, Kanagawa-shi. Japan; Nagoya Second Red Crow Hospital. Nagoya, Japan;

68 Center For Adult Diseases, Osaka, Japan; Hyogo College of medicine, Hyogo, Japan; Jichi Medical School, Tochigi-ken, Japan; Nihon University, Tokyo, Japan; University of Tokyo, Tokyo, Japan; Jordan University Hospital. Amman, Jordan: St Mary’s Hospital, Seoul. Korea; University of Malaya, Kuala Lumpur, Malaysia: University of Leiden~edic~ne, Leiden, The Netherlands: University of Leiden/Pediatrics, Leiden, The Netherlands; University of Nijmegen, Nijmegen, The Netherlands: Rotterdam Radio-Therapeutic Institute. Rotterdam. The Netherlands; Auckland Hospital, AuckHospital, Christchurch New Zealand: land, Christchurch, New Zealand; Wellington School of Medicine, Wellington, New Zealand; Rikshospitalet, Oslo, Norway: Postgraduate Medical Center, Warsay, Poland; lnstituto Portugues de Oncologia, Lisbon, Portugal; King Faisal Specialist Hospital, Riyadh, Saudi Arabia: Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia; University of Cape Town Medical School, Cape Town, South Africa: University of Witwat~rsrand, Johannesburg. South Africa; Hospital General Vail d’tfebron, Barce!ona, Spain: Hospital Infantil Vail d’Hebron, Barcelona, Spain: University of Barcelona, Barcelona, Spain: Hospital Reina Sofia, Cordoba, Spain; Ciinica Puerta de Hierro. Madrid, Spain; Hospital de la Princesa, Madrid, Spain; Hospital Ramon y Cajal, Madrid, Spain; Hospital Marques De Valdecilla, Santander, Spain; Hospital La Fe. Valencia, Spain: Huddinge Hospital, Huddinge. Sweden; University of Goteborg, Goteborg, Sweden: University of Lund, Lund, Sweden; Kantonsspital, Basel, Switzerland; University Hospital, Zurich. Switzerland; Kinderspital Zurich, Zurich, Switzerland; National Taiwan University Hospital-Hemat ‘ogy, Taipei, Taiwan; Veterans General Hospital-Pediatrics, Taipei, Taiwan; Tao-Yuan General Hospital, Tao-Yuan. Taiwan; East Bi~ingham Hospital, Birmingham. UK; Queen Elizabeth Medical Center, Birmingham. UK; University Hospital of Wales, Cardiff, UK; Royal Infirmary cf ‘Edinburgh, Edinburgh, UK; Glasgow Royal Infirmary, Glasgow, UK; Royal Hospital for Sick Children, Glasgow, UK; St James’s University Hospital, Leeds, UK; Charing Cross and Westminster Medical School, London, UK; Institute of Child Health, London, UK: The London Clinic, London, UK; Royal Free Hospital, London, UK; Royal Marsden Hospital, London. UK: Royal Postgraduate Medical School (Leukl, London, UK; Royal Postgraduate Medical School (SAAI, London, UK; Westminster Children’s Hospital. London. UK; Royal Victoria Infirmary, Newcastle, UK; John Radcliffe Hospital, Oxford, UK; The London Hospital Whitechapel, Whitechapel, UK; Emory University, Atlanta, USA; The Johns Hopkins Oncology Center, Baltimore, MD. USA; Alta Bates Hospital, Berkeley, CA, USA; Medical University of South Carolina, Charleston, SC, USA; University of Virginia Medical Center. Charlottesville, VA, USA: Michael Reese Hospital and Medical Center, Chicago, IL, USA; Rush Presbyterian-St. Luke’s Hospital, Chicago, IL, IJSA; University of Chicago Hospital, Chicago. IL, USA: Children’s Hospital Medical Center, Cincinnati,

USA: University of Cincinnati Medical Center, Cincinnati, USA; Case Western F.eserve University, Cleveland, OH, USA; Cleveland Clinic, Cleveland, OH. USA; University of Colorado Health Science Center, Denver, CO, USA; City of Hope National Medical Center, Duarte, CA, USA; Duke University Medical Center, Durh-m, USA: University of Florida, Gainesville, FL, USA; University of Florida~ediatrics, Gainesville, FL, USA; St Francis Medical Center, Honolulu, HI, USA: Baylor College of Medicine, Houston, TX, USA; MD Anderson Hospital, Houston, TX, USA; St Joesph’s Hospital Medical Center, Houston, TX, USA; Texas Children’s Hospital, Houston, TX, USA: Indiana IJniversity Hospital, Indianapolis, IN, USA; University of Kansas, Kansas City, KS, USA; University of Tennessee Medical Center, Knoxville, TN, USA: Wilford Hall USAF Medical Center. Lackland AFb, USA; University of Kentucky. Lexington. KY, USA; Arkansas Children’s Hospital. Little Kock, AR, USA; UCLA Medical Center, Los Angeles, CA, USA; Unive~ity of CaIiforni~Medicine, Los Angeles, CA, USA; University of Californi~pediatrics, Los Angeles, CA, USA: So California Permanente Medical Group. Los Angeles, CA, USA; James Graham Brown Cancer Center, Louisville, USA; University of Wisconsin/Pediatrics. Madison, WI, USA; Marshfield Clinic, Marshfield. USA; Loyola University, Maywood, USA: Medical College of Wisconsin, Milwaukee, WI, USA; University of Minnesota, Minneapolis, MN, USA: Louisana State Medical Center, New Orleans, LA, USA; Louisiana State University Children’s Hospital, New Orleans, LA, USA; Memoridl Sloan-Kettering, New York City, NY, USA; Mt Sinai Hospital, New York City, NY, USA; University of Qklahoma, Oklahoma City. OK, USA; Bishop Clarkson Memorial Hospital, Omaha, NE, USA; University of Nebraska, Omaha, NE, USA: Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Hahnemann University, Philadelphia, PA, USA; Montefiore Hospital, Pittsburgh, USA; Oregon Health Sciences University, Portland, OR, USA; Strong Memorial Hospital, Rochester, USA; LDS Hospital, Salt Lake City, UT, USA; Pacific Presbyterian Medical Center, San Francisco, CA, USA; University of California, San Francisco, CA, USA; All Children’s Hospital, St Petersburg, USA; Stanford University Hospital, Stanford, CA, USA; H Lee Moffitt Cancer Center, Tampa, FL, USA; Georgetown University Medical center, Washington, WA, USA; Cancer Center of Kansas. Wichita, KS, USA; Ministr~~ of Health for Russia. Moscow, Russia; Hospital Central de Valenica, Valenica, Verezuela: University of Croatia, Zagreb, Croatia.

References I Ash RC, Horowitz MM, Gale RP er al (1991) Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T-cell depletion. Barre ~ur~~~~l ~r~ift,~~~~ffftr 7, 443

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Current status of allogeneic bone marrow transplantation.

Use of allogeneic bone marrow transplants continues to increase. During the 36-year period between 1955 and 1990, more than 33,000 patients received a...
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