The Gut Microbiome in FLT3- AL Undergoing Allo-HSCT With Or Without Sorafenib Maintenance

Study Overview
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Brief Summary
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This prospective trial investigates the effect of sorafenib maintenance therapy in FLT3 negative acute leukemia patients after allo-HSCT in terms of gut microbiome.

Detailed Description
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Acute leukemia is a heterogeneous group of clonal diseases. Leukemia relapse remains the main cause of treatment failure, including the patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Sorafenib, an inhibitor of multiple kinases including FLT3, has shown promising activity in FLT3-ITD-positive AML. The investigator's previous studies demonstrated that sorafenib maintenance post-transplantation could improve the outcomes of FLT3-ITD positive AML patients, which was associated with sorafenib enhancing the graft-versus-leukemia (GVL) effect. Recent studies have shown that sorafenib is also effective in patients with FLT3-negative acute leukemia. The investigator's previous exploratory study found that salvage therapy such as sorafenib combined with chemotherapy and donor lymphocyte infusion could significantly improve the CR rate and survival in patients with recurrent FLT3-negative acute leukemia after allo-HSC. More and more studies have shown that sorafenib and allo-HSCT have synergistic GVL effect. Some studies have demonstrated that gut microbiome is associated with graft-versus-host-disease (GVHD) and GVL. However, the exact mechanism of sorafenib enhancing the GVL effect and the influence of gut microbiome on sorafenib maintenance after allo-HSCT in FLT3 negative acute leukemia patients remain unknown.

Official Title
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The Gut Microbiome Changes in FMS-like Tyrosine Kinase 3 (FLT3) Negative Acute Leukemia (AL) Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) With or Without Sorafenib Maintenance Post-transplantation

Conditions
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Acute Leukemia, Allogeneic Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: FLT3 Negative Acute Leukemia Allo-HSCT Recipients Exclusion Criteria: intolerance to sorafenib pretransplantation cardiac dysfunction (particularly congestive heart failure) hepatic abnormalities (bilirubin ≥ 3 mg/dL, aminotransferase> 2 times the upper limit of normal) renal dysfunction (creatinine clearance rate < 30 mL/min) Any abnormality in a vital sign (e.g., heart rate, respiratory rate, or blood pressure) Patients with any conditions not suitable for the trial (according to the investigators' decision)

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| sorafenib group<br>FLT3- acute leukemia patients who receive sorafenib maintenance therapy after allo-HSCT. Sorafenib will be used from day 30 to 180 post-transplantation. The initial dose of sorafenib is 400 mg orally twice daily and is adjusted in case of suspected toxicity or resistance (dose range, 200-800 mg daily). | Drug: Sorafenib<br>* The initial dose of sorafenib is 400 mg orally twice daily and is adjusted in case of suspected toxicity or resistance (dose range, 200-800 mg daily).<br>* Other names: BAY 545-9085;|
| non-sorafenib group<br>FLT3- acute leukemia patients who do not receive sorafenib maintenance therapy after allo-HSCT. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation of Gut Microbiota Composition and Diversity | Variation of gut microbiota composition and diversity, as determined by 16sV3V4 rRNA sequencing of serial stool samples, during Sorafenib maintenance therapy and the period without Sorafenib maintenance. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation of gut barrier integrity | As determined by serum levels of zonulin, I-FABP, and citrulline or other potential candidates. | 3 months | 
| NRM | Non-relapse mortality | 1 year | 
| Acute GVHD | The cumulative incidence of overall grades II-IV and grades III-IV acute GVHD will be assessed through six months after transplantation. Acute GVHD will be assessed using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria. | 100 days | 
| Chronic GVHD | The cumulative incidence of overall grades of chronic GVHD will be assessed through 1 year after transplantation according to the 2014 NIH Consensus. | 1 year | 
| AEs | Adverse Events | 1 year | 
| OS | Overall Survival | 1 year | 
| LFS | Leukemia-Free Survival | 1 year | 
| Relapse | Cumulative incidence of relapse | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematopoietic Stem Cell Transplantation, Gut Microbiome, Sorafenib, Acute Leukemia