Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less".

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Citation

Heemskerk, M. B. A. (2006, September 28). Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less". Retrieved from https://hdl.handle.net/1887/4578

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the_{Institutional Repository of the University of Leiden} Downloaded from: https://hdl.handle.net/1887/4578

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How to improve the search for an unrelated

haematopoietic stem cell donor.

Faster is better than more!

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Abstract

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Introduction

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Material and methods

The patients

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Search strategies

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Data collection

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Statistics

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Table 1a: The characteristics of the 275 paediatric patients for whom a UD search was activated. Period of search activation

1987-1990 1991-1995 1996-2000 Total

1XPEHURISDWLHQWV Q Q Q Q

Characteristics

6H[PDOHIHPDOH

deviation from 50/50 ratio* S 16 S S

$JHPHGLDQUDQJH 1:(XURSHDQQRQ1:QRQ1: (XURSHDQRULJLQ Diagnosis n (%) ! ALL AML CML MDS Lymphoma - Other malignancies SAA ,PPXQHGHÀFLHQFLHV Other non malignant diseases disease risk category:

standard

high

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Percentage of successful donor searches for patients of Northwest European origin.

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Table 1b: The characteristics of the 273 adult patients for whom a UD search was activated. Period of search activation

1987-1990 1991-1995 1996-2000 Total

QXPEHURISDWLHQWV Q Q Q Q 273

characteristics

6H[PDOHIHPDOH

deviation from 50/50 ratio* S S 16 S 16 $JHPHGLDQUDQJH 1:(XURSHDQQRQ1:QRQ1: (XURSHDQRULJLQ Diagnosis n (%) ! ALL AML CML MDS Lymphoma - Other malignancies SAA

Other non malignant

dis-eases

disease risk category ß:

standard

high

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probability to transplant over time (Odds Ratio= 1.5; p = 0.001). The only other variable LQÀXHQFLQJWKHSUREDELOLW\WRWUDQVSODQWZDVKDYLQJDIUHTXHQW+/$SKHQRW\SH2GGVUDWLR S+RZHYHULWVKRXOGEHQRWHGWKDWQRWDOOSDWLHQWVZLWKDQDFFHSWDEOHGRQRU ZHUHWUDQVSODQWHGDVVRPHEHFDPHPHGLFDOO\XQ¿WWRSURFHHGZLWKWUDQVSODQWDWLRQ%HWZHHQ DQG RI WKH SDWLHQWV ZHUH WUDQVSODQWHG ZLWKLQ D PHGLDQ WLPH VSDQ RI PRQWKVWDEOHIURPWKHVWDUWRIWKHVHDUFKXQWLOWKHDFWXDOWUDQVSODQWDWLRQDVDOVRVKRZQLQ ¿JXUH7KHPHGLDQWLPHEHWZHHQWKHORFDWLRQRIDQDFFHSWDEOHGRQRUDQGWUDQVSODQWDWLRQ PRQWKVKRZHYHUGLGQRWFKDQJHWKURXJKRXWWKHZKROHSHULRG

Figure 1: Cumulative incidence of patients of Northwest European origin for whom

a donor was found within one year._The

Cumulative incidence increased per period (Hazard Ratio= 1.7; p < 0.001)

Figure 2: Cumulative incidence of patients of Northwest European origin that received

a graft in one year after search start._The

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Period of search activation

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Donor search variables

(13)

Searches for patients with a frequently occurring HLA phenotype ,QRUGHUWRLQYHVWLJDWHZKHWKHUWKHQXPEHURIGRQRUVLQ%0':ZDVVWLOODOLPLWLQJIDFWRU IRUWKH8'VHDUFKHVVWDUWHGLQWKHWLPHSHULRGWKHVHDUFKRXWFRPHVIRUSDWLHQWV ZLWKIUHTXHQWO\RFFXUULQJ+/$SKHQRW\SHVLHRUPRUHGRQRUVLQ%0':Q ZHUH DQDO\VHG)RUSDWLHQWVZLWKVXFKDIUHTXHQWO\RFFXUULQJSKHQRW\SHDGRQRUVKRXOGEHDYDLODEOH DQGIDLOXUHWRWUDQVSODQWFRXOGEHDWWULEXWHGWRVHDUFKHI¿FLHQF\,QWKHSHULRG RIWKHSDWLHQWVZLWKDIUHTXHQWO\RFFXUULQJSKHQRW\SHZHUHWUDQVSODQWHG7KHRWKHU RIWKH8'VHDUFKHVHQGHGLQWKHSDWLHQWVEHFRPLQJPHGLFDOO\XQ¿WIRUWUDQVSODQWDWLRQEHIRUH DGRQRUFRXOGEHORFDWHG7KHUHZDVQRGLIIHUHQFHLQWLPHVSDQEHWZHHQWKHVHDUFKHVIRU SDWLHQWVZLWKDIUHTXHQWO\RUOHVVIUHTXHQWO\RFFXUULQJSKHQRW\SHS 16

Reasons for not achieving transplantation

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Tabel 3: Disease risk category and its impact on the percentage of Northwest European patients receiving a graft.

1987-1990 1991-1995 1996-2000 total period 1XPEHURISDWLHQWV Q Q Q Q Q Donor search variables

High risk patients Q Q Q Q Q Deteriorated clinical condition, n (%) Patients transplanted, n (%) No donor found, n (%) Standard risk patients Q Q Q Q Q Deteriorated clinical condition, n (%) Patients transplanted, n (%) No donor found, n (%) $QRWKHUSRVVLEOHFDXVHIRUQRWUHDFKLQJWUDQVSODQWDWLRQEHFDXVHRIDGHWHULRUDWHGFOLQLFDO FRQGLWLRQLVWKDWWKHSDWLHQWDOUHDG\KDVDQDGYDQFHGGLVHDVHVWDWHDWWKHVWDUWRIWKHVHDUFK +LJKULVNSDWLHQWVGLGKDYHDKLJKHURGGVWREHFRPHPHGLFDOO\XQ¿WIRUWUDQVSODQWDWLRQ EHWZHHQDQGWDEOHS 7KLVKRZHYHUGLGQRWUHVXOWLQDVLJQL¿FDQW GLIIHUHQFHLQWKHFKDQFHRIUHFHLYLQJDJUDIWS 167KHJHQGHUDQGDJHRIWKHSDWLHQWDOVR GLGQRWLQÀXHQFHWKHRFFXUUHQFHRIGHWHULRUDWHGFOLQLFDOFRQGLWLRQ)URPXQWLO WKHFOLQLFLDQVLQGLFDWHGKLJKDQGVWDQGDUGWUDQVSODQWXUJHQF\RQWKHEDVLVRIWKHLUFOLQLFDO DVVHVVPHQWDWWKHVWDUWRIDOOGRQRUVHDUFKHV7KHPHGLDQWLPHVSDQEHWZHHQWKHVWDUWRIWKH VHDUFKDQGWUDQVSODQWDWLRQIRUWKHVHKLJKXUJHQF\VHDUFKHVZDVPRQWKVFRPSDUHGWR PRQWKVIRUVWDQGDUGXUJHQF\VHDUFKHV0DQQ:KLWQH\UWHVWS 7KHUHZDVQHLWKHUD GLIIHUHQFHLQWKHSHUFHQWDJHRISDWLHQWVWUDQVSODQWHGQRULQWKHIDLOXUHWRWUDQVSODQWGXHWRD GHWHULRUDWHGFOLQLFDOFRQGLWLRQGDWDQRWVKRZQS 16

The time span of the donor search process

(15)

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Patients of non-Northwest European origin

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months (range) - Patients receiving a graft, n (%) Deteriorated clinical condition, n (%) No donor can be found, n (%) Median time span until transplantation in

(16)

Discussion

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Acknowledgements

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References

(1) Gratwohl A, Baldomero H, Horisberger B, Schmid C, Passweg J, Urbano-Ispizua A. Current trends in hematopoietic stem cell transplantation in Europe. Blood. 2002 Oct 1;100(7):2374-86.

(2) World Marrow Donor Association. Donor Registries Annual Report, 5th_{edn. 2002} (3) Bone Marrow Donors Worldwide. www.bmdw.org.

(4) Ottinger H, Grosse-Wilde M, Schmitz A, Grosse-Wilde H. Immunogenetic marrow donor search for 1012 patients: a retrospective analysis of strategies, outcome and costs. Bone Marrow Transplant.1994;14 Suppl 4:S34-8.

(5) Dini G, Lanino E, Lamparelli T, et al. Unrelated donor marrow transplantation: initial ex-perience of the Italian bone marrow transplant group (GITMO). Bone Marrow Transplant. 1996 Jan;17(1):55-62.

2XGVKRRUQ0&RUQHOLVVHQ--)LEEH:(HWDO3UREOHPV DQG SRVVLEOH VROXWLRQV LQ ÀQGLQJ3UREOHPVDQGSRVVLEOHVROXWLRQVLQÀQGLQJ an unrelated bone marrow donor. Results of consecutive searches for 240 Dutch patients. Bone Marrow Transplantat. 1997 Dec;20: 1011-1017.

(7) Howe C. W. S., Radde-Stepaniak T. Hematopoietic cell donor registries. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic cell transplantation, second edition. Blackwell science; 1999:503-512.

(8) Dini G, Cancedda R, Locatelli F, et al. Unrelated donor marrow transplantation: an update of the experience of the Italian Bone Marrow Transplant Group (GITMO). Haematologica. 2000 Nov;85(11 Suppl):30-6.

(9) Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ. Searching forSearching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant. 2002;8(5):257-60.

(10) Hurley CK, Vina MF, Setterholm M. Maximizing optimal hematopoietic stem cell donor se-lection from registries of unrelated adult volunteers. Tissue Antigens. 2003 Jun;61(6):415-Tissue Antigens. 2003 Jun;61(6):415-24.

(11) Dini G, Valsecchi MG, Micalizzi C, et al. Impact of marrow unrelated donor search dura-Impact of marrow unrelated donor search dura-tion on outcome of children with acute lymphoblastic leukemia in second remission. Bone Marrow Transplant. 2003 Aug;32(3):325-31.2003 Aug;32(3):325-31.

6FKLSSHU5)'·$PDUR-2XGVKRRUQ07KH SUREDELOLW\ RI ÀQGLQJ D VXLWDEOH UHODWHG GRQRU7KHSUREDELOLW\RIÀQGLQJDVXLWDEOHUHODWHGGRQRU for bone marrow transplantation in extended families. Blood. 1996 Jan 15;87(2):800-4.Blood. 1996 Jan 15;87(2):800-4. (13) van der Meer A, Joosten I, Schattenberg AV, de Witte TJ, Allebes WA. Cytotoxic T-lym-Cytotoxic

(20)

(14) Oudshoorn M, Doxiadis II, van den Berg-Loonen PM, Voorter CE, Verduyn W,Claas FH. Functional versus structural matching: can the CTLp test be replaced by HLA allele typ-ing? Hum Immunol. 2002 Mar;63(3):176-84.Hum Immunol. 2002 Mar;63(3):176-84.

(15) van Walraven SM, Heemskerk MB, Lie JL, et al. The importance of identifying a back-upThe importance of identifying a back-up donor for unrelated stem cell transplantation. Bone Marrow Transplant.;35:437-40.

(16) Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods for the analysis and presen-tation of the results of bone marrow transplants. Part I: unadjusted analysis. Bone Marrow Transplant. 2001 Nov;28(10):909-15.

(17) Confer DL. The National Marrow Donor Program. Meeting the needs of the medically underserved. Cancer. 2001 Jan 1;91(1 Suppl):274-8.

(18) Müller CR, Ehninger G, Goldmann SF. Gene and haplotype frequencies for the loci hLA-A, hLA-B, and hLA-DR based on over 13,000 german blood donors. Hum Immunol. 2003Hum Immunol. 2003 Jan;64(1):137-51.

(19) Petersdorf EW, Gooley TA, Anasetti C, et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood. 1998 Nov 5;92(10):3515-20.

(20) Petersdorf EW, Anasetti C, Martin PJ, Hansen JA. Tissue typing in support of unrelated hematopoietic cell transplantation. Tissue Antigens. 2003 Jan;61(1):1-11.

0RULVKLPD<6DVD]XNL7,QRNR+HWDO7KHFOLQLFDOVLJQLÀFDQFHRIKXPDQOHXNRF\WHDQWL-gen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002 Jun 1;99(11):4200-6.

(22) Beatty PG, Mori M, Milford E. Impact of racial genetic polymorphism on the probability RIÀQGLQJDQ+/$PDWFKHGGRQRU7UDQVSODQWDWLRQ2FW

(23) Armitage S, Warwick R, Fehily D, Navarrete C, Contreras M. Cord blood banking in Lon-GRQWKHÀUVWFROOHFWLRQV%RQH0DUURZ7UDQVSODQW-XO

(24) Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leu-kocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Blood. 2001 May 15;97(10):2957-61.

(25) Gluckman E. Hematopoietic stem-cell transplants using umbilical-cord blood. N Engl J Med. 2001 Jun 14;344(24):1860-1.

(26) Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001 Jun 14;344(24):1815-22.

(21)

(28) Michel G, Rocha V, Chevret S, et al. Unrelated cord blood transplantation for childhoodUnrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord group analysis. Blood. 2003 Dec 15;102(13):4290-7 (29) Souillet G, Rey S, Bertrand Y, et al. Outcome of unrelated bone marrow donor searches in

174 children resulting in 45 patients transplanted in the HLA-matched and -mismatched situation. Bone Marrow Transplant. 2000 Jul;26(1):31-43.2000 Jul;26(1):31-43.

(30) Oudshoorn M, Falkenburg JH, Ebeling LJ, et al. Unrelated bone marrow transplantation asUnrelated bone marrow transplantation as a rescue procedure following inadvertent loss of an autologous bone marrow graft. Bone Marrow Transplant. 1996 Aug;18(2):461-3.

(31) Lane TA. Cord blood banking and transplantation: state-of-the-art review and future directions. Cytotherapy. 2003; 5 (6): 572-576

8QLWHG6WDWHV*HQHUDO$FFRXQWLQJ2IÀFH%RQHPDUURZWUDQVSODQWV'HVSLWHUHFUXLWPHQW successes, national program may be underutilized. 2002 Oct. GAO-03-182