Treatment of leukemia with partially matched related bone marrow transplantation

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1 Bone Mrrow Trnsplnttion, (1997) 19, Stockton Press All rights reserved /97 $12. Tretment of leukemi with prtilly mtched relted bone mrrow trnsplnttion RK Munn 1, PJ Henslee-Downey 1,4, EH Romond 1, EJ Mrcinik 1, DR Fleming 1,5, MJ Messino 1,6, JS Mcdonld 1,7, MK Ryens 2, EJ Hrder 1,8, GL Phillips 1 nd JS Thompson 3 Mrkey Cncer Center, Divisions of 1 Hemtology nd Oncology, 3 Allergy nd Immunology, 2 Deprtment of Internl Medicine nd Deprtment of Sttistics, University of Kentucky Medicl Center, Lexington, KY, USA Summry: donor. 1 Alterntive donor sources for llogeneic trnsplnttion include prtilly mtched relted donors (PMRD) or The results of prtilly mtched relted donor (PMRD) unrelted donors (URD). Ech source hs limittions; mrrow trnsplnttion for 82 ptients with leukemi neither is clerly preferred when mrrow from n HLAmtched re reported, including 45 who received two ntigen disprte sibling is unvilble. grfts. Following intensive rdiochemotherpy, Unlike mny cses of URD trnsplnts, prtilly ptients received grfts which were prtilly depleted mtched relted donor trnsplnt cn often be performed of T cells by the monoclonl ntibody T1B9 nd comp- promptly, s most siblings will hve been tissue typed in n lement. Acturil probbility of engrftment ws 86% ttempt to find histocomptible donor. While the Ntionl (95% CI = 78 93%). The medin dy to engrftment Mrrow Donor Progrm (NMDP) hs reported success in ws similr mong recipients of grfts disprte t one, finding serologiclly mtched unrelted donor for 51% of two or three ntigen loci. The incidence of severe ptients, 2 the medin intervl between serch initition nd (grdes III nd IV) cute grft-versus-host disese nd trnsplnttion ws 28 dys (rnge dys). 2 extensive chronic grft-versus-host disese ws 13% Also, the probbility tht n URD will be found for nd 6%, respectively. The probbility of disese-free member of n ethnic minority group is low. Despite recruit- survivl for the entire cohort of ptients is 31% t 3 ment efforts, less thn 5% of registry prticipnts re yers. Age 3 yers, erly or intermedite stge disese Africn-Americn. 3 A PMRD is likely to be the only option nd grft disprte t one or two loci predicted for llogeneic stem cell dontion for these individuls. longer disese-free survivl in multivrint nlysis. Severl investigtors hve reported results of PMRD Moreover, 47% of ptients receiving PMRD grfts dis- mrrow trnsplnttion. 4 9 The lrgest single institution series prte t two loci who hd both these fvorble pretrnsplnt report, tht from Settle, Wshington, utilized T replete chrcteristics were live nd free of disese mrrow. 4 Smller series hve utilized vrious methods of 3 yers fter trnsplnttion. We believe tht the utiliztion T cell depletion (TCD). While TCD hs not been shown of PMRDs, especilly those with two ntigen dis- conclusively to improve survivl fter PMRD (or unrelted prte grfts, cn extend llogeneic trnsplnttion to donor) trnsplnts, it ppers to decrese the risk of cute dditionl leukemic ptients lcking histocomptible grft-versus-host disese (GVHD), 6 mjor cuse of tretment-relted donor, with cceptble results. mortlity. The Interntionl Bone Mrrow Keywords: mismtched BMT; leukemi; T cell depletion Trnsplnt Registry (IBMTR) reported lrge series of ptients receiving PMRD trnsplnts. 6 Those receiving T cell-depleted grfts experienced incresed rtes of grft filure nd decresed GVHD, however overll, leukemi-free Allogeneic hemtopoietic stem cell trnsplnttion regi- survivl ws not improved. mens, utilizing either mrrow or blood, represent the only Our institution hs utilized TCD with monoclonl nticurtive option for mny ptients with leukemi. Unfortu- body rised by one of us (JST) plus complement to deplete ntely the mjority of ptients who re cndidtes for llo- specific popultion of CD3 T cells. Detils regrding this geneic trnsplnttion do not hve histocomptible sibling ntibody hve been previously reported. 1 We report the results of 82 PMRD mrrow trnsplnttions for ptients with leukemi performed t our institution between 1988 Correspondence: Dr RK Munn, Mrkey Cncer Center, Room CC41, 8 Rose Street, Lexington, KY , USA nd Present ddresses: 4 Center for Cncer Tretment nd Reserch, University of South Crolin, 7 Richlnd Memoril Prk, Columbi, SC 2923; 5 Jmes Grhm Brown Cncer Center, 529 S Jckson St, Louisville, KY 4292; 6 Regionl Oncology Assocites, 445 Biltmore Avenue, Suite Mterils nd methods G19, Asheville, NC 2881; 7 Temple University, Comprehensive Cncer Center, 3322 N Brod St, Phildelphi, PA 1914; nd 8 Lexington Infec- Ptient selection tious Disese Consultnts, Centrl Medicl Plz, 178 Nicholsville Rd, Suite 63, Lexington, KY 453, USA Received 15 Jnury 1996; ccepted 17 October 1996 Between 1988 nd 1992, 82 ptients with leukemi received prtilly mtched relted bone mrrow trnspln-

2 Prtilly mtched relted donor BMT 422 ttion t the University of Kentucky. None of these ptients selection of the donor ws mde ccording to previously hd n HLA-mtched sibling donor. Additionl eligibility published guidelines. 12,13 criteri included the presence of suitble relted hploidenticl donor, ge 5 yers, the bsence of life-thretening infection, nd ner norml crdic, heptic, pulmonry Trnsplnt procedure nd renl function. Relpse nd survivl t the dte of lst Ptients were conditioned prior to trnsplnttion with totl contct were nlyzed s of April Medin follow-up body irrdition, 14 cgy in nine frctions (dose rte of of surviving ptients is 5 yers (rnge 3 7 yers). Ptient 12.5 cgy/min) over 3 dys using high energy liner ccelertor chrcteristics re shown in Tble 2. beginning on dy 9 nd continuing to dy 7. Totl lung doses were reduced to 7 cgy by 5% trnsmission Donor recipient HLA comptbility/donor selection blocks. Subsequently, etoposide (2 mg/kg) ws given on dy Ptients nd donors were HLA typed ccording to stndrd 6, cytrbine (3 g/m 2 every 12 h for six doses) on dys techniques. 11 HLA A, B, nd DR dt re complete for 81 4, 3 nd 2, nd cyclophosphmide (5 mg/kg) on dys of 82 ptients. DR typing is incomplete for two ptients. 2 nd 1. Methylprednisolone (1 mg/m 2 ) ws strted t The degree of donor recipient HLA-disprity is shown in 8. pm on dy 2 nd continued every 12 h for four totl Tble 1. doses. All doses were clculted utilizing the ptient s idel Among fmily members who were potentilly PMRDs, body weight. The men number of mononucler cells hrvested preference ws given to the fmily member who most ws /kg of recipient body weight (rnge closely mtched the ptient. If more thn one fmily mem ). ber ws vilble for mrrow dontion using this criteri, The men number of mononucler cells infused ws Tble 1 Ptient chrcteristics n = /kg recipient body weight (rnge ). Mrrow grfts were prtilly depleted ex vivo of T cells with monoclonl ntibody T1B9 (1A-31) nd rbbit serum complement. The verge TCD chieved with this ntibody Chrcteristic Number ws logs. 1 Post-trnsplnt grft-versus-host prophylxis consisted of either nti-cd5 monoclonl ntibody linked to ricin A chin (Xomzyme; Xom Corpor- Ptient ge (yers) Medin 19 tion, Berkley, CA, USA).1 mg/kg intrvenously dily Rnge (.7 49) for 7 12 dys beginning between dy 5 nd dy 1 posttrnsplnt, Disese nd/or cyclosporine 5 mg/kg/dy, strting on ALL 35 dy 2 with dose djustment beginning on dy +3 post- AML 15 trnsplnt ccording to serum levels nd renl function. CML 28 Ptients lso received methylprednisolone 3 mg/m 2 begin- MDS 4 ning dy +5 nd continuing to dy +16. In the bsence of Disese sttus b GVHD, the dose ws then tpered by 1% week. Erly 1 Intermedite 29 Supportive cre included nursing in privte, positive Advnced 43 pressure HEPA filtrtion rooms. Ptients with positive CMV serology were treted with high-dose cyclovir until HLA mtching 1 Antigen disprte 14 engrftment. Gncyclovir replced cyclovir during the 2 Antigen disprte 45 conditioning nd post-engrftment period in 199. Intr- 3 Antigen disprte 2 venous gmmglobulin nd trimethoprim-sulfmethoxzole Phenotypiclly mtched 1 or inhled pentmidine ws given to prevent Pneumocystis DR typing incomplete 2 crinii. Brod-spectrum ntibiotics nd ntifungl therpy Ptient/donor CMV sttus / 18 were dministered s indicted. /+ 18 +/ 18 +/+ 26 Outcome definitions?/+ 1 Engrftment ws defined s the 3rd consecutive dy on +/? 1 which ptients hd n bsolute neutrophil count (ANC) Ptient/donor sex /l. Ptients who died dy 21 post-trnsplnt Mle Mle 29 were excluded from this nlysis. 14 GVHD ws grded Mle Femle 25 using published criteri. 15 Ptients who experienced erly Femle Mle 1 Femle Femle 18 deth (prior to dy 21) or non-engrftment were excluded from nlysis of GVHD. Ptients who engrfted nd lived ALL = cute lymphoblstic leukemi; AML = cute myelogenous leukemi; longer thn 1 dys fter trnsplnttion were evluted CML = chronic myelogenous leukemi; MDS = myelodysplstic syn- for chronic grft-versus-host disese (cgvhd). Disese drome. b sttus prior to trnsplnttion ws ctegorized s erly, Erly = cute leukemi in first remission or CML in chronic phse; Interintermedite or dvnced. Acute leukemi in first remission medite = cute leukemi in ny remission other thn first nd CML in ccelerted phse; Advnced = refrctory nd relpsed leukemi nd CML in blst crisis. nd chronic myelogenous leukemi in chronic phse were defined s erly disese. Ptients with cute leukemi in

3 Prtilly mtched relted donor BMT ny remission other thn first, nd CML ptients in cceler- the ptients trnsplnted with grfts disprte t one, two, ted phse were considered to hve intermedite disese. nd three ntigen loci. Advnced disese ptients hd refrctory leukemi, relpsed leukemi, or CML in blst crisis. Ptients with myelodsyplsi without evolution to cute leukemi were Engrftment deemed to hve erly disese, while those with 3% mr- Eight ptients who died before dy +21 were excluded from row blsts were clssified s dvnced. Remission ws the engrftment nlysis. Of the 74 remining ptients, 1 defined s n M1 mrrow ( 5% blsts), norml cytogen- filed to engrft. Two of these 1 ptients subsequently etics nd norml flow cytometry. engrfted fter mrrow boosts. Interestingly, nine of those filing to engrft were trnsplnted for chronic myelogenous Sttisticl methods leukemi. The medin dy to engrftment for the remining 64 Acturil probbilities of overll survivl nd disese-free ptients ws 18 dys (rnge 7 35 dys). The cturil probsurvivl were clculted using stndrd life-tble bility of engrftment by dy 14 post-trnsplnt ws 86% methods. 16 Comprison between groups ws performed (95% CI = 78 93%), nd ws not ffected by the overll using the Wilcoxon test. 17 Kpln Meier curves were n- degree of HLA disprity between the donor nd the recipient lyzed to determine the effect of ge, degree of HLA disprity, or the HLA disprity in the rejection direction nd disese stte on overll survivl nd disese-free (Figure 1). survivl. Rtes of non-engrftment, the medin time to engrftment, the effect of HLA disprity on engrftment, the incidence of GVHD nd cgvhd ccording to the Acute nd chronic GVHD degree of HLA disprity re reported. The 2 goodness of The 66 ptients who engrfted were nlyzed for GVHD. fit test ws used to ssess ssocition between ctegoricl Tble 3 depicts the grde of GVHD developing t ech vlues. level of HLA disprity. Fifteen of 66 (22%) ptients experienced grde II, 11 of 66 ptients (17%) developed severe (grdes III or IV) GVHD by dy 1 post-trnsplnt. The Results frequency of severe GVHD mong ptients receiving one, two, or three ntigen disprte grfts ws similr (13%, Ptient chrcteristics 18% nd 18%, respectively). We nlyzed the effect of vrious GVHD prophylxis Chrcteristics of those trnsplnted re reported in Tble regimens in the 45 ptients trnsplnted with grfts dispr- 1. Thirty of the 82 ptients were less thn ge 16. However, te t two loci. Twenty-four of these ptients received 26 ptients were older thn 3 t the time of trnsplnt nd immunotoxin-ricin A chin prophylxis, 2 received cyclo- 11 were ge 4 or older. Only 1 ptients (12%) hd erly, sporine prophylxis, nd one received both. The incidence while 29 ptients (35%) hd intermedite, nd 43 (52%) of severe (grde III or IV) GVHD ws similr in the group hd dvnced stge disese. receiving immunotoxin nd the cyclosporine-treted group All ptients received grfts which were mismtched (P =.877). genotypiclly, in one cse, the donor ws phenotypiclly All ptients live t dy 1 post-trnsplnt (n = 45) were mtched, nd in two cses, DR typing ws incomplete (of evluble for chronic GVHD. Forty-seven ptients of dy these two ptients, one ws mtched t both the A nd B 1 survivors hd no evidence of cgvhd, 47% developed loci, while the other ws mismtched t A nd mtched t limited nd 6% hd extensive cgvhd. The incidence of B). Of the remining 79 ptients, 14 received grfts which were one ntigen disprte, 45 received two ntigen disprte grfts nd 2 received three ntigen disprte grfts. Tble 2 contins ge, nd disese sttus chrcteristics of Tble 2 Ptient chrcteristics within HLA disprity groups,b 1Ag 2Ag 3Ag Age (in yers) Disese sttus Erly Intermedite Advnced The ptient phenotypiclly mtched (ge 3, erly stge disese). b DR typing incomplete for two ptients (one 3, intermedite disese; Time (dys) one 3 39, dvnced disese). Figure 1 Probbility of engrftment. Percent with engrftment 8 7 6

4 Prtilly mtched relted donor BMT 424 Tble 3 Acute/chronic grft-versus-host disese. Degree of HLA disprity in the GVHD direction GVHD (n = 66) Grde GVHD Disprity Ptients /I II III/IV Unknown cgvhd (n = 45) Stge cgvhd Disprity Ptients L E Survivl Disese-free survivl Unknown 1 1 Figure 3 Probbility of survivl nd disese-free survivl. Probbility of survivl nd disese-free survivl DR typing incomplete. Incidence of GVHD fter PMRD BMT for ptients trnsplnted with grfts disprte t, 1, 2 nd 3 loci. P vlue is 2 goodness of fit for ssocition of risk of severe (grde III/IV) GVHD with degree of HLA disprity of grft received. cgvhd ws not ffected by the degree of HLA disprity between the donor nd the recipient. Non-relpse mortlity Non-relpse mortlity occurred only in the 1st yer fter trnsplnt with probbility of 47% (95% CI = 42 64%, Figure 2). Fifty-three of the 82 ptients died. The mjor trnsplnt-relted cuses of deth were infection (n = 1), GVHD (n = 7), cgvhd (n = 3), non-engrftment (n = 9). Another three ptients died of bleeding, four of veno- occlusive disese, nd three of other cuses. Among those 1 ptients dying of infection, three died of bcteril sepsis, one of bcteril meningitis, one of disseminted cndidi- sis, two of disseminted denovirus, two of CMV pneumoni nd one of pneumoni presumed secondry to CMV. Thirty-eight ptients died t or before dy 1 post-trns- plnt. Relpse The probbility of relpse during the first 3 yers fter PMRD BMT (see Figure 2) is 3% (95% CI = 17 43%). With medin follow-up of 4.1 yers, 18 ptients hve relpsed (only one ptient with erly disese, six ptients with intermedite disese nd 11 ptients with dvnced disese). While the impct of disese sttus t the time of trnsplnttion did not rech sttisticl significnce, trend ws demonstrted, with dvnced disese ptients hving greter likelihood of relpse thn those trnsplnted with either erly or intermedite disese (P =.6). The degree of HLA disprity between ptient nd donor did not hve significnt effect on the risk of relpse (dt not shown). Probbility of non-relpse mortlity nd relpse Figure 2 Non-relpse mortlity Relpse Probbility of non-relpse mortlity nd probbility of relpse. Disese-free survivl nd survivl The probbility of disese-free survivl fter PMRD BMT (see Figure 3) is 31% t 3 yers (95% CI = 26 46%). The likelihood of surviving free of disese fter PMRD BMT ws influenced by ge, disese sttus t time of trnsplnt, nd degree of disprity of the grft received (see Tble 4). Tble 4 Disese sttus Relpse-free survivl. Survivors/number trnsplnted Degree of HLA disprity 1 Ag 2 Ag 3 Ag Erly nd intermedite 4/8 9/19 1/1 Advnced 3/6 7/26 /1 Two dditionl ptients with erly/intermedite disese survive, the first received phenotypiclly mtched grft, nd the second received grft incompletely typed t DR locus.

5 Disese-free survivl ws significntly longer for those trnsplnted t ge 3 yers thn for those trnsplnted t ge 3 (P =.4) (Figure 4). Anlysis of two subsets of ptients trnsplnted t ge 16 nd 17 3 reveled no difference in disese-free survivl. 1 Percent surviving P =.4 Age 3 > Age b AG mismtch AG mismtch P =.5 3 AG mismtch Percent surviving c Percent with relpse Lte disese Erly/intermedite 2 1 P = Figure 4 Probbility of disese-free survivl ccording to ge (), degree of HLA disprity of grft received (b) nd disese sttus t time of trnsplnttion (c). The P vlues reflect univrint nlysis. Prtilly mtched relted donor BMT The probbility of disese-free survivl ws higher for ptients with erly or intermedite stge disese t the time of trnsplnttion thn for those trnsplnted with dvnced disese (P =.3) (see Figure 4). However, even ptients trnsplnted with dvnced disese (including ptients with refrctory leukemi) hd probbility of disese-free survivl of pproximtely 22% (95% CI = 1 35%). The probbility of 3-yer disese-free survivl for ptients receiving mrrow mismtched t one locus ws 53%, 36% for ptients receiving mrrow mismtched t two loci, nd 5% for ptients receiving mrrow mismtched t three loci (Figure 4). Results chieved within ech subset of ptients were ffected by the ge nd disese sttus of ptients t the time of trnsplnttion. Detiled results of the 45 ptients receiving two ntigen disprte grfts re s follows: 13 of the 3 ptients ge 3 yers t trnsplnttion remin live nd free of disese, while only three of 15 ptients trnsplnted t ge 3 survived. Nineteen of these 45 ptients hd erly/intermedite disese t the time of trnsplnttion; nine survive. Of the 26 trnsplnted with dvnced disese only seven survive (six were ge 3). Only nine ptients in the two ntigen disprte subset hd both fvorble pretrnsplnt chrcteristics (ge 3 nd disese of either erly or intermedite type). Seven of these ptients remin live. All ptients receiving three ntigen disprte grfts hd either intermedite or dvnced disese. Only three of these 2 ptients remin live. Nine of these 2 ptients were ge 3 t the time of trnsplnttion. The overll probbility of 3-yer survivl fter PMRD BMT ws 35% (95% CI = 24.5% 45.3%) (see Figure 3). The men survivl for ptients with dvnced disese ws 13 weeks compred to 61 months for those with erly or intermedite disese. Discussion TCD PMRD trnsplnttion offers 35% probbility of long-term disese-free survivl to ptients with leukemi. The frequency of nonengrftment, cute nd chronic GVHD, deth due to trnsplnt-relted toxicities, nd relpse hve been reported. 4 9 The cturil probbility of grft filure in our series ws 14%. Interestingly, we were unble to demonstrte tht the rte of non-engrftment or the medin time to engrftment ws incresed with incresing grft HLA disprity. These results re t odds with those of other investigtors. 6,9 The smll numbers of ptients trnsplnted in our series my prevent us from hving the sttisticl power to demonstrte the effect of HLA disprity on engrftment with sttisticl significnce. The incidence of GVHD nd cgvhd in our series is cceptble. One ntigen disprte PMRD BMT is performed frequently t severl institutions. We trnsplnted 15 ptients with this degree of HLA disprity; only one experienced severe (grde III or IV) GVHD. Thirty-four of 45 ptients trnsplnted with two ntigen disprte grfts were evluble for GVHD; 17% of these ptients experienced severe GVHD. This incidence ws not significntly differ- 425

6 Prtilly mtched relted donor BMT 426 ent thn tht for ptients receiving three ntigen disprte Acknowledgements grfts. The bsence of strong ssocition between HLA dis- We wish to thnk the Xom Corportion (Berkley, CA) for providing prity nd GVHD incidence in our study differs from the the nti-cd5 monoclonl ntibody. Mr Roger Ynkey nd findings of other investigtors nd it is possible tht the Ms Beth Plummer ssisted with the dt nlysis nd Ms Brend ddition of in vivo T cell depletion to the post-trnsplnt Frzier ssisted with mnuscript preprtion. GVHD prophylxis regimen explins this result. Certinly this effect cnnot be excluded in the ptients trnsplnted with three ntigen disprte grfts s the mjority of these References ptients received cyclosporine, immunotoxin nd steroids s GVHD prophylxis. However, the effect of the nti- 1 Westoff CF. Fertility in the United Sttes. Science 1986; 234: CD5-ricin A conjugte could be investigted in the two ntigen disprte subset in which ptients received either 2 Hnsen JA, Ansetti C, Petersdorf E et l. Mrrow trnsplnts the immunotoxin or cyclosporine. GVHD prophylxis in from unrelted donors. Trnsplnt Proc 1994; 26: this cohort ws well blnced between cyclosporine nd 3 Perkins HA, Hnsen JA. The US Ntionl Mrrow Donor Pro- grm. Am J Peditr Hemtol Oncol 1994; 16: nti-cd5-ricin A. The incidence of GVHD nd the sur- 4 Betty PG, Cift RA, Mickelson EM et l. Mrrow trnsplnvivl of this subset of ptients ws not ffected by the postttion from relted donors other thn HLA-identicl siblings. trnsplnt GVHD prophylxis utilized. The impct of nti- New Engl J Med 1985; 313: CD5-ricin A conjugte on GVHD hs lso been investi- 5 Powles RL, Ky HEM, Clink HM et l. Mismtched fmily gted in URD BMT. A rndomized tril evluting this donors for bone-mrrow trnsplnttion s tretment for cute immunotoxin s GVHD prophylxis in unmnipulted leukemi. Lncet 1983; 1: URD BMT reveled tht the immunotoxin ws not more 6 Ash RC, Horowitz MM, Gle RP et l. Bone mrrow trnseffective in decresing GVHD frequency nd severity thn plnttion from relted donors other thn HLA-identicl sib- methotrexte, cyclosporine nd prednisone prophylxis. 18 lings: effect of T cell depletion. Bone Mrrow Trnsplnt Non-engrftment nd GVHD remin significnt 1991; 7: Trigg ME, Gingrich R, Goeken N et l. Low rejection rte obstcles to PMRD BMT. However, we report encourging when using unrelted donor or hploidenticl donors for childisese-free survivl results for cohort of ptients trnsdren with leukemi undergoing mrrow trnsplnttion. Bone plnted with two ntigen disprte grfts. In this group, the Mrrow Trnsplnt 1989; 4: probbility of disese-free survivl during the first 3 yers 8 Vowels MR, Tng RLP, Mmeghn H et l. Bone mrrow fter trnsplnt is 47% for those trnsplnted with erly or trnsplnttion in children using closely mtched relted nd intermedite disese. Not surprisingly, results re better for unrelted donors. Bone Mrrow Trnsplnt 1991; 8: those trnsplnted t younger ge. Somewht surprising, 9 Ansetti C, Amos D, Betty PG et l. The effect of HLA however, is the 27% probbility of disese-free survivl for comptibility on engrftment of bone mrrow trnsplnts in those trnsplnted with dvnced disese. Outcomes my ptients with leukemi or lymphom. New Engl J Med 1989; be further improved by incresing the number of CFU-GM 32: Mrcinik E, Romond EH, Thompson JS, Henslee PJ. Lborinfused nd defining the optiml conditioning regimen for tory control in predicting clinicl efficcy of T cell-depletion ptients with refrctory leukemi. procedures used for prevention of grft-versus-host disese: The high relpse rte seen in recipients of HLA-identicl importnce of limiting dilution nlysis. Bone Mrrow Trnssibling trnsplnts receiving T-depleted grfts 2 hs not plnt 1988; 3: been seen in trnsplnttion utilizing lterntive mrrow 11 Terski PI, McLelln JD. Microdroplet ssy of humn serum sources. 21,22 The probbility of relpse in our series ws not cytotoxins. Nture 1964; 24: ffected by the degree of HLA disprity of the grft 12 Henslee-Downey PJ. Choosing n lterntive bone mrrow received. Disese sttus prior to trnsplnt ws the only donor mong vilble fmily members. Am J Peditr fctor which pproched sttisticl significnce. Becuse of Hemtol/Oncol 1993; 15: this finding we believe tht ptient suitble for BMT with 13 Henslee PJ, Byers VS, Jennings CD et l. A new pproch to the prevention of grft-versus-host disese using XomZyme n lterntive mrrow source should be trnsplnted before H-65 following histo-incomptible prtilly T-depleted mrdvnced disese develops. This finding lso indictes tht row grfts. Trnsplnt Proc 1989; 21: lengthy delys of trnsplnttion while serching for n 14 Chmplin RE, Horowitz MM, VnBekkum DW et l. Grft URD my diminish ptient s chnce for fvorble out- filure following bone mrrow trnsplnttion for severe plcome. PMRDs re typiclly prents or siblings. This stic nemi. Risk fctors nd tretment results. Blood 1989; increses the likelihood tht mrrow dontion nd trns- 73: plnttion cn be ccomplished expeditously. 15 Glucksberg H, Storb R, Fefer A et l. Clinicl mnifesttions The optiml source for hemtopoietic stem cell dontion of grft-versus-host disese in humn recipients of mrrow remins n HLA-mtched sibling. Unfortuntely, this from HLA mtched sibling donors. Trnsplnttion 1974; 18: source is vilble to only 3% of ptients who re cndi Kpln EL, Meier P. Nonprmetric estimtion from incomdtes for this tretment. One ntigen disprte PMRD trnsplete observtions. J Am Stt Assoc 1958; 53: plnttion is n ccepted lterntive for these ptients. 23,24 17 Cox D. Regression models nd life tbles (with discussion). We believe tht the use of two ntigen disprte PMRD JR Stt S [B] 1972; 34: stem cell trnsplnttion with T cell depeletion cn extend 18 Weisdorf D, Filipovich A, McGlve et l. Combintion grftthe option of trnsplnttion to some of the remining versus-host disese. prophylxis using immunotoxin (ntiptients who re otherwise good cndidtes. CD5-RTA (Xomzyme-CD5)) plus methotrexte nd cyclo-

7 Prtilly mtched relted donor BMT sporine or prednisone fter unrelted donor mrrow trnspln- mrrow trnsplnttion for chronic myelogenous leukemi. ttion. Bone Mrrow Trnsplnt 1993; 12: Blood 1994; 83: Avers R, Tbilio A, Terenzi A et l. Successful engrftment 22 Ash RC, Csper JT, Chitmbr CR et l. Successful llogeneic of T-cell-depleted hploidenticl three-loci incomptible trnsplnttion of T-cell depleted bone mrrow from closely trnsplnts in leukemi ptients by ddition of recombinnt HLA-mtched unrelted donors. New Engl J Med 199; 322: humn grnulocyte colony-stimulting fctor-mobilized peripherl blood progenitor cells to bone mrrow inoculum. 23 Ansetti C, Betty PG, Storb R et l. Effect of HLA incom- Blood 1994; 84: ptibility on grft-versus-host disese, relpse nd survivl 2 Mrninchi D, Blise D, Rio B et l. Impct of T-cell fter mrrow trnsplnttion for ptients with leukemi or depletion on outcome of llogeneic bone-mrrow trnsplnttion lymphom. Hum Immunol 199; 29: for stndrd-risk leukemis. Lncet 1987; 1: Betty PG. Mrrow trnsplnttion using volunteer unrelted 21 Drobyski WR, Ash RC, Csper JT et l. Effect of T-cell donors in comprison of mismtched fmily donor trnsdepletion s grft-versus-host disese prophylxis on plnts: Settle perspective. Bone Mrrow Trnsplnt 1994; engrftment, relpse, nd disese-free survivl in unrelted 14 (Suppl. 4):