Clinical trial NCT00589602: T-Cell Depletion, Donor Hematopoietic Stem Cell Transplant (HSCT), and T-Cell Infusions in Treating Patients With Hematologic Cancer or Other Diseases
Official title: Phase II Feasibility Study of T-Cell Depletion in Allogeneic Unrelated Bone Marrow Transplantation (MUD ALLO BMT) Followed by Delayed T-Cell Infusions
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Malignant Plasma Cell Neoplasms
Myelodysplastic Syndromes
Precancerous/Nonmalignant Condition
Secondary Myelofibrosis
Keywords: Adult leukemia
lymphoma
myelodysplastic syndromes
plasma cell disorders
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-01-09
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Allogeneic Hematopoietic Stem Cell Transplantation
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment-related Mortality (TRM)
timeFrame: 180 days after transplant
Secondary outcomes:
measure: The Rate of Acute Graft Versus Host Disease (GVHD)
timeFrame: D+100 from transplant
measure: Number of Participants With Duration of Absolute Neutropenia
timeFrame: D+100 from transplant
measure: Number of Participants Able to Receive T-cell Add Backs
timeFrame: through D+100
measure: Number of Participants With Relapse-free Survival
timeFrame: after 7 years of follow up
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Brian J. Bolwell, MD
role: STUDY_CHAIR
affiliation: The Cleveland Clinic
name: Jarek Maciejewski, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: