Low-dose ATG/PTCy for graft-versus-host disease prevention in haploidentical transplantation: influences of ATG doses and pre-ATG absolute lymphocyte count

doi:10.21203/rs.3.rs-4867612/v1

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Low-dose ATG/PTCy for graft-versus-host disease prevention in haploidentical transplantation: influences of ATG doses and pre-ATG absolute lymphocyte count

https://doi.org/10.21203/rs.3.rs-4867612/v1

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The combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) has been administered for graft-versus-host disease (GVHD) prophylaxis of haploidentical transplantation (haplo-HSCT) in recent years. However, the optimal doses of ATG and PTCy are yet to be determined. Here, we report the joint use of low-dose ATG (7.5 or 5 mg/Kg) and PTCy (29 mg/Kg) for GVHD prophylaxis in our center and analyze the impact of different ATG doses and absolute lymphocyte count (ALC) before ATG infusion. Fifty-one consecutive leukemia patients who underwent haplo-HSCT with this regimen were included, with 27 and 24 patients receiving 7.5 and 5.0 mg/Kg ATG, respectively. The 100-day cumulative incidences (CIs) of grade I-IV, II-IV and III-IV acute GVHD were 42.0%, 34.0% and 12.0%, respectively. no significant difference on acute GVHD was observed between two ATG groups. Interestingly, with a cutoff point of 0.585×10⁹/L, low pre-ATG ALC group (18 patients) showed reduced CIs of grade I-IV (16.7% versus 56.3%, p=0.01), II-IV (16.7% versus 43.8%, p=0.07) and III-IV (0 versus 18.8%, p=0.05%) acute GVHD as compared to high ALC group (32 patients). The results suggested that this low-dose ATG/PTCy regimen was feasible and pre-ATG ALC levels could influence the occurrence of acute GVHD in this regimen.

Health sciences/Health care/Therapeutics/Stem-cell therapies

Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia

anti-thymocyte globulin

post-transplant cyclophosphamide

graft-versus-host disease

haploidentical hematopoietic stem cell transplantation

absolute lymphocyte count

During the past 20 years, the outcome of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been dramatically improved, thanks to effective graft-versus-houst disease (GVHD) prophylaxis strategies with anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy). In China, ATG-based regimen is much more widely used. Compared to identical sibling HSCT, haplo-HSCT with ATG may achieve similar overall survival (OS) and disease-free survival (DFS) in acute myeloid leukemia (AML) patients, but incidences of acute and chronic GVHD were still significantly higher [1]. In addition, the application of ATG is usually associated with higher risk of infections, especially virus reactivation [2–5].

In recent years, the combination of ATG and PTCy was reported to effectively reduce GVHD in HSCT patients. Low-dose PTCy (14.5 mg/Kg for 2 days) was demonstrated to augment the protective effect of ATG on GVHD and boost the reconstitution of regulatory T cells in a HSCT mouse model [6]. In subsequent prospective trials for haplo-HSCT with maternal or collateral relative donors, the group with low-dose PTCy plus standard-dose ATG (2.5 mg/Kg for 4 days) showed significantly lower incidences of GVHD and comparable relapse and OS, as compared to ATG alone [6, 7]. Besides, the joint use of ATG and PTCy at other doses and timings was also implemented in multiple studies with haplo- or unrelated donor-HSCT, resulting in promising outcomes [8–14].

So far, the optimal doses of ATG and PTCy have not been determined during the joint use. Here, we report the low-dose ATG/PTCy regimen for haplo-HSCT in our center, which includes 2.5 mg/Kg ATG for 2 or 3 days (from day − 4 or -3 to day − 2) and 14.5 mg/Kg PTCy for 2 days (day + 3 and + 4). In addition, the impact of different total ATG doses (5 mg/Kg versus 7.5 mg/kg) and absolute lymphocyte count (ALC) before ATG infusion was analyzed in attempt to further optimize this ATG/PTCy regimen.

Patient selection

We included 51 consecutive leukemia patients who underwent haplo-HSCT with the low-dose ATG/PTCy regimen in the First Affiliated Hospital of Anhui Medical University, Hefei, China, from February 2018 to March 2022. All patients had a Karnofsky Performance Score (KPS) > 60%. Clinical features, post-transplant outcomes and adverse events were collected retrospectively. This study was conducted in accordance with the Declaration of Helsinki and approved by the Hospital Ethics Committee.

HLA typing and donors

High-resolution molecular typing for HLA-A, -B, -C, -DRB1, -DQB1 and –DPB1 was done for both recipients and donors. Young and male donor is the first choice for the transplant. Donors were mobilized with granulocyte colony-stimulating factor (7.5–10 µg/kg per day), and collection of bone marrow/peripheral blood stem cells or both, which usually took one or two days, started from the 5th day of mobilization. A minimum dose of 2×10⁶ CD34⁺ cells/Kg recipient body weight was required for the transplant.

Transplant procedures

The conditioning regimen consisted of the following: busulfan (BU), 3.2 mg/kg intravenously for 4 days from day − 7 to -4; cyclophosphamide (Cy), 50 mg/Kg intravenously for 2 days from day − 3 to -2; rabbit ATG (thymoglobulin; Genzyme-Sanofi, Lyon, France), 2.5 mg/Kg for 3 or 2 days from day − 4 or -3 to day − 2; simustine, 250 mg/m² orally on day − 8 for all acute lymphoid leukemia (ALL) patients and a proportion of AML patients. Two doses of 14.5 mg/Kg Cy were given on days + 3 and + 4. In addition, patients received cyclosporine, mycophenolate mofetil and short-term methotrexate for GVHD prophylaxis. Cyclosporine was administered at a dose of 2.5 mg/Kg intravenously from day − 2 and adjusted to achieve a therapeutic level of 200 to 300 µg/L. Cyclosporine taping started around day + 60 to + 75 for all patients without GVHD. Mycophenolate mofetil was given orally at a dose of 0.5 g q12h from day − 2 and discontinued on around day + 30 if no acute GVHD was present.

Granulocyte colony-stimulating factor (5 µg/kg) and recombinant human thrombopoietin (300 U/Kg) were administered subcutaneously from day + 5. Prophylactic anti-bacterial (levofloxacin), anti-fungal (micafungin or voriconazole), anti-viral (ganciclovir from day − 7 to -2, and acyclovir after stem cell infusion) and anti-pneumocystis Jiroveci pneumonia (oral septra) therapies were administered to all patients. Pre-emptive therapy with ganciclovir was given once cytomegalovirus (CMV) deoxyribonucleic acid (DNA) was > 1000 IU/ml by quantitative polymerase chain reaction (PCR). Rituximab was pre-emptively given once Epstein–Barr virus (EBV) DNA was > 10⁵ IU/ml.

Engraftment and chimerism analysis

Neutrophil engraftment was defined as the first of 3 consecutive days when absolute neutrophil count exceeds 0.5×10⁹/L, and platelet engraftment was defined as the first day of 7 consecutive days with a platelet count more than 20×10⁹/L without platelet transfusion. The whole blood and leukocyte chimerism after the transplant was analyzed using PCR of short tandem repeats.

Statistical analysis

The last follow-up was updated in March 2024. Patient characteristics were reported as descriptive statistics. Chi-square and Fisher’s exact tests were used to compare categorical variables between two ATG groups, while the Mann-Whitney test was used for continuous variables.

Competing risk analysis was applied for the calculation of cumulative incidences (CIs) of GVHD, relapse (CIR), non-relapse mortality (NRM) and CMV/EBV viremia. Death from any cause was treated as the competing risk for acute GVHD, chronic GVHD and CMV/EBV viremia, while relapse and NRM were as the competing risk for each other. Kaplan-Meier method was applied to estimate DFS and OS. Receiver operating characteristic (ROC) analysis was performed to determine an optimal cutoff value of ALC for acute GVHD of any grade.

All p-values are two-tailed, and P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 20.0 (SPSS, Inc. Chicago, IL, NY) and R software version 3.5.3 (http://www.r-project.org).

Patient characteristics

Characteristics of a total of 51 patients are summarized in Table 1. The median age of all patients at transplantation was 39 years (range, 14–58 years). Thirty-one patients were diagnosed with acute myeloid leukemia, 17 with acute lymphoblastic leukemia/lymphoblastic lymphoma and 2 with chronic myelogenous leukemia. The median follow-up was 858 days (range, 25-2209 days). Before December of 2020, we applied 7.5 mg/Kg of ATG in our transplant protocol, and then changed the dose of ATG to 5 mg/Kg. In total, 27 patients received 7.5 mg/Kg ATG and 24 patients received 5.0 mg/Kg ATG for GVHD prophylaxis. The median follow-up was 1359 days (range, 25-2209 days) and 792 days (range, 55-1157 days) for 7.5 mg/Kg and 5 mg/Kg ATG groups, respectively. There was no significant difference between two groups regarding patients’ age, gender, disease type, disease risk index, etc. However, the infused CD34⁺ cell numbers (median, 4.05×10⁶/Kg) of 7.5 mg/Kg ATG group were marginally higher than those (median, 3.49×10⁶/Kg) of 5 mg/Kg ATG group (p = 0.08).

Engraftment

Median time to neutrophil and platelet engraftment of total 51 patients was 11 days (range, 9–26 days) and 12 days (range, 9-135 days), respectively. In 7.5 mg/Kg ATG group, 1 patient had primary and 1 had secondary graft failure. The patient with primary graft failure had positive class I donor-specific anti-HLA antibody (mean fluorescence intensity 8447) and desensitization treatments were performed before the transplant. The secondary graft failure of the other patient was possibly precipitated by virus infections (CMV and human herpesvirus 6). In 5.0 mg/Kg ATG group, no graft failure occurred, while 2 patients had primary delayed platelet engraftment. There was no significant difference between two ATG groups regarding time to neutrophil (median, 11 versus 11 days, p = 0.58) and platelet (median, 12 versus 12 days, p = 0.77) engraftment.

GVHD

The 100-day CIs of grade I-IV, II-IV and III-IV acute GVHD of total 51 patients were 42.0% (95% CI, 28.1%-55.2%), 34.0% (95% CI, 21.2%-47.2%) and 12.0% (95% CI, 4.8%-22.7%), respectively (Supplementary Fig. 1A-C). The median time to onset of grade I-IV acute GVHD was 22 days (range, 8–97 days). Forty-seven patients survived for more than 100 days after transplant and were eligible for chronic GVHD evaluation. The 2-year CIs of overall and moderate-to-severe chronic GVHD were 42.0% (95% CI, 28.1%-55.3%) and 26.0% (95% CI, 14.7%-38.8%), respectively (Supplementary Fig. 1D-E). The median time to onset of chronic GVHD was 154 days (range, 100–341 days).

Regarding comparison between 7.5 mg/Kg and 5.0 mg/Kg ATG groups, no significant difference was observed regarding the CIs of grade I-IV (42.3% versus 41.7%, p = 0.91), II-IV (30.8% versus 37.5%, p = 0.62) or III-IV (11.5% versus 12.5%, p = 0.92) acute GVHD (Fig. 1A-C). The CIs of overall (34.6% versus 50.0%, p = 0.27) and moderate-to-severe (19.2% versus 33.3%, p = 0.25) chronic GVHD were similar as well (Fig. 1D-E).

Regimen-related toxicity and virus reactivation

Hemorrhagic cystitis occurred in 20 patients with 3 of grade III-IV. Transplant-associated thrombotic microangiopathy and capillary leak syndrome were documented in 1 and 2 patients, respectively. The 180-day CIs of CMV and EBV reactivation of the whole cohort were 42.0% (95% CI, 28.1%-55.3%) and 62.7% (95% CI, 47.7%-74.6%), respectively. CMV disease was observed in 2 patients, while no post-transplant lymphoproliferative disorder was developed. No significant difference was observed between 7.5 mg/Kg and 5.0 mg/Kg ATG groups, regarding CMV (44.4% versus 39.5%, p = 0.52) and EBV (59.2% versus 66.7%, p = 0.46) reactivation (Fig. 2).

Transplant outcomes

The 2-year OS, DFS, NRM and CIR of the entire cohort were 66.7% (95% CI, 54.9–80.9%), 54.8% (95% CI, 42.7–70.4%), 25.5% (95% CI, 14.4%-38.1%) and 19.7% (95% CI, 10.0%-31.7%), respectively (Supplementary Fig. 2). Up to the final follow-up, 10 patients relapsed. Median time to relapse was 359 days (range, 82–726 days). Fourteen patients experienced NRM. Causes of death were relapse in 8 (36%) patients, GVHD in 7 (32%) patients, infection in 5 (23%) patients and graft failure in 2 (9%) patients.

Two ATG groups (7.5 mg/Kg versus 5.0 mg/Kg) showed similar results in 2-year OS (70.37% versus 62.5%, p = 0.88), DFS (59.3% versus 50%, p = 0.60), NRM (25.9% versus 25.0%, p = 0.75) and CIR (14.8% versus 25%, p = 0.33) (Fig. 3).

Impact of absolute lymphocyte count on acute GVHD

The median ALC on the first day of ATG administration of the whole cohort was 0.83×10⁹/L (range, 0.01–2.48×10⁹/L), and no significant difference on pre-ATG ALC was observed between 7.5 mg/Kg and 5.0 mg/Kg ATG groups (median, 0.90×10⁹/L versus 0.755×10⁹/L, p = 0.73). However, when we divided the whole cohort according to the occurrence of acute GVHD of any grade, significant difference on pre-ATG ALC was seen (no acute GVHD versus acute GVHD, 0.565 versus 1.060×10⁹/L, p = 0.01). Then, an optimal ALC cutoff value of 0.585×10⁹/L for grade I-IV acute GVHD was obtained using ROC analysis. With this ALC cutoff value, the CIs of grade I-IV (16.7% versus 56.3%, p = 0.01), II-IV (16.7% versus 43.8%, p = 0.07) and III-IV (0 versus 18.8%, p = 0.05%) acute GVHD were lower in low ALC group (18 patients) as compared to high ALC group (32 patients) (Fig. 4A-C).

Furthermore, we analyzed the impact of ALC on chronic GVHD (Fig. 4D-E), OS, DFS, NRM, CIR and CMV/EBV reactivation (Supplementary Fig. 3), and no significant differences were observed between two ALC groups.

ATG and PTCy are two main GVHD-prophylaxis strategies for unmanipulated haplo-HSCT. Controversies still exist whether ATG or PTCy brings better survival after transplant [15–17]. Alternatively, many transplant centers attempted to combine ATG and PTCy to further optimize their GVHD-prophylaxis regimens, in which various doses and timings of ATG and PTCy were applied [6, 13, 18]. In the present study, we report the low-dose ATG/PTCy regimen for haplo-HSCT in our center and the data are comparable to those in the literature, in which ATG and/or PTCy were used for GVHD prophylaxis, regarding GVHD and survival [4, 17–20].

In late 2020, we modified the ATG dose of our protocol from 7.5 mg/Kg to 5.0 mg/Kg, based on the results of a multicenter randomized study reported by Lin et. al. In this study, two doses (7.5 mg/kg and 10 mg/kg) of ATG without PTCy were compared in haplo-HSCT and 7.5 mg/kg ATG resulted in reduced EBV/CMV infections without increased incidence of GVHD [20]. In the present study, we analyzed the influence of two ATG doses and no differences were observed regarding incidences of GVHD, CMV/EBV reactivation and survival. To our knowledge, this is the first report comparing two ATG doses in a joint regimen of ATG and PTCy for haplo-HSCT.

ATG is a polyclonal IgG antibody which may bind to not only human T lymphocytes but also other immune cells including B lymphocytes, natural killer cells, dendritic cells, etc. [21] The serum levels of total ATG and so-called “active” ATG, the fraction specifically binding to lymphocytes [22], were assessed in multiple HSCT studies, and results showed that ATG serum levels varied greatly among patients and may impact GVHD incidences and immune reconstitution [23–26]. Therefore, targeted dosing of ATG based on concentration monitoring during conditioning regimen is reasonable and has been reported to bring favorable outcomes [27]. However, only a minority of transplant centers are capable of monitoring serum levels of ATG, especially the active fraction, mainly due to lack of commercially available clinical-grade detection kit and the operational complexity of the assay. It would be good to find surrogate parameters to predict the impact of ATG levels on transplant outcomes.

Population pharmacokinetics of ATG was investigated in several studies, which included various HSCT populations, transplant schedules and ATG administration plan. In some of these studies, besides body size indicators, e.g. total body weight and body mass index, pre-transplant ALC was determined as an important factor impacting ATG levels [28, 29], and its correlation with transplant outcomes was also supported by several studies [30–32]. However, conflicting data also exist. Heelan et al. reported a retrospective study which included 111 patients receiving matched unrelated donor HSCT with ATG, and pre-ATG ALC did not correlate with GVHD, relapse or mortality [33]. It is noteworthy that, in this study, the range of ALC was 0–0.19×10⁹/L, much lower than that in other studies mentioned above. Takahashi et al. reported a novel population pharmacokinetics model for ATG in the HSCT setting with minimal pre-ATG ALC (range 0–0.058×10⁹/L) [34]. In this model, influential covariates include ideal body weight, baseline serum albumin level, baseline serum IgG level and CD4⁺ T cell graft dose, rather than ALC. Taken together, it seems that severe lymphopenia may diminish the impact of ALC on ATG level and HSCT outcomes, and this is reasonable because lymphocytes, as the main “targets” of ATG, influence the ATG level through target-mediated drug disposition [34].

In the present study, the median ALC was 0.83×10⁹/L and an optimal cutoff point of 0.585×10⁹/L was calculated. Low ALC group had significant lower incidence of acute GVHD while two ALC groups did not show significant differences on chronic GVHD, OS, DFS, NRM, CIR and EBV/CMV infections. We consider that total ATG dose in our regimen is relatively lower than the “optimal” ATG dose, therefore patients may benefit from lower ALC, in line with the study of Jamani et. al. [29] However, Woo et. al. reported that, in the setting of matched related donor HSCT with 4.5 mg/kg total ATG dose, low ALC group (cutoff point 0.50×10⁹/L) had significantly higher NRM and inferior OS, although GVHD incidences were lower [32]. Therefore, the impact of ALC is supposed to be carefully evaluated for each transplant population and transplant regimen. In addition, based on our data, it seems that 2.5 mg/kg more ATG dose (7.5 mg/Kg as compared to 5 mg/Kg) is not enough to overcome the increased risk of acute GVHD which high ALC brings. Other strategies should be tried to further optimize GVHD prophylaxis, for example, addition of other cytotoxic drugs, e.g. fludarabine, in the conditioning regimen before ATG infusion to adjust pre-ATG ALC levels, or dose adjustment of PTCy based on pre-ATG ALC levels.

Our study has limitations. First, it is a retrospective analysis with a limited number of HSCT patients. Further large prospective clinical trials are needed to confirm the impact of ATG doses and ALC in our low-dose ATG/PTCy regimen. Second, we did not monitor post-transplant immune reconstitution, e.g. CD4⁺/CD8⁺ T cell and NK cell recovery. These objective indicators might better show the impact of ATG doses and ALC. Third, it would be better to monitor ATG levels in this study. Data on ATG pharmacokinetics might provide more evidence to support our findings.

In summary, our study shows that our low-dose ATG/PTCy regimen for GVHD prophylaxis of haplo-HSCT is feasible and pre-ATG ALC may has a greater impact on the incidence of acute GVHD as compared to body-weight-based total ATG dose (5 mg/Kg and 7.5 mg/Kg). Further attempts to improve GVHD prophylaxis based on ALC levels could be made for this haplo-HSCT regimen in the future.

Competing Interests

The authors declare no competing financial interests.

Funding

This work was supported by the Natural Science Foundation of Anhui Province (NO. 2208085QH243), the Basic and Clinical Collaborative Research Improvement Project of Anhui Medical University (No. 2022xkjT021), the School Foundation of Anhui Medical University (2021xkj154) and 2021 Clinical Research Startup Program of the First Affiliated Hospital of Anhui Medical University (LCYJ2021YB007).

Author contributions

JH performed the transplant in patients, collected and analyzed the data, and wrote the manuscript. XL, JL, MR, ZL, JD, LL, MY performed the transplant in patients and collected the data. SZ and JG helped the data analysis and critically edited the manuscript. MY and QL designed and supervised the study and critically reviewed the manuscript.

Acknowledgements

We thank all patients and their families, and our transplant team.

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Table 1 is available in the Supplementary Files section.

The authors have declared there is NO conflict of interest to disclose.

supplementaryfigures.pdf
Supplementary Fig. 1. GVHD incidences of the whole cohort. Cumulative incidences of I-IV (a), II-IV (b) and III-IV (c) acute GVHD and overall (d) and moderate-to-severe (e) chronic GVHD are shown. Supplementary Fig. 2. OS, DFS, NRM and CIR of the whole cohort. Supplementary Fig. 3. OS, DFS, NRM, CIR and CMV/EBV reactivations of low and high ALC groups.
table1final.xlsx
Table 1. Patient characteristics. Abbreviations: BM=bone marrow, PB=peripheral blood.

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Low-dose ATG/PTCy for graft-versus-host disease prevention in haploidentical transplantation: influences of ATG doses and pre-ATG absolute lymphocyte count

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Abstract

Figures

Introduction

METHODS

Patient selection

HLA typing and donors

Transplant procedures

Engraftment and chimerism analysis

Statistical analysis

Results

Patient characteristics

Engraftment

GVHD

Regimen-related toxicity and virus reactivation

Transplant outcomes

Impact of absolute lymphocyte count on acute GVHD

Discussion

Declarations

Competing Interests

Funding

Author contributions

Acknowledgements

References

Table

Additional Declarations

Supplementary Files

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