Bräutigam, Michelle

Buser, Andreas

Drexler, Beatrice

Halter, Jörg

Heim, Dominik

Holbro, Andreas

Infanti, Laura

Passweg, Jakob R

Plattner, Alexandra

Volken, Thomas

ZHAW digitalcollection

www.ebmt.org#EBMT18
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative treatment
option for patients with malignant and non-malignant diseases. Matching for HLA-class I and II
is currently standard practice in HSCT and improved HLA-typing through molecular techniques
has eventually improved transplant outcome. HLA-antibodies are antibodies against foreign
HLA antigens potentially triggering several immunological reactions with a wide range of clinical
consequences, i.e. platelet transfusion refractoriness, graft rejection in solid organ
transplantation and primary graft failure in HLA mismatched HSCT, mainly in cord blood and
haploidentical transplantations.
Background
Acknowledgements
This work was supported by an unrestricted grant from the Blood Transfusion Center; Swiss 
Red Cross, Basel, Switzerland.
Our data show that HLA antibodies are frequently present in patients undergoing HSCT and
that they should be measured at the day of transplantation. Additionally, some patients develop
new, including presumably donor-derived HLA-antibodies. This might have some impact
regarding both transfusion strategies (platelet transfusion refractoriness) as well as transplant
outcome. Since HLA-mismatched (incl. haploidentical) HSCT are increasingly performed
worldwide, further studies on the significance of HLA-antibodies in these settings are
warranted. On the other hand, HPA-antibodies seem to play a minor role and should be
assessed only in selected patients.
Conclusions
Results
References
Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, et al. Donor-specific anti-HLA Abs and graft failure in matched unrelated 
donor hematopoietic stem cell transplantation. Blood. 2011;118(22):5957-64.
Linjama T, Niittyvuopio R, Tuimala J, Pyorala M, Rintala H, Rimpilainen J, et al. Platelet donor selection for HLA-immunised
patients; the impact of donor-specific HLA antibody levels. Transfus Med. 2017.
Brown CJ, Navarrete CV. Clinical relevance of the HLA system in blood transfusion. Vox sanguinis. 2011;101(2):93-105
Taniguchi K, Yoshihara S, Maruya E, Ikegame K, Kaida K, Hayashi K, et al. Donor-derived HLA antibody production in patients 
undergoing SCT from HLA antibody-positive donors. Bone marrow transplantation. 2012;47(10):1338-42.
Fasano RM, Mamcarz E, Adams S, Donohue Jerussi T, Sugimoto K, Tian X, et al. Persistence of recipient human leucocyte 
antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem 
cell transplantation. British journal of haematology. 2014;166(3):425-34.
Ciurea SO, Cao K, Fernadez-Vina M, Kongtim P, Malki MA, Fuchs E, et al. The European Society for Blood and Marrow 
Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in 
Haploidentical Hematopoietic Cell Transplantation. Bone marrow transplantation. 2018.
At baseline, HLA-antibodies were detected in 49 patients (98%) (mean number of antibody 
specifities: 13; range 0-102) and in only 25 donors (50%) (mean number: 6; range 0-51). Of the 
HLA-antibody-positive donors at baseline, 13 (52%) were female and 12 (48%) were male.
Overall, both number and mean fluorescence intensity (MFI) of class I antibodies were higher
compared to those of class II antibodies. At baseline, the total number was 348 for class I
(mean MFI: 2330) and 310 for class II antibodies (mean MFI: 1637). The highest mean MFI for
class I and class II antibodies were 4126 and 3735, respectively.
Surprisingly, a considerable increase of the number and intensity of antibodies was observed 
within a few days, from baseline to the day of transplantation. At HSCT the total number of 
antibodies was 706 for class I with a mean highest MFI of 6007 and 353 for class II antibodies 
with a mean highest MFI of 3482, respectively. Thereafter, the number of antibodies as well as 
MFI-levels - measured weekly - remained stable until the end of observation. This finding was 
similar after adjusting for gender, age, diagnosis, conditioning, GVHD prophylaxis, CMV status, 
and ABO incompatibility (Figure 2).
Michelle Bräutigam,1,2 Thomas Volken,3 Alexandra Plattner,1 Jakob R Passweg,2 Jörg P Halter,2 Andreas S Buser,1,2
Laura Infanti,1,2 Beatrice Drexler,1,2 Dominik Heim,2 and Andreas Holbro1,2
Occurence and dynamics of HLA 
and HPA antibodies in the setting 
of matched related HSCT
Methods
Patients and their matched related donors were prospectively included in the IRB approved study
after informed consent. HLA- and HPA-antibodies were determined by Luminex® technique at
predefined time points. For patients, samples were drawn at baseline (before HSCT), at HSCT
and weekly thereafter until 4 weeks after HSCT and for donors at eligibility assessment and at
donation. We used generalized estimating equation models of the Gaussian and negative
binomial family with log links and robust standard errors in order to assess temporal trajectories
of patients’ average mean fluorescence intensity (MFI), highest MFI, and the number of
antibodies with MFI > 500.
Between November 2013 and February 2016 we prospectively included 50 patients and their
corresponding 50 matched related donors in our study.
Among those patients, 26 (51%) were female and median age at transplantation was 51 years. The
majority of patients had AML (37%) and MM (15.7%), received myeloablative conditioning (58.8%)
and GvHD prophylaxis consisted mainly of cyclosporine and ATG containing regimens (Table 1).
Table 1. Patient, disease and transplant characteristics 
                                             Number                           total               % 
Number of patients                                                               51     100 
Females          26              51 
Age at transplantation (median; range):          51.46 years; 32-65 years 
Diseases 
 AML         19     37.3 
 ALL         5    9.8 
 BCL                      5    9.8 
 TCL         3    5.9 
 MM         8   15.7 
 MDS         5    9.8 
 SAA                                                              1    2 
 HL         2               3.9 
 Other         3    5.9 
Disease stage1   
 0         4               7.8 
 1                      29             56.9 
 2         15             29.4 
 3         3               5.9  
                      
Conditioning: 
 MAC         30             58.8 
 RIC         21             41.2 
GVHD Prophylaxis: 
 CYA+MTX                                                                                                                4    7.8 
 CYA+MMF                                                                                                               5    9.8 
 CYA+MTX+ATG                                                                                                      29    56.9 
 CYA+MTX+KRP                                                                                                        3    5.9 
 CYA+ATG                                                                                                                  2    3.9 
 CYA+Campath                                                                                                         1    2 
 CYA+MMF+KRP                                                                                                      1    2 
 CYA+MMF+ATG                                                                                                      4    7.8 
 CYA+MTX+MMF                                                                                                     1    2 
 No GvHD-Prophylaxis (syngen)                                                                            1    2 
CMV Status (D/R): 
 -/-           16    31.4 
 +/-           5    9.8 
 -/+           13    25.5 
 +/+           17    33.3 
1: Disease risk index according to CIBMTR; 
Abbreviations: AML: acute myelogenus leukemia; ALL: acute lymphatic leukemia; BCL: B-Cell-Lymphoma; TCL: T-Cell-Lymphoma, MM: 
Multiple Myeloma, MDS: Myelodysplastic Syndrome; SAA: Severe Aplastic Anaemia; HL: Hodgkin Lymphoma; MAC: Myeloablative 
Conditioning; RIC: Reduced intensity Conditioning; CYA: Cyclosporin A; MTX: Methotrexat; ATG: Antithymocyte Globuline; MMF: 
Mycophenolate Mofetile; KRP: Study drug. 
   
Figure 2. Dynamics of HLA antibodies  over the period, unadjusted (A, C, and E) and adjusted (B, D, and F) for age, 
gender, diagnosis, conditioning, GvHD prophylaxis, CMV-status and ABO-incompatibility.
Table 2:  Patients with new antibodies emerging between measurement V3 (day 7 posttransplant) and V6 (day 28 post-
transplant), potentially donor derived
Furthermore, 48 of the 50 patients (96%) developed new HLA antibodies over the observed time 
period. New class II antibodies occurred more often and at higher intensities than new class I 
antibodies. 
In 14 of the 50 patients (28%) the molecular specifities of the emerging antibodies were the same as
those found in their corresponding donors, suggesting a potential transfer of donor-derived antibodies
(Table 2).
Figure 1. Consort diagram
1 Blood Transfusion Center, Swiss Red Cross, Basel, Switzerland
2 Division of Hematology, University Hospital Basel, Switzerland
3 Zurich University of Applied Sciences, School of Health Professions, Winterthur, Switzerland
By contrast, only one of the 50 patients had low-level HPA antibodies and HPA-antibodies were 
not detected in the donors.  
A-B Average MFI for the observed period unadjusted and adjusted (for above mentioned parameters)
C-D Highest Mean MFI for the observed period unadjusted and adjusted
E-F Number of antibodies (MFI>500) for observed periiod unadjusted and adjusted
Age
(at 
Tx)
Gen-
der
Disease Disease Stage
(DRI-Group)
Conditioning GvHD-Prophylaxis Nr. of new Antibodies
(MFI range)
Class I               Class II
Nr. of 
Transfusions 
RBC/PLT
Chimerism at d+30
CD3/Whole blood
62 F AML 2 MAC CYA MTX 3                   0
(517-1614)
4/6 83/76
60 M MDS 2 MAC CYA MTX ATG 0                        24
(504-1823)      
0/0 28/100
56 F AML 1 MAC CYA MTX ATG 6                        4
(788-1288)      (545-674)
11/13 93/100
55 F AML 2 RIC CYA MTX ATG 10                       8
(955-3469)      (527-950)
4/3 94/ 84
62 M MM 1 RIC CYA MTX ATG 23                       45
(547-4558)      (523-6262)
8/10 100/100
58 M MDS 2 RIC CYA MTX ATG 3                          0
(1250-2218)
6/8 100/---
49 F AML 3 MAC CYA ATG 1                          5
(544)       (579-1757)
8/8 94/100
62 M MM 1 RIC CYA MTX ATG 2                          0
(509-854)
4/8 100/100
45 F AML 2 MAC CYA MTX ATG 1                          13
(567) (509-939)
6/3 87/100
59 F BCL 1 RIC CYA ATG MMF 2                           4
(2141-2236)       (659-2467)
12/56 78/100
49 M MM 1 RIC CYA MTX ATG 3                           2
(594-894) (504-640)
9/17 0/0
62 F AML 1 MAC CYA MTX ATG 6                          27
(524-739) (506-1457)
5/4 66/100
33 F SAA 0 RIC CYA Campath 2                           0
(585-628)
3/4 100/100
55 M AML 1 MAC CYA MTX ATG 18   15
(501-1315) (516-971)
11/15 100/100
View publication stats


Occurence and dynamics of HLA and HPA antibodies in the setting of matched related HSCT

ZHAW Zürcher Hochschule für Angewandte Wissenschaften

www.ebmt.org#EBMT18Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative treatmentoption for patients with malignant and non-malignant diseases. Matching for HLA-class I and IIis currently standard practice in HSCT and improved HLA-typing through molecular techniqueshas eventually improved transplant outcome. HLA-antibodies are antibodies against foreignHLA antigens potentially triggering several immunological reactions with a wide range of clinicalconsequences, i.e. platelet transfusion refractoriness, graft rejection in solid organtransplantation and primary graft failure in HLA mismatched HSCT, mainly in cord blood andhaploidentical transplantations.BackgroundAcknowledgementsThis work was supported by an unrestricted grant from the Blood Transfusion Center; Swiss Red Cross, Basel, Switzerland.Our data show that HLA antibodies are frequently present in patients undergoing HSCT andthat they should be measured at the day of transplantation. Additionally, some patients developnew, including presumably donor-derived HLA-antibodies. This might have some impactregarding both transfusion strategies (platelet transfusion refractoriness) as well as transplantoutcome. Since HLA-mismatched (incl. haploidentical) HSCT are increasingly performedworldwide, further studies on the significance of HLA-antibodies in these settings arewarranted. On the other hand, HPA-antibodies seem to play a minor role and should beassessed only in selected patients.ConclusionsResultsReferencesCiurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, et al. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood. 2011;118(22):5957-64.Linjama T, Niittyvuopio R, Tuimala J, Pyorala M, Rintala H, Rimpilainen J, et al. Platelet donor selection for HLA-immunisedpatients; the impact of donor-specific HLA antibody levels. Transfus Med. 2017.Brown CJ, Navarrete CV. Clinical relevance of the HLA system in blood transfusion. Vox sanguinis. 2011;101(2):93-105Taniguchi K, Yoshihara S, Maruya E, Ikegame K, Kaida K, Hayashi K, et al. Donor-derived HLA antibody production in patients undergoing SCT from HLA antibody-positive donors. Bone marrow transplantation. 2012;47(10):1338-42.Fasano RM, Mamcarz E, Adams S, Donohue Jerussi T, Sugimoto K, Tian X, et al. Persistence of recipient human leucocyte antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem cell transplantation. British journal of haematology. 2014;166(3):425-34.Ciurea SO, Cao K, Fernadez-Vina M, Kongtim P, Malki MA, Fuchs E, et al. The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation. Bone marrow transplantation. 2018.At baseline, HLA-antibodies were detected in 49 patients (98%) (mean number of antibody specifities: 13; range 0-102) and in only 25 donors (50%) (mean number: 6; range 0-51). Of the HLA-antibody-positive donors at baseline, 13 (52%) were female and 12 (48%) were male.Overall, both number and mean fluorescence intensity (MFI) of class I antibodies were highercompared to those of class II antibodies. At baseline, the total number was 348 for class I(mean MFI: 2330) and 310 for class II antibodies (mean MFI: 1637). The highest mean MFI forclass I and class II antibodies were 4126 and 3735, respectively.Surprisingly, a considerable increase of the number and intensity of antibodies was observed within a few days, from baseline to the day of transplantation. At HSCT the total number of antibodies was 706 for class I with a mean highest MFI of 6007 and 353 for class II antibodies with a mean highest MFI of 3482, respectively. Thereafter, the number of antibodies as well as MFI-levels - measured weekly - remained stable until the end of observation. This finding was similar after adjusting for gender, age, diagnosis, conditioning, GVHD prophylaxis, CMV status, and ABO incompatibility (Figure 2).Michelle Bräutigam,1,2 Thomas Volken,3 Alexandra Plattner,1 Jakob R Passweg,2 Jörg P Halter,2 Andreas S Buser,1,2Laura Infanti,1,2 Beatrice Drexler,1,2 Dominik Heim,2 and Andreas Holbro1,2Occurence and dynamics of HLA and HPA antibodies in the setting of matched related HSCTMethodsPatients and their matched related donors were prospectively included in the IRB approved studyafter informed consent. HLA- and HPA-antibodies were determined by Luminex® technique atpredefined time points. For patients, samples were drawn at baseline (before HSCT), at HSCTand weekly thereafter until 4 weeks after HSCT and for donors at eligibility assessment and atdonation. We used generalized estimating equation models of the Gaussian and negativebinomial family with log links and robust standard errors in order to assess temporal trajectoriesof patients’ average mean fluorescence intensity (MFI), highest MFI, and the number ofantibodies with MFI > 500.Between November 2013 and February 2016 we prospectively included 50 patients and theircorresponding 50 matched related donors in our study.Among those patients, 26 (51%) were female and median age at transplantation was 51 years. Themajority of patients had AML (37%) and MM (15.7%), received myeloablative conditioning (58.8%)and GvHD prophylaxis consisted mainly of cyclosporine and ATG containing regimens (Table 1).Table 1. Patient, disease and transplant characteristics                                              Number                           total               % Number of patients                                                               51     100 Females          26              51 Age at transplantation (median; range):          51.46 years; 32-65 years Diseases  AML         19     37.3  ALL         5    9.8  BCL                      5    9.8  TCL         3    5.9  MM         8   15.7  MDS         5    9.8  SAA                                                              1    2  HL         2               3.9  Other         3    5.9 Disease stage1    0         4               7.8  1                      29             56.9  2         15             29.4  3         3               5.9                        Conditioning:  MAC         30             58.8  RIC         21             41.2 GVHD Prophylaxis:  CYA+MTX                                                                                                                4    7.8  CYA+MMF                                                                                                               5    9.8  CYA+MTX+ATG                                                                                                      29    56.9  CYA+MTX+KRP                                                                                                        3    5.9  CYA+ATG                                                                                                                  2    3.9  CYA+Campath                                                                                                         1    2  CYA+MMF+KRP                                                                                                      1    2  CYA+MMF+ATG                                                                                                      4    7.8  CYA+MTX+MMF                                                                                                     1    2  No GvHD-Prophylaxis (syngen)                                                                            1    2 CMV Status (D/R):  -/-           16    31.4  +/-           5    9.8  -/+           13    25.5  +/+           17    33.3 1: Disease risk index according to CIBMTR; Abbreviations: AML: acute myelogenus leukemia; ALL: acute lymphatic leukemia; BCL: B-Cell-Lymphoma; TCL: T-Cell-Lymphoma, MM: Multiple Myeloma, MDS: Myelodysplastic Syndrome; SAA: Severe Aplastic Anaemia; HL: Hodgkin Lymphoma; MAC: Myeloablative Conditioning; RIC: Reduced intensity Conditioning; CYA: Cyclosporin A; MTX: Methotrexat; ATG: Antithymocyte Globuline; MMF: Mycophenolate Mofetile; KRP: Study drug.    Figure 2. Dynamics of HLA antibodies  over the period, unadjusted (A, C, and E) and adjusted (B, D, and F) for age, gender, diagnosis, conditioning, GvHD prophylaxis, CMV-status and ABO-incompatibility.Table 2:  Patients with new antibodies emerging between measurement V3 (day 7 posttransplant) and V6 (day 28 post-transplant), potentially donor derivedFurthermore, 48 of the 50 patients (96%) developed new HLA antibodies over the observed time period. New class II antibodies occurred more often and at higher intensities than new class I antibodies. In 14 of the 50 patients (28%) the molecular specifities of the emerging antibodies were the same asthose found in their corresponding donors, suggesting a potential transfer of donor-derived antibodies(Table 2).Figure 1. Consort diagram1 Blood Transfusion Center, Swiss Red Cross, Basel, Switzerland2 Division of Hematology, University Hospital Basel, Switzerland3 Zurich University of Applied Sciences, School of Health Professions, Winterthur, SwitzerlandBy contrast, only one of the 50 patients had low-level HPA antibodies and HPA-antibodies were not detected in the donors.  A-B Average MFI for the observed period unadjusted and adjusted (for above mentioned parameters)C-D Highest Mean MFI for the observed period unadjusted and adjustedE-F Number of antibodies (MFI>500) for observed periiod unadjusted and adjustedAge(at Tx)Gen-derDisease Disease Stage(DRI-Group)Conditioning GvHD-Prophylaxis Nr. of new Antibodies(MFI range)Class I               Class IINr. of Transfusions RBC/PLTChimerism at d+30CD3/Whole blood62 F AML 2 MAC CYA MTX 3                   0(517-1614)4/6 83/7660 M MDS 2 MAC CYA MTX ATG 0                        24(504-1823)      0/0 28/10056 F AML 1 MAC CYA MTX ATG 6                        4(788-1288)      (545-674)11/13 93/10055 F AML 2 RIC CYA MTX ATG 10                       8(955-3469)      (527-950)4/3 94/ 8462 M MM 1 RIC CYA MTX ATG 23                       45(547-4558)      (523-6262)8/10 100/10058 M MDS 2 RIC CYA MTX ATG 3                          0(1250-2218)6/8 100/---49 F AML 3 MAC CYA ATG 1                          5(544)       (579-1757)8/8 94/10062 M MM 1 RIC CYA MTX ATG 2                          0(509-854)4/8 100/10045 F AML 2 MAC CYA MTX ATG 1                          13(567) (509-939)6/3 87/10059 F BCL 1 RIC CYA ATG MMF 2                           4(2141-2236)       (659-2467)12/56 78/10049 M MM 1 RIC CYA MTX ATG 3                           2(594-894) (504-640)9/17 0/062 F AML 1 MAC CYA MTX ATG 6                          27(524-739) (506-1457)5/4 66/10033 F SAA 0 RIC CYA Campath 2                           0(585-628)3/4 100/10055 M AML 1 MAC CYA MTX ATG 18   15(501-1315) (516-971)11/15 100/100View publication stats

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Occurence and dynamics of HLA and HPA antibodies in the setting of matched related HSCT

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