Key Points
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Low-dose ATG/PTCy, standard-dose ATG, and PTCy regimens showed similar grade 2 to 4 aGVHD and 1-year GVHD-/relapse-free survival.
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ATG/PTCy significantly improved neutrophil and platelet recovery without increasing cGVHD or compromising survival outcomes.
Visual Abstract
Abstract
The optimal graft-versus-host disease (GVHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation remains controversial. In this open-label, phase 3 study, patients aged 14 to 70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose antithymocyte globulin (ATG; 5 mg/kg) plus posttransplant cyclophosphamide (PTCy; 50 mg/kg; referred to as ATG/PTCy), standard-dose ATG (total dose, 10 mg/kg), or a PTCy-based (total dose, 100 mg/kg) regimen for GVHD prophylaxis. The coprimary end points were the cumulative incidence (CI) of grade 2 to 4 acute GVHD (aGVHD) by day 100 and GVHD-free, relapse-free survival at 1 year after transplant. A total of 407 patients were randomized to receive an ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GVHD prophylaxis. By day +100, the CI of grade 2 to 4 aGVHD did not differ significantly among the 3 groups (P = .210). Although the overall incidence of chronic GVHD (cGVHD) was comparable across all groups (P = .110), the 2-year CI of moderate-to-severe cGVHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups than the PTCy group (28.3%), without reaching statistical significance (P = .095). No significant differences were observed in survival outcomes among the 3 groups. Notably, the CI of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group than in the other groups (P < .001). This trial suggested that the 3 GVHD prophylaxis strategies presented similar efficacy in preventing grade 2 to 4 aGVHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.
The use of haploidentical donors for allogeneic hematopoietic stem cell transplantation has greatly expanded its application, enabled by advances in graft-versus-host disease (GVHD) prevention, primarily the use of antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy). Yang and colleagues report the first randomized phase 3 trial to directly compare PTCy, ATG, and their low-dose combination for preventing GVHD after haploidentical peripheral blood stem cell (PBSC) transplantation for acute myeloid malignancies, finding no significant differences in any GVHD or survival end points across the 3 strategies. While several questions remain unresolved, these important data validate the use of either agent or the low-dose combination in practice.
Introduction
Graft-versus-host disease (GVHD) remains the greatest barrier to successful haploidentical hematopoietic stem cell transplantation. Standard-dose antithymocyte globulin (ATG) (Beijing protocol) and posttransplant cyclophosphamide (PTCy) (Baltimore protocol) are the most commonly used GVHD prevention strategies in T cell–replete haploidentical hematopoietic stem cell transplantation.1
The ATG-based regimen (10 mg/kg) for GVHD prevention is widely used in China due to its high engraftment rate and relatively low incidence of grade 2 to 4 acute GVHD (aGVHD). However, it is associated with higher rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation.2 The PTCy-based regimen has lower rates of aGVHD and chronic GVHD (cGVHD) but a higher rate of graft failure in bone marrow transplants.1 When using peripheral blood stem cells, the incidence of aGVHD increases.3 However, the PTCy-based regimen leads to fewer virus reactivation and infection-associated mortality due to faster immune reconstitution after transplant.4
Peripheral blood stem cell transplantation (PBSCT) is increasingly adopted due to its convenience, especially for patients with high-risk hematologic malignancies. However, the incidence of grade 2 to 4 aGVHD in haploidentical PBSCT (haplo-PBSCT) exceeds 40% for both regimens,2,5 significantly affecting patient prognosis. To optimize GVHD prophylaxis for haplo-PBSCT, combination strategies of ATG and PTCy have been developed to reduce GVHD incidence and address the limitations of single-agent regimens.6, 7, 8, 9, 10, 11 In our center, a low-dose ATG and PTCy combination (referred to as ATG/PTCy) has shown excellent control of aGVHD.12 Although ATG, PTCy, or their combinations are widely used for GVHD prophylaxis in haplo-PBSCT, the optimal regimen remains debated.11,13 To resolve this, we conducted a prospective, multicenter, randomized clinical trial to evaluate the efficacy of different regimens and assess whether the low-dose ATG/PTCy combination offers advantages for GVHD prophylaxis in haplo-PBSCT. Here, we present the results of the phase 3 trial (ClinicalTrials.gov identifier: NCT03608059).
Methods
Trial design
This clinical trial compares 3 GVHD prophylaxis regimens in haplo-PBSCT: low-dose ATG/PTCy-based (treatment group), ATG-based (referred to as ATG, control group 1) and PTCy-based (referred to as PTCy, control group 2) regimens. The study protocol was approved by the institutional review board of Shanghai General Hospital. All patients and donors (or their legally acceptable representative or guardian) provided written informed consent. The trial was funded by Shanghai Shenkang Hospital Development Center. The authors confirm the accuracy of the data and adherence to the trial protocol. All authors contributed to writing the article.
Patients and donors
Patients aged 14 to 70 years with acute myeloid leukemia in complete remission (CR) or active disease with ≤20% blasts or high-risk myelodysplastic syndromes with excess blasts I or II were eligible for enrollment.14 Family members selected as donors were typed for HLA-A, -B, -C, -DRB1, and -DQB1 at high resolution with ≥3 loci mismatch.
Treatment
Nearly all patients received busulfan-based conditioning regimens according to local institutional practice. Myeloablative conditioning was prescribed to patients aged <55 years and with a hematopoietic cell transplantation–specific comorbidity index of ≤2. Otherwise, reduced-intensity conditioning was used.
The treatment (ATG/PTCy) group received the following: ATG (thymoglobulin, rabbit-derived; Sanofi) 2.5 mg/kg per day on days −2 and −1; cyclophosphamide (Cy) 50 mg/kg on day +3 (details provided in the protocol); cyclosporine (CsA) or tacrolimus (FK506) starting on day +4 (CsA IV at 2-3 mg/kg per day to achieve a trough level of 200-300 ng/mL; FK506 IV at 0.02 to 0.03 mg/kg per day to achieve a trough level of 5-15 ng/mL); and mycophenolate mofetil (MMF) 15 mg/kg per dose orally (maximum, 1 g) 3 times daily from day +4 to day +34. The control (ATG) group 1 received: ATG 2.5 mg/kg per day on day −4 to −1; CsA/FK506 dosing as described earlier, starting on day −5; and MMF dosing as described earlier, starting from day +1 to day +30; and methotrexate 15 mg/m2 on day +1, 10 mg/m2 on day +3 and +6. The control (PTCy) group 2 received: Cy 50 mg/kg per day on day +3 and +4. CsA/FK506 dosing as described earlier, starting on day +5; and MMF dosing as described earlier, starting from day +5 to day +35 (Figure 1A). Granulocyte colony-stimulating factor was administered to all patients from day +5 until neutrophil recovery.
Figure 1.
Prophylaxis regimens, randomization, treatment, and follow-up. (A) Schematic representation of the prophylaxis regimens. Purple circles indicate the initiation of CsA (2-3 mg/kg per day IV, target trough 200-300 ng/mL) or tacrolimus (FK506; 0.02-0.03 mg/kg per day IV, target trough 5-15 ng/mL), with tapering permitted from day 90 and discontinuation targeted by day 180. Red diamonds denote the initiation of MMF (15 mg/kg per dose orally, maximum 1 g thrice daily) administered for 30 days. Blue triangles represent ATG (2.5 mg/kg), orange triangle indicates MTX (15 mg/m2), yellow triangles indicate MTX (10 mg/m2), and green triangles represent Cy (50 mg/kg). (B) Cinsolidated Standards of Reporting Trials flow diagram: 3-group randomized trial of ATG, ATG/PTCy, and PTCy regimens. MTX, methotrexate.
End points
The primary end points were (1) the cumulative incidence (CI) of grade 2 to 4 aGVHD within 100 days after haplo-PBSCT, assessed according to the modified Glucksberg criteria15; and (2) 1-year GVHD-/relapse-free survival (GRFS), defined as survival without grade 3 to 4 aGVHD, moderate or severe cGVHD (per National Institutes of Health consensus criteria16 requiring systemic therapy), or disease relapse/progression17 within 1 year after transplant. Secondary end points were the following: the CI of grade 3 to 4 aGVHD within 100 days; grade 1 to 4 aGVHD within 100 and 180 days; grade 2 to 4 and 3 to 4 aGVHD within 180 days; cGVHD16; hematologic recovery,18 defined as neutrophil recovery (the first of 3 consecutive days with an absolute neutrophil count of ≥0.5 × 109/L after the posttransplantation nadir) and platelet recovery (the first of 3 consecutive days with a platelet count of ≥20 × 109/L without transfusion support for 7 consecutive days); engraftment,18 defined as the achievement of full-donor chimerism (>95% donor-derived cells), which was assessed by short tandem repeat–based polymerase chain reaction (PCR) analysis on bone marrow CD3+ cells; overall survival (OS); disease-free survival (DFS); relapse; nonrelapse mortality (NRM); posttransplantation lymphoproliferative disorders; sinusoidal obstruction syndrome; transplant-associated thrombotic microangiopathy; virological outcomes, including CMV and EBV reactivation; and toxicity.
CMV and EBV reactivation, as secondary end points, were prospectively monitored using serial quantitative PCR assays on serum for CMV and whole blood for EBV. CMV DNAemia was defined as a viral load of >500 copies/mL and EBV DNAemia as >5000 copies/mL, according to institutional practice, irrespective of clinical symptoms. Viral reactivation required confirmation by at least 2 consecutive quantitative PCR measurements exceeding the predefined thresholds within 1 week.
Statistical analysis
Patients were randomly assigned to the treatment and control groups in a 2:1:1 ratio using a minimization method by a central monitoring center (Shanghai General Hospital, Shanghai, China) via the Interactive Web Response System. The stratified factors included study center, age (14-54, ≥55-70 years), and disease status before transplantation (CR or non-CR).
Based on literature and pretest results,2,5 the incidence of grade 2 to 4 aGVHD at 100 days was assumed to be 20% in the treatment group vs 40% in both control groups, requiring 324 patients to achieve 90% power, with a 1-sided α of .025%, and 5% attrition rate. At the midstudy point, GRFS was established as a second coprimary end point to further evaluate survival differences among the 3 groups. Specifically, the study targets 1-year GRFS, with projected rates of 70% (treatment group), 50% (control group 1), and 56% (control group 2). Using a 2-sided α of .025, 90% power, a 10% attrition rate, and accounting for 24-month enrollment plus 36-month follow-up, the required sample size was 418 participants (212 in the treatment group and 103 in each control group). In addition, we recalculated the required sample size for the CI of grade 2 to 4 aGVHD by day 100. After adjusting the 1-sided type 1 error (α = .025) used in the original estimation to a 2-sided α of .025 to align with the dual-primary end point framework, the updated required sample size was determined to be 412 participants. At last, the study had to enroll 418 participants to meet both end points of aGVHD and GRFS (protocol). The study statistician and study team remained blinded to the trial data during the amendment of the primary end point, ensuring that the change was made independently of outcome results.
Statistical analysis was performed, unless otherwise specified, according to the intention-to-treat population, with all patients who underwent randomization. Safety analyses included the patients who received the assigned study treatment. Statistical significance for both primary end points was considered sufficient to meet the study objective. Continuous variables were compared using the 1-way analysis of variance (for normally distributed data) or the Kruskal-Wallis test (for nonnormally distributed data). Categorical variables were compared using the χ2 or Fisher exact tests. OS, DFS, and GRFS were estimated using the Kaplan-Meier method, with between-group comparisons performed using the log-rank test. For end points subject to competing risks, CI functions were used. aGVHD and cGVHD, as well as relapse, were analyzed with death as the competing event, whereas NRM was analyzed with relapse or progression as the competing event. Between-group comparisons for these outcomes were conducted using the Gray test. A P value <.05 was considered statistically significant. Multivariable analyses were performed using a Cox mixed-effects model for end points without competing risks, and a Fine-Gray subdistribution hazards model for end points with competing risks. In both models, study center was included as a random effect, whereas patient age, pretransplant remission status, and treatment were included as fixed effects. Post hoc analyses included descriptive comparisons of immunosuppression-free survival rates by treatment groups and exploratory evaluations of recipient age, donor age, donor type, and HLA matching in relation to clinical outcomes. All secondary findings were exploratory in nature and should be interpreted with caution. Statistical analyses were performed using R (version 4.3.1).
Results
Patient population and baseline characteristics
Between 12 October 2018 and 3 August 2023, a total of 418 patients from 6 centers in China were assessed for eligibility (Table 1; supplemental Table 1 in the supplemental Appendix, available on the Blood website). Overall, 11 patients were excluded for not meeting the inclusion criteria. The remaining 407 patients were randomly assigned in a 2:1:1 ratio to receive ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GVHD prophylaxis. Of these, 9 patients did not receive the assigned treatment due to donor withdrawal (n = 5) or progressive disease (n = 4; Figure 1B). The baseline characteristics of the patients are summarized in Table 1 and supplemental Table 1, demonstrating well-balanced groups. The median follow-up time was 24.56 months (range, 0.27-73.33), with only 1 patient in the ATG/PTCy group lost to follow-up.
Table 1.
Baseline characteristics of patients in the intention-to-treat population
| Characteristic | ATG/PTCy (n = 185) | ATG (n = 113) | PTCy (n = 109) | All patients (N = 407) |
|---|---|---|---|---|
| Age, y (mean ± SD) | 45.25 ± 13.80 | 42.23 ± 14.39 | 44.33 ± 12.84 | 44.16 ± 13.74 |
| Male sex, n (%) | 90 (48.6) | 72 (63.7) | 58 (53.2) | 220 (54.1) |
| Diagnosis, n (%) | ||||
| Acute myeloid leukemia | 149 (80.6) | 91 (80.5) | 92 (84.4) | 332 (81.6) |
| Myelodysplastic syndromes with excess blasts 1 | 16 (8.6) | 14 (12.4) | 7 (6.4) | 37 (9.1) |
| Myelodysplastic syndromes with excess blasts 2 | 20 (10.8) | 8 (7.1) | 10 (9.2) | 38 (9.3) |
| ECOG, n (%) | ||||
| 0 | 109 (58.9) | 70 (61.9) | 71 (65.1) | 250 (61.4) |
| 1 | 67 (36.2) | 36 (31.9) | 33 (30.3) | 136 (33.4) |
| 2 | 9 (4.9) | 7 (6.2) | 5 (4.6) | 21 (5.2) |
| Donor age, y (mean ± SD) | 32.18 ± 12.66 | 32.02 ± 11.78 | 29.33 ± 11.25 | 31.37 ± 12.09 |
| Male donor, n (%) | 127 (68.6) | 71 (62.8) | 64 (58.7) | 262 (64.4) |
| Donor-recipient sex, n (%) | ||||
| Female-male | 25 (13.5) | 23 (20.4) | 25 (23.0) | 73 (17.9) |
| Others∗ | 160 (86.5) | 90 (79.6) | 84 (77.0) | 334 (82.1) |
| Matched donor-recipient blood type, n (%) | 107 (57.8) | 60 (53.1) | 59 (54.1) | 226 (55.5) |
| Preconditioning regimen, n (%) | ||||
| Myeloablative conditioning | 116 (62.7) | 72 (63.7) | 73 (67.0) | 261 (64.1) |
| Reduced-intensity conditioning | 69 (37.3) | 41 (36.3) | 36 (33.0) | 146 (35.9) |
| Follow-up time, d (mean ± SD) | 840.83 ± 561.77 | 859.08 ± 564.14 | 900.04 ± 579.45 | 861.75 ± 566.33 |
Plus-minus values are means ± SD. Percentages may not total 100 because of rounding.
ECOG, Eastern Cooperative Oncology Group; SD, standard deviation.
Other donor-recipient sex combinations include male donor to male recipient, female donor to female recipient, and male donor to female recipient.
Primary end points
The primary analysis was conducted in the intention-to-treat population. The cumulative incidence of grade 2 to 4 aGVHD by day 100 showed no significant differences among the 3 groups (P = .210; Table 2; Figure 2A), with rates of 13.0% (95% confidence interval [CI], 8.6-18.3) in the ATG/PTCy group, 15.9% (95% CI, 9.9-23.3) in the ATG group, and 19.3% (95% CI, 12.5-27.2) in the PTCy group. This trend persisted through day 180 (Table 2).
Table 2.
Primary, secondary, and exploratory end points
| End point | ATG/PTCy (n = 185) |
ATG (n = 113) |
PTCy (n = 109) |
P value |
|---|---|---|---|---|
| 95% CI | ||||
| Grade 2-4 aGVHD at d 100 (primary end point) | 13.0 (8.6-18.3) | 15.9 (9.9-23.3) | 19.3 (12.5-27.2) | .210 |
| 1-Year GRFS (primary end point) | 72.4 (66.2-79.1) | 69.0 (61.0-78.1) | 70.6 (62.6-7) | .611 |
| CI of aGVHD at day 180∗ | ||||
| Grade 1-4 | 23.2 (17.4-29.6) | 34.5 (25.9-43.3) | 33.0 (24.4-41.9) | .079 |
| Grade 2-4 | 13.5 (9.1-18.9) | 17.7 (11.3-25.3) | 21.1 (14.0-29.2) | .210 |
| Grade 3-4 | 5.4 (2.8-9.3) | 7.1 (3.3-12.8) | 10.1 (5.3-16.6) | .310 |
| 2-Year survival | ||||
| GRFS | 67.5 (61.0-74.7) | 63.2 (54.7-72.9) | 64.2 (55.6-74.1) | .611 |
| OS | 75.4 (69.2-82.1) | 74.9 (67.1-83.7) | 77.8 (70.1-86.3) | .756 |
| DFS | 73.9 (67.8-80.7) | 72.8 (64.9-81.7) | 78.3 (70.7-86.6) | .511 |
| CI of cGVHD at 2 y | 28.3 (21.5-35.5) | 37.4 (28.1-46.8) | 41.1 (31.3-50.6) | .110 |
| CI of moderate-severe cGVHD at 2 y | 17.4 (11.9-23.7) | 17.3 (10.7-25.2) | 28.3 (19.7-37.5) | .095 |
| CI of 2 y NRM | 14.1 (9.5-19.5) | 12.9 (7.4-20.1) | 15.0 (9.0-22.5) | .870 |
| CI of 2 y relapse | 12.0 (7.6-17.3) | 14.3 (8.5-21.5) | 7.8 (3.6-14.1) | .180 |
| CI of neutrophil recovery at d 30 | 97.8 (94.0-99.2) | 95.6 (89.1-98.2) | 95.4 (88.9-98.1) | <.001 |
| CI of platelet recovery at d 90 | 98.1 (91.5-99.6) | 95.6 (89.1-98.2) | 97.1 (88.7-99.3) | <.001 |
| CI of CMV reactivation at 1 y | 41.5 (34.4-48.6) | 37.5 (28.5-46.5) | 36.9 (27.5-46.3) | .676 |
| CI of EBV reactivation at 1 y | 41.0 (33.9-48.1) | 54.5 (45.2-63.8) | 9.7 (4.1-15.3) | <.001 |
| Immunosuppression-free survival† | .360 | |||
| At 6 mo | 84.8 (79.8-90.2) | 82.3 (75.6-89.6) | 83.5 (76.8-90.8) | |
| At 1 y | 53.3 (46.6-60.1) | 46.0 (37.7-56.2) | 48.6 (40.1-59.0) | |
| At 2 y | 49.4 (42.6-57.3) | 41.5 (33.3-51.7) | 44.7 (36.2-55.1) | |
The definition of aGVHD was based on the modified Glucksberg criteria.15
Immunosuppression-free survival is defined as survival without relapse and without ongoing immunosuppressive therapy and analyzed using Kaplan-Meier methods.
Figure 2.
CI of aGVHD and cGVHD, and GRFS in the intention-to-treat population and subgroups. (A) CI of grade 2 to 4 aGVHD at day 100 and day 180. (B) One- and 2-year GRFS (the coprimary end point). (C) CI of grade 1 to 4 aGVHD at day 100 and day 180. (D) CI of grade 1 to 4 aGVHD at day 100 and day 180 in patients with AML. (E) Overall CI of cGVHD. (F) CI of moderate-to-severe cGVHD. Vertical dashed lines are included to mark key time points: 100 and 180 days for panels A,C-D; 1 year for panel B; and 2 years for panels B,E-F. AML, acute myeloid leukemia.
GRFS did not differ significantly among the 3 groups, as assessed by the log-rank test (P = .611; Table 2; Figure 2B). The GRFS rates at 1 and 2 years are shown in Table 2.
Secondary end points
aGVHD and cGVHD
The CI of grade 1 to 4 aGVHD by day 100 was numerically lower in the ATG/PTCy group in the overall study population, although the difference did not reach statistical significance (P = .079; Figure 2C). In the acute myeloid leukemia subgroup, the CI of grade 1 to 4 aGVHD by day 100 was significantly lower in the ATG/PTCy group than in the ATG and PTCy groups (P = .044, supplemental Table 2; Figure 2D). No significant differences were observed in grade 3 to 4 aGVHD incidence (P = .310; supplemental Figure 1).
Although the overall incidence of cGVHD was comparable among groups (P = .110), the 2-year cumulative incidence of moderate-to-severe cGVHD was numerically lower in the ATG/PTCy (17.4%; 95% CI, 11.9-23.7) and ATG (17.3%; 95% CI, 10.7-25.2) groups than in the PTCy group (28.3%; 95% CI, 19.7-37.5), with this difference approaching, but not attaining, statistical significance (P = .095; Table 2; supplemental Table 3; Figure 2E-F). The maximum severity of cGVHD is presented in supplemental Table 4.
Survival outcomes, relapse, and NRM
No significant differences were observed among the 3 groups in 2-year OS (P = .756) and DFS (P = .511; Table 2; supplemental Figure 2A-B). All patients with active disease achieved CR after transplantation. The 2-year CI of relapse had no significant difference (P = .180; Table 2; supplemental Figure 2C). The 2-year NRM was also comparable across the groups (P = .870; Table 2; supplemental Figure 2D). Notably, age of ≥55 years was identified as an independent predictor of inferior OS (hazard ratio [HR], 1.66; 95% CI, 1.09-2.54, P = .018), poorer DFS (HR, 1.64; 95% CI, 1.08-2.47; P = .019), and increased NRM (HR, 2.51; 95% CI, 1.47-4.28; P < .001; (supplemental Tables 5-7; supplemental Figure 3A-C). Causes of death are summarized in Table 3 and supplemental Table 8.
Table 3.
Causes of death by treatment arm in the intention-to-treat population
| n/N (%) |
P value | |||
|---|---|---|---|---|
| ATG/PTCy (n = 185) | ATG (n = 113) | PTCy (n = 103) | ||
| Causes of death | .073 | |||
| Recurrence | 18/185 (9.7) | 15/113 (13.3) | 7/103 (6.8) | |
| Infection∗ | 15/185 (8.1) | 6/113 (5.3) | 8/103 (7.8) | |
| aGVHD | 3/185 (1.6) | 1/113 (0.9) | 3/103 (2.9) | |
| cGVHD | 1/185 (0.5) | 0 | 1/103 (1.0) | |
| Posttransplant lymphoproliferative disorder | 2/185 (1.1) | 4/113 (3.5) | 0 | |
| Transplant-associated thrombotic microangiopathy | 0 | 2/113 (1.8) | 0 | |
| Thrombotic thrombocytopenic purpura | 1/185 (0.5) | 0 | 0 | |
| Sinusoidal obstruction syndromes | 1/185 (0.5) | 0 | 0 | |
| Multiple organ failure | 3/185 (1.6) | 0 | 0 | |
| Pneumorrhagia | 0 | 0 | 1/103 (1.0) | |
| Cerebral hemorrhage | 1/185 (0.5) | 1/113 (0.9) | 0 | |
| Secondary tumors of the head and neck | 0 | 1/113 (0.9) | 0 | |
| Secondary graft failure | 0 | 0 | 3/103 (2.9) | |
| Pericardial tamponade | 0 | 0 | 1/103 (1.0) | |
| Total deaths | 45/185 (24.3) | 30/113 (26.5) | 24/103 (23.3) | |
Infections included pulmonary infections, skin and soft tissue infections, COVID-19, bloodstream infections, and infections of unknown cause.
Hematologic recovery and engraftment
The median time to neutrophil recovery was comparable across the 3 groups, with 14 days (range, 10-28) in the ATG/PTCy group, 14 days (range, 10-54) in the ATG group, and 15 days (range, 11-39) in the PTCy group. At 30 days after transplant, neutrophil recovery was significantly higher in the ATG/PTCy group (97.8%; 95% CI, 94.0-99.2) than in the ATG (95.6%; 95% CI- 89.1-98.2) and PTCy (95.4%; 95% CI, 88.9-98.1; P < .001) groups. Platelet recovery showed a similar pattern. The median time to platelet recovery was 13 days (range, 7-55) in the ATG/PTCy group, 14 days (range, 10-91) in the ATG group, and 15 days (range, 9-75) in the PTCy group. At 90 days, the cumulative incidence of platelet recovery was highest in the ATG/PTCy group (98.1%; 95% CI, 91.5-99.6) compared with the ATG (95.6%; 95% CI, 89.1-98.2) and PTCy (97.1%; 95% CI, 88.7-99.3) groups (P < .001; supplemental Table 9; Figure 3).
Figure 3.
CI of neutrophil (30-day) and platelet (90-day) engraftment by treatment group. (A) CI of neutrophil engraftment (absolute neutrophil count of ≥0.5 × 109/L) by 30 days. (B) CI of platelet engraftment (≥20 × 109/L) by 90 days. Dashed vertical lines indicate the 30-day (A) and 90-day (B) time points.
The proportion of patients with full-donor chimerism at day 100 was similar across the 3 groups (P = .856; supplemental Table 10).
Infections and immune reconstitution
The 1-year cumulative incidence of CMV reactivation was similar across the groups: 41.5% (95% CI, 35.2-47.9) with ATG/PTCy, 37.5% (95% CI, 30.1-45.2) with ATG, and 36.9% (95% CI, 29.4-44.8) with PTCy (P = .676). However, the EBV reactivation rate was markedly lower in the PTCy group (9.7%; 95% CI, 5.4-15.6) than in the ATG/PTCy (41.1%; 95% CI, 34.5-48.0) and ATG (54.5%; 95% CI, 46.2-62.3) groups (P < .001). No significant differences were observed in incidence of CMV disease (P = .894) or EBV posttransplantation lymphoproliferative disorders (P = .658; supplemental Table 11).
Immune reconstitution was assessed in evaluable patients. The median lymphocyte counts by subsets (CD3+, CD4+, CD8+, CD19+, natural killer–positive, and regulatory T cell–positive [Treg+] cells) are shown in supplemental Table 12 and supplemental Figure 4. The median counts of Treg+ and CD4+ T cells were consistently higher in the PTCy group than those in the ATG/PTCy and ATG groups within the first year. Significant differences in CD3+, CD8+, and CD19+ counts were observed among the groups at 1 month after transplantation, whereas no significant differences were found at later time points (3-12 months). Notably, the ATG/PTCy and ATG groups had higher natural killer cell counts than the PTCy group at 1, 3, and 9 months, with declining statistical significance by 12 months (P < .001 to P = .311).
Additional and subgroup analyses
A post hoc analysis showed that the immunosuppression-free survival at 6 months, 1 year, and 2 years after transplantation was comparable across the groups (Table 2).
The incidence of grade 2 to 4 aGVHD was comparable between patients aged ≥55 and <55 years (supplemental Table 13; supplemental Figure 5A). However, younger patients (aged < 55 years) demonstrated superior GRFS and OS, improved DFS, and lower NRM (supplemental Table 13; supplemental Figure 5B-E). Additionally, donor age (≤30 vs >30 years; supplemental Table 14; supplemental Figure 6), donor type (first-degree vs second-degree haploidentical donors; supplemental Tables 15 and 16; supplemental Figure 7), and HLA matching levels (5/10, 6/10, or 7/10; supplemental Tables 17 and 18; supplemental Figure 8) had no significant impact on clinical outcomes.
Finally, in an exploratory post hoc safety analysis, the incidence and spectrum of early cardiac toxicities by day +100 were comparable among the ATG/PTCy, ATG, and PTCy groups (supplemental Table 19). No significant differences were observed in overall cardiac events or in specific subtypes, including arrhythmia, heart failure, and pericardial effusion.
Discussion
This prospective, multicenter study represents the, to our knowledge, first head-to-head randomized comparison of 3 distinct GVHD prophylaxis strategies, standard-dose ATG, or PTCy, and a low-dose ATG/PTCy combination, in patients with myeloid malignancies undergoing haplo-PBSCT. In our trial, no statistically significant differences were observed among the 3 strategies with respect to the incidence of grade 2 to 4 aGVHD or key survival outcomes. Nevertheless, our findings provide prospective comparative evidence to help inform the selection of GVHD prophylaxis strategies in the haplo-PBSCT setting.
Previous studies have reported conflicting outcomes of ATG, PTCy, and their combination for GVHD prophylaxis in haplo-PBSCT. Although European Society for Blood and Marrow Transplantation registry data indicated that the addition of low-dose ATG to PTCy reduced the overall incidence of cGVHD without survival benefits,19 another study found that supplementing standard-dose ATG with low-dose PTCy was associated with improved GVHD control and survival.8 Xu et al13 demonstrated superior 3-year OS and leukemia-free survival with ATG compared with PTCy or PTCy plus low-dose ATG, whereas Bazarbachi et al11 observed that PTCy combined with low-dose ATG significantly decreased the incidence of grade 2 to 4 aGVHD, and improved survival compared with ATG alone. Notably, the aforementioned studies were predominantly retrospective with heterogeneous cohorts, whereas this study was prospectively designed with randomized treatment allocation.
In this trial, the incidence of grade 2 to 4 aGVHD in the ATG group (17.7%) was lower than the 25% to 57% reported in previous studies using standard-dose ATG.2,13,20 This difference may be attributable, at least in part, to the use of high-dose MMF (3 g per day). Similarly, the incidence of grade 2 to 4 aGVHD observed with the PTCy-based regimen (21.1%) was lower than the 28% to 42% reported in the literature,5,11 which may reflect ethnic differences. The relatively smaller sample size might be another reason for not reaching the primary end point. Importantly, in contrast to previous retrospective reports describing delayed engraftment with PTCy combined with ATG,13 the low-dose ATG/PTCy regimen in our study was associated with prompt myeloid and platelet recovery. The routine use of granulocyte colony-stimulating factor in all patients may have mitigated between-group differences in neutrophil recovery.
Several studies have evaluated the impact of ATG-containing regimens on cGVHD in haplo-PBSCT. Battipaglia et al reported a significantly lower risk of cGVHD with ATG plus PTCy compared with PTCy alone (HR, 0.46; 95% CI, 0.23-0.93; P = .03).19 Similarly, a prospective study showed a lower incidence of moderate-to-severe cGVHD with anti–T lymphocyte globulin plus PTCy compared with PTCy alone (10% vs 31%; P = .07).21 Other studies have also reported numerically lower rates of moderate-to-severe cGVHD with ATG-containing regimens.22,23 Consistent with these findings, our study showed a trend toward improved cGVHD control with ATG-containing regimens. Although higher CD3+ cell doses in PBSC grafts have been associated with an increased risk of cGVHD in PTCy-based haplo-PBSCT,24 infused CD34+ and CD3+ cell doses were well balanced across treatment groups in our randomized trial, making differences in cell dose alone unlikely to fully explain the higher incidence of moderate-to-severe cGVHD observed in the PTCy group. Instead, differences in in vivo T-cell exposure between ATG- and PTCy-based approaches may contribute, as ATG induces T-cell depletion at graft infusion, whereas PTCy is administered early after transplantation and selectively eliminates rapidly proliferating alloreactive T cells,25 potentially resulting in a higher early posttransplant T-cell burden and an increased risk of cGVHD.
In the preletermovir era, the incidence of CMV reactivation after haploidentical transplantation remained high, ranging from 38% to 58% with PTCy-based GVHD prophylaxis, and 30% to 78.6% with ATG-based regimens.1,8,26,27 In contrast, during the letermovir era, the incidence of CMV reactivation has been significantly reduced.28,29 However, letermovir was only approved in China in January 2022, and during the study period (2018-2023), it was administered for CMV prophylaxis in only a subset of patients. This limited use of letermovir likely accounts for the overall high rate of CMV reactivation observed in our cohort. Notably, the incidence of CMV reactivation in this study was comparable with that reported in the preletermovir era, suggesting that the relatively high incidence of CMV reactivation was not attributable to differences in the diagnostic criteria for CMV DNAemia.
Comparative analyses of immune reconstitution among ATG-, PTCy-, and ATG/PTCy-based regimens remain limited. Our study revealed that PTCy promoted Treg reconstitution more effectively than either ATG or the ATG/PTCy combination, likely by selectively depleting alloreactive conventional T cells and preserving Tregs.30,31 PTCy also facilitated faster CD4+ T-cell recovery, which is consistent with findings from myeloablative allogeneic PBSCT studies.32,33 Rapid Treg and CD4+ T-cell recovery with PTCy promotes the establishment of immune homeostasis after transplantation,34,35 which may, in turn, facilitate the recovery of EBV-specific T cells; however, the exact mechanisms underlying EBV protection with PTCy remain unclear.36
Several limitations of this study should be acknowledged. First, although numerical trends favored the combination regimen across several end points, the relatively small sample size limits the ability to draw definitive conclusions. Second, the median age of the study population was relatively young (44 years) compared with that of contemporary haploidentical transplantation cohorts, in which the median age is often in the mid-50s. Because age is an important determinant of transplant-related toxicity, immune reconstitution, and GVHD risk, the generalizability of our findings to older patients should be interpreted with caution. Third, the lack of quality-of-life assessments precluded a more comprehensive evaluation of treatment impact. Fourth, the trial did not include all possible ATG/PTCy dose combinations, and therefore direct comparison with alternative strategies, such as low-dose ATG combined with full-dose PTCy, was not feasible. Fifth, all the patients enrolled in this study were Asian. Finally, results for secondary and exploratory end points should be interpreted cautiously, given the lack of statistical significance for the primary end point.
In summary, although the combination of ATG and PTCy did not show significant advantages over ATG or PTCy alone in terms of aGVHD prevention and survival outcomes, the comparable efficacy observed among the 3 strategies highlight the feasibility of tailoring GVHD prophylaxis according to institutional experience and patient characteristics. Further studies are warranted to identify patient subgroups that may preferentially benefit from the combination regimen.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Acknowledgments
The authors thank the patients and their families, and clinical personnel for their participation in this trial; the trial team members for their contributions to trial planning and execution; and DAP Software (Beijing) Co Ltd for data management.
The trial was funded by a 3-year development project from Shanghai Shenkang Hospital Development Center (SHDC2020CR1012B) (X.S.).
Authorship
Contribution: X.S. and J.Y. designed the study; J.Y., X.H., F.Z., X.N., J.W., Y.D., M.K., X.Y., C.J., L. Wang, L. Wan, Y.C., C.H., H.Q., X.D., Y.T., B.D., and K.Z., recruited patients for this study; Y.J. collected the data; J.Y. and Y.J. conducted the data analysis, interpreted the results, and drafted the manuscript; and all authors gave final approval for submission for publication, and have read and approved the submitted manuscript and agree to be accountable for the work.
Footnotes
J.Y., Y.J., X.H., and F.Z. contributed equally to this study.
Data are available from the corresponding author, Xianmin Song (shongxm@sjtu.edu.cn), on request.
The online version of this article contains a data supplement.
There is a Blood Commentary on this article in this issue.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Supplementary Material
References
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