ATG/PTCy in Haplo-PBSCT Randomized Controlled,Multi-center

Study Overview
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Brief Summary
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A novel regimen, which is composed of a low dose of ATG (5 mg/kg) and low-dose PTCy (one dose of PTCy, 50mg/kg) for GvHD prophylaxis in Haplo-PBSCT for patients with hematologic malignancies, was designed to decrease the risk of aGvHD and lower the incidence of virus reactivation.

Detailed Description
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Acute graft-versus-host disease (aGvHD) is the most important obstacle of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for treatment of patients with hematologic malignancies. In the last two decades, the results of Haplo-HSCT have been conspicuously improved due to effective prophylaxis strategies for aGvHD, such as in vivo T cell depletion (TCD) with anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). The regimens for prophylaxis of GvHD based on rabbit anti-human thymocyte immunoglobin (ATG 10mg/kg, Thymoglobin®, Genzyme Polyclonals S.A.S) effectively prevented the occurrence of grade II-IV aGvHD with an incidence of 33.4%-46%, grade III-IV aGvHD 12%-14.9%, but the reactivation incidences of cytomegalovirus (CMV) and EB virus (EBV) were higher due to a slower immune reconstitution(2-4). The 100-day CIs of CMV and EBV viremia were 61%-64%and over 50%, respectively. Although ATG-based regimens have achieved excellent results, the incidences of aGvHD and the post-transplant virus reactivation are still higher, affecting the long-term survival of the patients. The regimen of PTCy for prevention of GvHD was developed in 1999 by St. Johns Hopkin's group in Baltimore (1) and had outstanding results with the CIs of 34% grades II-IV and of 6% grades III-IV aGvHD by day 200 in haplo-bone marrow transplantation (Haplo-BMT) (7), respectively. The incidences of viral and fungal infection in Haplo-HSCT with PTCy for GvHD prophylaxis were much lower than ATG based regimens. Ruggeri A（8）et al retrospectively analyzed the effects of different stem cell source (BM vs PBSC) on the transplant results in Haplo-HSCT with PTCy. The results showed that BM was associated with a lower incidence of grades II-IV and grades III-IV acute GVHD (21% vs 38%, P ≤ .01; and 4% vs 14%, P < .01, respectively), which was further confirmed by Bashey A et al' study（9）. These data indicated that PTCy regimen don't have the same effects for GvHD prophylaxis with PBSC graft as compared with BM graft in Haplo-HSCT. A novel regimen, which is composed of a low dose of ATG (5 mg/kg) and low-dose PTCy (one dose of PTCy, 50mg/kg) for GvHD prophylaxis in Haplo-PBSCT for patients with hematologic malignancies, was designed to decrease the risk of aGvHD and lower the incidence of virus reactivation. A prospective, phase II clinical trial (Clinicaltrials.org NCT03395860) was performed to evaluate the efficacy with low dose ATG followed by low dose PTCy as GvHD prophylaxis.Thirty-two patients diagnosed with hematological malignancies were enrolled in this trial. All patients received myeloablative conditioning regimens except for three patients. The cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD were 19.4% (95% CI, 5.5-33.3%) and 6.9% (95% CI 0-16.3%) by day 100, respectively. The one-year probability of relapse was 25.1% (95% CI, 7.3-42.9%). The one-year probabilities of disease free-survival (DFS) and overall survival (OS) was 59% (95% CI, 33.3%-84.7%) and 78.4% (95% CI, 63%-93.8%), respectively. The CIs of CMV reactivation and EBV reactivation by day 180 were 37.5% (95% CI, 19.8-55.2%) and 40.6% (95% CI, 22.6-58.6%), respectively. The results suggested that low dose ATG with low dose PTCy as GvHD prophylaxis in Haplo-PBSCT had promising activity. A prospective randomized trial is required to compare the efficacies of this regimen with ATG-based or PTCy-based regiments in Haplo-PBSCT.

Official Title
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Shanghai General Hospital Affiliated to Shanghai Jiao Tong University

Conditions
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Myeloid Tumor

Intervention / Treatment
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* Drug: ATG/PTCy
* Drug: standard ATG
* Drug: standard PTCy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of hematologic malignancies (AML CR/blast cell≤20% high-risk MDS) were enrolled in this study. Diagnosis was according to the criteria of 2008 World Health Organization (WHO) classification of myeloid tumors. Family members selected as donors were typed at the HLA-A, -B, -DQB1, -C and -DRB1 locus at high-resolution level. Haplotype was defined as recipient-donor number of HLA mismatches > 3. 3.14 to 70 years old. 4.Performance status scores no more than 2 (ECOG criteria). 5.Adequate organ function as defined by the following criteria: alanine transaminase （ALT）, aspartate transaminase（AST） and total serum bilirubin <2×ULN (upper limit of normal). Serum creatinine and blood urea nitrogen (BUN) <1.25×ULN. 6.Adequate cardiac function without acute myocardial infarction, arrhythmia or atrioventricular block, heart failure, active rheumatic heart disease and cardiac dilatation(the patients has been improved after treatment of the disease and are not expected to affect transplant can include in the study). 7.Absence of any other contraindications of stem cell transplantation. Willingness and ability to perform HSCT. 8.Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all 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: DSA strong positive (titer >10000MFI) Life expectancy < 3 months because of other severe diseases. Presence of any fatal disease, including respiratory failure, heart failure, liver or kidney function failure. Uncontrolled infection. Pregnancy or breastfeeding. Has enrolled in another clinical trials. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 70 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: ATG+PTCy
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATG/PTCy<br>The GvHD prophylaxis consisted of ATG 2.5mg/kg administered on day -2 to -1 and cyclophosphamide (Cy) 50 mg/kg on day +3, cyclosporine A (CsA) and mycophenolate mofetil (MMF) initiating on day +4. CsA was prescribed at 2 mg/kg as a continuous infusion. The CsA doses were modified to obtain nadir serum levels between 200 and 300 ng/ml. MMF was administered at 15 mg/kg oral 3 times per day (maximum dose 3g per day) until day +34 and was then stopped if no aGvHD. Mycophenolate Sodium Enteric-coated Tablets (MPA) can be used instead of MMF, one tablet MPA corresponds to one tablet MMF. CsA was tapered from day +90 to day +180. | Drug: ATG/PTCy<br>* low dose Antithymocyte Globulin plus low dose post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation<br>|
| Active Comparator: standard ATG<br>The GvHD prophylaxis consisted of ATG 2.5mg/kg administered on day -4 to -1 , cyclosporine A (CsA) initiating on day -5 and mycophenolate mofetil (MMF) initiating on day +1 . CsA was prescribed at 2 mg/kg as a continuous infusion. The CsA doses were modified to obtain nadir serum levels between 200 and 300 ng/ml. MMF was administered at 15 mg/kg oral 2 times per day (maximum dose 2g per day) until day +30 and was then stopped if no aGvHD. Mycophenolate Sodium Enteric-coated Tablets (MPA) can be used instead of MMF, one tablet MPA corresponds to one tablet MMF. CsA was tapered from day +90 to day +180. | Drug: standard ATG<br>* in vivo T cell depletion (TCD) with anti-thymocyte globulin (ATG) as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation<br>* Other names: ATG;|
| Active Comparator: standard PTCy<br>The GvHD prophylaxis consisted of cyclophosphamide (Cy) 50 mg/kg on day +3, +4,cyclosporine A (CsA) and mycophenolate mofetil (MMF) initiating on day +5. CsA was prescribed at 2 mg/kg as a continuous infusion. The CsA doses were modified to obtain nadir serum levels between 200 and 300 ng/ml. MMF was administered at 15 mg/kg oral 3 times per day (maximum dose 3g per day) until day +35 and was then stopped if no aGvHD. Mycophenolate Sodium Enteric-coated Tablets (MPA) can be used instead of MMF, one tablet MPA corresponds to one tablet MMF. CsA was tapered from day +90 to day +180. | Drug: standard PTCy<br>* post-transplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell<br>* Other names: PTCy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The cumulative incidences of acute GVHD | The cumulative incidences of aGvHD was defined as the number and the ratio of the participants with aGVHD | 100 days after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukocyte engraftment | Leukocyte engraftment:(was defined as the first of three consecutive days of peripheral white blood count >1000/ul. | 1 month | 
| Platelet engraftment | Platelet engraftment:(was defined as the first of seven consecutive days of platelet counts of >20000/ul. | 1 month | 
| Donor chimerism | Quantitative chimerism analyzes were performed using short-tandem-repeat-based polymerase chain reaction technique sat regular intervals for every 4 weeks after allografting in bone marrow. | 2 years | 
| Relapse incidence (RI) | RI was defined as the number and ratio of the participants with relapse after transplantation | 2 YEARS] | 
| chronic GVHD | cGvHD was diagnosed and graded according to the 2014 National Institutes of Health (NIH) consensus criteria: mild, moderate or severe respectively.The number and ratio of participants with cGVHD after transplatation | 2 years | 
| infection | CMV and EB infections(The number and ration of participants with infection after transplantaton) | 2 years | 
| OS | overall survival | 2 years | 
| DFS | disease free survival | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATG, PTCy, haplo-PBSCT, GVHD