Post-transplant cyclophosphamide plus anti-thymocyte globulin lowered serum IL-6 levels compared with post-transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation

doi:10.21203/rs.3.rs-4856013/v1

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Post-transplant cyclophosphamide plus anti-thymocyte globulin lowered serum IL-6 levels compared with post-transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation

https://doi.org/10.21203/rs.3.rs-4856013/v1

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Background: Post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are both common prophylactic strategies for graft-versus-host disease (GVHD) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.

Method: This study compared the clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023.

Results: Forty patients who underwent haplo-HSCT were analyzed. There was a significant difference in IL-6 levels 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 CRS grade 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grade II-IV acute GVHD (r = 0.547, p <0.001). The cumulative incidence (CI) of grade II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p <0.001). There was no significant difference in the CI of chronic GVHD 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 compared with 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).

Conclusion: Serum IL-6 levels were higher with PTCy alone than with PTCy plus ATG. The addition of ATG before stem cell infusion affects IL-6 levels and reduces the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of the clinical outcomes and complications of HSCT.

IL-6

post-transplantation cyclophosphamide

Anti-thymocyte globulin

GVHD

Hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is an essential treatment method for curing blood cancers [1]. Recently, haplo-identical HSCT (haplo-HSCT) has become widely used, with consistent improvements in its treatment outcomes [2, 3]. Consequently, donor availability is no longer a major obstacle in allogeneic HSCT [4]. Nevertheless, graft-versus-host disease (GVHD) remains a major concern in the implementation of haplo-HSCT [5, 6]. Despite recent advances in the treatment of GVHD, 10–20% of patients experience severe acute GVHD after allogeneic HSCT and one-third of patients develop extensive chronic GVHD [7, 8]. Such severe grades of acute and chronic GVHD constitute a significant portion of non-relapse mortality (NRM) and cause long-term sequelae, profoundly affecting the patient’s quality of life. Therefore, the prevention of severe GVHD is crucial for improving the clinical outcomes of haplo-HSCT [9]. Currently, the most commonly used regimens for GVHD prevention in T-cell-replete haplo-HSCT are anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) [7, 10]. ATG, containing antibodies that primarily destroy T cells, prevents GVHD via T cell depletion in vivo [11]. Meanwhile, PTCy effectively eliminates donor-derived alloreactive T cells after allogeneic HSCT while preserving hematopoietic stem cells and regulatory T cells, thereby demonstrating its preventive effect against GVHD [12, 13].

No prospective study has compared the efficacy of PTCy and ATG in haplo-HSCT. A retrospective analysis using data from the European Society for Blood and Bone Marrow Transplantation (EBMT) registry showed that a PTCy-based regimen led to better outcomes relative to an ATG-based regimen in patients with acute myeloid leukemia (AML) [7]. The PTCy-based regimen resulted in longer durations of leukemia-free, GVHD-free, and relapse-free survival, along with lower incidences of GVHD and NRM. Furthermore, in a recent meta-analysis, a PTCy-based regimen demonstrated superior overall survival (OS) and GVHD prevention effects compared with an ATG-based regimen even in unrelated donor allogeneic HSCT [14]. Therefore, PTCy is considered a new standard for GVHD prophylaxis in haplo-HSCT and unrelated donor HSCT [15, 16].

Despite the use of PTCy-based regimens, some patients experience severe GVHD or cytokine release syndrome (CRS), occasionally leading to life-threatening complications [17, 18]. Previously, we reported that 10–20% of patients receiving a PTCy-based regimen experienced severe CRS and acute GVHD, resulting in serious neurological complications such as autoimmune limbic encephalitis [19]. Therefore, to reduce the incidences of CRS and severe acute GVHD, clinical trials combining PTCy and ATG have recently been conducted [14, 20, 21]. Additionally, interleukin-6 (IL-6) is under investigation as a biomarker to predict acute GVHD or CRS in haplo-HSCT using PTCy [22, 23]. Thus far, no study has compared IL-6 levels between groups using PTCy alone vs. PTCy plus ATG. We conducted this study to analyze correlations between IL-6 levels and clinical outcomes in both groups.

Patients and treatments

We retrospectively analyzed consecutive adults (age > 18 years) with hematological malignancies who underwent human leukocyte antigen (HLA) haplo-identical donor allogeneic HSCT in Chungnam National University Hospital (CNUH, Daejeon, South Korea) between January 2019 and February 2023. PTCy (50 mg/kg) was administered on days + 3 and + 4. Rabbit ATG (thymoglobulin, 1.5 mg/kg; Sanofi-Aventis, Paris, France) was administered from day − 3 to day − 1. The regimen included tacrolimus beginning on day + 5 with a target level of 5 to 15 ng/mL; mycophenolate mofetil was administered from day 5 to day 35, up to 3 g/day in divided doses. Two conditioning regimens were used. In the myeloablative conditioning (MAC) regimen, 3.2 mg/kg busulfan was administered for 4 days and 30 mg/m² fludarabine was administered for 5 days. In the reduced intensity conditioning (RIC) regimen, 3.2 mg/kg busulfan was administered for 2 days and 30 mg/m² fludarabine was administered for 5 days. RIC was administered to patients aged > 55 years or patients with comorbidities. The busulfan dose was not pharmacokinetically adjusted. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSCs; target CD34 + cell count, 5 × 10⁶/kg). Filgrastim (5 µg/kg) was administered from day + 5 until neutrophil recovery. No therapy was added to prevent relapse after allogeneic HSCT, such as donor lymphocyte infusion, hypomethylating agents, or tyrosine kinase inhibitors.

Study end points and definitions

The primary study outcome was the difference in IL-6 levels and their correlations with acute GVHD between two treatment groups: PTCy alone and PTCy plus ATG. Secondary outcomes were OS, the incidences and severities of acute and chronic GVHD, leukemia-free survival, relapse rate, NRM, cytokine release syndrome (CRS), veno-occlusive disease (VOD), and cytomegalovirus (CMV) and Epstein–Barr virus (EBV) reactivation in each group. Acute GVHD was graded using the modified Seattle Glucksberg criteria, and chronic GVHD was graded according to the revised Seattle criteria [24, 25]. NRM was defined as death from any cause except relapse. CRS was graded according to the American Society for Transplantation and Cellular Therapy scale [26]. All CRS manifestations occurred within the first 6 days after transplantation. CMV and EBV reactivation were defined as the detection of viral DNA in whole blood by polymerase chain reaction on at least one occasion.

Sample Collection and Analysis

Peripheral blood samples were collected from patients on day + 3 after haplo-HSCT. Serum IL-6 levels were measured by chemiluminescent immunoassay (CLIA) using the Elecsys IL-6 kit (Roche Diagnostics, Mannheim, Germany) in a clinical laboratory at CNUH. In accordance with the manufacturer’s instructions, the serum IL-6 reference values were set to 0–7.0 pg/mL.

Statistical analysis

Categorical variables were compared using the chi-square test, and logistic regression was performed to examine correlations. Overall and leukemia-free survival durations were assessed using the Kaplan–Meier method. Survival rates were compared using the log-rank test. Cumulative incidence (CI) functions were used to estimate the rates of acute and chronic GVHD, as well as the relapse rate and NRM. A p-value < 0.05 was considered statistically significant. Cox proportional hazards regression was used to evaluate OS. Clinically relevant factors with a p-value < 0.05 in univariate analyses were entered into multivariate analysis. All statistical analyses were performed using SPSS ver. 24.0 software (IBM, Armonk, NY, USA).

Patient and Transplantation Characteristics

The study included 40 patients undergoing haplo-HSCT, divided into two groups based on the GVHD prophylaxis received: PTCy plus ATG (n = 23) or PTCy alone (n = 17). Table 1 summarizes the baseline characteristics. The median ages at diagnosis were 60 and 56 years, respectively. No significant differences were observed between the groups in terms of sex, disease type, conditioning intensity, poor-risk disease, and HCT-CI. Although the difference was not significant, the MAC regimen was administered to a greater proportion of the PTCy alone group (47.1% vs. 30.4%, respectively; p = 0.336). There was no difference in EBV reactivation between the two groups. The rate of CMV reactivation was significantly higher in the PTCy alone group (82.4% vs. 26.1%, p < 0.001). In the PTCy plus ATG group, 9 of 23 (39.0%) patients received letermovir, compared with none in PTCy alone group (p = 0.005). The incidence of VOD was significantly higher in the PTCy alone group than in PTCy with ATG group (24.0% vs. 0.0%, p = 0.026). Grade III/IV acute GVHD occurred more frequently in the PTCy alone group than in PTCy with ATG group (26.7% vs. 0.0%, p = 0.029). The total number of patients with CRS grade 0 was higher in the PTCy plus ATG group compared to PTCy alone group (87.0% vs. 5.9%, p < 0.001). The median follow-up durations in the PTCy plus ATG and PTCy alone groups were 9.3 (range 3.3–22.8) and 5.5 (range 0.3–40.5) months, respectively.

Table 1

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 risk*	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 (x10⁸ 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
*Poor risk includes sAML, tAML, AML with poor risk group in NCCN guideline, poor cytogenetics in ALL.
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.

IL-6 levels and acute GVHD and CRS

There was a significant difference in IL-6 levels between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67, respectively; p = 0.003, Fig. 1A). IL-6 levels increased concurrently with the severity of acute GVHD (r = 0.547, p < 0.001, Fig. 1B). The grade of CRS severity was correlated with the IL-6 level (r = 0.801, p < 0.001, Fig. 1C) and positively correlated with the degree of acute GVHD (p = 0.004, Fig. 1D).

GVHD and CRS between PTCy with ATG and PTCy alone

The CI of grade II-IV acute GVHD on day 100 was significantly higher in the PTCy alone group than in PTCy plus ATG group (67.9% vs. 4.8%; p < 0.001, Fig. 2A). PTCy alone recipients were more likely to have grade III/IV acute GVHD compared with PTCy plus ATG recipients (26.7% vs. 0.0%, respectively; p = 0.010, Fig. 2B). There were no significant differences between PTCy plus ATG and PTCy alone groups in the 1-year CI of chronic GVHD (75.7% vs. 65.1%; p = 0.485, Fig. 2C) or 1-year CI of extensive chronic GVHD (13% vs. 44%; p = 0.375, Fig. 2D).

Fever within 6 days after stem cell infusion occurred in 22 of 40 patients (55%). A regular pattern of fever was noted, generally disappearing within 48 h after initial cyclophosphamide administration and fully resolving for all patients by day + 7. The PTCy alone group was more likely to develop grade 2 CRS compared to PTCy plus ATG group (35.3% vs. 0.0%, p < 0.001).

Survival outcomes

The CI of 1-year NRM was significantly higher in the PTCy alone group (42.2% vs. 15.9%; p = 0.022, Fig. 3A), but there was no significant difference in 1-year relapse mortality between the two groups (PTCy plus ATG, 30.3% vs. PTCy alone, 28.5%; p = 0.550, Fig. 3B). The causes of NRM were infection, GVHD, and intra-cranial hemorrhage. The 1-year OS was significantly better in the PTCy plus ATG group than in PTCy alone group (75.9% vs. 44.0%; p = 0.041, Fig. 3C).

Next, we performed univariate and multivariate analyses of OS and NRM (Tables 2 and 3). Univariate analysis showed that non-CR1 status at transplantation, grade II-IV acute GVHD, and serum IL-6 levels were associated with poor OS. Multivariate analysis confirmed that IL-6 levels were an independent adverse risk factor for OS in patients who underwent haplo-HSCT (hazard ratio [HR] = 47.462, p = 0.002).

Table 2

Univariate and Multivariate analysis for risk factors of OS
Variables	Univariate analysis		Multivariate analysis
Variables	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)
Extensive chronic GVHD vs. Non-extensvie	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

Table 3

Univariate and Multivariate analysis for risk factors of NRM
Variables	Univariate analysis		Multivariate analysis
Variables	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 vs. CR1	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)
Extensive chronic GVHD vs. Non-extensive	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

And the PTCy alone regimen of GVHD prophylaxis, grade II-IV acute GVHD and IL-6 levels were associated with NRM in the univariate analyses (Table 3). According to multivariate analysis, IL-6 levels were the only risk factor associated with NRM (HR = 1.012, p = 0.005).

Recently, several retrospective studies have explored the use of ATG plus PTCy to prevent GVHD [20, 21, 27]. However, there are no reports concerning the utility of IL-6 as an indicator for acute GVHD in the context of haplo-HSCT using PTCy or PTCy plus ATG. In this study, we demonstrated that the addition of ATG to PTCy reduced post-transplant IL-6 levels, contributing to lower severities of CRS and acute GVHD after haplo-HSCT, thereby improving survival outcomes.

IL-6 is a pro-inflammatory cytokine that serves as biomarker for CRS and acute GVHD after haplo-HSCT [18, 22]. The main source of IL-6 is monocyte lineage cells; monocytes are presumably stimulated to secrete IL-6 upon alloreactive T cell activation after haplo-HSCT [28]. IL-6 inhibits transforming growth factor (TGF)-β-induced T cell differentiation into regulatory T (Treg) cells and downregulates Foxp3 expression by regulatory T cells [29, 30]. Elevated IL-6 levels are suspected to reduce Treg activity, ultimately resulting in increased acute GVHD severity. Previously, we demonstrated that the Treg population was reduced upon elevation of post-transplant IL-6 levels in patients who underwent haplo-HSCT using PTCy. Moreover, there was a substantial decrease in the active subpopulation of Tregs, contributing to the onset of severe CRS and encephalopathy [19].

Greco et al. measured IL-6 on day 7 post-transplantation, whereas we measured it on day 3. We utilized this approach because our previous study serially analyzing IL-6 and other inflammatory cytokines after haplo-HSCT using PTCy showed that the highest IL-6 values occurred on post-transplant day 3 [19]. Furthermore, the peak clinical manifestations of CRS, primarily represented by fever, occur immediately prior to PTCy administration. Therefore, we measured IL-6 on post-transplant day 3 and analyzed clinical outcomes associated with the IL-6 level. Furthermore, in our study, IL-6 was the only predictor of survival and treatment-related mortality, suggesting that IL-6 measurement after haplo-HSCT with PTCy may be useful for predicting both acute GVHD and post-transplant prognosis.

In the previous studies comparing PTCy plus ATG with PTCy alone, the addition of ATG to PTCy appeared to reduce the incidences of acute and chronic GVHD without increasing the rate of relapse [31–33]. Battipaglia et al. reported that PTCy plus ATG was associated with a lower risk of chronic GVHD relative to PTCy alone, without higher rates of transplantation toxicity, mortality, or relapse [31]. El-Cheikh et al. also reported that the addition of ATG to PTCy reduced the incidence of acute GVHD and increased OS in HSCT [32]. In our study, PTCy plus ATG significantly reduced the incidences of VOD and NRM, leading to improved OS. And PTCy plus ATG did not affect relapse incidence. To investigate the mechanisms underlying these effects, Makanga et al. analyzed T and NK cells in the peripheral blood of patients undergoing haplo-HSCT using PTCy and ATG; they suggested that slower T cell reconstitution is involved in the reduced incidence of GVHD, whereas faster-recovering subtypes of NK cells help to prevent relapse [33].

The optimal dosage when adding ATG to PTCy has not been determined. Some studies have been conducted to explore lower dosages of ATG and PTCy [20, 21]. Xu et al. compared low-dose ATG (5 mg/kg) plus low-dose PTCy (one dose of 50 mg/kg) with the standard dose of ATG (10 mg/kg); they reported that low-dose ATG plus PTCy reduced GVHD risk and NRM [20]. A retrospective analysis of a large sample with long-term follow-up suggested that low-dose ATG/PTCy effectively prevented severe acute GVHD [34]. Wang et al. reported that low-dose PTCy (14.5 mg/kg on days 3 and 4) plus ATG reduced acute and chronic GVHD relative to the standard dose ATG regimen [21]. Additionally, Kim et al. adjusted the ATG dose according to the absolute lymphocyte count on day 3 before haplo-HSCT and administered a total of 80 mg of PTCy. They reported that the dual T cell-depleting regimen improved survival compared with ATG alone [35]. Intriguingly, they reported that the rate of life-threatening infections in the post-engraftment period was lower in the ATG/PTCy combination group than in the ATG alone group. Therefore, further research is needed to determine the optimal dosages of ATG and PTCy when used in combination.

This study had some limitations. First, it was a retrospective single-center analysis with a small number of patients. Thus, future multicenter studies with more patients are needed to generalize our findings. However, this study analyzed consecutive patients treated with the same protocol at the same institution, which may have reduced selection bias. Second, the rate of CMV reactivation was higher in the PTCy alone group, contrary to the generally accepted notion that increased immunosuppressive therapy strength is associated with a greater likelihood of CMV reactivation. This result may have occurred because national health insurance coverage for letermovir became available within South Korea in March 2021. However, there were no deaths from CMV disease, indicating that the difference was unlikely to influence OS.

In conclusion, the addition of ATG to PTCy lowered IL-6 levels, reducing the incidences of CRS, acute GVHD, and NRM, and improving OS. IL-6 levels measured 3 days after haplo-HSCT with PTCy could be used to predict OS, NRM, and GVHD.

Consent for publication

Not applicable

Author contributions

Conceptualization: JS Koh, MW Lee, IC Song

Supervision: DY Jo, HJ Yun, HJ Lee

Methodology: TTD Pham, BY Heo, S Choi, SW Lee

Funding: JS Koh, IC Song

Validation: W Seo, S Kang, SB Lee

Formal analysis: CH Kim, H Ryu, HS Eun

Investingation: JS Koh, MW Lee

Data curation: JS Koh, MW Lee

Writing original draft preparation: JS Koh, MW Lee, IC Song

Writing review & editing: JS Koh, MW Lee, IC Song

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2021R1C1C1012397) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (HR20C0025010020) and the Korean Society of Hematology research fund (ICKSH-2023-04).

Ethics approval and consent to participate

The study protocol was approved by the Institutional Review Board of Chungnam National University Hospital. The requirement for informed patient consent was waived due to the retrospective nature of the analysis.

Competing interests

Ik-Chan Song was the Associate Editor of Blood Research while conducting this study. The Associate Editor status has no bearing on editorial consideration.

Availability of data and material

Original data can be requested from the corresponding author ([email protected])

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No competing interests reported.

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Post-transplant cyclophosphamide plus anti-thymocyte globulin lowered serum IL-6 levels compared with post-transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation

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Abstract

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Introduction

Materials and Methods

Patients and treatments

Study end points and definitions

Sample Collection and Analysis

Statistical analysis

Results

Patient and Transplantation Characteristics

IL-6 levels and acute GVHD and CRS

GVHD and CRS between PTCy with ATG and PTCy alone

Survival outcomes

Discussion

Declarations

References

Additional Declarations

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