Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

Study Overview
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Brief Summary
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This phase II trial is for patients with acute lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome or chronic myeloid leukemia who have been referred for a peripheral blood stem cell transplantation to treat their cancer. In these transplants, chemotherapy and total-body radiotherapy ('conditioning') are used to kill residual leukemia cells and the patient's normal blood cells, especially immune cells that could reject the donor cells. Following the chemo/radiotherapy, blood stem cells from the donor are infused. These stem cells will grow and eventually replace the patient's original blood system, including red cells that carry oxygen to our tissues, platelets that stop bleeding from damaged vessels, and multiple types of immune-system white blood cells that fight infections. Mature donor immune cells, especially a type of immune cell called T lymphocytes (or T cells) are transferred along with these blood-forming stem cells. T cells are a major part of the curative power of transplantation because they can attack leukemia cells that have survived the chemo/radiation therapy and also help to fight infections after transplantation. However, donor T cells can also attack a patient's healthy tissues in an often-dangerous condition known as Graft-Versus-Host-Disease (GVHD). Drugs that suppress immune cells are used to decrease the severity of GVHD; however, they are incompletely effective and prolonged immunosuppression used to prevent and treat GVHD significantly increases the risk of serious infections. Removing all donor T cells from the transplant graft can prevent GVHD, but doing so also profoundly delays infection-fighting immune reconstitution and eliminates the possibility that donor immune cells will kill residual leukemia cells. Work in animal models found that depleting a type of T cell, called naïve T cells or T cells that have never responded to an infection, can diminish GVHD while at least in part preserving some of the benefits of donor T cells including resistance to infection and the ability to kill leukemia cells. This clinical trial studies how well the selective removal of naïve T cells works in preventing GVHD after peripheral blood stem cell transplants. This study will include patients conditioned with high or medium intensity chemo/radiotherapy who can receive donor grafts from related or unrelated donors.

Detailed Description
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OUTLINE: Patients are assigned to 1 of 4 treatment arms. CONDITIONING: ARMS A AND C (high-intensity myeloablative conditioning): Patients undergo total body irradiation twice daily (BID) on days -10 to -7. Patients also receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. ARMS B AND D (lower-intensity myeloablative conditioning): Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation once daily (QD) on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with granulocyte colony-stimulating factor (GCSF)-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: ARMS A AND C: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or orally (PO) (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. ARMS B AND D: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on days -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the principal investigator. After completion of study treatment, patients are followed up at 80-100 days, 360 days, and then yearly for up to 5 years.

Official Title
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A Phase II Study Evaluating Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors for Prevention of GVHD

Conditions
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Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Biphenotypic Leukemia, Acute Leukemia of Ambiguous Lineage, Acute Undifferentiated Leukemia, Allogeneic Hematopoietic Stem Cell Transplant Recipient, Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Blastic Plasmacytoid Dendritic Cell Neoplasm, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Donor, Lymphoblastic Lymphoma, Myelodysplastic Syndrome With Excess Blasts, Myelodysplastic Syndrome With Excess Blasts-1, Myelodysplastic Syndrome With Excess Blasts-2, Recurrent Acute Lymphoblastic Leukemia, Recurrent Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Refractory Acute Lymphoblastic Leukemia, Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia in Remission

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Drug: Mycophenolate Mofetil
* Procedure: Peripheral Blood Stem Cell Transplantation
* Procedure: Peripheral Blood 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 (Arms A or C only) Acute myeloid leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 (Arms A or C only) Refractory anemia with excess blasts (RAEB-1 and RAEB-2) (if the patient has received previous induction chemotherapy within 60 days) Chronic myelogenous leukemia with a history of accelerated phase or blast crisis (if the patient has received at least one course of induction chemotherapy) Other acute leukemia or related neoplasm (including but not limited to 'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma) Patients 0-49 years old will be enrolled in Arm A or C (high-intensity) Patients 50-60 years old will be enrolled in Arm B or D (lower intensity); patients eligible for Arms B or D also include those who have received previous allogeneic HCT, or who have co-morbid conditions rendering them unsuitable for high-dose conditioning, determined in consultation with the principal investigator Patient with a HLA-matched (HLA-A, B, C, and DR beta 1 [DRB1] molecularly matched) unrelated donor or related donor capable of donating PBSC DONOR INCLUSION: HLA-matched related donors >= 18 years and capable and willing to donate PBSC (Arms A and B) HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution typing) capable and willing to donate PBSC (Arms C and D) 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 Patient weight >= 100 kg; patients >= 70 kg with MUDs must be discussed with the principal investigator Patients who are human immunodeficiency virus positive (HIV+) Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician (upper respiratory tract viral infection does not constitute an uncontrolled infection in this context) Patients with organ dysfunction ARM A OR C EXCLUSION: Creatinine > 1.5 mg/dl at the present time; patients with a known history of creatinine > 1.5 mg/dl must have a current estimated creatinine clearance of > 40 ml/min Cardiac ejection fraction < 45% Diffusing capacity of the lung for carbon monoxide (DLCO) corrected < 60%; 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 Liver function abnormality; patients who have liver function tests (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 the high-intensity arms of protocol is contraindicated for that patient the patient may be considered for treatment on the lower intensity arm of the protocol or 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 high-intensity arms of the protocol ARM B OR D EXCLUSION: Creatinine > 2.0 mg/dl at the present time; patients with a known history of creatinine > 1.5 mg/dl must have a current estimated creatinine clearance > 40 ml/min Cardiac ejection fraction < 35% DLCO corrected < 50%; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the O2 saturation is < 92% on room air; patients with a DLCO 50-60% must also have a partial pressure of oxygen (pO2) of > 80 mmHg Liver function abnormality; patients who have LFTs >= twice the upper limit of normal should be evaluated by a GI physician unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded Patients will be excluded from Arms A and C if they have received a previous myeloablative transplant; patients who have received a prior HCT at least 6 months prior may be considered for inclusion on Arms B or D after discussion with the principal investigator (PI) 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, methotrexate (Arm A or C) or MMF (Arm B or D) DONOR EXCLUSION: 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 Donors who fail eligibility requirements for donation of cells or tissue for donation of a Human Cell and Tissue Products (HCT/P) will be excluded unless use of the cells complies urgent medical need or allogeneic use in a first-degree or second-degree relative Unrelated donors donating outside of the United States of America (USA)

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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Accepts Healthy Volunteers

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 |
| --- | --- |
| Experimental: Arm A (MRD)<br>HIGH-INTENSITY MYELOABLATIVE CONDITIONING: Patients undergo total body irradiation BID on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with GCSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSCT<br>* Other names: HSCT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;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 PBSCT with GCSF-mobilized CD34-enriched PBSC<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSCT with CD45RA-depleted cells<br>* Other names: Peripheral Stem Cell Transplantation;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;|
| Experimental: Arm B (MRD)<br>LOWER-INTENSITY MYELOABLATIVE CONDITIONING: Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation QD on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with GCSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on day -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the Principal Investigator. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSCT<br>* Other names: HSCT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given IV and PO<br>* Other names: MMF;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSCT with GCSF-mobilized CD34-enriched PBSC<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSCT with CD45RA-depleted cells<br>* Other names: Peripheral Stem Cell Transplantation;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;|
| Experimental: Arm C (MUD)<br>HIGH-INTENSITY MYELOABLATIVE CONDITIONING: Patients undergo total body irradiation BID on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with G-CSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSCT<br>* Other names: HSCT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;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 PBSCT with GCSF-mobilized CD34-enriched PBSC<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSCT with CD45RA-depleted cells<br>* Other names: Peripheral Stem Cell Transplantation;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;|
| Experimental: Arm D (MUD)<br>LOWER-INTENSITY MYELOABLATIVE CONDITIONING: Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation QD on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with G-CSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on day -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the Principal Investigator. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSCT<br>* Other names: HSCT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given IV and PO<br>* Other names: MMF;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSCT with GCSF-mobilized CD34-enriched PBSC<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSCT with CD45RA-depleted cells<br>* Other names: Peripheral Stem Cell Transplantation;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of chronic graft-versus-host disease (GHVD), defined operationally as the occurrence of compatible symptoms meeting National Institutes of Health criteria and requiring systemic pharmacological immunosuppression | Match related donor (MRD)-high intensity (Arm A), MRD-lower intensity (Arm B), match unrelated donor (MUD)-high intensity (Arm C) and MUD-lower intensity (Arm D) cohorts will be analyzed separately. | Up to 5 years | 
| Use of additional immune suppressive agents other than first line therapy (prednisone and tacrolimus/cyclosporine) |  | Up to 5 years | 
| Time to completion of prednisone |  | Up to 5 years | 
| Time to completion of all immunosuppression |  | Up to 5 years | 
| Requirement of immunosuppression after transplant |  | At 2 years after transplant | 
| Presence of acute graft-versus-host disease (GVHD) grades II-IV | Defined operationally as the occurrence of compatible symptoms or signs in the skin, gastrointestinal tract, or liver. | Up to day 100 | 
| Requirement for secondary systemic therapy for acute graft-versus-host disease (GVHD) management |  | Up to day 100 | 
| Graft failure | Defined operationally as failure to reach an absolute neutrophil count (ANC) of > 500/ul for 3 consecutive days by day 28 or irreversible decrease in ANC to < 100 after an established donor graft. | Up to day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to absolute neutrophil count (ANC) of > 500/uL on the first of three consecutive days |  | Up to 5 years | 
| Time to absolute neutrophil count (ANC) of > 1,000/uL on the first of three consecutive test results |  | 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 | 
| Chimerism analysis | Will be analyzed from peripheral blood or marrow. | Up to 360 days | 
| 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 |