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


Phase 2
N/A
45 Years
Not Enrolling
Both
Graft Versus Host Disease, Leukemia, Myelodysplastic Syndromes

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Risk of developing grades III-IV acute graft-vs-host disease (GVHD)

Safety Issue:

No

Principal Investigator

Ann Woolfrey, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

1965.00

NCT ID:

NCT00450983

Start Date:

December 2006

Completion Date:

July 2010

Related Keywords:

  • Graft Versus Host Disease
  • Leukemia
  • Myelodysplastic Syndromes
  • graft versus host disease
  • adult acute lymphoblastic leukemia in remission
  • recurrent adult acute lymphoblastic leukemia
  • childhood acute lymphoblastic leukemia in remission
  • recurrent childhood acute lymphoblastic leukemia
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia in remission
  • recurrent adult acute myeloid leukemia
  • childhood acute myeloid leukemia in remission
  • recurrent childhood acute myeloid leukemia
  • secondary acute myeloid leukemia
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • accelerated phase chronic myelogenous leukemia
  • blastic phase chronic myelogenous leukemia
  • childhood chronic myelogenous leukemia
  • relapsing chronic myelogenous leukemia
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • childhood myelodysplastic syndromes
  • Graft vs Host Disease
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
Seattle Cancer Care AllianceSeattle, Washington  98109