T-cell Depleted Alternative Donor Transplantation

A Phase II Study Using the CliniMACS® Device for CD34+ Cell Selection and T Cell Depletion for Graft-versus-Host Disease Prophylaxis in Alternative Donor Stem Cell Transplant Recipients

The primary purpose is to determine the ability of CD34+ selection and T cell depletion using the CliniMACS® device to prevent severe acute graft-versus-host disease (GVHD) in patients receiving a stem cell transplant from an alternative (unrelated and mismatched related) donor. The secondary objectives include evaluation of engraftment, immune recovery, and post-transplant infections.

Patients requiring stem cell transplants for either malignant (cancerous) or non-malignant disease will be included in the study. The recipients will be grouped into one of two groups based on whether the donor is mismatched related (Cohort A) or unrelated (Cohort B). The patient will receive a conditioning regimen including chemotherapy drugs and/or total body irradiation based on the disease for which the transplant is performed.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Chronic Myeloid Leukemia; Myelodysplastic Syndrome; Immune Deficiency; Lymphomas; Bone Marrow Failure; Osteopetrosis; Hemoglobinopathy
• Intervention / Treatment: Device: CliniMACS® (T cell depletion)

Detailed Description

A major issue in alternative donor (mismatched related and unrelated donor transplantation is the development of graft-versus-host disease (GVHD). Several clinical trials have shown that the use of T-cell depleted peripheral blood stem cells (PBSC) reduces GVHD in alternative donor transplants. The purpose of this study is to determine the ability of CD34 positive selection and T cell depletion using the CliniMACS® Device as the only GVHD prophylaxis to prevent severe acute GVHD in recipients of an alternative donor PBSC transplant. Mismatched related donors will match at least 3 of 6 Human leukocyte antigens(HLA)(haplocompatible) and unrelated donors will match at least 6 out of 8 HLA antigens with the transplant recipient. The conditioning therapy including chemotherapy, anti-thymocyte globulin (ATG), +/- total body irradiation (TBI) will be based on the patient's diagnosis. The transplant recipient will be followed for 5 years after transplant for GVHD, engraftment, post-transplant infections, disease relapse, and overall survival. In addition, this study will serve as a platform for a companion study of therapy to accelerate immune recovery after transplant.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Children's Hospital, Carolinas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age < 30 years
• Patient must have a malignant or non-malignant disease that can benefit from alternative stem cell transplantation. Examples include acute and chronic leukemias, myelodysplastic syndrome, lymphoma, severe acquired and congenital cytopenias, white and red blood cell abnormalities, and immunodeficiencies.
• Patients with acute lymphoblastic leukemia must be in morphological remission (< 5% blasts) at the time of transplant. Patients with acute non-lymphocytic leukemia will preferably be in morphologic remission but may be enrolled when aplastic after chemotherapy or with < 20% blasts. Patients with lymphoma must be in complete or close to complete remission (if residual adenopathy, PET scan must be negative or only have slight uptake, eg. SUV < 2).
• Patients must lack a healthy HLA-identical related donor of at least one year of age.

• Patient must have a mismatched related or an unrelated donor who is:

  1. Able to receive G-CSF and undergo apheresis either through placement of catheters in antecubital veins or a temporary central venous catheter,
  2. Healthy,
  3. Willing,
  4. For recipients of an unrelated donor transplant, recipient eligibility will be restricted as follows if in the judgment of the recipients' transplant physician, the recipient cannot receive a transplant with combined positive and negative fractions as described in Section 6.1.3.2 or an unmanipulated PBSC product.
  5. Meets eligibility criteria for donors.
• If only one mismatched related relative is available, an acceptable unrelated donor must be identified as a backup.
• Patient or authorized guardian must sign informed consent for this study.

Exclusion Criteria:

• Patient with an anticipated life expectancy of < 1 month
• Active infectious hepatitis or CMV infection
• HIV or HTLV-I/II infection
• Serious infection (bacterial, fungal, viral) within the last 4 weeks
• Cardiac ejection fraction < 45%; can be lower if patient is not in clinical cardiac failure and a reduced intensity conditioning regimen is used.
• Creatinine clearance <60 ml/min/1.72 m2; can be lower if a reduced intensity conditioning regimen is used.
• Pulmonary diffusion capacity (adjusted for Hgb), FEV1, or FVC <60% of predicted or O2 sat < 94% if unable to perform PFTs; can be lower if a reduced intensity conditioning regimen is used.
• Serum ALT > 3 x upper limit of normal (can be up to 5 x upper limit of normal if a reduced intensity conditioning regimen is used) or bilirubin > 2. The bilirubin criteria for sickle cell disease patients is direct bilirubin >2x upper limit of normal.
• Performance score (Lansky/Karnofsky) < 50
• Any condition that compromises compliance with the procedures of this protocol, as judged by the principal investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CliniMACS® (T cell depletion); Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device.

Device: CliniMACS® (T cell depletion); Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.; Other Names: CliniMACS device; T-cell depletion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Severe Graft vs. Host Disease (GVHD).	Severe GVHD defined as grade III/IV GVHD.	Within 30 days after stem cell transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival		2 years
Number of Participants With Engraftment and Time to Engraftment	Engraftment was measured as time to absolute neutrophil count >500	Within 28 days after stem cell transplant
Number of Participants With Post-transplant Infections		1 year
Number of Participants With EBV-related Post Transplant Lymphoproliferative Disorder (PTLD)		5 years
Number of Participants With Post-transplant Leukemia Relapse		5 years
Number of Participants With Transplant-related Mortality	Transplant-related mortality includes death due to regimen-related toxicity or GVHD (all causes other than disease relapse). Those who died due to disease relapse are not included in the analyzed population for that time point.	2 year
Number of Participants With Transplant-related Toxicities		1 year
Device Performance: Dose of CD34+ Cells and CD3+ Cells Given	For mismatched related donors, the target cell dose after processing is >/= 20 x 10^6 CD34+ cells/kg patient body weight, but >/= 8 x 10^6 is acceptable. For unrelated donors the target cell dose after processing is >/= 10 x 10^6 CD34+ cells/kg patient body weight, but >/= 4 x 10^6 is acceptable. The target T cell dose is </= 3 x 10^4 CD3+ cells/ kg.	Length of the trial (5 years)

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences

Publications and helpful links

General Publications

• Gilman AL, Eckrich MJ, Epstein S, Barnhart C, Cannon M, Fukes T, Hyland M, Shah K, Grochowski D, Champion E, Ivanova A. Alternative donor hematopoietic stem cell transplantation for sickle cell disease. Blood Adv. 2017 Jun 28;1(16):1215-1223. doi: 10.1182/bloodadvances.2017005462. eCollection 2017 Jul 11.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: August 28, 2009
• First Submitted That Met QC Criteria: August 28, 2009
• First Posted (Estimate): August 31, 2009

Study Record Updates

• Last Update Posted (Actual): April 22, 2022
• Last Update Submitted That Met QC Criteria: April 20, 2022
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: T cell depleted; Matched unrelated donors; Haplocompatible donors
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Myeloproliferative Disorders; Bone Diseases; Leukemia, Lymphoid; Bone Diseases, Developmental; Osteochondrodysplasias; Osteosclerosis; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Immunologic Deficiency Syndromes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hemoglobinopathies; Bone Marrow Failure Disorders; Pancytopenia; Osteopetrosis
• Other Study ID Numbers: LCH BMT 09-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO