Anti-A isoagglutinin as a risk factor for the development of pure red cell aplasia after major ABO-incompatible allogeneic bone marrow transplantation

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1 Bone Mrrow Trnsplnttion (2) 25, Mcmilln Pulishers Ltd All rights reserved / $5. Anti-A isogglutinin s risk fctor for the development of pure red cell plsi fter mjor ABO-incomptile llogeneic one mrrow trnsplnttion J-H Lee, K-H Lee, S Kim, J-S Lee, S-H Kim, S-W Kwon 2 nd W-K Kim Division of Oncology-Hemtology, Deprtments of Medicine nd 2 Clinicl Pthology, Asn Medicl Center, University of Ulsn, Seoul, Kore Summry: Delyed erythropoiesis nd pure red cell plsi (PRCA) hve een reported fter mjor ABO-incomptile BMT. We ttempted to find risk fctors for the development of PRCA in 27 ptients who underwent mjor ABO-incomptile BMT. In ll ptients, the donor mrrow ws depleted of RBCs efore infusion. In 22 ptients, isogglutinins were determined until they disppered. In eight (29.6%) out of 27 ptients, one mrrow exmintion following BMT showed the findings of PRCA. We nlyzed vrious clinico-pthologic risk fctors nd isogglutinin type ws the only significnt risk fctor. Ptients with nti-a isogglutinins ginst donor RBC developed PRCA more frequently thn ptients with nti-b (8/7 vs /9). Medin dys to the disppernce of isogglutinins tended to e longer in ptients with PRCA (PRCA vs non-prca, 2 vs 66 dys) nd in cses with nti-a isogglutinins (nti-a vs nti-b, 6 vs 5 dys). Times to disppernce of isogglutinins correlted with times to reticulocytes over % nd initil ppernce of donor type RBC (R 2 =.78 nd.7). In conclusion, RBC engrftment following mjor ABO-incomptile BMT ws dependent on the disppernce of isogglutinins ginst donor RBC, nd nti-a isogglutinin ws risk fctor for the development of PRCA fter mjor ABO-incomptile llogeneic BMT. Bone Mrrow Trnsplnttion (2) 25, Keywords: nti-a isogglutinin; PRCA; ABO-incomptile BMT Mjor donor recipient ABO incomptiility is not considered to e contrindiction to successful one mrrow trnsplnttion (BMT). Acute hemolysis y nti-a or nti-b isogglutinins of recipient origin t the time of donor mrrow infusion cn effectively e prevented y the removl of nti- A or nti-b isogglutinins from the recipients or y the depletion of red lood cells from mrrow grfts. 4 Previous studies showed no significnt effect of mjor ABO mismtch on the incidence of grft rejection, the incidence of grft- Correspondence: Dr J-H Lee, Deprtment of Medicine, Asn Medicl Center, 388- Poongnp-dong, Songp-ku, Seoul 38-4, Kore Received 25 June 999; ccepted 5 Septemer 999 versus-host disese (GVHD) or survivl. 5,6 However, severl reports hve descried delyed hemolytic nemi, delyed onset of erythropoiesis nd pure red cell plsi (PRCA) fter mjor ABO-incomptile llogeneic BMT. 7 We mde n ttempt to identify risk fctors for the development of PRCA in ptients who received mjor ABO-incomptile one mrrow grft. Ptients nd methods Ptients One hundred nd five dult ptients underwent llogeneic BMT t Asn Medicl Center from Decemer 993 to June 999. Among those, 49 ptients (46.7%) received ABOincomptile one mrrow grfts: 5 (4.3%) with mjor difference, 7 (6.2%) with mjor nd minor difference, nd 7 (6.2%) with minor difference. Among 32 ptients who underwent mjor or mjor nd minor ABO-incomptile BMT, five were not nlyzed for the following resons: erly deth in three, generlized engrftment filure in one nd indequte dt in one. The remining 27 ptients were trnsplnted for cute myelogenous leukemi (AML) (n = 3), cute lympholstic leukemi (ALL) (n = 3), chronic myelogenous leukemi (CML) (n = 4), myelodysplstic syndrome (MDS) (n = 3), idiopthic myelofirosis (n = ), non-hodgkin s lymphom (NHL) (n = ), nd severe plstic nemi (SAA) (n = 2). Twenty-two donors were HLA-identicl silings, one ws one-locus mismtched siling, nd four were HLA-mtched unrelted volunteers. BMT procedure Conditioning regimens were BuCy (usulfn 6 mg/kg nd cyclophosphmide 2 mg/kg) for ptients with leukemi/mds/nhl nd Cy-ATG (cyclophosphmide 2 mg/kg nd ntithymocyte gloulin 9 mg/kg) for SAA. All ptients received cyclosporine nd methotrexte for the prophylxis of grft-versus-host disese (GVHD). Cyclosporine ws given strting on dy nd methotrexte ws dministered on dys, 3, 6 nd. Heprin ws dministered to those ptients who received the BuCy regimen for the prevention of heptic veno-occlusive disese (VOD). In ll ptients, the donor mrrow ws depleted of red lood cells y the CS-3 collection device efore infusion. Recipients isogglutinins were not reduced efore BMT.

2 8 Tle Anti-A isogglutinin nd PRCA fter BMT J-H Lee et l Detils of six ptients who developed PRCA following mjor ABO-incomptile llogeneic BMT UPN Sex/Age Dignosis ABO group Dy of disppernce Dy of ppernce of Dy of reticulocyte Dy of cyclosporine of isogglutinins donor RBC count over % discontinution Recipient Donor ginst donor RBC 28 M/44 AML B + A M/34 AML O + A F/28 SAA O + A F/3 CML B + A F/2 AML B + A M/24 AML O + A M/45 MDS B + A c NA NA 2 F/22 AML O + A c NA NA NA = not pplicle. Donor-type RBC ppered trnsiently from dy 28 to 46 post trnsplnt. Isogglutinins ginst donor RBC were still detected t the lst test. c Donor-type RBC did not pper t the lst test. Tle 2 Chrcteristics of the ptients who developed PRCA vs those who did not Ptient chrcteristics Ptients with PRCA Ptients without PRCA P vlue (n = 8) (n = 9) Sex (M/F) 4/4 /8.76 Age, yers (medin, rnge) 29 (2 45) 33 (6 45).73 Amount of trnsfusion prior to BMT Red lood cells (medin, rnge) 3 (2 3) 2 ( 75).979 Pltelets (medin, rnge) 4 ( 59) 63 ( 5).56 Liver function tests AST (medin, rnge) 2 (3 5) 5 (4 49).58 ALT (medin, rnge) 34 (8 67) 9 (5 99).265 Positivity of heptitis B virus ntigen Negtive Positive 3 BM cell dose MNC, 8 /kg (medin, rnge).5 (.3.2).9 (.4.4).63 CD34, 6 /kg (medin, rnge). (.3 2.8) 2. (. 7.9).3 Isogglutinin type ginst donor RBC Anti-A Anti-B 9 Both Isogglutinin titer efore BMT, reciprocl vlues (medin, rnge) 32 (4 28) 6 (8 64).882 Anti-A vs Anti-B. Lortory evlution Complete lood counts including reticulocyte counts were mesured dily until dischrge from the hospitl nd were susequently mesured per visit (once per or 2 weeks ccording to the ptients sttus). Bone mrrow iopsy nd spirtion ws performed when neutrophil engrftment ws estlished, then usully performed t 3, 6 nd 9 months post trnsplnt. PRCA ws dignosed when reticulocytopeni (reticulocyte count %) persisted over 6 dys fter BMT nd one mrrow iopsy showed isolted depletion of erythroid precursors. In 22 ptients, isogglutinins were determined until they disppered. Tests for ABO/Rhesus type nd IgM isogglutinin titers were performed using stndrd lood nking procedures. Anti-A nd nti-b isogglutinin titers were determined y incuting stndrd type A nd B RBC suspension in sline with two-fold seril dilutions of ptient serum t room temperture followed y centrifugtion nd scoring for gglutintion. Isogglutinin titers were mesured until disppernce of isogglutinins ginst donor RBC. Sttisticl nlysis The dy of RBC engrftment ws defined in two wys: the lst dy of RBC trnsfusion when the ptients were RBC trnsfusion independent for month nd the first dy of three consecutive tests showing reticulocyte counts equl to or more thn.%. The dy of neutrophil engrftment ws defined s the first of 2 consecutive dys with n solute neutrophil count (ANC) 5/ l following the posttrnsplnt ndir. The dy of pltelet engrftment ws defined s the first of 7 consecutive dys with pltelet count 2 / l without pltelet trnsfusion. Ctegoricl vlues were expressed s frequency nd percentges. Nonprmetric vriles were expressed s Bone Mrrow Trnsplnttion

3 Anti-A isogglutinin nd PRCA fter BMT J-H Lee et l Tle 3 Effect of PRCA on clinicl outcomes fter BMT 8 Ptients with PRCA Ptients without PRCA P vlue (n = 8) (n = 9) Engrftment, dy Reticulocyte % 28 (77 427) 26 (6 32). RBC trnsfusion independence 29 (7 399) 3 (3 88).54 Neutrophils 5/ l 6 (4 9) 7 ( 2).237 Pltelets 2 3 / l 25 (5 42) 2 (2 88).4 Trnsfusion mount, units Red cells ( dy 6 post trnsplnt) 8 (8 6) 8 (4 3).725 Red cells ( dy 6 post trnsplnt) 2 ( 69) 2 ( 6).938 Pltelets ( dy 6 post trnsplnt) 87 (35 86) 9 (36 363).9 Pltelets ( dy 6 post trnsplnt) ( 66) ( 59).283 GVHD Acute (yes/no) /8 5/4.8 Chronic (yes/no) 2/6 2/7.9 Veno-occlusive disese (yes/no) 3/5 9/.637 Overll survivl, dys medin vlues nd rnges. Differences in ctegoricl vriles etween ptients with or without PRCA were tested using the chi-squre test, wheres nonprmetric dt were compred using the Mnn Whitney U test. Sttisticl nlysis of risk fctors for PRCA ws univrite in ech cse. The proilities of engrftment, ppernce of donor-type RBC, nd disppernce of isogglutinins ginst donor RBC were clculted using the Kpln Meier method nd compred y log-rnk nlysis. Person s correltion coefficients were computed using the ivrite correltion procedure to mesure how vriles re relted. Results Occurrence of PRCA following mjor ABO-incomptile BMT In eight (29.6%) out of 27 ptients who underwent mjor ABO-incomptile llogeneic BMT, reticulocytopeni persisted over 6 dys fter BMT with one mrrow iopsies showing findings comptile with PRCA. ABO-type of recipient/donor pir of eight PRCA ptients ws O + /A + in four nd B + /A + in four (Tle ). Ptient UPN 28 hd no detectle donor-type RBC up to 35 dys fter BMT, wheres neutrophil nd pltelet engrftment ws chieved on dys 7 nd 33 post trnsplnt, respectively. In ptient UPN 32, donor-type RBC ppered trnsiently from dys 28 to 46 post trnsplnt, ut sustined donor-type erythropoiesis ws chieved only fter dy 94. Isogglutinin ginst donor RBC initilly disppered on dy 28, reppered on dy 46 nd eventully disppered on dy post trnsplnt. On dy 73 post trnsplnt, one mrrow iopsy showed PRCA. Ptient UPN 36 hd PRCA on one mrrow exmintion performed fter neutrophil engrftment. No donor RBC were detectle until 4 months fter BMT. The isogglutinin titer ginst donor RBC initilly decresed over the first month fter BMT ut this decline ws not sustined (Figure ). The titer incresed susequently nd persisted t reltively high level for severl months until dy 455 post trnsplnt when the titer ecme undetectle. Ptient UPN 39 hd no detectle donor RBC until dy 77 post trnsplnt. Isogglutinins ginst donor RBC were still detected t tht time. The chnges of isogglutinins in ptient UPN 5 were similr to ptient UPN 36 (Figure ). On dy 3 post trnsplnt, one mrrow iopsy showed isolted depletion of erythroid precursors, wheres ctive trilinege regenertion ws noted in the one mrrow iopsy of dy 282. In ptient UPN 6, the isogglutinin titer decresed over 4 months fter BMT nd donor RBC ppered on dy 25 post trnsplnt. In ptients UPN 98 nd 2, reticulocytopeni persisted until dys 8 nd 8, respectively nd nti-a isogglutinins were still detected t those times. There ws no correltion etween cyclosporine dministrtion nd recovery of erythropoiesis. In five of eight PRCA ptients, donor-type red cells ppered while cyclosporine ws still eing dministered (Tle ). Risk fctors for PRCA In n ttempt to identify risk fctors for the development of PRCA, we nlyzed vrious vriles such s sex, ge, the mount of pre-bmt trnsfusion, level of AST/ALT t BMT, HBV sttus, one mrrow cell dose, isogglutinin type ginst donor RBC, nd pre-bmt isogglutinin titers (Tle 2). Isogglutinin type ws the only risk fctor nd ptients with nti-a isogglutinins ginst donor RBC developed PRCA more frequently thn ptients with nti- B (8/7 vs /9, P =.3). Effect of PRCA on clinicl outcomes fter BMT Medin dys to reticulocytes over % were longer y out 3 months in ptients with PRCA thn in those with timely RBC engrftment (28 vs 26 dys, P.). Medin times to the lst dy of trnsfusion when the ptients were Bone Mrrow Trnsplnttion

4 Anti-A isogglutinin nd PRCA fter BMT J-H Lee et l P = Anti-A Isogglutinin titer (reciprocl vlue) Reticulocyte (%) 4 2 Anti-B P = Isogglutinin titer (reciprocl vlue) Figure Chnges of Anti-A isogglutinin titer ( ) nd reticulocyte count ( ) in two ptients who developed PRCA following mjor ABOincomptile BMT: () UPN 36; () UPN 5. RBC trnsfusion independent for month were lso delyed in ptients with PRCA (29 vs 3 dys, P =.54). Those ptients who developed PRCA showed comprle speed of neutrophil nd pltelet engrftment when compred to the ptients who did not develop PRCA. The mounts of pltelet nd RBC trnsfusion did not show significnt differences ccording to the occurrence of PRCA. The development of PRCA did not influence the occurrence of GVHD or heptic VOD, s well s overll survivl (Tle 3) Reticulocyte (%) 4 2 PRCA( ) PRCA(+) Figure 2 Time to disppernce of isogglutinins ginst donor RBC. Medin dys were prolonged in ptients with nti-a isogglutinins () or in ptients who developed PRCA (). RBC engrftment kinetics Times to disppernce of isogglutinins ginst donor RBC or ppernce of donor RBC were correlted with types of isogglutinin or the occurrence of PRCA. Medin dys to the disppernce of isogglutinins ginst donor RBC were delyed in ptients with nti-a isogglutinins (nti-a vs nti-b 6 vs 5 dys, P =.27) or PRCA (PRCA vs non-prca 2 vs 66 dys, P =.6; Figure 2). Medin dys to initil ppernce of donor-type RBC were lso delyed in ptients with nti-a isogglutinins (nti-a vs nti-b 6 vs 3, P =.) or PRCA (PRCA vs non- PRCA 35 vs 33 dys, P.; Figure 3). Times to disppernce of isogglutinins ginst donor RBC were significntly correlted with times to reticulocytes over % nd initil ppernce of donor type RBC (R 2 =.78 nd.7; Figure 4). Discussion Although mjor ABO incomptiility etween donors nd recipients does not ffect the ultimte outcome of llogeneic BMT, it cn cuse severl immedite nd delyed complictions. The ltter include delyed red cell engrftment nd PRCA. Post-BMT PRCA occurs in out 2% of the ptients who receive mjor ABO-incomptile Bone Mrrow Trnsplnttion

5 Anti-A isogglutinin nd PRCA fter BMT J-H Lee et l Anti-B P =. Anti-A Times to reticulocyte >% (dy) R2 = Times to disppernce of isogglutinin (dy) PRCA( ) PRCA(+) P <. Figure 3 Time to initil ppernce of donor RBC. Medin dys were prolonged in ptients with nti-a isogglutinins () or in ptients who developed PRCA (). grft, nd presents cliniclly with prolonged reticulocytopeni, selective erythroid hypoplsi, nd incresed red lood cell trnsfusion requirements. 7,8,,2 The prole mechnism of this phenomenon is the presence of recipient isogglutinins directed t ABH ntigens on donor red cells. There re reltively few dt regrding ABH ntigen expression on humn erythroid precursor cells. Sieff et l 3 demonstrted tht only minority of BFU-E were strongly positive (7%) to nti-a ntiody, ut this proportion incresed during differentition to CFU-E (38%). Shovic et l 4 studied mjor ABO-incomptile BMT recipient with PRCA using flow cytometric nlysis of ABH ntigen expression y colony cells grown in vitro. They hypothesized tht the mechnism of PRCA fter ABO-incomptile BMT is complement-medited immune destruction of erythroid progenitors pst the stge of BFU-E in differentition. Gmür et l 8 reported tht RBC engrftment nd reticulocyte recovery coincided with the decrese of isogglutinin titers elow 6, nd PRCA is ntiody-dependent in this setting. Our dt lso suggested tht RBC engrftment ws dependent on the disppernce of isogglutinins ginst donor RBC. We ttempted to identify risk fctors for PRCA fter mjor ABO-incomptile BMT. All eight ptients who developed PRCA fter BMT hd nti-a isogglutinins ginst donor RBC nd nti-a isogglutinin ws the only Times to reticulocyte >% (dy) R2 =.7 4 Times to disppernce of isogglutinin (dy) Figure 4 Correltion of time to disppernce of isogglutinins with times to reticulocyte over % () nd initil ppernce of donor RBC (). risk fctor for PRCA. Wernet et l 5 mesured isogglutinins serilly following ABO-incomptile BMT nd found tht it took longer for nti-a to dispper thn nti-b. Most cses of PRCA fter BMT reported in the literture involve recipients with nti-a isogglutinins ginst donor RBC, 8,4,6 8 lthough few cse reports showed the occurrence of PRCA fter BMT when recipients hd nti-b isogglutinins ginst donor RBC. 9,2 Bär et l suggested tht lood group O ws significntly more frequent in the mjor ABO-incomptile ptients with delyed onset of donor erythropoiesis thn with timely onset of erythropoiesis. However, the recipient/donor ABO-type of eight PRCA ptients in our study ws O + /A + in four nd B + /A + in four suggesting tht nti-a isogglutinin ginst donor RBC is more importnt in the development of PRCA thn lood group O. Although we cnnot scertin why nti-a isogglutinins ginst donor RBC produced PRCA more frequently, it my e ssumed tht ntiody ffinity nd expression density of lood group A ntigens re higher on RBC precursors thn those of lood group B ntigens. Some uthors reported tht dely of RBC engrftment fter ABO-incomptile BMT ws ttriutle to high pre- 5 Bone Mrrow Trnsplnttion

6 84 Anti-A isogglutinin nd PRCA fter BMT J-H Lee et l trnsplnt isogglutinin titers. However, others found no correltion etween pretrnsplnt isogglutinin titers nd the development of PRCA. 6,8,2 In our ptients, pre-bmt isogglutinin titers did not differ etween ptients with nd without PRCA. Gmür et l 8 oserved tht post-trnsplnt rise nd persistence of high nti-a gglutinin titers ws ssocited with dely of RBC engrftment. Bär et l showed tht 3 months fter mjor ABO-incomptile BMT, seven ptients with PRCA hd detectle isogglutinin titers in rnge higher thn the other ptients without PRCA. Our dt lso showed tht in three (UPN 32, 36, 5) of six ptients with PRCA, post-trnsplnt isogglutinin titers initilly decresed with susequent trnsient increment nd eventul disppernce (Figure ). Severl uthors suggested tht cyclosporine might hve role in the development of PRCA fter ABO-incomptile BMT. 8,22,23 However, we did not oserve correltion of cyclosporine nd erythropoiesis in mjor ABO-incomptile BMT. It ws lso suggested tht mesures tken for the prevention of cute hemolysis y isogglutinins of recipient origin t the time of donor mrrow infusion my influence RBC engrftment fter mjor ABO-incomptile BMT. 3 In ll our ptients, donor mrrow ws depleted of red lood cells efore infusion nd recipients isogglutinins were not reduced efore BMT. The incidence of PRCA (29.6%) in our study is somewht higher thn the incidence reported previously in the literture. In the study y Gmür et l, 8 timely recovery of erythropoiesis ws oserved in ll seven ptients who underwent lrge volume plsm exchnge efore BMT, ut three of seven ptients who received n RBC-depleted grft developed PRCA fter mjor ABOincomptile BMT. In summry, RBC engrftment following mjor ABOincomptile BMT ws dependent on the disppernce of isogglutinins ginst donor RBC, nd nti-a isogglutinin ws risk fctor for the development of PRCA complicting mjor ABO-incomptile BMT. References Brine HG, Sensenrenner LL, Wright SK et l. 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