Evaluation of Plasmatic Levels of Busulfan in Patients Undergoing Hematopoietic Stem Cell Transplantation

Study Overview
=================
Brief Summary
-----------------
The purpose of this prospective study is evaluate the best dose of busulfan for each patient undergoing Haematopoietic Stem Cell Transplantation

Detailed Description
-----------------
Busulfan is an alkylating antineoplastic agent used commonly during the conditioning regimen in patients undergoing Haematopoietic Stem Cell Transplantation (HSCT). Due to the fact that this drug has a variable metabolism in different individuals, the investigators performed the plasmatic dosage of chemotherapy before starting the conditioning regimen (test dose) as a way to predict the best dose to them during the conditioning. Busulfan toxicities depends on the Area Under Curve and Concentration Steady State (CSS). The investigators randomized in groups according to the route of drug administration: per oral and intravenously. Dose test will be performed before conditioning and othe pharmacokinetics (Pk) study will be made in the first day of conditioning. The test dose of P.O busulfan will be 1 mg/Kg/dose and 32 mg/m2 for I.V busulfan. The target dose of busulfan during the conditioning will depends on the Pk obtained during the test dose. In the first day of regimen, other samples will be analysed and the new AUC will be adjusted. We will have a control group who have never performed monitoring before (retrospective group) Test Dose for oral busulfan will be performed with peripheral blood samples at the time: 0h (before taking busulfan), 30', 1h, 1,5h, 2h, 3h, 4h, 5h and 6h. In the first day of conditioning other samples will be collected again in the same moments. Test dose for I.V busulfan will be performed on time 0h, 30', 45', 1h, 2h, 3h, 4h, 5h, 6h and 8h after receiving I.V busulfan. If the patients will receive I.V busulfan during conditioning, the blood samples should be collected on time 0h, 30', 1h, 2h, 3h, 4h, 5h, 6h, 7h and 8h after taking busulfan. The blood samples will be centrifuged (4º C/ 3200 rpm/10 minutes) and analysed. Patients will be monitored with pharmacokinetic's drug and clinical outcomes. The investigators will evaluate acute and chronic toxicities after Stem Cell Transplantation.

Official Title
-----------------
Evaluation of Plasmatic Levels of Busulfan in Patients Undergoing Hematopoietic Stem Cell Transplantation

Conditions
-----------------
Acute Leukemia, Chronic Leukemia, Lymphoproliferative Disease, Myeloproliferative Disease, Immunodeficiency

Intervention / Treatment
-----------------
* Other: Analyze the pharmacokinetics of busulfan for transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of hematologic or non-hematologic pathology using as part of the conditioning regimen busulfan; Men, women and children regardless of age; Performance Status> 80 or ECOG <2; Total bilirubin <2 mg / dl and transaminases <3 times the upper limit of normal; Creatinine <1.5 mg / dl; LVEF> 50% by echocardiogram or MUGA at rest; Pulmonary function test with FEV1> 70%; Consent form signed before the start of any specific procedure. Exclusion Criteria: Presence of infectious process in uncontrolled activity; Presence of psychiatric disorder; Pregnancy;
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Orally Busulfan PK<br>Evaluate the Pharmacokinetics of orally busulfan | Other: Analyze the pharmacokinetics of busulfan for transplantation<br>* Evaluate the Bu pharmacokinetics (PK) when the drug will be received by P.O or I.V and we will establish the target Area Under Curve- AUC based on a single daily dose (test dose) before HSCT. The test dose of orally Bu is 1 mg/Kg and the blood samples are collected and processed in time: 0h, 30 min, 1h, 1,5h, 2h, 3h, 4h, 5h and 6h after drug intake. After extraction of the plasma samples busulfan, quantitative analyzes of busulfan on human plasma will be performed by the liquid chromatograph. For the patients that will receive intravenously busulfan, the test dose is 32 mg/m2 and blood samples are collected in time: 0h, 30', 45', 1h, 2h, 3h, 4h, 5h, 6h and 8h after drug intake. The dose during the conditioning will depend on the test dose and the AUC target.<br>* Other names: Myleran;|
| Other: Intravenously Busulfan PK<br>Evaluate the Pharmacokinetics of intravenously busulfan | Other: Analyze the pharmacokinetics of busulfan for transplantation<br>* Evaluate the Bu pharmacokinetics (PK) when the drug will be received by P.O or I.V and we will establish the target Area Under Curve- AUC based on a single daily dose (test dose) before HSCT. The test dose of orally Bu is 1 mg/Kg and the blood samples are collected and processed in time: 0h, 30 min, 1h, 1,5h, 2h, 3h, 4h, 5h and 6h after drug intake. After extraction of the plasma samples busulfan, quantitative analyzes of busulfan on human plasma will be performed by the liquid chromatograph. For the patients that will receive intravenously busulfan, the test dose is 32 mg/m2 and blood samples are collected in time: 0h, 30', 45', 1h, 2h, 3h, 4h, 5h, 6h and 8h after drug intake. The dose during the conditioning will depend on the test dose and the AUC target.<br>* Other names: Myleran;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dosing of plasmatic levels of busulfan | To study the effectiveness dosing of busulfan plasma levels during the administration of orally busulfan or intravenous prior to HSCT (test dose) and correlate with the respective plasma measurements in the first days of conditioning | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Evaluation of 5-years overall survival in patients who underwent different formulations of busulfan during stem Cell Transplantation | 5 years | 
| Cumulative incidence of relapse and non relapse mortality | Evaluate 5-years cumulative incidence of relapse and non relapse mortality in patients that underwent stem cell transplantation with busulfan in conditioning regimen | 5 years | 
| Disease Free Survival | Evaluate 1-year Disease Free Survival in patients that underwent stem cell transplantation with busulfan in conditioning regimen who enter complete remission after | 1 year | 
| Toxicity | Evaluate hematological and non hematological toxicity in patients that underwent stem cell transplantation with busulfan in conditioning regimen | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Busulfan, plasmatic dosage, Stem Cell Transplantation