The Optimization of Haploidentical Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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The goal of this observational study is to compare the incidence of relapse in G-CSF/ATG based and PT-Cy based haploidentical transplantation] in [patients aged 18 to 55 years with a diagnosis of hematological malignancies who unmanipulated haplo-HSCT with myeloablative conditioning]. The main question it aims to answer are: Primary objective: To compare the incidence of relapse in G-CSF/ATG based and PT-Cy based haploidentical transplantation and illustrate the possible immune mechanism. Secondary objectives: To compare CMV infection, GVHD and survival outcomes, and to observe the dynamic immune reconstitution of G-CSF/ATG based or PT-Cy based model. Exploratory objectives: To compare the long-term quality of life among recipients who receive G-CSF/ATG based or PT-Cy based protocol.

Official Title
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A Multi-center, Prospective Study of Clinical Outcome and Immune Reconstruction in G-CSF/ATG and PT-Cy Based Haploidentical Transplantation

Conditions
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Hematological Malignancy

Intervention / Treatment
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* Drug: ATG
* Drug: Post-transplantation cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects diagnosed as acute leukemia with transplant indications in ≤ CR2; Lack of available, HLA-identical, related sibling or unrelated donor; Female or male, age: 18-55 years old; ECOG performance status 0-2; Adequate organ function as defined by the following criteria: Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5× upper limit of normal (ULN), or AST and ALT ≤5× ULN if liver function abnormalities are due to underlying malignancy Total serum bilirubin≤1.5× ULN Serum creatinine≤2.5× ULN Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment; Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Exclusion Criteria: Uncontrollable active infection; Severe organic impairment: hepatic and renal impairment; Any of the following within 6 months prior to starting study treatment: myocardial infarction, severe/unstable angina, congestive heart failure, or cerebrovascular accident including transient ischemic attack; Pregnancy or breastfeeding; Psychiatric disorders; Don't sign the informed consent; Prior/concurrent clinical study experience; Other conditions: Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with section 1.61 of the ICH-GCP Ordinance E6) Any specific situation during study implementation/course that may rise ethics considerations Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| G-CSF/ATG group<br>Patients in the G-CSF/ATG group received a modified Bu/Cy plus ATG conditioning regimen as follows: cytarabine (4/g m2 per day IV.) on days -10 to -9; Bu (3.2 mg/kg per day IV.) on days -8 to -6; Cy (1.8 g/m2 per day IV.) on days -5 to -4; methyl chloride hexamethylene urea nitrate (Me-CCNU) (250 mg/m2 per day orally) once on day -3; and ATG (2.5 mg/kg per day IV; rabbit, Sang Stat, Lyon, France) on days -5 to -2. | Drug: ATG<br>* Patients with intermediate-high risk hematologic malignancy who are indicated for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and absence of HLA matched donors will be treated with haplo-HSCT, with G-CSF/ATG based protocol.<br>|
| PT-Cy group<br>Patients in PT-Cy group received a Bu/Flu/Cy-based conditioning regimen as follows: Flu (40 mg/m2 or 1 mg/kg IV) on days -8 to -4; Bu (3.2 mg kg/ d-1 IV) on days -7 to -4; Cy (14.5-40 mg/kg IV) on days -3 to -2;±cytarabine (3 g/m2/d IV) on days -9 to -8; and ± IDA (15 mg/m2/d IV) on days -9 to -8. The addition of IDA and/or cytarabine depended on the performance status of the patients and whether the patients were in relapse status. High-dose PTCy (50 mg/kg/d IV) was administered on days +3 and +4. | Drug: Post-transplantation cyclophosphamide<br>* Patients with intermediate-high risk hematologic malignancy who are indicated for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and absence of HLA matched donors will be treated with haplo-HSCT with PT-Cy based protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of participants with disease relapse | The cumulative incidence of relapse of the primary disease. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of CMV disease | The cumulative incidences of CMV disease in participants after transplantation | 6 months | 
| Cumulative incidences of aGVHD | The diagnosis and grading of aGVHD are based on the modified Glucksberg grading standard. | 100 days | 
| Cumulative incidences of cGVHD | Chronic GVHD can be classified as limited or extensive according to the Seattle criteria, and also be classified as mild or moderate or severe according to the National Institutes of Health (NIH) criteria. | 1 year | 
| Percent of participants with overall survival | Overall survival (OS) is defined as the time from randomization to death resulting from any cause. | 1 year | 
| Dynamic immune reconstitution | The main immune cell subsets include: T cell, B cell, NK cell, and Monocytes | 1 year | 
| Neutrophil engraftment | Neutrophil engraftment is defined as the first of 3 consecutive days with an absolute neutrophil count > 0.5 × 10^9/L. | 1 month | 
| Platelet engraftment | Platelet engraftment is defined as the first of 7 consecutive days with an absolute platelet count > 20 × 10^9/L independent from transfusion | 1 month | 
| Transplantation-related mortality | Death due to causes unrelated to the underlying disease | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haploidentical Transplantation, G-CSF/ATG, PT-Cy