Blood Res (2025) 60:5
Published online January 15, 2025
https://doi.org/10.1007/s44313-024-00049-z
© The Korean Society of Hematology
Correspondence to : Ik‑Chan Song
petrosong@cnu.ac.kr
†Jeong Suk Koh and Myung-Won Lee contributed equally to this work.
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
BackgroundPost-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common prophylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.
MethodThe clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023.
ResultsForty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).
ConclusionSerum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.
Keywords IL-6, Post-transplantation cyclophosphamide, Anti-thymocyte globulin, GVHD, Hematopoietic stem cell transplantation
Blood Res 2025; 60():
Published online January 15, 2025 https://doi.org/10.1007/s44313-024-00049-z
Copyright © The Korean Society of Hematology.
Jeong Suk Koh1†, Myung‑Won Lee1†, Thi Thuy Duong Pham2,3, Bu Yeon Heo2,3, Suyoung Choi2,3, Sang‑Woo Lee2, Wonhyoung Seo1, Sora Kang1, Seul Bi Lee1, Chul Hee Kim1, Hyewon Ryu1, Hyuk Soo Eun1, Hyo‑Jin Lee1, Hwan‑Jung Yun1, Deog‑Yeon Jo1 and Ik‑Chan Song1,2,3*
Correspondence to:Ik‑Chan Song
petrosong@cnu.ac.kr
†Jeong Suk Koh and Myung-Won Lee contributed equally to this work.
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
BackgroundPost-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common prophylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.
MethodThe clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023.
ResultsForty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).
ConclusionSerum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.
Keywords: IL-6, Post-transplantation cyclophosphamide, Anti-thymocyte globulin, GVHD, Hematopoietic stem cell transplantation
Clinical characteristics between PTCy with ATG and PTCy groups underwent haplo-HSCT (n = 40).
PTCy + ATG (n = 23). | PTCy (n = 17). | p-value. | |
---|---|---|---|
Median Age, year (range). | 60, (18–71). | 56, (28–72). | 0.997. |
Gender, M: F. | 12: 11. | 10: 7. | 0.755. |
Type of diseases. | 0.476. | ||
AML. | 16 (69.6%). | 12 (70.6%). | |
ALL. | 3 (13.0%). | 4 (23.5%). | |
MDS & PMF. | 4 (17.4%). | 1 (5.9%). | |
Conditioning intensity. | 0.336. | ||
MAC. | 7 (30.4%). | 8 (47.1%). | |
RIC. | 16 (69.6%). | 9 (52.9%). | |
Disease status at transplant. | 0.053. | ||
1st CR. | 19 (82.6%). | 12 (70.6%). | |
2nd CR. | 0 (0.0%). | 3 (17.6%). | |
3rd CR. | 0 (0.0%). | 1 (5.9%). | |
MDS & PMF. | 4 (17.4%). | 1 (5.9%). | |
Poor riska. | 12 (60.0%). | 10 (62.5%). | 1.000. |
HCT-CI. | 0.389. | ||
0. | 15 (65.2%). | 12 (70.6%). | |
1–2. | 5 (21.7%). | 5 (29.4%). | |
3-. | 3 (13.0%). | 0 (0.0%). | |
EBV reactivation. | 2 (8.7%). | 0 (0.0%). | 0.499. |
CMV reactivation. | 6 (26.1%). | 14 (82.4%). | < 0.001. |
CMV prophylaxis with letermovir. | 9 (39.0%). | 0 (0.0%). | 0.005. |
VOD incidence. | 0 (0.0%). | 4 (24.0%). | 0.026. |
Acute GVHD (evaluable). | 0.029. | ||
None. | 15 (65.2%). | 6 (40.0%). | |
Grade I/II. | 8 (34.8%). | 5 (33.3%). | |
Grade III/IV. | 0 (0.0%). | 4 (26.7%). | |
Stem cell source. | -. | ||
PB. | 23 (100%). | 17 (100%). | |
BM. | 0 (0.0%). | 0 (0.0%). | |
CRS grading. | < 0.001. | ||
No CRS. | 20 (87.0%). | 1 (5.9%). | |
Grade 1. | 3 (13.0%). | 10 (58.8%). | |
Grade 2. | 0 (0.0%). | 6 (35.3%). | |
Cell count, median (range). | |||
TNC count (× 108 cells/kg). | 13.90 (6.09–23.28). | 13.18 (6.41–21.71). | 0.576. |
CD34 + cell (x106cells/kg). | 8.56 (4.50–17.77). | 10.68 (2.88–25.85). | 0.224. |
Median F/U duration, month (range). | 5.5 (0.3–40.5). | 9.3 (3.3–22.8). | 0.255. |
PBSCT Peripheral blood stem cell transplantation, CR Complete remission, HCT-CI Hematopoietic stem cell transplantation comorbidity index, CMV Cytomegalovirus, VOD Veno occlusive disease, PB Peripheral blood, BM Bone marrow, MAC Myeloablating conditioning, RIC Reduced intensity conditioning, TNC Total nucleated cell.
aPoor risk includes sAML, tAML, AML with poor risk group in NCCN guideline, poor cytogenetics in ALL.
Univariate and Multivariate analysis for risk factors of OS.
Variables. | Univariate analysis. | Multivariate analysis. | ||
---|---|---|---|---|
p value. | HR (95% CI). | p value. | HR (95% CI). | |
Age ≥ 57 vs < 57. | 0.254. | 1.912 (0.628–5.821). | ||
GVHD prophylaxis. | ||||
PTCy + ATG vs. PTCy. | 0.051. | 0.333(0.110–1.006). | ||
Conditioning intensity. | ||||
Myeloablative vs Reduced intensity. | 0.124. | 2.765 (0.757–10.097). | ||
HCT-CI score ≥ 3 vs. 0–2. | 0.957. | 0.945 (0.120–7.438). | ||
Non-CR1 status at transplant. | 0.011. | 5.830 (1.504–22.592). | 0.233. | 3.178 (0.475–21.285). |
Cytogenetic Risk status at diagnosis. | ||||
Poor vs. favorable or intermediate. | 0.999. | 1.001 (0.491–2.040). | ||
Acute GVHD II-IV vs. 0-I. | 0.001. | 7.986 (2.473–25.788). | 0.283. | 2.632 (0.450–15.379). |
Severe chronic GVHD vs. Non-severe. | 0.239. | 0.406 (0.090–1.823). | ||
IL-6 levels. | < 0.001. | 1.009 (1.005–1.014). | 0.011. | 1.009 (1.002–1.016). |
CRS severity: grade 2 or greater vs. 0 or 1. | 0.238. | 2.173 (0.599–7.891). |
Tx Treatment, OS Overall survival, GVHD Graft versus host disease, HCT-CI Hematopoietic stem cell transplantation comorbidity index, CR Complete remission, CRS Cytokine release syndrome.
Univariate and Multivariate analysis for risk factors of NRM.
Variables. | Univariate analysis. | Multivariate analysis. | ||
---|---|---|---|---|
p value. | HR (95% CI). | p value. | HR (95% CI). | |
Age ≥ 57 vs. < 57. | 0.318. | 1.897 (0.540–6.664). | ||
GVHD prophylaxis. | ||||
PTCy + ATG vs. PTCy. | 0.034. | 0.235 (0.061–0.898). | 0.453. | 2.470 (0.233–26.216). |
Conditioning intensity. | ||||
Myeloablative vs Reduced intensity. | 0.118. | 3.470 (0.730–16.486). | ||
HCT-CI score ≥ 3 vs. 0–2. | 0.788. | 1.329 (0.168–10.523). | ||
Non-CR1 status at transplant. | 0.070. | 4.517 (0.885–23.047). | ||
Cytogenetic Risk status at diagnosis. | ||||
Poor vs. favorable or intermediate. | 0.586. | 1.293 (0.512–3.266). | ||
Acute GVHD II-IV vs. 0-I. | 0.006. | 6.717 (1.748–25.805). | 0.418. | 2.756 (0.237–32.113). |
Severe chronic GVHD vs. Non-severe. | 0.187. | 0.250 (0.032–1.963). | ||
IL-6 levels. | < 0.001. | 1.010 (1.005–1.014). | 0.005. | 1.012 (1.004–1.020). |
CRS severity: grade 2 or greater vs. 0 or 1. | 0.139. | 2.747 (0.720–10.489). |
NRM Non-relapse mortality, Tx Treatment, OS Overall survival, GVHD Graft versus host disease, HCT-CI Hematopoietic stem cell transplantation comorbidity index, CR Complete remission, CRS Cytokine release syndrome.
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