HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation
Abstract
1. Introduction
2. Patients and Methods
3. Definitions and Grading
4. Statistical Methods
5. Results
5.1. Impact of ATG on Overall Survival—Entire Cohort
5.2. Impact of ATG on Overall Survival—HLA-Matched PBSCT in Malignant Diseases
5.3. Impact of ATG on Non-Relapse Mortality
5.4. Impact of ATG on aGVHD Grade 3–4
5.5. Impact of ATG on aGVHD-Associated NRM
5.6. Impact of ATG on cGVHD
5.7. Impact of ATG on Relapse
6. Discussion
Acknowledgements
Author Contributions
Conflicts of Interest
References
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Variable | N (%) |
---|---|
Cohort Size, Overall | 775 |
Transplant Indication | |
Myeloid malignancies | 520 (67.1) |
AML/MDS | 408 |
Myeloproliferative and MDS/MPN overlap neoplasia | 112 |
Lymphoid malignancies | 228 (29.4) |
ALL, including lymphoblastic lymphoma | 110 |
Lymphoma, including CLL | 77 |
Myeloma | 41 |
Non-malignant disorders | 27 (3.5) |
Disease Stage at Transplant | |
Early/low-risk | 288 (37.2) |
Intermediate or advanced/high-risk | 487 (62.8) |
Conditioning Regimen | |
Myeloablative (including reduced toxicity myeloablative) * | 527 (68.0) |
Reduced intensity or non-myeloablative ** | 248 (32.0) |
Donor Type | |
Sibling | 393 (50.7) |
HLA matched | 388 |
1 Ag mismatched | 5 |
Unrelated | 382 (49.3) |
HLA matched (10/10 or 12/12 including DRB3-5) | 246 |
HLA mismatched | 136 |
Graft Source | |
Bone marrow | 143 (18.5) |
Peripheral blood (G-CSF mobilized) | 632 (81.5) |
Incorporation of ATG | |
No | 425 (54.8) |
Yes | 350 (45.2) |
ATG-Fresenius (Grafalon, Neovii) | 256 |
Lower dose *** | 160 |
Higher dose *** | 96 |
Thymoglobuline | 87 |
Lower dose *** | 71 |
Higher dose *** | 16 |
Alemtuzumab *** | 7 (0.9) |
Post-grafting Immunosuppression | |
MTX-based (mainly CsA/MTX) | 340 (43.9) |
MTX-free (mainly CsA/MMF) | 435 (56.1) |
HLA-C KIR-L Status | |
C1/1 | 291 (37.5) |
C1/2 | 363 (46.9) |
C2/2 | 121 (15.6) |
Cohort (n) Variable (Reference Group) | Risk Ratio | p-Value |
---|---|---|
All KIR-L States (n = 775) | ||
ATG—all dose levels (ref.: no ATG) | 0.71 | 0.014 |
unrelated donor (ref.: related donor) | 1.45 | 0.015 |
disease status—int./advanced (ref.: early) | 2.17 | <0.0001 |
HLA mismatch (ref.: HLA match) | 1.42 | 0.008 |
donor age (continuous, per year) | 1.01 | 0.020 |
MTX-based GVHD prophylaxis (ref.: no MTX) | 0.78 | 0.014 |
ATG—lower dose levels (ref.: no ATG; n = 660) | 0.61 | 0.001 |
C1/1 KIR Ligand State (n = 291) | ||
ATG—all dose levels (ref.: no ATG) | 0.50 | 0.003 |
disease status—int./advanced (ref.: early) | 2.00 | 0.0001 |
unrelated donor (ref.: related donor) | 1.84 | 0.008 |
ATG—lower dose levels (ref.: no ATG; n = 237) | 0.42 | 0.001 |
C1/2 KIR Ligand State (n = 363) | ||
ATG—all dose levels (ref.: no ATG) | 0.70 | 0.065 |
disease status—int./advanced (ref.: early) | 2.04 | <0.0001 |
unrelated donor (ref.: related donor) | 1.55 | 0.034 |
sex mismatch—female to male (ref.: all other) | 1.38 | 0.038 |
MTX-based GVHD prophylaxis (ref.: no MTX) | 0.63 | 0.008 |
RIC Regimen (Ref.: myeloablative) | 0.71 | 0.039 |
ATG—lower dose levels (ref.: no ATG; n = 322) | 0.60 | 0.018 |
C2/2 KIR Ligand State (n = 121) Inclusion of all ATG dose levels (121) | ||
ATG—all dose levels (ref.: no ATG) | 1.50 | 0.17 |
disease status—int./advanced (ref.: early) | 3.46 | <0.0001 |
donor age (continuous, per year) | 1.03 | 0.011 |
ATG—lower dose levels (ref.: no ATG; n = 101) | 1.69 | 0.15 |
Cohort (n)/Variable | Risk Ratio | p-Value |
---|---|---|
All KIR-L States (n = 507) | ||
ATG—all dose levels (ref.: no ATG) | 0.73 | 0.08 |
disease status—int./advanced (ref.: early) | 2.31 | <0.0001 |
MTX-based GVHD prophylaxis (ref.: no MTX) | 0.76 | 0.04 |
ATG—lower dose levels (ref.: no ATG; n = 449) | 0.62 | 0.02 |
C1/1 KIR Ligand State (n = 190) | ||
ATG—all dose levels (ref.: no ATG) | 0.55 | 0.04 |
disease status—int./advanced (ref.: early) | 2.14 | 0.0005 |
ATG—lower dose levels (ref.: no ATG; n =160) | 0.38 | 0.005 |
C1/2 KIR Ligand State (n = 251) | ||
ATG—all dose levels (ref.: no ATG) | 0.70 | 0.17 |
disease status—int./advanced (ref.: early) | 2.39 | 0.0001 |
MTX-based GVHD prophylaxis (ref.: no MTX) | 0.62 | 0.03 |
ATG—lower dose levels (ref.: no ATG; n = 231) | 0.62 | 0.10 |
C2/2 KIR Ligand State (n = 66) | ||
ATG—all dose levels (ref.: no ATG) | 2.59 | 0.06 |
Disease status—int./advanced (ref.: early) | 4.97 | 0.0005 |
unrelated donor | 0.32 | 0.03 |
ATG—lower dose levels (ref.: no ATG; n = 58) | 4.99 | 0.08 |
Clinical Endpoint | Entire Cohort n = 775 | C1/1 n = 291 | C1/2 n = 363 | C2/2 n = 121 |
---|---|---|---|---|
aGVHD III–IV (12 mo) | 27.1 (23.2–31.7) | 30.6 (24.2–38.6) | 26.4 (20.9–33.4) | 21.1 (13.5–33.1) |
without ATG (%) | n = 425 | n = 161 | n = 193 | n = 71 |
aGVHD III–IV (12 mo) | 21.9 (18.0–26.7) | 21.1 (15.1–29.5) | 23.0 (17.5–30.3) | 20.4 (11.8–35.5) |
with ATG (%) | n = 350 | n = 130 | n = 170 | n = 50 |
ATG effect by multivariate | RR, 0.63 | RR, 0.44 | RR, 0.77 | RR, 0.49 |
analysis | p = 0.02 | p = 0.01 | p = 0.35 | p = 0.28 |
GVHD-ass. NRM * (24 mo) | 24.9 (21.1–29.4) | 28.1 (21.9–36.0) | 23.5 (18.2–30.4) | 21.2 (13.6–33.3) |
without ATG (%) | n = 425 | n = 161 | n = 193 | n = 71 |
GVHD-ass. NRM (24 mo) | 20.5 (16.6–25.3) | 18.4 (12.5–26.9) | 21.2 (15.8–28.5) | 24.1 (14.7–39.5) |
with ATG (%) | n = 350 | n = 130 | n = 170 | n = 50 |
ATG effect by multivariate | RR, 0.51 | RR, 0.28 | RR, 0.55 | RR, 1.34 |
analysis | p = 0.001 | p = 0.0002 | p = 0.04 | p = 0.6 |
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Clausen, J.; Böhm, A.; Straßl, I.; Stiefel, O.; Buxhofer-Ausch, V.; Machherndl-Spandl, S.; König, J.; Schmidt, S.; Steitzer, H.; Danzer, M.; et al. HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation. Biomedicines 2017, 5, 13. https://doi.org/10.3390/biomedicines5020013
Clausen J, Böhm A, Straßl I, Stiefel O, Buxhofer-Ausch V, Machherndl-Spandl S, König J, Schmidt S, Steitzer H, Danzer M, et al. HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation. Biomedicines. 2017; 5(2):13. https://doi.org/10.3390/biomedicines5020013
Chicago/Turabian StyleClausen, Johannes, Alexandra Böhm, Irene Straßl, Olga Stiefel, Veronika Buxhofer-Ausch, Sigrid Machherndl-Spandl, Josef König, Stefan Schmidt, Hansjörg Steitzer, Martin Danzer, and et al. 2017. "HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation" Biomedicines 5, no. 2: 13. https://doi.org/10.3390/biomedicines5020013
APA StyleClausen, J., Böhm, A., Straßl, I., Stiefel, O., Buxhofer-Ausch, V., Machherndl-Spandl, S., König, J., Schmidt, S., Steitzer, H., Danzer, M., Kasparu, H., Weltermann, A., & Nachbaur, D. (2017). HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation. Biomedicines, 5(2), 13. https://doi.org/10.3390/biomedicines5020013