T-Cell Depletion, Donor Hematopoietic Stem Cell Transplant (HSCT), and T-Cell Infusions in Treating Patients With Hematologic Cancer or Other Diseases

Phase II Feasibility Study of T-Cell Depletion in Allogeneic Unrelated Bone Marrow Transplantation (MUD ALLO BMT) Followed by Delayed T-Cell Infusions

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When 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 the T cells from the donor cells before transplant may stop this from happening. Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help destroy any remaining cancer cells (graft-versus-tumor effect).

PURPOSE: This phase II trial is studying T-cell depletion in donor stem cell transplant followed by delayed T cell infusions in treating patients with hematologic cancer or other disease.

Study Overview

• Status: Terminated
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Precancerous/Nonmalignant Condition; Secondary Myelofibrosis; Multiple Myeloma and Malignant Plasma Cell Neoplasms
• Intervention / Treatment: Procedure: peripheral blood lymphocyte therapy; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: total-body irradiation (TBI)

Detailed Description

OBJECTIVES:

Primary

• Determine if T-cell depletion of a peripheral blood progenitor cell (PBPC) graft followed by delayed add-backs of defined doses of donor lymphocytes decreases the rate of graft-versus-host disease and its complications in matched unrelated donor (MUD) allogeneic peripheral blood progenitor cell (PBPC) transplantation in patients with hematologic cancers or other diseases.
• Determine whether targeted T-cell dosages in the PBPC graft can be achieved in these patients by positive CD34+ selection using the Baxter Inc. Isolex 300i v. 2.5.
• Determine the effects of T-cell depletion on the rate of engraftment in these patients.
• Develop a matched unrelated donor (MUD) allogeneic transplantation regimen that will decrease overall treatment-related mortality in these patients.

OUTLINE: This is a non-randomized study.

• Myeloablative preparative regimen: Patients receive cyclophosphamide IV once daily on days -5 and -4 followed by total body irradiation twice daily on days -3, -2, and -1. Patients also receive tacrolimus on day -1 administered by continuous IV infusion over 24 hours.
• Peripheral blood progenitor cell graft transplantation: Patients receive T-cell depleted, peripheral blood progenitor cells (PBPC) by IV infusion on day 0. Beginning 1 day after completion of the PBPC infusion, patients receive filgrastim (G-CSF) subcutaneously once daily until blood counts recover.
• Post transplantation T cell add-backs: Patients receive defined doses of donor T cells by IV infusion on days 45 and 100, in the absence of active graft-versus-host disease (GVHD) requiring steroids*.

NOTE: *A T cell add-back may be given in the presence of GVHD, if the investigator considers the risk from relapse or overwhelming viral infection to outweigh the risk of exacerbating GVHD.

Patients will be followed periodically for relapse and survival.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of any of the following hematologic cancers or other diseases:

  • Acute myelogenous leukemia

    • Relapsed or refractory disease with poor-risk cytogenetics

  • Acute lymphoblastic leukemia

    • Relapsed or refractory disease with poor-risk cytogenetics

  • Chronic myelogenous leukemia

    • Persistent disease after at least 6 months of treatment with imatinib mesylate (Gleevec)

  • Myelodysplasia, meeting 1 of the following criteria:

    • French-American-British Classification of refractory anemia with excess blasts (RAEB) or RAEB with transformation
    • International Prognostic Scoring System score > 2

  • Lymphoid malignancies, including non-Hodgkin lymphoma, Hodgkin disease, chronic lymphocytic leukemia, and prolymphocytic leukemia

    • Relapsed or refractory disease after at least 1 prior therapy

  • Myelofibrosis

    • Transfusion dependent (RBC's, platelets, or both)
  • Paroxysmal nocturnal hemoglobinuria (transfusion dependent)
  • Myeloproliferative disorder
  • Eosinophilic leukemia

  • Severe aplastic anemia

    • Corrected reticulocyte count < 1%
    • Platelet count < 30,000/mm³ (untransfused)
    • Bone marrow biopsy with < 15% cellularity
  • Plasma cell leukemia
• No essential thrombocytopenia or polycythemia vera
• No matched related donor available
• Must have an 8/8 or 7/8 serologic HLA matched unrelated donor available

PATIENT CHARACTERISTICS:

• Cardiac ejection fraction ≥ 45% (if < 45%, then cardiac consult required)
• Not pregnant or nursing
• Negative pregnancy test
• FEV_1 and DLCO ≥ 45% predicted
• Creatinine < 2.0 mg/dL
• Bilirubin < 2.0 mg/dL
• HIV negative

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior allogeneic bone marrow transplantation
• No concurrent administration of steroids with T-cell add-backs

INCLUSION CRITERIA:

• Patient actual weight must not be greater than 1.5x their ideal body weight
• Cardiac ejection fraction >45%. If less than 45%, a Cardiac consult will be obtained.
• A suitably matched unrelated donor that is at least a 7 out of 8 HLA serologic match.
• Patient is not pregnant.
• FEV 1 and DLCO > 45% predicted on pulmonary function testing.
• Serum creatinine <2.0 mg/dl, serum bilirubin <2.0 mg/dl.
• Patient and donor are HIV negative.
• Diagnosis of one of the following diseases
• Acute myelogenous leukemia
• Relapsed disease,
• Refractory disease, or
• With poor-risk cytogenetics
• Acute lymphoblastic leukemia
• Relapsed disease,
• Refractory disease, or
• With poor-risk cytogenetics
• Chronic myelogenous leukemia
• Persistent disease after at least 6 months of treatment with Imatinib Mesylate (Gleevec)
• Myelodysplasia
• FAB Classification of RAEB or RAEB-T -Or-
• IPSS score >2
• Lymphoid malignancies, including non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia and prolymphocytic leukemia
• Relapsed or refractory disease after at least 1 prior therapy
• Myelofibrosis
• Transfusion dependence (RBC's, platelets, or both)
• Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Transfusion dependent
• Myeloproliferative Disorder
• Eosinophilic Leukemia
• Severe aplastic anemia (<1% corrected reticulocyte count, <30,000 untransfused platelet count, bone marrow biopsy with <15% cellularity)
• Plasma cell leukemia
• Patients with ET or PV will not be candidates unless their disease has transformed to end stage myelofibrosis or acute leukemia, for which eligibility criteria for myelofibrosis or acute leukemia would apply.
• Patient must signed written informed consent.

EXCLUSION CRITERIA:

• Inability to give informed consent
• Absence of any of the above mentioned medical conditions
• Availability of matched-related donor
• History of prior allogeneic BMT

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: T-Cell Depletion Transplant; Our protocol is designed to attempt to improve the current results of matched unrelated donor (MUD) allo bone marrow transplant (BMT) and will be a major step towards the introduction and refinement of graft engineering. Our approach will address in a rational fashion all major technical and clinical aspects of MUD allo BMT. Peripheral blood lymphocyte therapy; cyclophosphamide, tacrolimus, peripheral blood stem cell transplantation; total-body irradiation; 'allogeneic hematopoietic stem cell transplantation'

Procedure: peripheral blood lymphocyte therapy; T-cell depletion will be accomplished using CD34 selection with the Baxter Isolex 300i v. 2.5 device. The desirable T-cell dose will be >0.5 x 105 but <1.0 x 105 CD3+ cells per kg. The targeted CD34 cell dose will be >2 x 106 cells/kg.; Other Names: T-cell depletion; Procedure: allogeneic hematopoietic stem cell transplantation; Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: peripheral blood stem cell transplantation; Peripheral blood stem cell transplantation; Radiation: total-body irradiation (TBI); Treatment will be delivered using 6MV photons twice daily for 3 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-related Mortality (TRM)	The complication rate in matched unrelated donor (MUD) allogeneic bone marrow transplant (allo BMT) is known to be high. Graft failure and severe graft versus host disease (GvHD) are the most significant contributors to treatment related mortality (TRM). This treatment regimen will be considered unacceptable if the number of patients that experience TRM is 55% or greater, and effective if TRM is 33% or less.	180 days after transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Rate of Acute Graft Versus Host Disease (GVHD)		D+100 from transplant
Number of Participants With Duration of Absolute Neutropenia		D+100 from transplant
Number of Participants Able to Receive T-cell Add Backs	Patients receive defined doses of donor T cells by IV infusion on days 45 and 100, in absence of active graft-versus-host disease (GVHD) requiring steroids.	through D+100
Number of Participants With Relapse-free Survival	number of patients that were still alive and relapse free	after 7 years of follow up

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Brian J. Bolwell, MD, The Cleveland Clinic; Principal Investigator: Jarek Maciejewski, MD, PhD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: January 1, 2008
• First Submitted That Met QC Criteria: January 1, 2008
• First Posted (Estimate): January 9, 2008

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 18, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: lymphoma; myelodysplastic syndromes; Adult leukemia; plasma cell disorders
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Preleukemia; Plasmacytoma; Myeloproliferative Disorders; Precancerous Conditions
• Other Study ID Numbers: CCF-6501; P30CA043703 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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