Donor Peripheral Stem Cell Transplant and Donor Natural Killer Cell Transplant After Total-Body Irradiation, Thiotepa, Fludarabine, and Muromonab-CD3 in Treating Patients With Leukemia or Other Blood Diseases

Leukemia Clinical Trial

Official title:

Transplantation of Haploidentical CD34+ Purified Peripheral Blood Stem Cells With NK-Cell Add-Back Following Conditioning With Total Body Irradiation, Thiotepa, Fludarabine and OKT3

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00450983
• Other study ID #: 1965.00
• Secondary ID: R01AI053193P30CA
• Status: Completed
• Phase: Phase 2
• First received: March 20, 2007
• Last updated: August 24, 2010
• Start date: December 2006
• Est. completion date: July 2010

Study information

• Verified date: August 2010
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell and donor natural killer 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 certain 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.

PURPOSE: This phase II trial is studying how well giving a donor peripheral stem cell transplant and a donor natural killer cell transplant after total-body irradiation, thiotepa, fludarabine, and muromonab-CD3 works in treating patients with leukemia or other blood diseases.

Description:

OBJECTIVES:

Primary

• Determine the effect of haploidentical donor CD34+ purified peripheral blood stem cells and donor natural killer (NK) cells on the risk of developing grades III-IV acute graft-vs-host disease in patients with leukemia or other hematologic diseases.

Secondary

• Determine the risk for mortality from infection before day 180 in patients treated with this regimen.

• Determine the risk for graft rejection in patients treated with this regimen.

• Determine the risk for life-threatening infections in patients treated with this regimen.

• Determine the concentration of subsets of NK, NK-T, T cells, and dendritic cells in the CD34+ NK/NK-T-enriched graft.

• Determine cytomegalovirus-specific T-cells in product and donor graft.

• Determine the genotype and phenotype of donor killer cell immunoglobulin-like receptor expression according to time after hematopoietic stem cell transplantation (HSCT).

• Determine the reconstitution of NK function according to time after HSCT.

• Determine the expression of NKG2 ligands of leukemic blasts.

OUTLINE: Patients are stratified according to age (≤ 7 years vs > 7 years).

• Conditioning regimen: Patients 7 years of age or younger undergo total-body irradiation (TBI) twice daily on days -11 to -9. Patients over 7 years of age undergo TBI once on day -9. All patients receive thiotepa IV over 2 hours on days -8 and -7, fludarabine phosphate IV on days -6 to -3 and muromonab-CD3 on days -6 to 6. Patients with acute lymphoblastic leukemia or leukemia in the spinal fluid also receive methotrexate intrathecally prior to and after donor peripheral blood stem cell (PBSC) transplantation .

• Donor PBSC transplantation: Patients undergo donor PBSC transplantation comprising CD34+ purified PBSCs and natural killer (NK) cells on day 0.

Blood samples are collected in weeks 1-4, 6, 8, and 12. Analysis of samples includes quantitation of NK, NK-T, and T-cell subsets (CD3, CD4, and CD8) by flow cytometry; donor killer cell immunoglobulin-like receptor genotype and phenotype; interferon-gamma levels; and NK cytotoxicity. Samples are also analyzed by leukemic blast assay to determine if ligands that activate NK cells are expressed.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: July 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 45 Years

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following life-threatening hematological malignancies:

• Acute lymphoblastic leukemia meeting 1 of the following criteria:

• Advanced beyond first remission

• In first remission with high-risk prognostic features, including any of the following:

• Philadelphia chromosome-positive disease

• Chromosome 11q23 abnormality

• Hypodiploid

• Failed to achieve first remission within 1 month after induction

• Acute myeloid leukemia (AML) meeting 1 of the following criteria:

• Advanced beyond first remission

• First remission with high-risk prognostic features, including any of the following:

• Chromosome 11q23 abnormality

• Chromosome del 7q

• Secondary AML

• Failed to achieve first remission within 1 month after induction

• Myelodysplastic syndromes with International Prognostic Score > 1

• Chronic myelogenous leukemia in accelerated or blastic phase

• No active CNS disease

• No suitable HLA-matched related or unrelated donor available

• Haploidentical family member available as donor of partially HLA-matched peripheral blood stem cells

• Least degree of mismatch to HLA-A, B, C, DRB1, and DQB1

• No mismatch for a single HLA-A, B, C, DRB1, or DQB1 antigen

• Donor killer cell immunoglobulin-like receptor ligand group expression preferably different than patient

PATIENT CHARACTERISTICS:

• LVEF = 45%

• DLCO = 60% of predicted

• AST and ALT = 2 times upper limit of normal (ULN) (unless due to malignancy)

• Bilirubin = 2 times ULN (unless due to malignancy)

• No life expectancy < 6 months due to coexisting disease other than the malignancy

• No active infection (e.g., polymerase chain reaction [PCR] evidence for cytomegalovirus, human herpes virus 6, or invasive fungal infection)

• No prior infections without evidence of resolution by PCR or imaging studies within the past 2 months

• No hypersensitivity to murine antibodies

• No known HIV positivity

• Not pregnant or nursing

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior marrow transplantation with total body irradiation > 400 cGy

• No concurrent therapies for seizure disorder

• No growth factors for 21 days after transplantation

Study Design

Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Graft Versus Host Disease
• Graft vs Host Disease
• Leukemia
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Biological:
• muromonab-CD3

• natural killer cell therapy

Drug:
• fludarabine phosphate

• methotrexate

• thiotepa

Genetic:
• gene expression analysis

Other:
• flow cytometry

• immunologic technique

Procedure:
• allogeneic hematopoietic stem cell transplantation

• in vitro-treated peripheral blood stem cell transplantation

Radiation:
• total-body irradiation

Locations

Country	Name	City	State
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Risk of developing grades III-IV acute graft-vs-host disease (GVHD)			No
Secondary	Risk for mortality from infection before day 180			No
Secondary	Risk for graft failure			No
Secondary	Risk for life-threatening infections			No
Secondary	Concentration of NK, NK-T, T-cells, and dendritic cell subsets in the CD34+ NK/NK-T-enriched graft			No
Secondary	Cytomegalovirus-specific T cells in product and donor graft			No
Secondary	Genotype and phenotype of donor killer cell immunoglobulin-like receptor expression according to time after hematopoietic stem cell transplantation (HSCT)			No
Secondary	Reconstitution of NK function according to time after HSCT			No
Secondary	Expression of NKG2 ligands of leukemic blasts			No