The Use of Eltrombopag Post HSCT in BMFS

Study Overview
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Brief Summary
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Bone marrow failure disease(BMFD) is a kind of bone marrow due to congenital or acquired hematopoietic stem cells (hemopoietic stem cell, HSC) function damage. Allogenic hemopoietic stem cell transplantation (Allo-HSCT) might be the most possible treatment to cure the disease.However, 5-26% of patients have been reported to have delayed platelet engraftment (DPE), which is defined as persistent severe thrombocytopenia (<20 × 109/L) for >35 days after transplantation . To date, no standard treatment and prevention has been recommended for DPE. In patients with DPE, the amount of transfusion, the increased risk of infection, and the prolonged average hospital stay were independent risk factors affecting the prognosis of allo-HSCT patients. Due to continuous and progressive failure in the bone marrow hematopoiesis, thrombocytopenia post HSCT is more common in BMFD patients and often achieves low response to conventional therapy, such as platelet transfusion. Therefore, it is of great significance to effectively promote hematopoietic reconstruction to improve the prognosis of transplant patients.

Detailed Description
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Bone marrow failure disease(BMFD) is a kind of bone marrow due to congenital or acquired hematopoietic stem cells (hemopoietic stem cell, HSC) function damage. Generally, BMFD can be divided into two categories based on pathogenesis, which is primary and secondary BMFD. The latter is commonly seen secondary to infection, cancer, drugs, while aplastic anemia(AA), myelodysplastic syndromes(MDS), paroxysmal nocturnal haemoglobinuria(PNH) and Fanconi anaemia(FA) are included in primary BMFD. Although immunotherapy or allogenic hemopoietic stem cell transplantation (Allo-HSCT) can be selected based on different individuals, allo-HSCT is still the most effective treatment for diseases that pose a greater threat to life or have a higher degree of malignancy, such as sereve aplastic anemia(SAA), MDS and PNH. Patients undergoing allo-HSCT typically achieve neutrophil and megakaryocyte reconstruction within 2 weeks and 3 weeks after transplantation respectively. However, 5-26% of patients have been reported to have delayed platelet engraftment (DPE), which is defined as persistent severe thrombocytopenia (<20 × 109/L) for >35 days after transplantation . To date, no standard treatment and prevention has been recommended for DPE. In patients with DPE, the amount of transfusion, the increased risk of infection, and the prolonged average hospital stay were independent risk factors affecting the prognosis of allo-HSCT patients. Due to continuous and progressive failure in the bone marrow hematopoiesis, thrombocytopenia post HSCT is more common in BMFD patients and often achieves low response to conventional therapy, such as platelet transfusion. Therefore, it is of great significance to effectively promote hematopoietic reconstruction to improve the prognosis of transplant patients.

Official Title
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A Multicenter Clinical Study of a TPO Receptor Agonist (Eltrombopag) in the Acceleration of Engraftment Post Hematopoietic Stem Cell Transplantation of Bone Marrow Failure Diseases

Conditions
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Stem Cell Transplant Complications

Intervention / Treatment
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* Drug: Eltrombopag 25 MG Oral Tablet
* Drug: Supportive care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed as bone marrow failure disease who received allo-HSCT; Physical strength score 0-3 according to WHO standard Exclusion Criteria: single or double umbilical cord blood transplantation; allergic to any of the research drugs involved in the protocol; simultaneously suffering from another malignant tumor; pregnant or lactating women; participating in other clinical researchers at the same time; patients with at least one following high risk factors of thrombosis: past medical history of thromboembolism, concurrent grade 2 to 3 hypertension (systolic BP>=160mmHg or diastolic BP>=100mmHg) , diabetes, obesity(BMI>30), family history of stroke, smoke for more than 10 years , or history of catheter thrombosis; severe cataract; Severe infectious diseases (uncured tuberculosis, pulmonary aspergillosis, viral infection, active hepatitis B/C; for positive HBsAg and HBcAg, patient is excluded if hepatitis B DNA nucleic acid test is positive, DNA negative patients can enter this clinical trial; patients with hepatitis C who have a positive hepatitis C RNA nucleic acid test are excluded).; Abnormal liver and kidney function: creatinine level ≥177 μmol/l (1.5mg/dl), transaminase and bilirubin levels increased significantly (3 times or more than the upper limit of normal), and who cannot be enrolled at the discretion of clinician. In moribund condition or concurrent severe liver, kidney, heart, nerve, lung, infectious or metabolic diseases, the severity of which will cause the patient to be unable to tolerate the treatment regimen, or may die within 7-10 days

Ages Eligible for Study
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Minimum Age: 12 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: supportive care<br>patients in this group will receive supportive care, including blood products transfusion, anti-infective therapy rather than rhTPO or TPO-RAs. | Drug: Supportive care<br>* Patients receive transfusion of blood products, including platelets and red blood cells.<br>* Other names: support;|
| Experimental: Eltrombopag group<br>Eltrombopag treatment will be started at the dose of 50mg/d from the 1st day post hematopoietic stem cell transplantation, and the dose will be titrated by 25mg each every 7 days up to 100mg/d according to the tolerability. If not tolerable, reduce the dose to the previous tolerable level (if not tolerable at 50mg/d, reduce to 25mg/d) and maintain this dose for the following 7 days, with the attempt to restart dose escalation after this 7-day period. | Drug: Eltrombopag 25 MG Oral Tablet<br>* Since thrombopoietin receptor agonists (TPO-RAs) have never been regularly used for promotion of cell engraftment post hematopoietic stem cell transplantation HSCT), we design this eltrombopag intervention to evaluate the safety and efficacy of TPO-RAs post HSCT.<br>* Other names: TPO-RA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and proportion of platelet engraftment on day 35 post HSCT. | Platelet engraftment is defined as platelet count >20×109/L in consecutive 7 days (namely day 28 to day 35 after HSCT) without platelet transfusion in the prior 7 days (in other words, no platelet transfusion after day 21). | From day 28 to 35 post HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and proportion of subjects achieving neutrophil engraftment at day 35 post HSCT. | Neutrophil engraftment is defined as ANC>0.5×109/L for consecutive 3 days without administration of G-csf | From day 28 to 35 post HSCT | 
| Hematopoietic reconstruction time. | Reconstruction time is defined as the time from day 1 after allo-HSCT to platelet or neutrophil engraftment | From day 1 to day 180 post HSCT | 
| Overall survival (OS) | OS is defined as the time from the date of day 1 post HSCT to the date of death due to any cause. | From day 1 to day 720 post HSCT or the time of the patients enrolled dead or quitting | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematopoietic stem cell transplantation, Bone marrow failure syndrome, Eltrombopag, Thrombocytopenia