Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying how well giving treosulfan together with fludarabine phosphate and total-body irradiation followed by donor stem cell transplant works in treating patients with high-risk acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and methotrexate before and after transplant may stop this from happening

Detailed Description
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PRIMARY OBJECTIVES: I. Decrease the incidence of relapse to < 15% at 6 month post transplant in patients with high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transplanted from related or unrelated donors, without unacceptably increasing toxicity (10% non-relapse mortality [NRM] at 6 months). SECONDARY OBJECTIVES: I. Evaluate the incidence of NRM at 180 days and 1 year after hematopoietic cell transplantation (HCT). II. Evaluate overall survival (OS) and relapse-free survival (RFS). III. Incidence of grades II-IV acute graft-versus-host disease (GVHD). IV. Incidence of chronic GVHD. V. Donor chimerism on days +28 and +100. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or orally (PO) twice daily (BID) on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. After completion of study treatment, patients are followed up periodically.

Official Title
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A Multi-Center Study of Conditioning With Treosulfan, Fludarabine and Escalating Doses of TBI for Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL)

Conditions
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Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), 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), Blastic Phase Chronic Myelogenous Leukemia, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: treosulfan
* Drug: fludarabine phosphate
* Radiation: total-body irradiation
* Procedure: peripheral blood stem cell transplantation
* Drug: tacrolimus
* Procedure: allogeneic bone marrow transplantation
* Procedure: allogeneic hematopoietic stem cell transplantation
* Drug: methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute myeloid leukemia (AML): All AML patients beyond 1st remission; Intermediate or high risk AML patients (based on South West Oncology Group [SWOG] cytogenetic criteria) in 1st complete remission Myelodysplastic syndrome (MDS) Other myeloid malignancies as chronic myelogenous leukemia (CML), CML accelerated phase, CML blast crisis, chronic myelomonocytic leukemia (CMML) (to be approved by patient care conference [PCC]) With Karnofsky Index or Lansky Play-Performance Scale > 70% on pre-transplant evaluation Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years) Previous autologous or allogeneic HCT is allowed Donors must be: Human leukocyte antigen (HLA)-identical related donors or Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for one HLA allele, except for HLA-C where no mismatch is allowed Able to undergo peripheral blood stem cell collection or bone marrow harvest In good general health, with a Karnofsky or Lansky Play Performance score > 90% Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years) Acute lymphoblastic leukemia (ALL): all ALL patients not eligible for other protocols Exclusion Criteria: Receiving umbilical cord blood With impaired cardiac function as evidenced by ejection fraction < 35% or cardiac insufficiency requiring treatment or symptomatic coronary artery disease With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and diffusing capacity of the lung for carbon monoxide (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; or receiving supplementary continuous oxygen With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2x upper normal limit or dialysis-dependent With hepatic dysfunction as evidenced by total bilirubin or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.0 x upper normal limit or evidence of synthetic dysfunction or severe cirrhosis With active infectious disease requiring deferral of conditioning, as recommended by an Infectious Disease specialist With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis because of possible risk of lethal infection when treated with immunosuppressive therapy With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiating conditioning (day -6) With life expectancy severely limited by diseases other than malignancy Women who are pregnant or lactating because of possible risk to the fetus or infant With known hypersensitivity to treosulfan and/or fludarabine Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6) Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent Ineligible donors will be those: Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis Who are HIV-positive With active infectious hepatitis Females with a positive pregnancy test Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent

Ages Eligible for Study
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Maximum Age: 60 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: Treatment (allogeneic transplantation)<br>CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. | Drug: treosulfan<br>* Given IV<br>* Other names: tresulfon;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Low dose starting at 2Gy<br>* Other names: TBI;Procedure: peripheral blood stem cell transplantation<br>* Given IV per institutional standard practice<br>* Other names: transplantation, peripheral blood stem cell;Drug: tacrolimus<br>* Given IV or PO<br>* Other names: Prograf;Procedure: allogeneic bone marrow transplantation<br>* Given IV per institutional standard practice<br>* Other names: transplantation, allogenic bone marrow;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Given IV per institutional standard practice<br>Drug: methotrexate<br>* Given IV<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse Incidence |  | At 6 months | 
| Non Relapse Mortality (NRM) Incidence | Cumulative incidence of NRM at 6 months. NRM includes all deaths without relapse or disease progression. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non Relapse Mortality Incidence |  | 1 year after HCT | 
| Overall Survival (OS) |  | at 2 years | 
| Relapse-free Survival |  | at 2 years | 
| Incidence of Grades II-IV Acute GVHD |  | at 6 months | 
| Incidence of Chronic GVHD |  | at 6 months | 
| Median Donor CD3 + T Lymphocyte Chimerism in Peripheral Blood | Donor chimerism was evaluated in peripheral blood T cells | Day 28 after HCT |