A Study of TKI Maintenance Therapy Following Allo-HSCT in Newly Diagnosed Ph+ Adult ALL

Study Overview
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Brief Summary
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This project is a key clinical research project approved by the Clinical Research Center of the First Affiliated Hospital of Xi 'an Jiaotong University.Tyrosine kinase inhibitors (TKI) combined with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT) are routinely used in patients with philadelpha-positive lymphoblastic leukemia (Ph+ALL). However, TKI maintenance therapy post-HSCT remains controversial. In this study, Ph+ALL patients are enrolled and given dasatinib combined with chemotherapy followed by allo-HSCT. Then patients in the group A continuing to use dasatinib for 1 year is compared with those in the group B receiving dasatinib for 6 months after HSCT. The measurable residual disease (MRD), complete remission (CR), overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and the incidence of graft versus host disease (GVHD) will be observed to determine the optimal duration of TKI maintenance therapy post-HSCT.

Detailed Description
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About 25% of adult patients with acute lymphoblastic leukemia (ALL) are associated with t (9; 22), positive philadelphia chromosome (Ph+ ALL), in whom BCR/ABL fusion gene can be detected in the bone marrow and peripheral blood. Although current treatment strategies using tyrosine kinase inhibitors (TKIs) such as dasatinib combined with chemotherapy have achieved high complete remission (CR) rates, the duration of remission is short, and most Ph+ ALL patients relapse within 2 years. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) bridging to CR remains the only strategy to cure Ph+ ALL. However, TKI maintenance therapy post-HSCT remains controversial. In this study, Ph+ALL patients are enrolled. The participants will receive dasatinib combined with induction and consolidation chemotherapy to obtain molecular remission and then undergo allo-HSCT. After the above treatments, the patients will be randomly divided into two groups. The subjects in the group A will continue to use dasatinib for 1 year, while the patients in the group B receive dasatinib for 6 months post-HSCT. The measurable residual disease (MRD), CR, overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and the incidence of graft versus host disease (GVHD) will be observed to determine the optimal duration of TKI maintenance therapy post-HSCT.

Official Title
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A Randomized Controlled Study of Tyrosine Kinase Inhibitor Maintenance Therapy Following Allogeneic Hematopoietic Stem Cell Transplantation in Newly Diagnosed Philadelphia Chromesome Positive Adult Acute Lymphoblastic Leukemia

Conditions
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Precursor Cell Lymphoblastic Leukemia-Lymphoma, Philadelphia-Positive Acute Lymphoblastic Leukemia, ALL, Adult

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-65 years old, newly diagnosed as Ph+ALL. Sign the informed consent. Have appropriate allo-HSCT donors. Accept allo-HSCT. Accept follow-up. Exclusion Criteria: Liver and kidney function impairment: serum transaminase > 2 times of the upper limit of normal value, total bilirubin > 1.5 times of the upper limit of normal value, serum inosine > the upper limit of normal value (97 umol/L). Active hepatitis B, hepatitis C or tuberculosis infection. Can not tolerate the adverse effects of dasatinib. Pregnancy. Diagnosis of mental disorders. Failed to reach molecular complete remission (MCR) after the early treatment. Do not accept follow-up.

Ages Eligible for Study
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Minimum Age: 18 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: Dasatinib for 1 year<br>After the allo-HSCT treatment, the patients in this group will continue to take dasatinib orally for 1 year. | Drug: Dasatinib<br>* Take Dasatinib orally for 1 year or 6 months post-HSCT.<br>* Other names: Dasatinib tablet;|
| Experimental: Dasatinib for 6 months<br>After the allo-HSCT treatment, the patients in this group will receive dasatinib for 6 months. | Drug: Dasatinib<br>* Take Dasatinib orally for 1 year or 6 months post-HSCT.<br>* Other names: Dasatinib tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients with Measurable Residual Disease (MRD) Positivity | MRD means the subclinical levels of residual leukemia. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 
| Percentage of Patients with Complete Remission (CR) | CR means that the blood counts have returned to normal, the leukemia cannot be seen when a bone marrow sample is examined under the microscope, and the signs and symptoms of the ALL are gone. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival (DFS), months | The measure of time after allo-HSCT during which no sign of ALL is found. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 
| Overall Survival (OS), months | The length of time from the date of allo-HSCT that Ph+ ALL patients are still alive. | From date of randomization until the date of death from any cause, whichever came first, assessed up to 36 months. | 
| Non-relapse Mortality (NRM), rate or percentage | NRM means death without recurrent or progressive disease after allo-HSCT. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 
| Incidence of graft versus host disease (GVHD), rate or percentage | GVHD is a condition that might occur after allo-HSCT. In GVHD, the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. | From date of randomization until the date of GVHD occurrence or date of death from any cause, whichever came first, assessed up to 36 months. | 
| Adverse Effects (AE) | An adverse effect is any untoward medical occurrence in clinical investigation subject administered dasatinib and which does not necessarily have a causal relationship with this treatment. | From date of randomization until the date of death from any cause, whichever came first, assessed up to 36 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Philadelphia-Positive, Adult Acute Lymphoblastic Leukemia, Allogeneic Hematopoietic Stem Cell Transplantation, Tyrosine Kinase Inhibitors