Population PK-guided ATG Dosing in Haplo-HSCT

Pharmacokinetic Guided ATG Targeted Dosing Strategy in Unmanipulated Haploidentical Haematopoietic Stem-cell Transplantation

To evaluate the safety and efficacy of a population pharmacokinetics (PK)-guided targeted ATG dosing strategy in haploidentical stem cell transplantation and to observe the GVHD-free, relapse-free survival (GRFS) in the cohort receiving this strategy.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has demonstrated remarkable clinical efficacy in treating hematologic malignancies and has become the primary allogeneic transplantation modality in China. However, graft-versus-host disease (GVHD) remains a critical complication that significantly reduces early survival and long-term quality of life (QoL). GVHD not only severely suppresses immune function but also presents challenges in treatment, including complexity, high costs, prolonged duration, and limited efficacy. Therefore, optimizing GVHD prevention strategies offers greater clinical value than expanding treatment options, as it effectively reduces acute and chronic GVHD incidence and improves overall survival (OS) and long-term QoL.

Anti-thymocyte globulin (ATG), a polyclonal immunosuppressant, is widely used in related haplo-HSCT. The conventional high-dose rabbit ATG (Thymoglobulin, 10 mg/kg) effectively promotes engraftment and prevents fatal GVHD but significantly increases the risk of severe viral infections (e.g., CMV, EBV) and may increase relapse rates due to excessive immunosuppression weakening the graft-versus-leukemia (GVL) effect. Dose reduction studies have shown trade-offs: lowering ATG from 10 mg/kg to 6 mg/kg reduced infections but increased severe acute GVHD from 4.5% to 16.1%; a 7.5 mg/kg regimen lowered severe acute GVHD to 7.9% but with significantly higher viral reactivation.

The area under the concentration-time curve (AUC) better reflects ATG exposure than single pharmacokinetic (PK) parameters. The investigators established an ATG-AUC assay and analyzed 106 haplo-HSCT patients receiving uniform 10 mg/kg ATG, revealing substantial inter-individual AUC variability. Some patients had ATG-AUC above or below the optimal exposure window. Modeling of over 1,000 concentration samples (2022) identified the optimal ATG-AUC range as 100-148.5 IU/day/mL. A targeted individualized dosing technique was developed (2023) and validated in a prospective single-arm trial (2024), showing that individualized dosing achieved more patients within or closer to the optimal AUC range compared to fixed dosing. This approach improved post-transplant CD4+ T-cell immune reconstitution, reduced viral reactivation risk without increasing GVHD, and improved long-term survival and QoL.

The next step involves statistical modeling and clinical validation of clinical-biologic parameters (body weight, age, body surface area, lymphocyte count at infusion, graft T-cell count, HLA matching degree) with ATG-AUC from 94 patients to develop a predictive model for individualized ATG dosing. A prospective, single-arm clinical study will be conducted to validate the safety and efficacy of population PK-guided targeted ATG dosing in haplo-HSCT, including the optimal AUC attainment rate (100-148.5 IU/day/mL). Outcomes to be observed include GVHD-free, relapse-free survival (GRFS), viral reactivation rate, acute/chronic GVHD incidence, treatment-related mortality (TRM), disease-free survival (DFS), OS, and immune reconstitution. The goal is to establish the optimal ATG regimen for haplo-HSCT to improve survival and QoL.

Inclusion Criteria:

1. Patients with indications for allogeneic hematopoietic stem cell transplantation, with malignant hematologic diseases in CR1 or CR2 before transplantation.
2. Have an HLA-matched sibling, unrelated, or haploidentical donor.
3. Age ≥ 14 years and ≤ 65 years.
4. Liver function: ALT and AST ≤ 2.5 × upper limit of normal, bilirubin ≤ 2 × upper limit of normal.
5. Renal function: creatinine ≤ upper limit of normal.
6. No uncontrolled infection or severe mental or psychological disorders.
7. ECOG performance status score of 0-2.
8. Signed informed consent.

Exclusion Criteria:

1. No HLA-matched donor.
2. Malignant hematologic disease in CR3 or higher disease stage, or refractory/relapsed status，or second transplantation.
3. Patient age < 14 years or > 65 years.
4. Pregnancy of either the donor or the recipient.
5. Presence of mental illness or other conditions that preclude compliance with the protocol.