Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

Study Overview
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Brief Summary
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New conditioning regimens are still needed to maximize efficacy and limit treatment-related deaths of allogeneic transplantation for advanced hematologic malignancies. Over the past several years, the investigators have evaluated several new conditioning regimens that incorporate fludarabine, a novel immunosuppressant that has limited toxicity and that has synergistic activity with alkylating agents. Recent data have suggested that fludarabine may be used in combination with standard doses of oral or IV busulfan, thus reducing the toxicity previously observed with cyclophosphamide/ busulfan regimens.

Detailed Description
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Treatment-related mortality and recurrence of disease account for the majority of treatment failures in allogeneic transplantation for advanced hematologic malignancies. The most commonly utilized conditioning regimens consist of cyclophosphamide and total-body irradiation or busulfan and cyclophosphamide. Other agents such as etoposide or thiotepa are sometimes added to maximize the antileukemic effect. New conditioning regimens are however still needed to maximize efficacy and limit treatment-related deaths. Over the past several years, the investigators have evaluated several new conditioning regimens that incorporate fludarabine, a novel immunosuppressant that has limited toxicity and that has synergistic activity with alkylating agents. Recent data have suggested that fludarabine may be used in combination with standard doses of oral or IV busulfan, thus reducing the toxicity previously observed with cyclophosphamide/ busulfan regimens.

Official Title
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Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

Conditions
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Acute Myeloid Leukemia, Acute Leukemia, Chronic Myelogenous Leukemia, Malignant Lymphoma, Hodgkin's Disease, Multiple Myeloma, Lymphocytic Leukemia, Myeloproliferative Disorder, Polycythemia Vera, Myelofibrosis, Aplastic Anemia

Intervention / Treatment
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* Drug: fludarabine/busulfan
* Drug: fludarabine/ melphalan
* Drug: ATG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with the following diseases: Acute myeloid or lymphocytic leukemia in first remission at standard or high-risk for recurrence. Acute leukemia in greater than or equal to second remission, or with early relapse, or partial remission. Chronic myelogenous leukemia in accelerated phase or blast-crisis. Chronic myelogenous leukemia in chronic phase Recurrent or refractory malignant lymphoma or Hodgkin's disease Multiple myeloma. Chronic lymphocytic leukemia, relapsed or with poor prognostic features. Myeloproliferative disorder (polycythemia vera, myelofibrosis) with poor prognostic features. Severe aplastic anemia after failure of immunosuppressive therapy. Age 10-65 years. Zubrod performance status less than or equal to 2. Adequate cardiac and pulmonary function. Patients with decreased LVEF < 40% or DLCO < 50% of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this protocol. Patient or guardian able to sign informed consent. Exclusion Criteria: Life expectancy is severely limited by concomitant illness. Serum creatinine greater than 1.5 mg/dL or Creatinine Clearance less than 50 ml/min . Serum bilirubin greater than or equal to 2.0 mg/dl, SGPT greater than 3 x upper limit of normal Evidence of chronic active hepatitis or cirrhosis HIV-positive Patient is pregnant

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. | Drug: fludarabine/busulfan<br>* All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI.<br>* Other names: Myleran;Drug: ATG<br>* Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen.<br>* Other names: Thymoglobulin;|
| Active Comparator: Arm 2<br>All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. | Drug: fludarabine/ melphalan<br>* All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl).<br>* Other names: Alkeran;Drug: ATG<br>* Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen.<br>* Other names: Thymoglobulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Engraftment. | Median time to ANC engraftment and platelet engraftment in both groups as well as the transfusion requirements measured within 30 days after transplant. | Up to 30 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With 100 Day Transplant-related Mortality. | Day 100 transplant-related mortality was measured in both groups. | Up to 100 days post-transplant. | 
| Time to ANC and Platelet Engraftment | Days to ANC or platelet engraftment | Up to 30 days post-transplant | 
| Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD). | Acute GVHD grade 2-4 was assessed in patients in the FluBU and FluMel groups up to 100 days after transplant. | Up to 100 days post-transplant (acute GVHD). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, First remission, Acute lymphocytic leukemia, Acute leukemia, Second remission, Early relapse, Partial remission, Accelerated phase, Blast-crisis, Chronic myelogenous leukemia, Chronic phase, Recurrent malignant lymphoma, Refractory malignant lymphoma, Hodgkin's disease, Multiple myeloma., Chronic lymphocytic leukemia, Myeloproliferative disorder, Polycythemia vera, Myelofibrosis, Severe aplastic anemia