Busulfan, Etoposide, and Total-Body Irradiation in Treating Patients Undergoing Donor Stem Cell or Bone Marrow Transplant for Advanced Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy and total-body irradiation before a donor stem cell transplant or a donor bone marrow transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying the side effects and best way to give busulfan together with etoposide and total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell or bone marrow transplant for advanced hematologic cancer.

Detailed Description
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OBJECTIVES: To determine the efficacy of a preparative regimen comprising dose targeted busulfan, etoposide, and fractionated total-body irradiation followed by allogeneic hematopoietic stem cell or bone marrow transplantation in patients with advanced hematologic malignancies. To determine the efficacy of this regimen in patients with acute myeloid leukemia in first remission with unfavorable cytogenetics. To evaluate the early and late toxicities of this regimen. OUTLINE: Preparative chemotherapy regimen: Patients receive busulfan IV over 2 hours once every 6 hours on days -14 to -8 for a total of 16 doses and etoposide IV on day -3.* NOTE: *Patients also receive oral or IV dilantin 1-3 times daily on days -18 to -5 for prophylaxis of grand mal seizures. Fractionated total-body irradiation (FTBI): Patients undergo FTBI on days -7 to -4 for a total of 10 fractions. Allogeneic transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV or orally on days -1 to 50 followed by a taper to day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil orally or IV over 2 hours twice daily on days 0-27, followed by a taper until day 56. After completion of study treatment, patients are followed annually for 2 years.

Official Title
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Phase II Study of IV Busulfan Combined With 12 cGy of Fractionated Total Body Irradiation (FTBI) and Etoposide (VP-16) as a Preparative Regimen for Allogeneic Bone Marrow Transplantation for Patients With Advanced Hematological Malignancies

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: busulfan
* Drug: cyclosporine
* Drug: etoposide
* Drug: mycophenolate mofetil
* Procedure: allogeneic bone marrow transplantation
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: total-body irradiation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Acute myeloid leukemia (AML) Failed remission induction therapy or in relapse beyond second remission In first remission with poor risk cytogenetics (e.g., 11q abnormalities, -7, -5, complex abnormalities [i.e., > 3 abnormalities, 6;9 translocation and 3q abnormalities del (7q), del (5q), complex abnormalities ≥ abnormalities, 9q, 20q, 21q, 17q, t(9;21)]) Acute lymphoblastic leukemia (ALL) Failed remission induction therapy or in relapse beyond second remission Blastic phase chronic myelogenous leukemia Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation HLA -A, -B, -C, -DR identical sibling donor match available No relapse after prior bone marrow transplantation PATIENT CHARACTERISTICS: Cardiac ejection fraction ≥ 50% Serum creatinine ≤ 1.2 times upper limit of normal (ULN) or creatinine clearance > 80 mL/min Bilirubin ≤ 1.5 times ULN AST and ALT < 5 times ULN FEV_1 ≥ 50% of predicted normal DLCO ≥ 50% of predicted normal No psychological or medical condition that would preclude allogeneic transplantation (in the opinion of the treating physician) Not pregnant Negative pregnancy test PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 28 days since prior induction or reinduction therapy Prior etoposide and busulfan allowed No prior radiation therapy that would exclude total-body irradiation

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 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: Busulfan, FTBI and VP16<br>IV Busulfan + 12 cGy FTBI + VP16 prior to allogeneic Bone Marrow Transplant | Drug: busulfan<br> <br> Drug: cyclosporine<br> <br> Drug: etoposide<br> <br> Drug: mycophenolate mofetil<br> <br> Procedure: allogeneic bone marrow transplantation<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: total-body irradiation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 5 Years Post-Transplant. | Kaplan-Meier estimate of an event of death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%. | Date of Transplant to Five Years post-Transplant | 
| Disease-free Survival at Five Years Post-transplant | Kaplan-Meier estimate of an event of relapse or death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%. | Date of transplant to five years post-transplant | 
| Overall Survival Comparing Diagnosis Groups | Kaplan-Meier estimate of an event of death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%. | Date of Transplant to Five Years post-Transplant | 
| Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared. | Fine and Gray estimate of cumulative incidence of Relapse, with Death as the competing risk. Estimate is at five years post-transplant. Ninety-five percent confidence interval is by logit transformation of Greenwood variance to keep the interval within the probability space of 0% to 100%. | Date of Transplant to Five Years post-Transplant. Estimate is at Five Years post-Transplant. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent adult acute myeloid leukemia, adult acute myeloid leukemia in remission, recurrent childhood acute myeloid leukemia, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, blastic phase chronic myelogenous leukemia, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes