Post T-plant Infusion of Allogeneic Cytokine Induced Killer (CIK) Cells as Consolidative Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders

Study Overview
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Brief Summary
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Allogeneic stem cell transplantation (transplant of blood cells from another individual) is a treatment option for patients with myelodysplasia or myeloproliferative Disorders. During the course of this study, it will be evaluated whether a particular type of blood cell, called a cytokine-induced killer (CIK) cell, may add benefit to allogeneic stem cell transplantation. CIK cells are present in small quantities in the bloodstream but their numbers can be expanded after a brief period of nurturing in a laboratory.

Detailed Description
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Primary Objectives: To determine the rate of conversion to FDC following infusion of allogeneic CIK cells among patients with MDS, therapy-related myeloid neoplasms, or MPD who receive non myeloablative preparative regimen of TLI / ATG followed by allogeneic HCT and consolidation with allogeneic CIK cells. Secondary Objectives: To determine the 2 year overall survival (OS) and event free survival (EFS) To determine the incidence of acute GVHD following infusion of allogeneic CIK cells To assess the pre-transplant expression of NKG2D ligands in patients' bone marrow aspirates.

Official Title
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Post Transplant Infusion of Allogeneic Cytokine Induced Killer Cells as Consolidative Therapy After Non-Myeloablative Allogeneic Transplantation in Patients With Myelodysplasia or Myeloproliferative Disorders

Conditions
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Neural Tube Defects, Anemia, Leukemia, Myeloid, Bone Marrow Transplant Failure, Myelodysplastic Syndromes (MDS), Myeloproliferative Disorders

Intervention / Treatment
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* Drug: CIK cells
* Drug: Cyclosporine
* Drug: Mycophenolate Mofetil
* Drug: Thymoglobulin
* Radiation: Total Lymphoid Irradiation (TLI)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA, RECIPIENT WITH MYELODYSPLASTIC SYNDROME (MDS) Diagnosis of MDS classifiable by the World Health Organization (WHO) on the basis of: Refractory anemia Refractory anemia with excess blasts-1 Refractory anemia with excess blasts-2 Refractory cytopenia with multi-lineage dysplasia Refractory cytopenia with multi-lineage dysplasia and ringed sideroblasts Chronic myelomonocytic leukemia (CMML) MDS transformed to acute leukemia MDS-unclassified Participants with advanced MDS must have < 10% marrow blasts prior to receiving conditioning with TLI/ATG, documented by marrow examination within 1 month prior. Participants with evolution to acute leukemia (AML) must be in a morphologic leukemia free-state (MLFS) with blasts < 5% INCLUSION CRITERIA, RECIPIENT WITH MYELOPROLIFERATIVE DISORDER (MPD) Diagnosis of MPD on the basis of: Idiopathic myelofibrosis Polycythemia vera Essential thrombocythemia Chronic myelomonocytic leukemia (CML) CML, Philadelphia chromosome-negative Chronic neutrophilic leukemia Chronic eosinophilic leukemia Hypereosinophilic cyndrome Systemic mastocytosis < 10% marrow blasts prior to receiving conditioning with TLI/ATG, documented by marrow examination within 1 month prior. Participants with evolution to acute leukemia (AML) must be in a morphologic leukemia free-state (MLFS) with blasts < 5%. Presence of residual dysplastic features following cytoreductive therapy is acceptable. INCLUSION CRITERIA, RECIPIENT WITH THERAPY-RELATED MYELOID NEOPLASM (t MDS) < 10% marrow blasts prior to receiving conditioning with TLI/ATG, documented by marrow examination within 1 month prior. Morphologic leukemia free-state with blasts < 5 %. Age > 50 years, or < 50 years of age but at high-risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy Availability of a fully HLA-matched or single antigen/allele mismatched sibling or unrelated donor Prior malignancy diagnosed > 5 years ago without evidence of disease, or < 5 years ago with life expectancy of > 5 years are eligible (prior malignancy is not a requirement) INCLUSION CRITERIA, DONOR Donors must be HLA-matched or one allele mismatched. Donor age < 75 (EXCEPTION by Principal Investigator discretion) Must consent to PBSC mobilization with G-CSF; apheresis; and collection and donation of plasma Donor must consent to placement of a central venous catheter in the event that peripheral venous access is limited. EXCLUSION CRITERIA, RECIPIENT Any of the following: Uncontrolled CNS involvement with disease Pregnant Cardiac function: ejection fraction (EF) < 35% or uncontrolled cardiac failure Diffusing capacity of the lungs for carbon monoxide (DLCO) < 40% predicted Bilirubin > 3 mg/dL Aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN) Alanine aminotransferase (ALT) > 3x ULN Estimated creatinine clearance < 50 mL/min Karnofsky performance score (KPS) < 70% Documented fungal disease that is progressive despite treatment HIV-positive EXCLUSION CRITERIA, DONOR Any of the following: Identical twin to recipient Pregnant or lactating Prior malignancy within the preceding 5 years (EXCEPTION: non-melanoma skin cancers) HIV seropositivity

Ages Eligible for Study
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Minimum Age: 50 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: Allogeneic Cytokine-induced Killer Cells (CIK)<br>Target dose of ≥ 5 x 10e6 CD34+ cells/kg of recipient body weight plus an additional 2 x10e9 mononuclear cells. | Drug: CIK cells<br>* Standard of care<br>* Other names: Cytokine-induced Killer Cells;Drug: Cyclosporine<br>* 5 mg/kg, po<br>* Other names: cyclosporin A;Drug: Mycophenolate Mofetil<br>* 15 mg/kg, oral<br>* Other names: CellCept;Drug: Thymoglobulin<br>* 7.5 mg/kg, IV<br>* Other names: ATG;Radiation: Total Lymphoid Irradiation (TLI)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Donor Chimerism (FDC) | Proportion of patients achieving full donor T-cell chimerism (FDC) by on or before Day 90 post non-myeloablative allogeneic transplant with allogeneic cytokine-induced killer (CIK) cells will be determined. FDC is defined as the attainment of >95% donor type CD3+ cells. The outcome will be reported as number of participants who achieved full donor chimerism, a number without dispersion. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) is an expression of the number of participants that remain alive 2 years after cytokine-induced killer (CIK) infusion. The outcome will be reported as the number of participants alive 2 years after CIK infusion, a number without dispersion. | 2 years | 
| Event-free Survival (EFS) Rate | Event-free Survival (EFS) rate will be assessed on all enrolled participants and is defined as the duration of time after cytokine-induced killer (CIK) cell infusion that the participants remain alive with experiencing relapse, Grade 3 to 4 acute graft vs host disease (aGVHD), or death. The outcome will be reported as the number of participants, stratified by receipt of CIK cells, that did not experience a specified event, a number without dispersion. | 2 years | 
| Number of Participants That Experience Grade 2 to 4 aGvHD Within 100 Days and 1 Year | Acute graft vs host disease (aGvHD) Grade 2 to 4 was staged & graded using modified Keystone criteria, as below. The outcome is reported as the number of participants that experience Grade 2 to 4 aGvHD within 100 days and 1 year. Stage 1: Skin: rash < 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea 500 to 1000 mL/day or persistent nausea with positive biopsy for GvHD Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea 1000 to 1500 mL/day. Stage 3: Skin: rash > 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea > 1500 mL/day. Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin > 15 mg/dL. Gut: severe abdominal pain with or without ileus Grade of aGvHD was determined as follows. Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut Grade 4: Stage 4 Skin + or Stage 2 | 1 year | 
| Pre-transplant Expression of Natural-killer Group 2, Member D (NKG2D) Ligands | Pre-transplant expression of natural-killer group 2, member D (NKG2D) ligands MIC A, MIC B, and the UL16 binding proteins (ULBPs) will be assessed in participants' bone marrow aspirates. The outcomes is expressed as the number of participants whose expression level for each ligand was elevated compared to background, represented by the known levels for individual without cancer. | Pre-transplant |