Graft-Versus-Host Disease

Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT

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Abstract

A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5–18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0–3.9 and 4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34–4.85; P=0.004 for 2.0–3.9 mg/kg group and 1.79; 0.91–3.55; P=0.093 for 4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.

Introduction

Despite prophylaxis with immunosuppressive agents, acute GvHD remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. A standard first-line treatment for acute GvHD is systemic administration of corticosteroids, with a treatment failure rate of 40–60%.1, 2 There is no established second-line treatment for corticosteroid-resistant acute GvHD,3 resulting in high nonrelapse mortality (NRM) in such patients.4, 5

Antithymocyte globulin (ATG) has been widely used as a second-line treatment for acute GvHD, presumably on the grounds of its ready availability, convenience, relative inexpensiveness, and physicians’ familiarity and their prior experience. Efficacy and adverse effects of ATG were evaluated in several studies in the early 2000 s.6, 7, 8, 9, 10, 11, 12 Responses were obtained in 30–60% of patients with steroid-resistant acute GvHD. However, NRM was high mainly due to subsequent serious infections and EBV-lymphoproliferative disease.6, 7, 10, 12 Optimizing the dose of ATG to minimize infectious complications and retain the suppressive effect on GvHD may enhance its value as a second-line treatment for acute GvHD.

Thymoglobulin (Sanofi, Tokyo, Japan), which is produced by immunizing rabbits with human thymocytes, became covered by health insurance in Japan from the end of 2008. In the present study, a nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin as a second-line treatment for steroid-resistant acute GvHD was conducted. Because preceding studies performed in the United States of America or Europe raised alarm over serious infections after thymoglobulin therapy, quite a low dose of thymoglobulin was preferred in Japan. The unusual circumstances enabled us to evaluate the efficacy of low-dose thymoglobulin at a median total dose of 2.5 mg/kg.

Patients and methods

Patients

Clinical data for patients who received their first allogeneic hematopoietic stem cell transplantation from January 2009 to December 2012, received first-line treatment with systemic corticosteroid equivalent to prednisolone at 0.5 mg/kg or higher dose for at least 3 days for acute GvHD, and received second-line treatment with thymoglobulin were extracted from the Transplant Registry Unified Management Program system, which is a registry of the outcomes of Japanese transplant patients.13 Patients who received some systemic agent(s) other than prophylactic calcineurin inhibitors in addition to systemic corticosteroid therapy were excluded. Thymoglobulin was initiated when it was determined by the physicians at each hospital that the response to first-line treatment was less than satisfactory. The doses of thymoglobulin were determined at the physician’s discretion. This study was planned by the GvHD working group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) (Appendix) and approved by the Data Management Committee of JSHCT and the ethics committee of the Nagoya University School of Medicine (2014-0007).

Measurement of GvHD response to thymoglobulin therapy

Acute GvHD was diagnosed and graded according to established criteria.14 The GvHD response to thymoglobulin therapy in each organ involved was evaluated 28 days after the start of thymoglobulin therapy. If the patient died or received a third-line treatment 3–27 days after the start of thymoglobulin therapy, response was evaluated on that day. If the patient died or received a third-line treatment within 2 days after the start of thymoglobulin therapy, response was considered to be unevaluable due to the short follow-up after thymoglobulin therapy. Overall responses were defined as follows: complete response (CR), resolution of all symptoms attributed to GvHD; partial response (PR), improvement in one or more organ systems without deterioration in others; mixed response, improvement in one or more organ systems with deterioration in others; progressive disease, deterioration in one or more organ systems without improvement in others; and no change, no change in any organ system.

End points

The primary end point was the impact of thymoglobulin dose on the therapeutic response and NRM. The secondary end points were infectious complications and overall survival (OS) after thymoglobulin therapy.

Statistical analysis

Univariate and multivariate logistic regression analyses were used to identify factors associated with the response to thymoglobulin therapy. Variables significant at P<0.05 on univariate analyses and thymoglobulin dose were included in the multivariate analysis. The probability of NRM after thymoglobulin therapy was estimated on the basis of cumulative incidence curves in which relapse was treated as a competing event.15 OS after thymoglobulin therapy was estimated according to the Kaplan–Meier method.16 The groups were compared using the log-rank test. Competing risk regression analysis was used to identify factors associated with NRM after thymoglobulin therapy. The adjusted probability of OS after thymoglobulin therapy was estimated using Cox’s proportional hazards model, with consideration of other significant variables.17 All tests were two-sided, and P<0.05 was considered significant. The following covariates were considered for the multivariate models: patient age, patient sex, sex mismatch between patient and donor, disease, CMV serological status, stem cell source, preconditioning, GvHD prophylaxis, in vivo T-cell depletion, year of transplantation, interval from the start of corticosteroid therapy to that of thymoglobulin therapy, first day of thymoglobulin therapy, grade and organ involvement of acute GvHD at the start of thymoglobulin therapy, thymoglobulin dose and response to thymoglobulin therapy. The data were analyzed by STATA version 12 statistical software (StataCorp LP, College Station, TX, USA).

Results

Patient characteristics

A total of 99 patients met the inclusion criteria. Patient characteristics are shown in Table 1. Patient age at transplantation ranged from 2 to 69 years, and 91 patients (92%) were 18 years or older. Of the 95 malignancies, 79 (83%) were high-risk malignancies. Of the 53 related donor transplantations, 16 (30%) were performed from HLA-A, B and DR serotypes 6/6-matched donor, including 11 donors whose HLA-A, B and DRB1 alleles were matched with the patient and five donors whose HLA allele types were unknown. Of the 40 unrelated donor transplantations, 13 (33%) were performed from HLA-A, B and DRB1 alleles 6/6-matched donor, including 11 donors whose HLA-C was matched with the patient and two donors whose HLA-C was unknown. No PBSC transplantation from unrelated donors was performed during this period in Japan. All cord blood transplantation was performed with a single unit. In vivo T-cell depletion was performed in 25 patients, all of whom received thymoglobulin. The median follow-up for living and all patients was 1110 (range, 506–1719) and 78 (range, 2–1719) days, respectively.

Table 1 Patient characteristics (n=99)

GvHD characteristics

The median onset of acute GvHD was day 18 (range, day 3–73) after transplantation, and the median first day of first-line treatment with systemic corticosteroid was day 25 (range, day 4–175) after transplantation. The grade of acute GvHD at the start of corticosteroid therapy was I for 6, II for 39, III for 41 and IV for 13 patients.

The median first day of second-line treatment with thymoglobulin was day 41 (range, day 8–182) after transplantation, and the median interval between the first day of corticosteroid therapy and thymoglobulin therapy was 11 days (range, 3–111 days). Characteristics of acute GvHD at the start of thymoglobulin therapy are shown in Table 2. Ninety-eight patients (99%) had grade II–IV acute GvHD and 74 patients (75%) had grade III–IV. Involvement of the skin, liver and gut was observed in 66%, 27% and 77% of patients, respectively. The timing of acute GvHD onset, organ involvement and grade of acute GvHD was not significantly different in patients with pre-transplant thymoglobulin than from those without pre-transplant thymoglobulin (data not shown).

Table 2 Characteristics of acute GvHD at the start of thymoglobulin therapy

GvHD response to thymoglobulin therapy

The median total dose of thymoglobulin was 2.5 mg/kg (range, 0.5–18.5 mg/kg): <2.0 mg/kg for 35 patients, 2.0–3.9 mg/kg for 32 patients and 4.0 mg/kg for 32 patients. Thymoglobulin was administered consecutively for 1–5 days (median, 2 days) according to the total dose: 1–4 days for <2.0 mg/kg, 1–2 days for 2.0–3.9 mg/kg and 2–5 days for 4.0 mg/kg. There was no association between the thymoglobulin total dose group and the severity of acute GvHD. Seven patients died or received third-line treatment within 2 days after the start of thymoglobulin therapy, and they were not evaluated for response to thymoglobulin therapy.

Of the 92 evaluable patients, overall improvement (CR+PR) of acute GvHD on day 28 of thymoglobulin therapy was observed in 55 patients (60%) (Table 3). Improvement was observed in 85% of patients with skin GvHD only, 58% of patients with gut GvHD only and 29% of patients with skin, liver and gut GvHD (Table 3). Improvement in the respective organ was observed in 72% of patients with skin (n=57), 29% of patients with liver (n=24) and 55% of patients with gut (n=67) involvement.

Table 3 GvHD response to thymoglobulin therapy

Of the 23 patients who achieved CR on day 28 of thymoglobulin therapy, 17 patients were alive on day 100 of thymoglobulin therapy. Of the 17 evaluable patients, 15 (88%) were alive with CR and 2 (12%) were alive without CR. Both patients were suffering from grade I acute GvHD and received neither thymoglobulin nor any other third-line treatment for GvHD. The remaining six patients died of relapse (n=4), sepsis (n=1) or fungal infection (n=1) before day 100 of thymoglobulin therapy.

Factors associated with improvement of acute GvHD by thymoglobulin therapy

On univariate analysis, male sex, grade III and IV acute GvHD and liver involvement were associated with a lower probability of improvement (CR+PR) of steroid-resistant acute GvHD by thymoglobulin therapy, whereas thymoglobulin dose was NS (Table 4). Overall improvement rates in patients with <2.0, 2.0–3.9 and 4.0 mg/kg thymoglobulin were 63%, 57% and 59%, respectively. On multivariate analysis with significant variables and thymoglobulin dose, male sex and grade III and IV acute GvHD were significant for ATG response, and thymoglobulin dose was not. None of in vivo T-cell depletion with thymoglobulin, the first day of ATG therapy (day 41,day 42), and the interval between the first days of corticosteroid therapy and ATG therapy (11 days, 12 days) was significant.

Table 4 Factors associated with improvement (complete or partial response) of steroid-resistant acute GvHD by thymoglobulin therapy

Factors associated with NRM after thymoglobulin therapy

The cumulative incidence of NRM at 1 year after thymoglobulin therapy in 99 patients was 71% (95% confidence interval, 60–80%). The cumulative incidences of NRM at 1 year after thymoglobulin therapy in patients with thymoglobulin at <2.0, 2.0–3.9 and 4.0 mg/kg were 63% (41–78%), 68% (49–82%) and 82% (62–92%), respectively (NS) (Figure 1a). The cumulative incidences of NRM at 1 year after thymoglobulin therapy in patients with and without improvement (CR+PR) of acute GvHD were 51% (35–64%) and 97% (80–100%), respectively (P<0.0001) (Figure 1b). The relapse rate at 1 year after thymoglobulin therapy in 99 patients was 30% (12–51%).

Figure 1
figure1

NRM after thymoglobulin therapy in patients with steroid-resistant acute GvHD. (a) The cumulative incidences of NRM after thymoglobulin therapy stratified by thymoglobulin dose are shown (short dotted line for <2.0 mg/kg, long dotted line for 2.0–3.9 mg/kg and solid line for 4.0 mg/kg). There is no significant difference among these groups. (b) The cumulative incidences of NRM after thymoglobulin therapy stratified by response of acute GvHD are shown (dotted line for CR or PR and solid line for other than CR/PR). Patients with CR/PR of acute GvHD have a significantly lower NRM compared with those without CR/PR (P<0.0001).

To identify predictive factors for higher NRM after thymoglobulin therapy, competing risk regression analysis was performed. On univariate analysis, higher patient age, higher grade acute GvHD, liver involvement and no achievement of CR/PR by thymoglobulin therapy were associated with higher NRM (Table 5). These variables and thymoglobulin dose were included in the multivariate analysis. Factors associated with significantly higher NRM included higher patient age (50 years), grade IV acute GvHD, no achievement of CR/PR and higher dose of thymoglobulin. Thymoglobulin at 2.0–3.9 mg/kg predicted a higher NRM (P=0.004), and thymoglobulin at 4.0 mg/kg showed a trend toward a higher NRM (P=0.093). Neither the first day of thymoglobulin therapy (day 41, day 42) nor the interval between the first days of corticosteroid therapy and thymoglobulin therapy (11 days, 12 days) was significant.

Table 5 Factors associated with nonrelapse mortality after thymoglobulin therapy

Infectious complications

Within the first 100 days after the start of thymoglobulin therapy, 58 patients (59%) developed an additional infection by one or more of the following: bacterial infection (n=28), deep fungal infection (n=11), CMV antigenemia (n=25) and viral infection (n=10). On univariate analysis, higher thymoglobulin dose was associated with a higher incidence of any additional infection (relative risk, 3.83; 95% confidence interval, 1.38–10.69; P=0.010 for 2.0–3.9 mg/kg group, and 2.86; 1.06–7.74; P=0.038 for 4.0 mg/kg group), though no significant factor was found on multivariate analysis.

Of 28 patients who developed bacterial infection, 10 (36%) died of the bacterial infection itself including sepsis (n=4), pneumonia (n=2), liver abscess (n=1) and no obvious focus (n=3). On univariate analysis, thymoglobulin dose 4.0 mg/kg was associated with a higher incidence of bacterial infections (relative risk, 3.31; 95% confidence interval, 1.07–10.21; P=0.038). However, no significant factor was found on multivariate analysis. Of 11 patients who developed deep fungal infection, one (9%) died of the fungal infection itself. Thymoglobulin dose of 2.0–3.9 mg/kg was associated with a higher incidence of CMV antigenemia on univariate analysis (relative risk, 3.60; 95% confidence interval, 1.10–11.80; P=0.034), though no significant factor was found on multivariate analysis. Viral infection (n=10) included one or more of the following: CMV (n=5), VZV (n=1), adenovirus (n=1), BK virus (n=6) and EBV (n=7). One (20%) of five patients who developed CMV infection died of the CMV infection itself. Three (43%) of seven patients who developed EBV infection died of EBV-lymphoproliferative disease.

OS rate

OS rate at 1 year after thymoglobulin therapy in 99 patients was 27% (95% confidence interval, 18–36%). OS rates at 1 year after thymoglobulin therapy in patients with thymoglobulin <2.0, 2.0–3.9 and 4.0 mg/kg were 32% (17–49%), 32% (17–49%) and 16% (6–30%), respectively (NS) (Figure 2a). OS rates at 1 year after thymoglobulin therapy in patients with and without improvement (CR+PR) of acute GvHD were 42% (29–54%) and 5% (1–16%), respectively (P<0.0001) (Figure 2b). After adjustment by patient age, grade of acute GvHD at initiation of thymoglobulin therapy and liver involvement of acute GvHD at initiation of thymoglobulin therapy, which were significant on univariate analyses, the OS rate was significantly higher in patients with an improvement of acute GvHD than in those without an improvement (hazard ratio, 3.73; 95% confidence interval, 2.26–6.15).

Figure 2
figure2

OS rates after thymoglobulin therapy in patients with steroid-resistant acute GvHD. (a) OS rates after thymoglobulin therapy stratified by thymoglobulin dose are shown (short dotted line for <2.0 mg/kg, long dotted line for 2.0–3.9 mg/kg and solid line for 4.0 mg/kg). There is no significant difference among these groups. (b) OS rates after thymoglobulin therapy stratified by response of acute GvHD are shown (dotted line for CR or PR and solid line for other than CR/PR). Patients with CR/PR of acute GvHD have a significantly higher OS rate compared with those without CR/PR (P<0.0001).

Discussion

The present study confirmed that low-dose thymoglobulin at a median total dose of 2.5 mg/kg provided an overall improvement (CR+PR) in 60% of patients with steroid-resistant acute GvHD. The efficacy of such a low dose of thymoglobulin as GvHD treatment has not been well evaluated. Surprisingly, the response rate was comparable to the previous reports for thymoglobulin therapy at a standard dose. McCaul et al.6 demonstrated that 10–15 mg/kg thymoglobulin provided an improvement in 20 of 34 patients (59%) with steroid-resistant acute GvHD. Graziani et al.10 reported that overall response was observed in 5 of 13 patients (38%) treated with 3.75 or 6.25 mg/kg thymoglobulin. In a prospective study of 27 patients who were treated with 6.25 mg/kg thymoglobulin and 5 mg/kg methylprednisolone reported by Van Lint et al.,12 improvement was obtained in 15 patients (56%). Use of equine ATG also provided a comparable response rate to these results (30–54%).7, 8, 9 Although the present study included some cases (n=6) with steroid-resistant acute GvHD after cord blood transplantation and some cases who had received first-line treatment with low-dose corticosteroid, which might increase sensitivity to ATG, the study showed that low-dose thymoglobulin (median, 2.5 mg/kg) has equivalent efficacy to standard-dose thymoglobulin.

The difference in thymoglobulin dose (<2.0, 2.0–3.9 and 4.0 mg/kg) was not a significant factor for the response rate in this cohort. As is known, the administered dose of ATG has a correlation with the area under the time–concentration curve and maximum concentration.19, 20 A recent study showed the association between higher area under the time–concentration curve of ATG and poorer CD4-positive T-cell reconstitution after hematopoietic stem cell transplantation.21 However, a dose-dependent effect of thymoglobulin in the low-dose range on T-cell depletion has not been well defined in post-transplant patients.22 Importantly, ATG has effects on not only T-cell depletion but also modulation of cell surface molecules that mediate leukocyte–endothelium interactions, induction of apoptosis in B-cell lineages, interference with dendritic cell functional properties, and induction of regulatory T cells and natural killer T cells.23, 24 The dose dependency of the ATG effect on the immune system except for T cells remains largely uninvestigated. Thus, low-dose thymoglobulin at even <2.0 mg/kg may have sufficient immunosuppressive activity.

The major drawback of ATG therapy is high NRM, mainly due to subsequent infectious disease and EBV-lymphoproliferative disease.6, 7, 10, 12 In fact, the present study demonstrated that NRM at 1 year after thymoglobulin therapy was 71%. Interestingly, multivariate analysis found a positive correlation between thymoglobulin dose (<2.0, 2.0–3.9 and 4.0 mg/kg) and NRM. A higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Given that the response rate of acute GvHD was not significantly different among the three dose groups, thymoglobulin therapy at the lowest dose (<2.0 mg/kg) is recommended for steroid-resistant acute GvHD. Alternatively, steroid-resistant acute GvHD, which has no response to thymoglobulin at around 2.0 mg/kg, may be indicated as an alternative treatment.

Consistent with previous reports,7, 8, 9 patients with skin involvement were more likely to respond to low-dose thymoglobulin (72%). Liver acute GvHD was more often resistant to low-dose thymoglobulin (29%), but the response rate of gut GvHD (55%) was not necessarily disappointing.

In summary, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously. From the perspective of balancing both efficacy and adverse effects, a dose of <2.0 mg/kg appears to be the optimal thymoglobulin dose as a second-line GvHD treatment. However, this retrospective study cannot draw firm conclusions due to the heterogeneity of the patient characteristics. Further prospective studies focusing on a low dose of thymoglobulin may clarify its value and limits in the treatment of steroid-resistant acute GvHD in the skin and gut.

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Acknowledgements

We would like to thank the physicians at each transplantation center and the data manager at the Japanese Data Center for Hematopoietic Cell Transplantation. This study was supported in part by a grant from the Japan Society for the Promotion of Science (JSPS) (15K09498 to MM) and the Japan Agency for Medical Research and Development (AMED) (15ek0510010h0003 to MM).

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Correspondence to M Murata.

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Competing interests

The authors declare no conflict of interest.

Appendix

Appendix

Institutes participating in this study: Hokkaido University Hospital; Sapporo Hokuyu Hospital; Sapporo City General Hospital; Aomori Prefectural Central Hospital; Iwate Medical University; University of Tsukuba Hospital; Jichi Medical University Hospital; Gunmaken Saiseikai Maebashi Hospital; Saitama Medical Center; Saitama Medical Center, Jichi Medical University; National Cancer Center Hospital; The Jikei University; Keio University Hospital; Toranomon Hospital; Medical Hospital, Tokyo Medical and Dental University; Kanagawa Cancer Center; Tokai University School of Medicine; Kanagawa Children’s Medical Center; Yokohama Municipal Citizen’s Hospital; Niigata University Medical & Dental Hospital; Toyama Prefectural Central Hospital; Shizuoka Cancer Center; Nagoya University Hospital; Nagoya Medical Center; Aichi Medical University Hospital; Osaka Medical Center for Cancer and Cardiovascular Diseases; Kinki University Hospital, Faculty of Medicine; Osaka University hospital; Osaka City University Hospital; Osaka City General Hospital; Osaka Medical Center and Research Institute for Maternal and Child Health; Matsushita Memorial Hospital; Sakai Hospital Kinki University, Faculty of Medicine; Hirakata Kohsai Hospital; Hyogo College of Medicine; Hyogo Cancer Center; Shimane Prefectural Central Hospital; Okayama University Hospital; Kawasaki Medical School Hospital; Hiroshima University Hospital; Tokushima Red Cross Hospital; Kochi Medical School Hospital; Kyushu University Hospital; Harasanshin Hospital; Hamanomachi Hospital; St Mary’s Hospital; Kurume University Hospital; National Kyushu Medical Center; Kitakyushu Municipal Medical Center; Nagasaki University Hospital; Oita University Hospital; Oita Prefectural Hospital.

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