Background In this study we tried to achieve successful transplantationin patients with acute leukemia with the use of hematopoieticstem cells from donors who shared only one HLA haplotype withthe recipient (a "full-haplotype mismatch"). To prevent graftfailure, large doses of T-cell–depleted hematopoieticstem cells were transplanted after a conditioning regimen ofenhanced myeloablation and immunosuppression was administeredto the recipient.
Methods Forty-three patients with high-risk acute leukemia whowere scheduled for transplantation received total-body irradiation,thiotepa, fludarabine, and antithymocyte globulin. The graftconsisted of peripheral-blood progenitor cells that had beenmobilized in the donor with recombinant granulocyte colony-stimulatingfactor and also, in 28 cases, bone marrow. Bone marrow fromthe donor was depleted of T lymphocytes by processing with soybeanagglutinin and E-rosetting. T-cell depletion of peripheral-bloodmononuclear cells was achieved by E-rosetting followed by positiveselection of CD34+ cells. No post-transplantation prophylaxisagainst graft-versus-host disease (GVHD) was administered.
Results In all the patients, full donor-type engraftment wasachieved. In none of the patients who could be evaluated didacute or chronic GVHD develop. Regimen-related toxicity wasminimal. Eleven of the 23 patients with acute lymphoblasticleukemia had a relapse, as did 2 of the 20 patients with acutemyeloid leukemia. Transplantation-related mortality was 40 percent.After a median follow-up of 18 months (range, 8 to 30), 12 ofthe 43 patients were alive and free of disease. All survivingpatients had a good quality of life.
Conclusions The main limitations of transplantation of bonemarrow from donors who are matched with the recipient for onlyone HLA haplotype — GVHD and graft failure — canbe overcome. Since most patients have a relative with one haplotypemismatch, advances in this method will increase the availabilityof hematopoietic-cell transplantation as curative therapy foracute leukemia.
Transplantation of bone marrow from an HLA-matched related1or unrelated2,3,4,5 donor is a potentially curative treatmentfor patients with acute leukemia. Despite the existence of aworldwide registry that includes more than 3 million HLA-typedvolunteers, about 40 percent of patients do not have an HLA-compatibledonor. The HLA genes are tightly linked and are inherited ina genetic unit called a haplotype. Haplotypes can be identifiedby testing for alleles at three loci: HLA-A, HLA-B, and HLA-DR.A child inherits one haplotype from each parent. For this reason,two siblings have a 25 percent chance of inheriting the sametwo parental haplotypes and thus of being HLA identical.
For patients for whom an HLA-identical donor is not found, thereis an excellent chance of identifying a family member who sharesone HLA haplotype with the patient but whose second HLA haplotypeis different. This situation is called an HLA full-haplotypemismatch, or an HLA-haploidentical mismatch at three loci.
During the 1980s, transplantation of bone marrow from familydonors who were not fully histocompatible with the recipientswas unsuccessful because of graft failure and severe graft-versus-hostdisease (GVHD), at times affecting as many as 90 percent ofrecipients.6,7 Thorough depletion of T cells from the donor'sbone marrow succeeded in preventing GVHD in children with severecombined immunodeficiency disease,8,9 but the results of thisprocedure were disappointing in patients with leukemia, becausethe benefit of preventing GVHD was offset by graft failure.10,11,12,13Resistance to engraftment appears to be mediated by host-derivedcytotoxic T-lymphocyte precursors that survive supralethal conditioning.10,11,14Experiments in mice have shown that histocompatibility barrierscan be overcome by infusing high doses of T-cell–depletedmarrow cells,15,16 even in sublethally irradiated animals, inwhich numerous T lymphocytes have survived the radiation.17Engraftment is also improved by the addition of selective anti–T-cellagents18 or myeloablative drugs such as thiotepa19 to total-bodyirradiation.
Applying these results in animals to patients, we observed ahigh rate of engraftment in recipients of T-cell–depletedmismatched transplants who were also given high numbers of hematopoieticstem cells from bone marrow and peripheral blood.20 To enhancethe conditioning regimen of immunosuppression and myeloablation,we added antithymocyte globulin and thiotepa to the combinationof total-body irradiation and cyclophosphamide. Although noimmunosuppressive treatment was given after transplantation,acute GVHD of grade II, III, or IV occurred in only 18 percentof the patients.
In the present study, to eliminate GVHD, the number of T lymphocytesin the transplants from related donors who had one mismatchedhaplotype was reduced to a mean of approximately 3x104 cellsper kilogram of the recipient's body weight, equivalent to 1/10the number administered in our previous study. In a murine model,total-body irradiation plus fludarabine caused a degree of immunosuppressionsimilar to that caused by total-body irradiation plus cyclophosphamide.21Therefore, in the effort to lower extramedullary toxicity, wesubstituted fludarabine for cyclophosphamide in the conditioningregimen.
Methods
Patients
Between October 1995 and August 1997, 43 patients with high-riskacute myeloid leukemia (AML) or acute lymphoblastic leukemia(ALL) received hematopoietic stem-cell transplants from familydonors with only one matched HLA haplotype at the Bone MarrowTransplant Unit, University of Perugia, Perugia, Italy (Table 1).The study patients were selected because they had no suitableunrelated donor or because their need for transplantation wasurgent. Written informed consent was obtained from the patientsor their guardians and from the donors.
Table 1. Patient Characteristics According to Status of Leukemia at Transplantation.
HLA Typing
Family members were assessed for HLA compatibility by serologictyping. In 22 cases the donor was a parent, in 18 cases a sibling,and in 3 cases a child of the recipient. All pairs of donorsand recipients were identical for one HLA haplotype (haploidentical)and incompatible at three loci (HLA-A, B, and DR) of the unsharedhaplotype. The donors and the recipients were heterozygous forHLA-A, B, and DR — that is, all the donor–recipientpairs were mismatched in both directions: host versus graftand graft versus host.6
Conditioning Regimen
Pretransplantation treatment included total-body irradiationand administration of thiotepa, antithymocyte globulin, andfludarabine (Figure 1). Total-body irradiation was given onday –10 (10 days before transplantation) in a single fractionat an instantaneous dose rate of 16 cGy per minute. The doserate was calculated at five body points (cranium, mediastinum,umbilicus, left lung, and pubic symphysis) on a coronal planeat half-body thickness. The total dose of 8 Gy was deliveredin 90 minutes at a mean dose rate of 9 cGy per minute. The lungswere shielded so that the first 10 patients received 6 Gy andthe others 4 Gy to reduce toxicity to the lungs (see below).The four children less than seven years old received 12 Gy (9Gy to the lungs), fractionated over a three-day period. Thiotepa(13 mg per kilogram of body weight in the first 11 patientsand 10 mg per kilogram in the others) was administered in twodoses on day –8. On days –6 to –2, antithymocyteglobulin (Fresenius, Oberursel, Germany) was infused at a dosageof 5 mg per kilogram daily over an eight-hour period. Fludarabinewas given at a dose of 240 mg per square meter of body-surfacearea over a six-day period in the first 11 patients and at 200mg per square meter over a five-day period in the others. Thelast 30 patients also received cyclosporine (1 mg per kilogram)daily as a continuous intravenous infusion from days –10to –3.
Figure 1. Pretransplantation Conditioning Regimen, Donor Hematopoietic Stem-Cell Processing, and Times of Infusions.
G-CSF denotes recombinant human granulocyte colony-stimulating factor, and SBA–EN– denotes lectin soybean agglutinin– and E-rosette–separated.
Stem-Cell Processing and Transplantation
Donor bone marrow was depleted of T lymphocytes by soybean agglutinationand two rounds of E-rosetting22 and was then cryopreserved.Recombinant human granulocyte colony-stimulating factor (G-CSF,filgrastim) was administered to donors subcutaneously at a dosageof 16 µg per kilogram daily for 7 days, beginning a medianof 12 days after bone marrow harvesting (Figure 1). Startingon day 4 of G-CSF administration, peripheral-blood mononuclearcells were collected by leukapheresis for four days with a discontinuousblood-cell separator (Haemonetics, Braintree, Mass.). The productof the first leukapheresis was stored at 4°C overnight andpooled the next day with the product of the second. T-cell depletionwas achieved by E-rosetting with sheep erythrocytes, followedby selection of CD34+ cells with use of an immunoadsorptionbiotin–avidin column23,24 (Ceprate SC, Cell Pro, Bothell,Wash.). The entire procedure took nine hours. The pooled cellswere infused immediately (day 0). The products of the thirdand fourth leukaphereses were pooled, processed, and infused,as described above, 48 hours later (day 2).
For 15 patients, the transplants consisted only of peripheral-bloodprogenitor cells, because if bone marrow had been added themean number of T lymphocytes would have exceeded the projecteddose of 3x104 cells per kilogram. In 28 patients the T-cell–depletedbone marrow was given after infusion of the peripheral-bloodprogenitor cells.
The inoculum was evaluated by measuring the quantity of granulocyte–macrophagecolony-forming units (CFU-GM), CD3+ cells, and CD34+ cells inthe bone marrow harvest, in the leukapheresis products afterpurification, and at each phase of cell manipulation, as describedelsewhere.25,26
No immunosuppressive treatment was given after transplantationfor prophylaxis against GVHD. All but three recipients receivedG-CSF (5 µg per kilogram per day) for a median of eightdays starting on the fourth day after transplantation. Antifungalprophylaxis consisted of amphotericin B (0.5 mg per kilogram)or liposomal amphotericin B (AmBisome, NeXstar, Boulder, Colo.;1 mg per kilogram) or both, from day 0 to day 30. Prophylaxisagainst cytomegalovirus infection included ganciclovir (5 mgper kilogram per day) from day 5 to day 20. Maintenance treatment,given two or three times weekly, continued until day 210.
Assessment of Engraftment and Immunologic Studies
Engraftment was assessed according to published criteria.27Chimerism was detected by karyotyping peripheral-blood lymphocytesand by polymerase-chain-reaction amplification of a panel ofvariable-number tandem-repeat regions with different DNA polymorphismpatterns.28,29,30 Subtypes of lymphoid cells present after transplantationwere identified by two-color immunofluorescence and flow cytometry.The frequencies of T cells responding to polyclonal activatorswere evaluated with a sensitive limiting-dilution assay in thepresence of phytohemagglutinin and feeder cells.31
The diagnosis and the degree of acute and chronic GVHD wereassessed according to consensus criteria.32
Statistical Analysis
Patients were considered able to be evaluated for acute GVHDat the time of engraftment and for chronic GVHD beginning 100days after engraftment. Rates of relapse and event-free survivalwere evaluated by Kaplan–Meier analysis. The log-ranktest was used for comparisons.
The reported outcomes are as of April 30, 1998.
Results
Recipients and Donors
Table 1 summarizes the characteristics of the patients. Theirmedian age was 22 years (range, 4 to 53); 11 patients were lessthan 16 years old, and 5 were older than 40. The median ageof the donors was 41 years (range, 18 to 59). Only one donor–recipientpair was negative for cytomegalovirus. All seven patients undergoingtransplantation during their first complete remission (threepatients with AML and four with ALL) had poor prognostic features.Most of the 22 patients in their second or third remission hada high risk of leukemic relapse or transplantation-related death;7 had had a relapse after autologous transplantation. Fourteenpatients (six with AML and eight with ALL) were in chemoresistantrelapse at the time of transplantation. Anti–donor-lymphocyteantibodies were detected in one patient who underwent plasmapheresisand successful engraftment.
Harvesting of bone marrow followed by mobilization of peripheral-bloodprogenitor cells was well tolerated by the donors. Moderatebone pain occurred in 43 percent and fever in 13 percent. Itwas not necessary to decrease the dose of G-CSF because of sideeffects. Two donors required central venous access.
Bone Marrow Fractionation
The final product of bone marrow fractionation contained 3.3x104to 39.1x104 CFU-GM per kilogram of the recipient's body weight(mean ±SD, 18.2x104 ± 10.9x104) and 0.2x106 to5.4x106 CD34+ cells per kilogram (mean, 1.2x106± 1.1x106).T-cell subgroup analysis demonstrated a 3.5 log10 depletionof CD3+ cells (the difference between the starting number ofcells and the final number in the inoculum, expressed logarithmically).
Mobilization and Processing of Peripheral-Blood Progenitor Cells
Table 2 lists the number of mononuclear cells, CFU-GM, CD34+cells, and CD3+ cells collected in four leukaphereses and recoveredat each stage of the purification procedure. The final productcontained approximately 74 percent of the starting populationof CD34+ cells, with a purity of 70 percent. A T-cell depletionof 4.3 log10 was achieved.
Table 2. Cell Contents of Unfractionated Leukapheresis Products and at Each Stage of Purification.
In 15 patients, the final inoculum (containing only peripheral-bloodprogenitor cells) contained 7.4x106 to 46.9x106 mononuclearcells per kilogram (mean, 19.9x106±12.0x106), 3.8x106to 33.7x106 CD34+ cells per kilogram (mean, 14.0x106±8.7x106),and 0.8x104 to 7.5x104 CD3+ cells per kilogram (mean, 2.7x104±2.0x104).In 28, the final inoculum (containing bone marrow and peripheral-bloodprogenitor cells) contained 16.5x106 to 112.1x106 mononuclearcells per kilogram (mean, 39.8x106±21.7x106), 3.1x106to 25.0x106 CD34+ cells per kilogram (mean, 10.6x106±5.4x106),and 0 to 21.5x104 CD3+ cells per kilogram (mean, 3.5x104±4.2x104).
Engraftment
In 41 of the 43 patients, the primary transplantation resultedin durable engraftment, with achievement of neutrophil countshigher than 1000 per cubic millimeter at a median of 11 days(range, 8 to 19). Platelet counts of 50,000 per cubic millimeterwere reached at a median of 29 days (range, 13 to 124). Twopatients (both with ALL) had primary graft failure between 16and 22 days after transplantation. One patient (a seven-year-oldchild) had received bone marrow and peripheral-blood cells containing25.0x106 CD34+ cells per kilogram and 21.5x104 CD3+ cells perkilogram. In both cases, rejection was reversed by the transplantationof T-cell–depleted peripheral-blood progenitor cells froma different family member after further immunosuppression withcyclophosphamide (80 mg per kilogram over a two-day period)and antithymocyte globulin (25 mg per kilogram over a five-dayperiod). Thus, sustained engraftment was achieved in all patients.No late rejection of a graft has been observed. Analysis ofDNA polymorphism documented full donor-type chimerism in boththe peripheral blood and the bone marrow of all the patients(data not shown).
GVHD
In none of the patients who could be evaluated did either acuteor chronic GVHD develop. To improve immunologic reconstitution,two patients received donor T lymphocytes (3x104 per kilogram)three months after transplantation. Despite the low number ofT cells infused, severe acute GVHD developed in one patient,and the patient died.
Immunologic Reconstitution
Peripheral-blood counts of natural killer cells returned tonormal within two to four weeks after transplantation. CD4+T-cell counts were below 100 and 200 cells per cubic millimeterfor as long as 10 and 16 months, respectively. The frequenciesof T cells responding to polyclonal activators in a sensitivelimiting-dilution assay were approximately 1 in 100 cells inthe first month and 1 in 10 cells 10 months after transplantation(with a control frequency of approximately 1 in 2).
Death from Causes Other Than Leukemia
Mortality from causes other than leukemic relapse was 40 percent.Sixteen of the 29 patients in remission (7 in a first remissionand 22 in a second or third remission) and 1 of the 14 in relapseat the time of transplantation died. Infection was the mostfrequent cause of death (Table 3). Five deaths were due to systemicbacterial infections (with pseudomonas in three cases and staphylococcusin two), five to fungal infections (aspergillus in three andcandida in two), and one to cytomegalovirus-associated pneumonia.High-grade B-cell lymphoproliferative disease occurred in twopatients. The other four patients died of toxic causes. Oneother patient with AML, who underwent transplantation in relapse,died of acute GVHD induced by a donor-lymphocyte infusion (3x104per kilogram) administered three months after transplantationin order to strengthen the antileukemic effect. No differencein transplantation-related mortality was observed between patientswith AML and those with ALL.
Two of the 20 patients with AML and 11 of the 23 patients withALL had a relapse. Of these 13 relapses, 7 occurred in patientswho were in relapse at the time of transplantation, 4 in patientswho were in a second remission, and 2 in patients who were ina third remission. The probability of relapse after transplantationwas 0.13±0.08 for patients with AML and 0.63 for patientswith ALL (P=0.004). The risk of leukemic relapse after transplantationreached borderline significance (P=0.056) in patients with ALLwho were in remission as compared with those who had had a relapse(Figure 2).
After two years, the mean (±SD) probability of relapse for the 8 patients with ALL who were in relapse at the time of transplantation was 0.85±0.13, and that for the 15 patients with ALL who were in remission (4 in first complete remission and 11 in second or third complete remission) at the time of transplantation was 0.44±0.17 (P=0.06). The probability of relapse for the 20 patients with AML was 0.13±0.08 during the 1.7-year observation period.
Survival
As of April 30, 1998, 12 of the 43 patients (28 percent) werealive and free of disease, with a median follow-up of 18 months(range, 8 to 30). Nine patients had been followed up for morethan one year. All surviving patients had a Karnofsky scoreof 100. The probability of disease-free survival differed betweenpatients with AML and those with ALL (P=0.052): it was 0.36±0.11at 1.5 years for the 20 patients with AML and 0.17±0.07at 2.5 years for the 23 patients with ALL (Figure 3). Of theseven patients at high risk who underwent transplantation duringa first remission, three were alive (two with AML and one withALL). Of the other four, one died of high-grade B-cell lymphoma,two of infections, and one of renal failure.
Figure 3. Probability of Disease-free Survival in Patients with ALL or AML.
The mean (±SD) probability of disease-free survival was 0.36±0.11 for the 20 patients with AML at 1.5 years. For the 23 patients with ALL, it was 0.17±0.07 at 2.5 years.
Discussion
Our study confirms and extends our previous finding that transplantationof bone marrow from related donors who share only one HLA haplotypewith the recipient, preceded by intensive chemoradiotherapyand consisting of the infusion of large numbers of T-cell–depletedhematopoietic stem cells, results in a rate of engraftment20,33that overlaps with the rate seen with HLA-matched transplantsfrom unrelated donors.27 The rapid engraftment seen in the presentseries was similar to that observed with transplantation ofHLA-identical allogeneic peripheral-blood CD34+ cells.34 Nolate graft failures occurred, and full donor-type chimerismwas achieved in all cases.
Fifteen patients received transplants consisting only of CD34+cells that had been positively selected from peripheral-bloodmononuclear-cell collections. Although the inoculum had beendepleted of cell subpopulations that can induce specific tolerancetoward donor-type antigens in animals,35,36,37,38 a high rateof engraftment was maintained. This finding provides strongevidence that supplementing peripheral-blood progenitor cellswith bone marrow in transplantations from mismatched donorsis unnecessary. In addition, it is possible that infusing largenumbers of purified CD34+ cells enhances engraftment. A recentstudy showed that human CD34+ cells were capable of reducingthe frequencies of cytotoxic T-lymphocyte precursors directedagainst the histocompatibility antigens of the infused cells,but not against third-party cells.39 Likewise, purified earlyhematopoietic progenitors with the Sca-1+Lin– phenotypesuccessfully overcame the residual immunity of the host in lethallyand sublethally irradiated mice.40,41
A striking finding was that there was no GVHD in these patientswith acute leukemia, most of whom were adults. Low rates ofGVHD have been reported in patients with severe combined immunodeficiencywho received haploidentical transplants, in whom a mean thresholddose of 4x104 T cells per kilogram was identified.42 Ten ofour patients who could be evaluated received 4x104 to 8x104T lymphocytes per kilogram, which was slightly above this threshold,but GVHD did not develop. The antithymocyte globulin, with aplasma half-life of six days, that was administered during conditioningmight have helped prevent GVHD by a cytotoxic effect againstdonor T lymphocytes.
Another aim of this study was to test a conditioning regimenthat would facilitate engraftment of an extensively T-cell–depletedmismatched transplant yet not have excessive nonhematologictoxicity, which has been a considerable problem in previousclinical trials.43,44,45 Substituting fludarabine for cyclophosphamidedid not reduce the degree of immunosuppression (even at thelower dosage of fludarabine), as indicated by the lack of clonableT cells in peripheral blood at the end of the conditioning regimenand the excellent engraftment. Furthermore, nonhematologic toxicitywas minimal: there was no veno-occlusive disease, and the incidenceof severe mucositis was low. Because lethal pulmonary decompensationoccurred in 2 of the first 10 patients, we reduced the dosesof thiotepa and lung radiation. After these modifications, thiscomplication did not occur again. For the last 30 patients,pretransplantation conditioning also included cyclosporine inan attempt to inhibit cytokine release after chemoradiotherapy,which has been observed in vitro46 and in vivo.47 The specificrole of cyclosporine in lowering transplantation-related mortalityin these patients would be extremely difficult to establish.
A serious problem in the transplantation of T-cell–depletedbone marrow is an increased risk of relapse after transplantation.48,49In our study, relapses occurred in patients with ALL, particularlythose in relapse at the time of transplantation. This resultwas not unexpected, and it mirrored the relapse rate in similarpatients with ALL after transplantation with unmanipulated matchedmarrow.50 To date, 2 of the 20 patients with AML have had arelapse, even though all were at high risk. Although follow-upis short, in our previous, pilot study the cumulative incidenceof relapse after transplantation was 28±17 percent at4.5 years (minimal follow-up, 3 years) in 12 patients with advancedAML. These results suggest that T-cell–depleted mismatchedtransplants trigger unique graft-versus-leukemia effector mechanisms.In many of the 43 donor–recipient pairs in the presentstudy, the donor's natural killer cells failed to recognizethe recipient's major-histocompatibility-complex allotypes and,consequently, were capable of killing hematopoietic targetsfrom the recipient in vitro. After transplantation, we weresurprised to find that the new repertoire of donor natural killercells contained high frequencies of donor-versus-recipient alloreactivenatural killer clones in absence of GVHD.50 Moreover, a largepercentage of reconstituting T cells displayed allotype recognitionsimilar to that of natural killer cells.51,52 Because AML butnot ALL blasts were targets of donor-versus-recipient natural-killer-cellalloreactivity, it is possible that these natural killer cellsare partly responsible for the low rate of relapse in patientswith AML.
The high incidence of infectious complications was probablydue to the delay in the reconstitution of T cells. Because ofthe extended period of susceptibility to infection, we administeredantiviral and antifungal prophylaxis, but bacterial and fungalinfections still occurred, resulting in 59 percent of all nonleukemicdeaths. Although all but one donor–recipient pair werecytomegalovirus-positive, cytomegalovirus pneumonia was preventedin all patients except one.
The slow rate of T-cell recovery appears to be due to the lowT-cell content of the graft. Immunologic reconstitution wasmuch faster in our previous series of patients, who received10 times as many T lymphocytes. Unfortunately, this approachresulted in an 18 percent incidence of severe GVHD.20 Previousstudies of T-cell–depleted transplants from unrelateddonors have been complicated by a high rate of lymphoproliferativedisorders related to Epstein–Barr virus.51,53 In thisstudy, the incidence of these disorders was relatively low (<5percent), perhaps because of the lack of post-transplantationimmunosuppressive therapy or the few B cells in the graft.
In conclusion, our overall results in terms of transplantation-relatedmortality and disease-free survival compare favorably with theoutcome expected in patients who have the same stage of diseaseand who receive transplants from matched unrelated donors.27The high rate of engraftment, the elimination of GVHD, and theminimal nonhematologic toxicity of the conditioning regimendemonstrate that the main obstacles that limited the use ofmarrow from relatives with only one matched haplotype have beenovercome. Since virtually every patient with hematologic cancerhas a haplotype-mismatched relative, further refinements ofthis strategy will increase the probability of a cure.
Supported in part by the Comitato per la Vita Daniele Chianelliand by grants from the Associazione Italiana Ricerche sul Cancro,the Associazione Italiana Leucemie e Linfomi, and the IstitutoSuperiore di Sanità Italy–USA Program on Therapyof Tumors.
We are indebted to Prof. E. Donnal Thomas and Prof. Robert R.Negrin for their critical review of the manuscript; to TizianaZei, Roberta Jacucci, and Fabiola Bariletti for their excellenttechnical assistance; and to Dr. Geraldine Boyd and CatherineGillies for assistance in the preparation of the manuscript.
Source Information
From the Hematopoietic Stem Cell Transplant Program, Department of Internal and Experimental Medicine (F.A., A. Tabilio, A.V., I.C., A. Terenzi, F.F., L.R., G.B., M.F.M.), and the Department of Radiotherapy (C.A., P.L.), University of Perugia, Perugia, Italy; and the Department of Immunology, Weizmann Institute, Rehovot, Israel (Y.R.). Other authors were Rita Felicini, M.D., Flavio Falcinelli, M.D., Alessandra Carotti, M.D., Katia Perruccio, M.D., Stelvio Ballanti, M.D., and Antonella Santucci, M.D. (Department of Internal and Experimental Medicine, University of Perugia), and Cesare Gambelunghe, M.D. (Blood Bank, Azienda Ospedaliera, Perugia).
Address reprint requests to Dr. Aversa at the Istituto di Ematologia, Università di Perugia, Policlinico Monteluce, Via Brunamonti, 06100 Perugia, Italy.
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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.
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Full Text
N Engl J Med 1999;
340:809-812, Mar 11, 1999.
Correspondence
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