Donor Stem Cell Transplant in Treating Patients With Myeloid Cancer or Other Disease

Leukemia Clinical Trial

Official title:

A Multicenter, Prospective Trial to Evaluate the Role of NK Cell KIR Epitope Mismatch on Mortality and Disease Relapse in T-Cell Depleted Hematopoietic Stem Cell Transplantation From HLA-C Mismatched, Unrelated Donors for Myeloid Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00392782
• Other study ID #: 2004UC035
• Secondary ID: UMN-MT2004-04UMN
• Status: Terminated
• Phase: Phase 2
• First received: October 25, 2006
• Last updated: December 3, 2017
• Start date: July 2005
• Est. completion date: May 2011

Study information

• Verified date: December 2017
• Source: Masonic Cancer Center, University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Giving total-body irradiation and chemotherapy, such as fludarabine and thiotepa, before a donor stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When healthy 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. Giving antithymocyte globulin and removing the T cells from the donor cells before transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well a donor stem cell transplant works in treating patients with myeloid cancer or other disease.

Description:

OBJECTIVES:

Primary

• Determine the incidence of disease-free survival at 1 year in patients with acute or chronic myeloid leukemias undergoing T-cell-depleted hematopoietic stem cell transplantation from HLA-C mismatched, unrelated donors.

Secondary

• Determine the incidence of disease relapse at 1 year in patients treated with this regimen.

• Determine the incidence and severity of acute graft-vs-host disease (GVHD) at 100 days and chronic GVHD at 1 year in these patients.

• Determine the incidence of graft failure at day 100.

• Determine the transplant-related mortality of these patients at 1 year.

• Determine the overall survival of these patients at 1 year.

OUTLINE: This is a prospective, multicenter study. Patients are stratified according to killer-cell immunoglobulin-like receptors (KIR) epitope mismatch (yes [experimental] vs no [control]).

• Myeloablative preparative regimen: Patients undergo total body irradiation twice daily on days -10 and -9 and receive thiotepa intravenously (IV) over 4 hours on days -8 and -7, fludarabine phosphate IV over 30-60 minutes on days -7 to -3, and antithymocyte globulin IV over 4-6 hours on days -5 to -2.

• Allogeneic peripheral blood stem cell (PBSC) transplantation: Patients undergo filgrastim (G-CSF)-mobilized, T-cell-depleted, CD34+-selected allogeneic PBSC transplantation on day 0.

After completion of study treatment, patients are followed periodically for at least 1 year.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 24
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 60 Years

Eligibility

Inclusion Criteria:

• Primary acute myeloid leukemia (AML)

• First complete remission (CR) with high risk features as defined by: failure to achieve remission by day 21 after induction chemotherapy, or the presence of chromosomal abnormalities involving any of the following: -5/de (5q), -7/del(7q), inversion 3q, abnormalities of 11q23, 20q, 21q, del(9q), translocation 6;9, translocation 9;22, abnormalities of 17p, or complex karyotype with > or = 3 abnormalities. Complete remission is defined as < 5% blasts in the marrow.

• Second CR or subsequent in remission

• Refractory or relapsed disease with absolute peripheral blood blasts < 2000/mcL

• Secondary AML in remission or relapse

• Chronic myelogenous leukemia (CML) in accelerated or blast phase

• Accelerated phase is defined by any one of the following:

• Blasts 10% to 19% of peripheral blood white cells or bone marrow cells

• Peripheral blood basophils at least 20%

• Persistent thrombocytopenia (<100 x 10^9/L) unrelated to therapy, or persistent thrombocytosis (>1000 x 10^9/L) unresponsive to therapy

• Increasing spleen size and increasing white blood cell (WBC) count unresponsive to therapy

• Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML)

• Resistance to tyrosine kinase inhibitors (imatinib or other) defined as no complete cytogenetic response even if the above criteria are not met.

• Blast phase is defined by either of the following:

• Blasts 20% or more of peripheral blood white cells or bone marrow cells

• Extramedullary blast proliferation

• Large foci or clusters of blasts in bone marrow biopsy

• Primary myelodysplastic syndrome (MDS) with an IPSS score >1

• Secondary MDS with any international prostate symptom score (IPSS)

• Age =60 years

• Co-Morbidity score 0-2

• At least 35 days following start of preceding leukemia induction therapy

Exclusion Criteria:

• Patients for whom a suitable HLA genotypically identical sibling or fully matched HLA-A, -B, -C, and -DRB1 unrelated donor is available.

• Patients greater than 60 years of age.

• Hypersensitivity to thymoglobulin.

• Symptomatic uncontrolled coronary artery disease or congestive heart failure.

• Hepatic disease with transaminases or bilirubin > 2 times upper limit of normal (ULN) except for isolated hyperbilirubinemia attributed to Gilbert's syndrome.

• Severe hypoxemia with room air - Partial Pressure of Oxygen in Arterial Blood - (PAO2) < 70, supplemental oxygen-dependence, or carbon monoxide diffusing capacity (DLCO) < 50% predicted.

• Impaired renal function with creatinine > 2 times upper limit of normal (ULN) or creatinine clearance measured by 24-hour urine collection < 50% normal for age, gender, and weight.

• Patients with central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy.

• Patients who are human immunodeficiency virus (HIV) seropositive.

• Patients who are pregnant or breast-feeding.

• Patients with active infections that are untreated, or failing to respond to appropriate therapy.

• Karnofsky performance status < 50%.

• Prior allogeneic or autologous bone marrow, peripheral blood stem cell, or umbilical cord blood transplant.

• Inability to provide informed consent.

• Co-morbidity score >2

• Less than 35 days from start of previous leukemia induction therapy

Related Conditions & MeSH terms

• Leukemia
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Biological:
• anti-thymocyte globulin
Rabbit thymoglobulin will be given intravenously at a dose of 2.5 mg/kg on days -5,-4, -3, and -2. The first dose of thymoglobulin will be given over six (6) hours and subsequent doses over four (4) or more hours as tolerated or, per institutional anti-thymocyte globulin (ATG) administration guidelines.

Drug:
• fludarabine phosphate
Fludarabine 40 mg/m^2/day intravenously (IV) over 30-60 minutes on days -7,-6,-5,-4,-3 (total dose 200 mg/m^2).
• thiotepa
Thiotepa 5 mg/kg/day intravenously (IV) over 4 hours on days -8, -7 (total dose 10 mg/kg).

Procedure:
• peripheral blood stem cell transplantation
Peripheral Blood Stem Cell (PBSC) Infusion. All patients will receive granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC on day 0 (or day+1 when available) following CD34 cell selection for ex vivo T cell removal. PBSC is infused via a central venous catheter using blood infusion tubing.

Radiation:
• total-body irradiation
The total-body irradiation (TBI) will be given in 2 fractions of 400 cGy each administered on day -10 and -9 via anterior and posterior fields for a total dose of 800 cGy.

Locations

Country	Name	City	State
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin
United States	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota	Center for International Blood and Marrow Transplant Research

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Disease-free Survival	Number of patients alive and without disease at 1 year after transplant.	1 Year
Secondary	Incidence of Disease Relapse	Number of patients with disease at 1 year.	1 Year
Secondary	Incidence of Grade II-IV Acute Graft-vs-host Disease (GVHD)	Number of patients with grade II-IV acute graft-versus-host disease at Day 100 post transplant. Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack. Grade I=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening.	Day 100
Secondary	Incidence of Chronic Graft-versus-host Disease (GVHD)	Number of patients with chronic graft-versus-host disease at 1 year post transplant. Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack. Grade I=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening. Chronic GVHD is an extension of acute GVHD.	1 Year
Secondary	Incidence of Graft Failure	Number of patients with graft failure is defined by lack of neutrophil engraftment by 100 days after transplant in patients surviving a minimum of 14 days.	Day 100
Secondary	Transplant-related Mortality	Number of patients with treatment related death at 1 year post transplant.	1 Year
Secondary	Overall Survival	Number of patients who were deceased at 1 year post transplant.	1 Year