Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts in Preventing GVHD in Children

Study Overview
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Brief Summary
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This phase II trial studies how well T cell depleted donor peripheral blood stem cell transplant works in preventing graft-versus-host disease in younger patients with high risk hematologic malignancies. Giving chemotherapy and total-body irradiation before a donor 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. 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. Removing a subset of the T cells from the donor cells before transplant may stop this from happening.

Detailed Description
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OUTLINE: CONDITIONING REGIMEN: Patients undergo total body irradiation (TBI) twice daily (BID) on days -10 to -7, receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or orally (PO) every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11. After completion of study treatment, patients are followed up for up to 5 years.

Official Title
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A Phase II Study of Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD in Children

Conditions
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Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Biphenotypic Leukemia, Acute Leukemia of Ambiguous Lineage, Acute Undifferentiated Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Myelodysplastic Syndrome With Excess Blasts-1, Myelodysplastic Syndrome With Excess Blasts-2, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Refractory Adult Acute Lymphoblastic Leukemia, Refractory Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Procedure: Peripheral Blood Stem Cell Transplantation
* Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation
* Drug: Tacrolimus
* Drug: Thiotepa
* Radiation: Total-Body Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses: Acute lymphocytic leukemia in first or subsequent remission Acute myeloid leukemia in first or subsequent remission Acute lymphocytic leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 Acute myeloid leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 Refractory anemia with excess blasts (RAEB-1 and RAEB-2) Chronic myelogenous leukemia with a history of accelerated phase or blast crisis Other acute leukemia (including but not limited to 'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia) Patient with a human leukocyte antigen (HLA)-identical (HLA-A, B, C, and ribonucleic acid [RNA] binding motif protein 45 [DRB1] molecularly matched) unrelated donor or related donor capable of donating PBSC DONOR: HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution typing) capable and willing to donate PBSC DONOR: HLA-matched related donors >= 18 years and capable and willing to donate PBSC Exclusion Criteria: Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation Patients on other experimental protocols for prevention of acute GVHD Patients who weigh >= 70 kg must be discussed with the principal investigator prior to enrolling on the protocol Patients who are human immunodeficiency virus positive (HIV+) Patients with uncontrolled infections for whom myeloablative hematopoietic stem cell transplant (HCT) is considered contraindicated by the consulting infectious disease physician (upper respiratory tract viral infection does not constitute an uncontrolled infection in this context) Creatinine > 1.5 mg/dl Cardiac ejection fraction < 45% Patients who can perform pulmonary function tests will be excluded if they have a diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) of < 60% predicted; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air Patients who have liver function test (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); if the GI physician considers that HCT on protocol 2660 is contraindicated for that patient the patient will be excluded from the protocol; patients with Gilbert's syndrome and no other known liver function abnormality and patients with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol Patients with a life expectancy < 3 months from co-existing disease other than the leukemia or RAEB Patients who are pregnant or breast-feeding Fertile patients of child bearing age unwilling to use contraception during and for 12 months post-transplant Patients with a significant other medical conditions that would make them unsuitable for transplant Patients with a known hypersensitivity to tacrolimus DONOR: Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection DONOR: Donors who fail eligibility requirements for donation of cells or tissue per section 21 Code of Federal Regulations (CFR) 1271 for donation of a HCT/product (P) will be excluded unless use of the cells complies with 21 CFR 1271.65(b)(iii) (urgent medical need) or with 21 CFR 1271.65(b)(i) (allogeneic use in a first-degree or second-degree relative) DONOR: Unrelated donors donating outside of the United States of America (USA) or Germany

Ages Eligible for Study
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Maximum Age: 21 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 (CD45RA+ T cell depleted PBSCT)<br>CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo CD45RA+ T cell-depleted allogeneic peripheral blood stem cell transplant<br>* Other names: HSCT;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo CD45RA+ T cell-depleted allogeneic peripheral blood stem cell transplant<br>* Other names: Peripheral Stem Cell Transplantation;Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation<br>* Undergo CD45RA+ T cell-depleted allogeneic peripheral blood stem cell transplant<br>Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft failure defined as failure to reach an absolute neutrophil count (ANC) of > 500/ul for 3 consecutive days or irreversible decrease in ANC to < 100 after an established donor graft | A true probability of graft failure of 10% will be considered excessive. If there is sufficient evidence to suggest that the true probability of graft failure exceeds 10%, the study will be stopped. | Up to 5 years | 
| Time to ANC of > 1,000/uL |  | Up to 5 years | 
| Time to ANC of > 500/uL |  | Up to 5 years | 
| Time to discontinuation of systemic immunosuppression |  | Time from transplant to the final discontinuation of all systemic immune suppression assessed up to 5 years | 
| Time to platelet count > 20,000/uL for 3 days without transfusion |  | Up to 5 years | 
| Time to platelet count > 50,000/uL for 3 days without transfusion |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of chronic GHVD meeting NIH criteria and requiring systemic pharmacological immunosuppression |  | Up to 5 years | 
| Presence of acute GVHD grade III-IV |  | Up to day 100 | 
| Presence of acute GVHD grades II-IV |  | Up to day 100 | 
| Presence of steroid refractory acute GVHD |  | Up to day 100 | 
| Relapse defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology |  | Up to 5 years | 
| Transplant related mortality defined as mortality in any patient for whom there has not been a diagnosis of relapse |  | Up to 5 years | 
| Use of additional immune suppressive agents other than first line therapy |  | Up to 5 years |