HMA+DLI vs DLI Preemptive Therapy Based on MRD for AL Undergoing Allo-HSCT

Study Overview
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Brief Summary
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Allogeneic hematopoietic cell transplantation (Allo-HSCT) is an effective therapy for acute leukemia, but relapse is the most common problem affecting long-term survivors of allo-HSCT. Therapy options for relapse include stopping immune suppression, re-induction of chemotherapy, donor lymphocyte infusion (DLI) or combination therapy. In this prospective randomized controlled study, the safety and efficacy of hypomethylating agents (HMA) + DLI and DLI preemptive therapy based on minimal residual disease in acute leukemia undergoing allo-HSCT are evaluated.

Detailed Description
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Allogeneic hematopoietic cell transplantation (Allo-HSCT) is an effective therapy for acute leukemia, but relapse is the most common problem affecting long-term survivors of allo-HSCT. Therapy options for relapse include stopping immune suppression, re-induction of chemotherapy, donor lymphocyte infusion (DLI) or combination therapy. One method of solving relapse is to intervene before hematologic or pathologic relapse occurs based on minimal residual disease (MRD) . DLI is an effective post-transplantation therapy based on MRD for relapse. Whether combination of hypomethylating agents (HMA) and DLI could improve outcomes remains unclear. In this prospective randomized controlled study, the safety and efficacy of HMA+DLI and DLI preemptive therapy based on minimal residual disease in acute leukemia undergoing allo-HSCT are evaluated.

Official Title
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Hypomethylating Agents + Donor Lymphocyte Infusion vs Donor Lymphocyte Infusion Preemptive Therapy Based on Minimal Residual Disease for Acute Leukemia Undergoing Allogenetic Hematopoietic Stem Cell Transplantation

Conditions
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Minimal Residual Disease,Acute Leukemia, Hypomethylating Agents, Donor Lymphocyte Infusion, Allogeneic Hematopoietic Cell Transplantation

Intervention / Treatment
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* Combination Product: HMA+DLI
* Biological: DLI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - A patient age of 14-65 years. AL patients who achieved CR at pre-transplantation undergoing allo-HSCT. Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. Exclusion Criteria: AL patients who were in NR at pre-transplantation undergoing allo-HSCT. Any abnormality in a vital sign (e.g., heart rate, respiratory rate, or blood pressure). Patients with any conditions not suitable for the trial (investigators' decision).

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 65 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HMA+DLI<br>For AL patients who achieved CR at pre-transplantation undergoing allo-HSCT, DLI was not given and immunosuppressant were withdrawn if patients were MRD persistently negative. MRD status were monitored every 30 days. If patients were MRD negative by Day+30 post-transplantation, MRD status would be continued to be monitored by Day+60. If patients were MRD positive by Day+30 post-transplantation, immunosuppressant were withdrawn. If MRD were persistently positive until Day+60 or MRD changed from negative by Day+30 to positive by Day +60 post-transplantation, HMA and DLI were given. DLI was given 48 hours after administration of HMA. DLI was given monthly until GVHD occurred or MRD became negative or a total of four times. If MRD changed from positive by Day+30 to negative by Day+60 post-transplantation, MRD status would be continued to be monitored by Day+90 post-transplantation. If patients were MRD positive by Day+90 post-transplantation, HMA and DLI were given as shown above. | Combination Product: HMA+DLI<br>* HMA: Decitabine was administered at 20mg/m2/day for five consecutive days or Ara-C was administered at 75mg/m2/day for seven consecutive days. DLI was administered at a median dose of 1.0 (range 0.7-1.4) ×10*8 mononuclear cells/kg.<br>|
| Experimental: DLI<br>For AL patients who achieved CR at pre-transplantation undergoing allo-HSCT, DLI was not given and immunosuppressant were withdrawn if patients were MRD persistently negative. MRD status were monitored every 30 days. If patients were MRD negative by Day+30 post-transplantation, MRD status would be continued to be monitored by Day+60 post-transplantation. If patients were MRD positive by Day+30 post-transplantation, immunosuppressant were withdrawn. If MRD were persistently positive until Day+60 or MRD changed from negative by Day+30 to positive by Day+60 post-transplantation, DLI was given. DLI was given monthly until GVHD occurred or MRD became negative or a total of four times. If MRD changed from positive by Day+30 to negative by Day+60 post-transplantation, MRD status would be continued to be monitored by Day+90 post-transplantation. If patients were MRD positive by Day+90 post-transplantation, DLI was given as shown above. | Biological: DLI<br>* DLI was administered at a median dose of 1.0 (range 0.7-1.4) ×10*8 mononuclear cells/kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse | Relapse was defined by reappearance of blasts in the peripheral blood, recurrence of BM blasts >5%, or development of extramedullary disease infiltrates at any site | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | DFS was defined as the time from transplantation to relapse or death in remission | 2 years | 
| Overall survival (OS) | OS was defined as the time from transplantation to death from all causes | 2 years | 
| Transplant-related mortality (TRM) | TRM was defined as death from any cause except relapse | 2 years | 
| Incidence of acute GVHD | Acute GVHD was graded according to standard criteria | 100 days | 
| Incidence of chronic GVHD | Chronic GVHD was assessed in patients alive after day 100 | 2 years |