Umbilical Cord Blood Transplantation in Treating Patients With High-Risk Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Umbilical cord blood transplantation may allow doctors to give higher doses of chemotherapy or radiation therapy and kill more cancer cells. PURPOSE: This phase II trial is studying allogeneic umbilical cord blood transplantation to see how well it works when given with chemotherapy or radiation therapy in treating patients with high-risk hematologic cancer.

Detailed Description
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OBJECTIVES: Determine the rates of hematologic and immune reconstitution in patients with high risk hematologic malignancies who are undergoing high dose chemoradiotherapy followed by unrelated umbilical cord blood (UCB) transplantation. Determine the incidence of graft-versus-host-disease in this setting. Describe the incidence of recurrent disease in these patients post UCB transplant. Describe the incidence of serious infections and secondary lymphoproliferative diseases following transplantation with UCB in these patients. Determine specifically whether larger recipients can be durably engrafted with unrelated UCB, and determine whether nucleated cell or progenitor cell content of the graft is predictive of hematological engraftment. OUTLINE: Patients may undergo a back-up peripheral blood stem cell collection prior to treatment. Patients receive 9 fractions of total body irradiation (TBI) on days -9 to -5 followed by melphalan IV for three days on days -4 to -2 and antithymocyte globulin IV or methylprednisolone IV for three days on days -3 to -1. On day 0, patients receive umbilical cord blood infusion. If TBI is not tolerated, busulfan is substituted and administered orally every 6 hours for 4 days on days -8 to -5. Cyclosporine and methylprednisolone begin on day -2 and continue for 6 months. Patients are followed at least monthly for 1 year, then every 6 months for the second year, and then annually thereafter. PROJECTED ACCRUAL: There will be a maximum of 48 patients accrued into this study over 4 years.

Official Title
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A Pilot Study of Unrelated Umbilical Cord Blood Transplantation in Patients With High Risk Hematologic Malignancies

Conditions
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Graft Versus Host Disease, Leukemia, Lymphoma, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: busulfan
* Drug: cyclosporine
* Drug: melphalan
* Drug: methylprednisolone
* Procedure: umbilical cord blood transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed high risk malignancy including: Acute nonlymphocytic leukemia (ANLL) after induction failure, or in first complete remission with high risk features including stem cell or biphenotypic classification (acute myeloid leukemia (AML) M0), erythroleukemia (AML M6), acute megakaryocytic leukemia (AML M7), cytogenic markers indicative of poor prognosis, or failure to achieve complete remission after standard induction therapy Acute lymphocytic leukemia (ALL) or ANLL in second or subsequent remission Chronic myeloid leukemia (CML) in chronic phase CML with accelerated phase or blast crisis are eligible after reinduction chemotherapy converts disease to chronic phase High risk ALL in first complete remission Myelodysplastic syndrome with evidence of evolution to acute myeloid leukemia Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation Non-Hodgkin's lymphoma (NHL), ANLL, or ALL with recurrent disease after autologous stem cell transplantation Must also meet all the following conditions: No HLA-ABC/DR identical related bone marrow or UCB donor No 5/6 antigen matched related bone marrow or UCB donor Condition precludes waiting to search and find a donor in the National Marrow Donor Registry Must have an available serologic matched umbilical cord blood unit in the New York Blood Center's Placental Blood Project No active CNS disease PATIENT CHARACTERISTICS: Age: Under 55 at time of umbilical cord blood transplantation Performance status: Zubrod 0-1 Karnofsky 80-100% Life expectancy: At least 3 months Hematopoietic: For patients with ALL or ANLL in remission, CML in chronic phase, or NHL without marrow involvement who elect to undergo autologous peripheral blood stem cell collection and storage: WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin no greater than 2.0 mg/dL ALT/AST no greater than 4 times normal Renal: Creatinine no greater than 2.0 mg/dL Creatinine clearance at least 50 mL/min Cardiovascular: Normal cardiac function by echocardiogram or radionuclide scan (shortening fraction or ejection fraction at least 80% of normal value for age) Pulmonary: FVC and FEV_1 at least 60% of predicted for age For adults: DLCO at least 60% of predicted Other: HIV negative No active infections at time of autologous stem cell harvest or pretransplant cytoreduction Not pregnant or nursing Effective contraception required of all fertile patients PRIOR CONCURRENT THERAPY: Biologic therapy: Prior autologous stem cell transplantation allowed Chemotherapy: See Disease Characteristics Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified

Ages Eligible for Study
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Maximum Age: 54 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

| Intervention/Treatment |
| --- |
|Biological: anti-thymocyte globulin|antithymocyte globulin IV for three days on days -3 to -1|
|Drug: busulfan|If TBI is not tolerated, busulfan is substituted and administered orally every 6 hours for 4 days on days -8 to -5.|
|Drug: cyclosporine|Cyclosporine begin on day -2 and continue for 6 months.|
|Drug: melphalan|melphalan IV for three days on days -4 to -2|
|Drug: methylprednisolone|Methylprednisolone IV for three days on days -3 to -1. Methylprednisolone begin on day -2 and continue for 6 months.|
|Procedure: umbilical cord blood transplantation|On day 0, patients receive umbilical cord blood infusion.|
|Radiation: radiation therapy|9 fractions of total body irradiation (TBI) on days -9 to -5|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rates of durable engraftment in patients | The primary study end point will be hematologic engraftment. Engraftment is defined as achieving ANC larger than or equal to 500 ul/mm3 of donor origin for three consecutive measurements on different days by day +42. | day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival by clinical and pathological disease assessment |  | at disease progression or death | 
| incidence of recurrent disease in patients post UCB transplant |  | post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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previously treated myelodysplastic syndromes, recurrent adult acute lymphoblastic leukemia, chronic phase chronic myelogenous leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, untreated childhood acute lymphoblastic leukemia, adult acute myeloid leukemia in remission, adult acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, recurrent childhood acute lymphoblastic leukemia, recurrent childhood lymphoblastic lymphoma, childhood acute lymphoblastic leukemia in remission, adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), childhood acute erythroleukemia (M6), childhood acute megakaryocytic leukemia (M7), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult Burkitt lymphoma, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes, graft versus host disease, adult acute minimally differentiated myeloid leukemia (M0), childhood acute minimally differentiated myeloid leukemia (M0), recurrent childhood small noncleaved cell lymphoma, recurrent childhood large cell lymphoma, recurrent mantle cell lymphoma, childhood chronic myelogenous leukemia, atypical chronic myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12), childhood myelodysplastic syndromes