CD34+ Enriched Transplants to Treat Myelodysplastic Syndrome

Study Overview
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Brief Summary
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This study will evaluate whether processing blood stem cell transplants using an investigational device (the CliniMACS system) results in fewer complications for patients who undergo transplant to treat a blood malignancy (cancer) or blood disorder. The CliniMACS system will be used to remove immune T-cells from the transplant donor's blood. Immune T-cells contribute to graft versus host disease (GVHD) - a serious complication that can happen after transplant. GVHD occurs when a patient's immune system attacks the donor's cells. The study aims to reduce the number of the donor immune T-cells thereby preventing or reducing the severity of GVHD.

Official Title
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A Phase II Trial of CD34+ Enriched Transplants From HLA-Compatible Related or Unrelated Donors for Treatment of Patients With Myelodysplastic Syndrome

Conditions
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Myelodysplastic Syndromes, Graft Vs Host Disease, Graft-versus-host-disease

Intervention / Treatment
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* Drug: Busulfan
* Drug: Melphalan
* Drug: Fludarabine
* Device: CliniMACS CD34+ enriched, T-cell depleted peripheral blood stem cell (PBSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myelodysplastic syndrome (MDS): Refractory anemia/refractory anemia with ring sideroblasts/refractory cytopenia with multilineage anemia (RA/RARS/RCMA) with high-risk cytogenetic features or transfusion dependence, as well as Refractory Anemia with Excess Blasts Type 1 and 2 (RAEB-1 and RAEB-2) Karnofsky (adult) Performance Status of at least 70% Adequate organ function measured by: Cardiac: asymptomatic or if symptomatic then left ventricular ejection fraction (LVEF) at rest must be 50% and must improve with exercise. Hepatic: < 3x upper limit of normal (ULN) aspartate aminotransferase (AST) and: 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused by the disease in which the patient is receiving a transplant [e.g., acute myeloid leukemia (AML) Chloroma obstructing the biliary tree]. Patients with higher bilirubin levels due to causes other than active liver disease is also eligible with Pl approval e.g., patients with paroxysmal nocturnal hemoglobinuria (PNH), Gilbert's disease or other hemolytic disorders. Renal: serum creatinine: <1.2 mg/dL (normal range 0.7-1.3) or if serum creatinine is outside the normal range, then creatinine clearance (CrCl) > 5940 mL/min (measured or calculated/estimated). Pulmonary: asymptomatic or if symptomatic, diffusion capacity of lung for carbon monoxide (DLCO) 50% of predicted (corrected for hemoglobin). Willing to participate and must sign an informed consent form Exclusion Criteria: Pregnant or breast-feeding Active viral, bacterial or fungal infection Patient seropositive for human immunodeficiency virus (HIV)-I /II; human T-lymphotropic virus (HTLV)-I /II Presence of leukemia in the central nervous system (CNS)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: CD34+ Peripheral Blood Progenitor Cell (PBSC) Transplant with Busulfan/Melphalan/Fludarabine Regimen<br>Cytoreduction therapy: 0.8 mg/kg q6h x 12 doses busulfan via IV injection 70 mg/m^2/day x 2 days melphalan via IV infusion over 30 minutes 25 mg/m^2/day x 5 days fludarabine vis IV infusion over 30 minutes CD34+ selected, T-cell depleted, allogeneic PBSC transplant using CliniMACS system to select CD34+ cells | Drug: Busulfan<br>* 0.8 mg/kg q6h x 12 doses via IV injection on Days -9, -8, and -7 prior to transplant<br>* Other names: Busulfex;Drug: Melphalan<br>* 70 mg/m^2/day x 2 days via IV infusion over 30 minutes on Days -6 and -5 prior to transplant<br>* Other names: Alkeran;Drug: Fludarabine<br>* 25 mg/m^2/days x 5 days via IV infusion over 30 minutes on Days -6, -5, -4, -3, and -2 prior to transplant<br>* Other names: Fludara;Device: CliniMACS CD34+ enriched, T-cell depleted peripheral blood stem cell (PBSC)<br>* CliniMACS system will be used to derive CD34+ enriched, T-cell depleted (T-cells limited to 1.0 x 10^5 CD3+ cells/kg) PBSC for transplant, which will occur on Day 0. PBSC (5 x 10^6 CD34+ cells/kg) are suspended in a volume of approximately 20-50 mL and delivered via IV infusion over 15 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in incidence of graft vs. host disease (GVHD) | Incidence of acute and chronic GVHD | Weekly until 3 months, monthly until 6 months, 12 months, 24 months | 
| Change in severity of acute graft vs. host disease (GVHD) | Severity of acute GvHD as graded using the International Bone Marrow Transplant Registry Severity Index, which includes assessment of skin, liver, and gut, grading each's severity from 0 to 4 (higher numbers reflecting the more severe disease). The overall assessment is based on the involvement and severity of each of the areas. A = Stage 1 skin involvement, no liver or gut involvement; B = Stage 2 skin involvement, Stage 1 to 2 gut or liver involvement; C = Stage 3 skin, liver or gut involvement; D = Stage 4 skin, liver, or gut involvement. | Weekly until 3 months, monthly until 6 months, 12 months, 24 months | 
| Change in severity of chronic graft vs. host disease (GVHD) | Severity of chronic GvHD as graded using the NIH scoring system, which includes assessment of skin, mouth, eyes, GI tract, liver, lungs, joint/fascia, and genital tract and grades the severity of affected organs from 0 to 3 (higher scores reflecting the more severe disease). The overall assessment is based on the number of organs/sites with clinically significant functional impairment (i.e., score 2-3). No GVHD = no organs/sites with significant functional impairment; Mild GVHD = involves two or fewer organs/sites with significant functional impairment; Moderate GVHD = involves three or more organs/sites with significant functional impairment -OR- involves one or zero organs/sites with NO significant functional impairment; Severe GVHD = Major disability caused by chronic GVHD. | Weekly until 3 months, monthly until 6 months, 12 months, 24 months | 
| Change in incidence of relapse-free mortality (transplant-related mortality) | Incidence of relapse-free mortality, defined as mortality related to the transplant rather than the disease | 6 months, 12 months, 24 months | 
| Change in overall survival | Incidence of overall survival, defined as time from transplant to death or last follow-up. | 6 months, 12 months, 24 months | 
| Change in disease-free survival | Incidence of disease-free survival, defined as the minimum time interval of relapse/recurrence, to death or to the last follow-up, from the time of transplant. | 6 months, 12 months, 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients receiving optimal vs. suboptimal CD34+/CD3+ PBSC doses | Proportion of patients receiving optimal CD34+ (>5 x 10^6/kg) and CD3+ (< 5 x10^4/kg) cell doses versus the proportion recurring suboptimal doses (<3 x 10^6/kg) CD34+ cells; and the proportion of patients receiving CD3+ T-cell doses (>5 x 10^4/kg) | Day 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stem cell transplant, allogeneic transplant