transplantation versus-host disease after matched ...

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1996 88: 4383-4389

Tacrolimus and minidose methotrexate for prevention of acute graftversus-host disease after matched unrelated donor marrow transplantation D Przepiorka, C Ippoliti, I Khouri, M Woo, R Mehra, D Le Bherz, S Giralt, J Gajewski, H Fischer, H Fritsche, AB Deisseroth, K Cleary, R Champlin, K Besien, B Andersson, R Maher and W Fitzsimmons

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Tacrolimus and Minidose Methotrexate for Prevention of Acute GraftVersus-Host Disease After Matched Unrelated Donor Marrow Transplantation By Donna Przepiorka, Cindy Ippoliti, lssa Khouri, Michael Woo, Rakesh Mehra, Donna Le Bherz, Sergio Giralt, James Gajewski, Harald Fischer, Herbert Fritsche, Albert B. Deisseroth, Karen Cleary, Richard Champlin, Koen van Besien, Borje Anderson, Rochelle Maher, and William Fitzsimmons Thirty adults with leukemia or lymphoma undergoing marrow transplantationfrom HLA-compatibleunrelated donors received tacrolimus (FK506). a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mglkgld intravenously (IV) by continuousinfusionfrom day -2, converted to oral at four times the IV dose following engraftment, and continuedthrough day 180 posttransplant. Methotrexate 5 mg/m2 was given IV on days 1.3,6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34%

(95% CI. 17% to 52%). and grades 3-4 GVHD in 17% (95% CI, 3% to 3190).Mild renal toxicity was common before day 100; 6390 of patients had a doubling of creatinine, and 5290 had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last IV dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 We concludethat tacroliyear was 4790(9590CI, 27% to 6696). mus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation. 0 1996 by The American Society of Hematology.

M

marrow transplantation has been encouraging. The inital reports suggested that tacrolimus could be used as salvage therapy for patients with chronic or acute GVHD even when resistant to cyclosporine and c o r t i ~ o s t e r o i d s .In ~ ~phase - ~ ~ I1 studies of HLA-identical marrow transplant recipients, the incidence of grades 2-4 acute GVHD was 41% to 44% with tacrolimus alone or in combination with short methotrexate or methylpredni~olone.'~~'~ Herein we report the results of a study of tacrolimus in combination with a reduced doseschedule of methotrexate for prevention of acute GVHD in recipients of marrow transplants from HLA-matched unrelated donors.

ARROW transplantation from HLA-matched unrelated donors has been established as a treatment option for patients with hematologic malignancies who have no suitable related d0n0r.I~In reports from multicenter groups and registries, survival after unrelated donor marrow transplantation has been 39% to 55% for patients with early leukemia and 13% to 23% for those with advanced dise a ~ e . * .Regimen-related ~-~ complications appear to be similar for recipients of matched related or unrelated donor but the risks of infections, graft failure and acute graft-versus-host disease (GVHD) are clearly higher in the latter group. ',8-10 Following unrelated donor marrow transplantation, grades 2-4 acute GVHD occurs in 59% to 79% of patients and grades 3-4 acute GVHD in 36% to 47% with most centers using the standard combination of cyclosporine and short methotrexate (15 mg/m' on day 1 and 10 mg/m' on days 3, 6, and 11) as pro phyla xi^.'.'.^,"'^.^' GVHD accounted for 29% to 33% of the mortality. The incidence of acute GVHD can be reduced by T-cell depletion of the marrow, but any potential benefit has been offset by higher incidences of graft failure, relapse and infection, and there was no improvement in survival.'." The addition of polyclonal or monoclonal anti-T-cell antibodies to the standard combination of cyclosporine and methotrexate for GVHD prophylaxis has not effectively reduced the incidence of GVHD,4.'2*13 and results using the triple combination of cyclosporine, methotrexate and methylprednisolone have been inconsistent. 14-'6 Tacrolimus (FK506) is an immunosuppressive macrolide lactone that blocks the earliest steps of T-cell activation by inhibiting the calcium-dependent signal transduction path~ a y . ' ~Although .'~ the mechanism of action, pharmacokinetics, and side-effect profile of tacrolimus are similar to those of cyclosporine, its immunosuppressive potency in vitro is 50 to 200 times greater than that of cyclosporine." In animal models that evaluated marrow transplantation with major disparities in histocompatibility, tacrolimus was active in preventing and treating acute GVHD.2'-23 The preliminary clinical experience with tacrolimus in Blood, Vol 88,No 1 1 (December l ) , 1996: pp 4383-4389

MATERIALS AND METHODS Patients. From January 1994 through December 1995, 30 adults with HLA-matched unrelated donors underwent transplantation using tacrolimus and minidose methotrexate for prevention of acute GVHD. In each case, the donor was serologically matched with the patient at HLA-A, -B, and -DR, and HLA-DR was further evaluated by sequence-specificprimer polymerase chain reaction.30All patients are at least 100 days from transplantation. Eligibility criteria for transplantation were as described." Patient characteristics are shown in Table 1. All patients had hematologic malignancies. The majority of the patients (77%) were not in remission or first chronic phase, and 37% had disease resistant to conventional therapy. The three

From the Departments of Hematology, Laboratory Medicine and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, rX; and Fujisawa USA, Deerjield, IL. Submitted April 3, 1996; accepted July 23, 1996. Supported in part by Fujisawa USA and Grant No. CA-16672 from the National Institutes of Health. Address reprint requests to Donna Przepiorka, MD, PhD, The U.T. M.D. Anderson Cancer Center, Section of Blood and Marrow Transplantation, 1515 Holcombe Blvd, Box 065, Houston, TX 77030. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.section 1734 solely to indicate this fact. 0 1996 by The American Society of Hematology. 0006-4971/96/881I -Oo29$3.Oo/O 4383

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PRZEPIORKA ET AL Table 1. Patient and Donor Characteristics

No. patients Median age (range) Patient sex Male Female Diagnosis CML in first chronic phase CML past first chronic phase ANL in first relapse ANL past first relapse MDS (RAEB) ALL past first relapse NHL in relapse CLL in relapse Resistant to therapy Prior transplant Preparative regimen CyclophosphamideflBl ThiotepalcyclophosphamidefrBl Thiotepa/busuIfan/cyclophosphamide

Median donor age (range) Histocompatibility HLA-A and -B serologic match HLA-DR serologic and molecular match HLA-DR serologic match and molecular mismatch Donor sex Male Female Patient-donor pair sex-mismatched Patient-donor CMV-seronegative pair

30 36 yr (22-49) 19 11 3 11 3 6 1

2 3 1 11 3 1 18 11 39 yr (19-53) 30 22

a 16 14

5 6

Abbreviations: ANL, acute nonlymphoblastic leukemia; MDS, myelodysplastic syndrome; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin’s lymphoma; CLL, chronic lymphocytic leukemia.

patients with chronic myelogenous leukemia in first chronic phase were 3.5, 5.5, and 8.5 years from diagnosis, respectively. Two patients had undergone autologous marrow transplantation and one patient had undergone unrelated donor marrow transplantation (from a different donor) at least 1 year previously. The protocol was approved by the Institutional Review Board oftheM.D. Anderson Cancer Center, and written informed consent was obtained from all participants. Preparative regimens and transplantation. The preparative regimens were administered as described previously.3’~3z Patients received either thiotepa (THIO) 5 mg/m2 intravenously (IV) on day -7, cyclophosphamide (CYC) 60 mgkg IV on days -6 and -5. and total body irradiation (TBI) 3 Gy on days -3, -2, -1 and 0; CYC 60 mgkg IV on days -7 and -6 followed by TB1 3 Gy on or THIO 250 mg/m’ TV on days -9, days -4, -3, -2, and -1; -8, and -7, busulfan (BU) 1 mgkg orally q 6 hours for 12 doses on days -6, -5, and -4, and CYC 60 mgkg IV on days -3 and -2. Patients with high-grade lymphoma, acute lymphoblastic leukemia, or a history of central nervous system involvement also received methotrexate 12 mg intrathecally or 6 mg intraventricularly with leucovorin rescue monthly from the 3rd through 12th months posttransplant. Day 0 is the day of marrowinfusion. Marrow harvests contained a median of 3.9 X 10’ nucleated cellskg (range 1.2 to 5.9) and were processed for ABO-incompatibility by standard measures when necessary. None of the marrows was depleted of T cells. Supportive care. The patients were hospitalized in laminar air-

flow rooms through engraftment. Filgrastim 5 pgkgld sc was given from day 7 through engraftment. Infection prophylaxis during the peritransplant period consisted of nonabsorbable antibiotics orally, vancomycin 1 gm IV daily, fluconazole 200 mg IV every 12 hours, and acyclovir 5 mgkg IV every 8 hours. All patients received broad spectrum antibiotics for neutropenic fever and hyperalimentation when needed. Blood products were irradiated at 25 Gy and filtered to remove leukocytes. Intravenous immunoglobulin 200 to 500 mg/ kgwasgiven weekly through day 100 andmonthly thereafter through 1 year. Once engrafted, the patients also received twiceweekly trimethoprim-sulfamethoxazoleorally or pentamidine by inhalation every 3 weeks. Cytomegalovirus (CMV)-seropositive patients received prophylactic ganciclovir 5 mgkg IV 5 days per week from engraftment through day 100. Foscarnet was given to patients unableto tolerate ganciclovir. Urine andbloodbuffy coats were tested for CMV by the shell vial assay before transplantation and weekly through day 100. CMV-seronegative patients with seronegative donors received acyclovir 400 mg orally twice daily through day 100. GVHD prophylaxis and treatmenf. Methotrexate 5 mg/mZIV was given on days 1, 3, 6, and 11. The dose was reduced or omitted for severe mucositis (oral ulceration or significant edema), reduction in creatinine clearance by more than 50%, or weightgainmore than 10 kg. Tacrolimus was administered at 0.03 mgkg/d IVby continuous infusion from day -2. Following engraftment when the patient was able to take medications orally, the 24-hour dose of tacrolimus was converted 1 IV:4 PO andgiven orally in a twicedaily divided dose. Doses were adjusted to maintain whole blood steady state or trough levels at 5 to 15 ng/mL byan automated microparticulate enzyme immunoassay (Abbott Laboratories, Abbott Park, IL).33Tacrolimus was discontinued or reduced in dose when blood levels were elevated or the serum creatinine was increased. For the first 10 patients, the dose of tacrolimus was tapered 33% at week 9 and at week 17, and tacrolimus was discontinued onday 180. For the remainder of the patients, tacrolimus was administered at full-dose through day 180 andtapered by 20% every 2 weeks thereafter. Patients were observed prospectively for development of acute GVHD. The diagnosis of GVHD was based on clinical evidence with histologic c~nfirmation,~~ and GVHD wasgradedaccording to the consensus criteria.’’ Patients who developed grade 24 GVHD were treated initially with methylprednisolone at 0.5 mgl kgIV q 6 hours. Toxicity grading. Early toxicity related to the preparative regimen (RRT) was graded according to the criteria of Bearman et al.3h In this system, grade 1 toxicity is reversible without treatment, grade 2 is not life-threatening but requires treatment, grade 3 requires lifesupport intervention, and grade 4 is fatal. RRT in each organ system was scored as the highest grade observed inthat organ system through day 28, except that deaths after day 28 as a result of RRT occurring before day 28 were also scored as grade 4. Adverse events that could be attributed to infection (culture-documented), bleeding, or other medications were not scored as RRT. The maximum toxicity score was the highest grade recorded in any individual organ system, and the cumulative toxicity score was the sum of the highest grades recorded for all eight organ systems. Assessment of engraftment. Neutrophil recovery was defined as the first of 3 consecutive days that the absolute neutrophil count (ANC) exceeded the target number (0.5 or 1.0 X 109L),and platelet recovery was defined as the day that the platelet count exceeded the target number (20 or 50 x 109/L)with no platelet transfusions the following week. Marrow biopsies and aspirates were examined at 1, 3, 6 , 12, 18, and 24 months after transplantation. Hematopoietic chimerism was evaluated by restriction fragment length polymorphisms at the AY-29 or YNH24 loci as de~cribed.~’ Statistical considerations. At the time of analysis, median inter-


FK506/MINI MTX FOR GVHD PROPHYLAXIS

val from transplantation was 12 months (range 3 to 26 months). Actuarial estimates of time to engraftment, discharge, GVHD, venoocclusive disease (VOD), infection, nephrotoxicity, relapse and death were calculated according to the method of Kaplan and Meier.38 RESULTS

Engrafhnent. Neutrophil recovery was delayed to day 35 in one patient because of autoimmune n e ~ t r o p e n i aand ,~~ the remainder engrafted by day 30 posttransplant. The median times to neutrophil recovery were 16 days (range, 11 to 35) for an ANC 20.5 X 109/Land 17 days (range, 12 to 36) for an ANC 21.0 X 109/L.Platelet recovery occurred in 84% of the patients by day 100. The median times to platelet recovery were 32 days (range 13 to loo+) for a platelet count 2 2 0 x lo9&,and 42 days (range, 16 to 100+) for a platelet count 2 5 0 X 109L GVHD. Ten patients developed grades 2-4 acute GVHD. Five patients had acute GVHD of the skin alone, and five had visceral involvement. The actuarial rate of grade 2-4 acute GVHD was 34% (95% CI, 17% to 52%), and that of grade 3-4 acute GVHD was 17% (95%CI, 3% to 31%) (Fig 1). The rates of grades 2-4 GVHD did not differ significantly between patients with molecularly matched donors and those without (28% v 50%, P = .15). Six patients had steroidresistant acute GVHD. Twenty-two patients survived at least 100 days posttransplant; the actuarial rate of chronic GVHD at 1 year was 59% (95% CI, 8% to 74%). GVHD prophylaxis compliance and toxicity through day 100. The full scheduled dose of methotrexate was administered to 100% of patients on day 1, 100% on day 3, 93% on day 6, and 43% on day 11. The most common reason for omitting the methotrexate was mucositis. Twenty-three (77%) patients developed grade 2 mucositis, and the remainder had grade 1 mucositis. For patients who were converted from IV to oral tacrolimus, the median last IV dose was 0.016 mgkg (53% of the scheduled dose). The median oral dose of tacrolimus on day

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100 was 0.049 mgkg (41% of the scheduled dose). Nine patients discontinued tacrolimus prematurely; 1 for nephrotoxicity, 2 for relapse, and 6 for terminal care or early death unrelated to nephrotoxicity. Before day 100.63% had a doubling of the creatinine from baseline, and 52% has a peak creatinine that exceeded 2.0 mg/dL (Fig 2). The median peak creatinine was 2.1 mg/dL (range 1.3 to 4.2). One patient was dialyzed. Other adverse events potentially related to tacrolimus included hyperkalemia (serum potassium >5.5 mEq/dL) (40%), tachycardia (3%), headache (3%), and seizure (3%). None of these events was life-threatening or fatal. Of the patients who were discharged from hospital, all required magnesium replacement, 59% required treatment of hypertension, and 5% required insulin. No patient developed hemolytic-uremic syndrome before day 100. Transplant-related complications through day 100. Seventy-seven percent of patients were discharged from hospital, and the median time of discharge was day 24 (range days 15 to 55). The incidence of grades 3-4 RRT was 3%. The median maximum RRT was 2, and the median cumulative RRT was 4 (range 2 to 8). Three (10%) patients developed VOD with a bilirubin exceeding 6 mg/dL, and for one patient this was fatal. Eleven patients (41%) developed hemorrhagic cystitis. Other life-threatening or fatal events included nonbacterial thrombotic endocarditis complicated by a myocardial infarction in one patient and toxic epidermal necrolysis presumably caused by an antibiotic in a second patient. Twenty-five patients had documented infections before day 100. These included 20 with gram positive bacteremia, 3 with gram negative bacteremia, 1 with anaerobic bacteremia, 1 with fungemia, 2 with invasive Aspergillus, and 11 with single or multiple viral infections (4 herpes simplex virus, 6 CMV, and 3 respiratory viruses). The actuarial incidence of CMV infection was 26% for seropositive patients or patients with seropositive donors. The CMV infections included 2 patients with viruria, 3 with pneumonia, and 2


PRZEPIORKA ET AL

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with enteritis. The CMV infections were diagnosed within the first 6 weeks posttransplant and contributed to 3 deaths. Relapse and survival. Seven patients had documented relapse posttransplant. The actuarial relapse rate at 1 year was 28% (Fig 3). Sixteen patients have expired. The causes of death include 6 infection, 2 GVHD and infection, 2 GVHD, 4 relapse, 1 VOD, and 1 nonbacterial thrombotic endocarditis. Day-100 survival is 73% (95% CI, 57%to 89%), and the survival at l year is 47% (95% CI, 27% to 66%) (Fig 3). DISCUSSION

Tacrolimus is a highly potent inhibitor of T-cell activation effective in the treatment and prevention of solid organ allograft rejection and in the treatment of selected autoimmune disorders." Phase I1 studies also suggested that tacrolimus is effective in the prevention of acute GVHD after HLAidentical marrow t r a n s p l a n t a t i ~ n .In ~ ~this . ~ ~study, we found that use of the combination of tacrolimus and minidose methotrexate resulted in a 34% incidence of grades 2-4 GVHD and a 17% incidence of grades 3-4 GVHD in adult recipients of HLA-matched unrelated donor marrow transplants. The incidence of severe GVHD is lower than reported with the standard combination of cyclosporine and methotrexate.1,2,4.6.11,12 Petersdorf et aI4' reported recently thatwhenusing cyclosporine and methotrexate as GVHD prophylaxis, the risk of acute GVHD after matched unrelated donor marrow transplantation was reduced for patients with donors genotypically identical for HLA-DRP1 alleles in comparison to those with molecularly-mismatched donors. The clinical impact, however, was not substantial. The group matched serologically and molecularly had an 88% incidence of grades 2-4 GVHD and 48% incidence of grades 3-4 GVHD.@Eight (27%) of our patients had donors with HLA-DR mismatches at the molecular level, and their incidence of GVHD was not significantly different from those with molecularly matched

donors, although the number of patients may be too small to detect a significant difference. Further evaluation is required to determine if using tacrolimus and methotrexate as prophylaxis obviates the need for molecular matching when identifying a suitable unrelated donor. Tacrolimus was tolerated well in this patient population. All patients achieved neutrophil recovery, and the intensity of regimen-related toxicitywasno greater thanreported historically for CYC/TBI and THIO/BU/CYC when cyclosporine was used for GVHD prophyla~is.".~' The spectrum of tacrolimus-related toxicities was also not worse than that reported for HLA-identical marrow transplant recipients receiving t a c r o l i m u ~ . ~In* fact, ~ ~ ~ the cumulative proportion of patients with doubling of the creatinine from baseline was somewhat less in our study. Because high concentrations of tacrolimus have been associated with renal ins~fficiency,"~.~' the lower rate of nephrotoxicity for our patients may have been due to the fact that our initial dose of tacrolimus (0.03 mg/kg/d) was less than used in the first Phase I1 study,2' and our target whole blood tacrolimus concentration range (5 to 15 ng/mL) was also narrower than in the phase I1 studies.'"'' We observed thatwith dose reductions for highblood concentrations and for nephrotoxicity, the majority of patients in our study received less tacrolimus than originally planned by protocol, suggesting that the initial dose of tacrolimus or the converson factor for using oral drug maynot be correct for these patients. The need for dose reductions may result from pharmacokinetic interactions between tacrolimus and other drugs used. Tacrolimus is metabolized by the hepatic cytochrome P450 IIIA system. Drugs such as fluconazole and nifedipine, which are used commonly by the marrow transplant patients, block this enzyme and are potent inhibitors of tacrolimus metaboli~m.~.~' Thus, the reduction in tacrolimus clearance by these drugs could account for the higher blood concentrations and lower dose requirements. Appropriate dosing of tacrolimus for the marrow transplant patients treated with fluconazole or other inhibitors of the cytochrome P450 system remains to be determined. The dose-schedule of short methotrexate (15 mg/m'on day 1 and 10 mg/m' on days 3, 6 , and 1 I ) used in combination with cyclosporine was determined in a canine marrow transplantation m0de1,~' andthe efficacy of the combination was established by randomized st~dies."~~' Combining cyclosporine with methotrexate did not reduce the amount of methotrexate that could be admini~tered;~and reducing or omitting the methotrexate on days 6 or 1 l was associated with a significant increase in the risk of acute GVHD shortly thereafter.49The minidose methotrexate regimen (5 mg/m' IV was given on days 1, 3, 6, and 1 1 ) was developed at the M.D. Anderson Cancer Center in an effort to reduce mucosal and hepatic complications, andithasproved effective in combination with cyclosporine for prevention of acute GVHD in HLA-identical marrow transplant recipient^.'",^' Our results show thatminidose methotrexate is also effective in combination with tacrolimus as GVHD prophylaxis in the unrelated donor marrow transplant recipients. The efficacy of the reduced dose-schedule of methotrexate was not due to an increase in the area under the time-concentration curve

From bloodjournal.hematologylibrary.org by guest on July 14, 2011. For personal use only. FK506/MINI MTX FOR GVHD PROPHYLAXIS

(AUC), because no differences in methotrexate AUC were found in a randomized study comparing tacrolimus to c y c l ~ s p o r i n enor , ~ ~does methotrexate alter the clearance of tacrolimus.28In view of the apparent reduction in risk of early morbidity without loss of efficacy, further evaluation of the minidose methotrexate schedule is warranted. Infections were clearly a problem in our patients. We found a 26% incidence of CMV infection in the patients at risk, and only half responded to treatment. These infections were not necessarily a failure of ganciclovir prophylaxis, since most developed during the initial period of neutropenia or just after engraftment but before initiation of ganciclovir prophylaxis. These findings may be related to the small population in this study. In a preliminary evaluation, we recently noted that the risks of acute GHVD and early survival for HLA-nonidentical marrow transplant recipients using tacrolimus and minidose methotrexate were similar to those for patients receiving partially T-cell-depleted marrow transplants and a cyclosporine-based GVHD prophylaxis regimen.53The ability to achieve control of GVHD comparable to that seen with partial T-cell depletion represents an advance for pharmacologic GVHD prophylaxis. Whether the increased risks of infection and relapse seen with T-cell depletion can be avoided by using tacrolimus without manipulations of the marrow is unknown. Controlled trials will be required to firmly determine the comparative activity of this new GVHD prophylaxis regimen. ACKNOWLEDGMENT We are grateful to the Transplant Clinical Nurse Specialists and the Nursing Staffs of IOLP and 12LP for excellent patient care. REFERENCES 1. Beatty PG, Hansen JA, Longton GM, Thomas ED, Sanders JE, Martin PJ, Bearman SI, Anasetti C, Petersdorf EW, Mickelson EM, Pepe MS, Appelbaum FR,Buckner CD, Clift RA, Petersen FB, Stewart PS, Storb RF, Sullivan KM, Tesler MC, Witherspoon R P Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies. Transplantation 5 1:443, 1991 2. Keman NA, Bartsch G, Ash RC, Beatty PG, Champlin R, Filipovich A, Gajewski J, Hansen JA, Henslee-Downey J, McCullough J, McGlave P, Perkins HA, Phillips GL, Sanders J, Stroncek D, Thomas ED, Blume KG: Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 328:593, 1993 3. Downie TR, Hows JM, Gore SM, Bradley BA, Howard MR: A survey of use of unrelated volunteer donor bone marrow transplantation at 46 centres worldwide, 1989-1993. Bone Marrow Transplant 15:499, 1995 4. Dini G , Lanino E, Lamparelli T, Barbanti M, Sacchi N, Carcassi C, Locatelli F, Porta F, Rosti G, Alessandrino EP, Aversa F, Marenco P, Guidi S, Uderzo C, Amoroso A, Di Bartolomeo P, Garbarino L, La Nasa G , Rosetti F, Miniero R, Soligo D, Manfredini L, Bacigalupo A: Unrelated donor marrow transplantation: inital experience of the Italian Bone Marrow Transplant Group (GITMO). Bone Marrow Transplant 17:55, 1996 5. Beatty PG, Ash R, Hows JM, McGlave PB: The use of unrelated bone marrow donors in the treatment of patients with chronic myelogenous leukemia: Experience of four marrow transplant centers. Bone Marrow Transplant 4:287, 1989

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