Allogeneic Stem Cell Transplantation for Myelofibrosis and Myelodysplastic Syndrome

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if using a combination of fludarabine, busulfan, and antithymocyte globulin (ATG) can help to control myelofibrosis or myelodysplastic syndrome in patients receiving a bone marrow or blood stem cell transplant. The safety of these drugs will also be studied.

Detailed Description
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Busulfan is a chemotherapy drug that kills cancer cells by binding to DNA, and is commonly used in stem cell transplants. Fludarabine is a drug that has anti-leukemia and immunosuppressive effects. ATG helps to reduce the risk of transplant rejection and to prevent graft versus host disease. You will receive fludarabine by vein over 1 hour on Days -5 to -2. You will receive busulfan by vein over 3 hours on Day -5 to -2 immediately after completing fludarabine. If you have an unrelated or a mismatched donor, you will receive ATG by vein over 6 hours on Days -3 to -1 to prevent graft versus host disease and to help engraftment. You will first receive a low-level test dose of busulfan, and blood samples (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) tests. This may be done as an outpatient prior to inpatient admission. PK tests measure the level of the study drug in the blood over different time points. This information will be used to decide the next dose needed to reach the target blood level that matches your body size. About 11 total samples of blood will be drawn for PK testing after the test dose and before the first high-dose busulfan treatment. A heparin lock will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for these blood level tests to be performed for technical or scheduling reasons or for any other reason, you will receive the standard fixed busulfan dose without the test dose. You will receive the donor bone marrow or blood stem cells by vein over about 1 hour on Day 0. Two (2) days before the stem cell infusion on Day -2, tacrolimus will be started as a non-stop infusion by vein and will be changed to oral tablets before you leave the hospital. You will continue to take tacrolimus by mouth, for at least 4 months. Four (4) doses of Methotrexate will be give as a short infusion Day 1, Day 3, Day 6 and Day 11 after stem cell infusion. Both these are given to decrease the risk of getting graft-vs-host disease (GvHD). Further immunosuppressive therapy with methylprednisolone (a steroid) or other drugs may also be used to treat GvHD if it occurs. You will have 3 teaspoonfuls of blood drawn for routine tests every day while you are in the hospital and at least 2 times a week for the first 100 days after transplant. You may need frequent blood transfusions and may have to be admitted to the hospital to receive antibiotics if you get a fever. Three (3) teaspoonful of blood and a bone marrow aspirate and biopsy will be taken 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months after the transplant to check the response to the treatment. After the first 2 years, your disease status will be followed by a yearly phone call or letter from you or your regular doctor to the study doctor. Tests and/or procedures may be performed before the scheduled time, if your doctor thinks it is needed. You will be taken off the study if your disease gets worse or if further treatment is not in your best interest. This is an investigational study. All the drugs to be used in this study are FDA approved and commercially available. About 110 patients will take part in this study. All will be enrolled at MD Anderson.

Official Title
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Allogeneic Stem Cell Transplantation for Myelofibrosis and Myelodysplastic Syndrome Using Reduced Intensity Busulfan and Fludarabine Conditioning

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine
* Drug: Thymoglobulin (ATG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Idiopathic Myelofibrosis or Myelofibrosis secondary to Polycythemia Vera or Essential Thrombocythemia or Myelodysplastic syndrome with or without fibrosis. Patients 75 years or younger Patients must have an HLA matched or at least a 9/10 antigen (A, B, C, DQ or DR) matched related or unrelated donor. Patients must have a Zubrod PS 2 or less. Creatinine < 1.6 mg/dl Ejection fraction >/= 40%, unless cleared by cardiology Serum direct bilirubin < 2 mg/dl (unless due to Gilbert's syndrome), serum glutamate pyruvate transaminase (SGPT) </= 4 x normal values Forced expiratory volume at one second (FEV1), forced vital capacity (FVC), or diffusing capacity of lung for carbon monoxide (DLCO) >/= 40% of expected. Negative Beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization. Exclusion Criteria: Uncontrolled life-threatening infections HIV positive Patients with Active viral hepatitis

Ages Eligible for Study
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Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine + Busulfan + Thymoglobulin<br>Fludarabine 40 mg/m^2 by vein daily over 1 hour x 4 days. Busulfan test dose = 32 mg/m^2 by vein x 1 day; 100 mg/m^2 by vein daily over 3 hours x 4 days. Thymoglobulin 2.5 mg/kg by vein over 6 hours x 3 days if there is an unrelated or a mismatched donor. | Drug: Busulfan<br>* Test dose = 32 mg/m^2 by vein x 1 day; 100 mg/m^2 by vein daily over 3 hours x 4 days<br>* Other names: Myleran;Drug: Fludarabine<br>* 40 mg/m^2 by vein daily over 1 hour x 4 days<br>* Other names: Fludarabine Phosphate;Drug: Thymoglobulin (ATG)<br>* 2.5 mg/kg by vein over 6 hours x 3 days if there is an unrelated or a mismatched donor<br>* Other names: ATG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Non-relapse Mortality at 100 Days Post-transplant | To evaluate the safety of Fludarabine/Busulfan as conditioned regimen for allogeneic stem cell transplantation in patients with myelofibrosis/myelodysplastic syndrome at 100 days post-transplant | Non-relapse mortality at 100 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of This Therapy 3 Years Post-transplant | Efficacy Assessed as Number of Participants with Overall Survival, Leukemia Progression, Primary Graft Failure and Complete Hematological Response. Primary graft failure is defined as failure to achieve an ANC >/= 0.5 x 10 (9)/L for 3 consecutive days and evidence of donor chimerism by Day +28. Complete hematological response is defined by hemoglobin >/= 120 g/L; or achievement of transfusion independence, with stable Hb > 110 g/L, for RBC transfusion-dependent participants; Spleen not palpable; platelet count 150 x 10 (9)/L; White blood cell 4 x 10 (9)/L to 10 x 10(9)/L. | Up to 3 years post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic Myelofibrosis, Myelofibrosis, Essential Thrombocythemia, Polycythemia Vera, Busulfan, Antithymocyte Globulin, ATG, Fludarabine, Thymoglobulin