Population PK-guided ATG Dosing for Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation (haplo HSCT) has demonstrated remarkable clinical efficacy in treating hematological malignancies and has become the predominant allogeneic transplant modality in China. However, post transplant graft versus host disease (GVHD) significantly compromises early survival and long term quality of life, representing a major life threatening complication. GVHD not only severely impairs immune function but also entails complex, costly, and prolonged management with limited therapeutic efficacy. Therefore, optimizing GVHD prevention strategies is of greater clinical value than expanding treatment options, as effective prevention can reduce the incidence of acute and chronic GVHD and improve overall survival and long term quality of life. The study group has achieved internationally advanced results in this field, and some findings have been reported for the first time in China. Further research is expected to consolidate this leading position and advance the project to the international forefront.

There remains substantial room for improvement in clinical outcomes and long term quality of life for haplo HSCT recipients. From the perspective of enhancing patient quality of life and socioeconomic benefits, establishing a robust GVHD prevention system to achieve prevention over treatment can effectively reduce early post transplant mortality and significantly improve long term survival and quality of life.

In the study center, the stem cell source is G CSF mobilized peripheral blood stem cells. Peripheral blood grafts are easy to collect with minimal donor discomfort but are associated with a higher risk of GVHD compared to bone marrow grafts.

In related haploidentical transplantation, anti thymocyte globulin (ATG) is widely used as a polyclonal immunosuppressant. The current standard regimen employs high dose rabbit ATG (Thymoglobulin) at 10 mg/kg, which effectively promotes engraftment and prevents fatal GVHD but significantly increases the risk of severe viral infections (e.g., CMV, EBV) post transplant. Furthermore, clinical observations suggest that this high dose regimen may elevate relapse rates of hematological malignancies, possibly due to attenuation of the graft versus leukemia (GVL) effect from excessive immunosuppression. Thus, optimizing ATG dosing while maintaining transplant efficacy is a critical clinical research question.

Previous domestic trials attempted to reduce the ATG dose from 10 mg/kg to 6 mg/kg in haplo-HSCT. Although viral infection rates decreased, severe acute GVHD increased from 4.5% to 16.1%. The 1 year disease free survival rates were not significantly different between the two groups (84.3% vs. 86.0%, P = 0.88), and the study was prematurely terminated. A subsequent trial using 7.5 mg/kg reduced severe acute GVHD from 16.1% to 7.9%, but viral infections increased markedly.

International studies have shown that the area under the concentration time curve (AUC) of active ATG affects clinical outcomes in pediatric patients undergoing myeloablative bone marrow or cord blood HSCT. Higher post transplant ATG AUC is associated with delayed CD4⁺T cell reconstitution, whereas higher pre-transplant ATG AUC reduces acute and moderate to severe chronic GVHD and lowers transplant related mortality.

Systematic pharmacokinetic studies conducted by the investigators have revealed that ATG metabolism is influenced by multiple factors, including dose, body weight, immune status, and age. AUC, as a more comprehensive measure of drug exposure than single pharmacokinetic parameters, is more clinically relevant for evaluating ATG effects on immune reconstitution and GVHD.

The investigators previously developed an assay for ATG AUC and measured it in 106 haplo HSCT patients. Despite a uniform dose of 10 mg/kg, there was substantial inter individual variability in ATG AUC, with some patients above and others below the optimal exposure range. Pharmacokinetic data indicate that ATG metabolism correlates with patient specific clinical and biological parameters. If the optimal ATG dose can be calculated based on these individual factors, achieving a balance between GVHD, infection, and relapse, clinical outcomes could be greatly improved.

In 2022, the study group analyzed ATG concentration data from over 1,000 samples from those 106 patients and defined the optimal ATG AUC range as 100-148.5 IU·day/mL. In 2023, the investigators developed a technique to individualize ATG dosing targeting this optimal range and conducted a prospective, single arm trial to evaluate the safety and efficacy of this individualized targeted dosing strategy. In 2024, to build a population pharmacokinetic model requiring larger sample sizes, the study center led a multicenter, two arm randomized controlled trial. That trial confirmed that patients in the individualized dosing group achieved ATG AUC values within the optimal range more frequently than the fixed dose group; even when not within the range, the individualized strategy brought AUC values closer to the optimal range. Long term results have consistently shown that individualized ATG dosing improves post transplant CD4 +T cell immune reconstitution, reduces viral reactivation without increasing GVHD, and enhances long term survival and quality of life.

In 2025, using clinical and biological parameters including body weight, age, body surface area, lymphocyte count at infusion, graft T cell count, and HLA matching degree, along with ATG AUC data from 61 patients, the investigators developed and validated a statistical model for predicting ATG AUC, which serves as a tool for individualized ATG dose calculation.

Currently, the investigators are planning to conduct a single center, prospective, randomized controlled trial of population pharmacokinetics (PopPK) guided targeted ATG dosing, compared with conventional ATG dosing, to further validate the safety and efficacy of this strategy and to assess the achievement rate of the optimal AUC target. The study will evaluate GVHD free, relapse free survival; viral reactivation rates; incidences of acute and chronic GVHD; treatment related mortality; disease free survival; overall survival; and immune reconstitution. The ultimate goal is to identify the optimal ATG administration model for haplo HSCT to improve survival and quality of life.