Treosulfan and Fludarabine in Treating Younger Patients Who Are Undergoing a Donor Stem Cell Transplant for Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as treosulfan and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving treosulfan and fludarabine together with a donor bone marrow transplant or a peripheral stem cell transplant may be an effective treatment for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. PURPOSE: This phase II trial is studying giving treosulfan together with fludarabine to see how well it works in treating patients who are undergoing a donor stem cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

Detailed Description
-----------------
OBJECTIVES: Primary Phase Determine the best dose of treosulfan when administered with fludarabine as a reduced-intensity conditioning regimen followed by allogeneic hematopoietic stem cell transplantation, in terms of incidence of severe to fatal toxicity to major organ systems and incidence of graft failure, in patients with acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome. Secondary Phase Determine the safety of this regimen, in terms of incidence of grade II-IV acute and chronic graft-versus-host disease, in these patients. Determine, preliminarily, the efficacy of this regimen, in terms of incidence of relapse, overall and disease-free survival, donor chimerism on days 28 and 100, and incidence of 200-day and 1-year nonrelapse mortality, in these patients. Determine the pharmacokinetic and pharmacodynamic profile of treosulfan in patients treated with this regimen. OUTLINE: This is a multicenter, dose-finding study of treosulfan. Reduced-intensity conditioning: Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Cohorts of 5-10 patients receive escalating/de-escalating doses of treosulfan until the best dose is determined among the 3 pre-selected doses. The best dose is defined as the dose preceding that at which 4 of 10 patients experience dose-limiting toxicity. Allogeneic hematopoietic cell transplantation (AHCT): Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. All male patients with acute lymphoblastic leukemia OR male patients with acute myeloid leukemia who have prior or current testicular involvement receive external-beam radiotherapy to the testicles before AHCT. After completion of study treatment, patents are followed periodically. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Official Title
-----------------
A Study of a Reduced-Intensity Conditioning Regimen With Treosulfan and Fludarabine for Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Leukemia

Conditions
-----------------
Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: fludarabine
* Drug: treosulfan
* Procedure: allogeneic blood or bone marrow transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome Any phase allowed, including any of the following: Disease in remission Relapsed or primary refractory disease No CNS leukemic involvement not clearing with prior intrathecal chemotherapy and/or cranial radiotherapy Planning to undergo unmanipulated allogeneic bone marrow or peripheral blood stem cell transplantation Filgrastim (G-CSF) mobilization of bone marrow or stem cells allowed Donor available, meeting 1 of the following criteria: HLA-identical related donor HLA-A, -B, -C, -DRB1, and -DQB1 matched unrelated donor by high-resolution DNA typing A single allele mismatch allowed PATIENT CHARACTERISTICS: Performance status Karnofsky 70-100% OR Lansky 70-100% Life expectancy Not specified Hematopoietic Not specified Hepatic Bilirubin ≤ 2 times upper limit of normal (ULN) AST ≤ 2 times ULN No evidence of synthetic dysfunction No severe cirrhosis No active infectious hepatitis Renal Creatinine clearance ≥ 50% Creatinine ≤ 2 times ULN Dialysis independent Cardiovascular No cardiac insufficiency requiring treatment No symptomatic coronary artery disease Ejection fraction ≥ 35% (for patients with history of cardiac disease or anthracycline exposure) Pulmonary PO_2 ≥ 70 mm Hg AND DLCO ≥ 70% of predicted OR PO_2 ≥ 80 mm Hg AND DLCO ≥ 60% of predicted Not requiring supplementary continuous oxygen Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other disease that would severely limit life expectancy No HIV positivity No active infection requiring deferral of conditioning No known hypersensitivity to the study drugs PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No prior allogeneic bone marrow or stem cell transplantation No concurrent umbilical cord blood or autologous transplantation Chemotherapy See Disease Characteristics Radiotherapy See Disease Characteristics Other More than 4 weeks since prior experimental drugs Concurrent enrollment on another protocol for graft-versus-host disease prophylaxis allowed

Ages Eligible for Study
-----------------
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: fludarabine|30 mg/m2, IV for 5 days|
|Drug: treosulfan|12 or 14 g/m2, IV for 5 days|
|Procedure: allogeneic blood or bone marrow transplantation|bone marrow or peripheral blood stem cells|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing Regimen-related Toxicity Events in Study Population | Proportion of patients experiencing regimen-related toxicity to major organ systems from day minus 6 to day 28. Major organ systems: cardiac, bladder/renal, pulmonary, hepatic, neurologic and gastrointestinal | 34 days and 2 years | 
| Number of Patients Experiencing Graft Failure | Graft versus Host Disease (GVHD) is a frequent complication of allogeneic bone marrow transplant in which the engrafted donor cells attacks the patient's organs and tissue. Acute GVHD (aGVHD) usually occurs during the first three months following an allogeneic BMT. Chronic GVHD (cGVHD) usually develops after the third month post-transplant. Patients may experience one, both or neither. | 42 days | 
| Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only) | NRM (Non relapse mortality) - death not attributed to the primary cancer. | 200 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival. |  | One year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, recurrent childhood acute lymphoblastic leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, myelodysplastic syndromes, childhood myelodysplastic syndromes