Clinical trial NCT00553202: Donor Stem Cell Transplant in Treating Young Patients With Acute Myeloid Leukemia With Monosomy 7, -5/5q-, High FLT3-ITD AR, or Refractory or Relapsed Acute Myelogenous Leukemia
Official title: Killer Immunoglobulin-like Receptor (KIR) Incompatible Unrelated Donor Hematopoietic Cell Transplantation (SCT) for AML With Monosomy 7, -5/5q-, High FLT3-ITD AR, or Refractory and Relapsed Acute Myelogenous Leukemia (AML) in Children: A Children's Oncology Group (COG) Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Keywords: recurrent childhood acute myeloid leukemia
childhood myelodysplastic syndromes
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-11-04
Enrollment: 158
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy before a donor stem cell transplant using stem cells that closely match the patient's stem cells, helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before transplant and cyclosporine, tacrolimus, and methotrexate before and after transplant may stop this from happening.

PURPOSE: Natural Killer (NK) cells from the donor's bone marrow may be important in fighting leukemia. Bone marrow donors can be selected based on the type of NK cells they have, specifically the killer immunoglobulin receptor (KIR) type. This study provides information on KIR type from potential donors, which can be used in selecting the bone marrow donor. This phase II trial of unrelated donor stem cell transplant in patients with high risk AML (monosomy 7, -5/5q-, high FLT3-ITD AR, or refractory or relapsed AML) in which KIR typing of the patients and potential donors will be available to the treating transplant physician at the time of donor selection.

Detailed description: OBJECTIVES:

* To define the relationship between the status of donor NK-cell receptor and patient outcomes after killer immunoglobulin-like receptor-incompatible unrelated donor (URD) and umbilical cord blood (UCB) hematopoietic cell transplantation (HCT) in young patients with acute myeloid leukemia with monosomy 7, -5/5q-, high FLT3 internal tandem duplication allelic ratio (High-FLT3-ITD AR), or refractory or relapsed acute myelogenous leukemia.
* To correlate the relationships between factors affecting NK receptor status and clinical events.
* To assess NK-cell development after URD and UCB HCT in patients with poor prognosis AML.
* To evaluate NK-cell reconstitution and receptor-acquisition pattern in these patients.

OUTLINE: This is a multicenter study.

* Preparative regimen: Patients receive 1 of the following regimens:

  * Hematopoietic stem cell transplantation (SCT): Patients receive busulfan IV every 6 hours on days -9 to -6, high-dose cyclophosphamide IV over 1 hour on days -5 to -2, anti-thymocyte globulin IV once or twice daily over 4 hours on days -3 to -1, and methylprednisolone IV on days -3 to -1.
  * Umbilical cord blood (UCB) transplantation: Conditioning regimen, infusion procedures, and post-transplant immunoprophylaxis for patients with an UCB donor are according to institutional guidelines and standards.
* Allogeneic hematopoietic stem cell transplantation (SCT) or umbilical cord blood (UCB) transplant: Patients undergo allogeneic SCT or UCB transplant on day 0.
* Graft-vs-host disease (GVHD) prophylaxis: Patients receive cyclosporine or tacrolimus IV or orally beginning on day -2 and continuing until day 50, followed by a taper until week 24. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Blood samples will be collected periodically from both patients and donors for studies of natural killer cells in support of the study objectives.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually for 3 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of one of the following:

  * Patients with primary refractory acute myeloid leukemia (AML), defined as ≥ 5% bone marrow blasts after two induction courses of chemotherapy
  * Primary refractory AML, defined as ≥ 5% bone marrow blasts after two induction courses of chemotherapy
  * AML or myelodysplastic syndrome with -5/5q- or monosomy 7 without inv(16)/t(16;16) or t(8;21) cytogenetics or NPM or CEBPα mutations
  * Relapsed AML (≥ 5% bone marrow blasts) who meet the customary WHO criteria for AML
  * AML and high FLT3 internal tandem duplication allelic ratio (high FLT3-ITD AR), defined as \> 0.4
  * All cases of therapy-related AML (therapy-related AML is considered high risk)
  * Patients with AML, without inv(16)/t(16;16) or t(8;21), monosomy 7, -5/5q-, NPM, or CEPBα mutations, or high FLT3-ITD AR, but with evidence of residual AML (≥ 0.1%) at the end of Induction I; or if a minimal residual disease (MRD) is not performed, then with \> 15% bone marrow blasts by morphology after one induction course of chemotherapy

    * Any flow-based MRD is eligible for AAML05P1 for patients not on AAML1031, whereas patients on AAML1031 must utilize the central lab as per the AAML1031 protocol guidelines
* No Fanconi anemia
* Recipients of unrelated marrow or cord blood are eligible for this study

PATIENT CHARACTERISTICS:

* Karnofsky performance status (PS) (for patients over 16 years of age) or Lansky PS (for patients 16 and under) 50-100%
* Total bilirubin ≤ 2 mg/dL
* SGOT (AST) or SGPT (ALT) ≤ 2.5 times upper limit of normal
* DLCO ≥ 50% OR a normal chest x-ray and pulse oximetry in patients who are unable to undergo pulmonary function tests
* Shortening fraction ≥ 27% by ECHO
* Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min OR creatinine adjusted according to age
* HIV negative
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Patients with proven or suspected bacterial sepsis, pneumonia, or meningitis are eligible provided appropriate therapeutic measures have been initiated to control the presumed or proven infection, and systemic signs are not life-threatening
* No evidence or presence of a fungal infection within the past 30 days

PRIOR CONCURRENT THERAPY:

* Prior chemotherapy, radiotherapy or any antileukemic therapy allowed provided patients meet 1 of the following criteria:

  * Received initial treatment for relapsed AML
  * Patients with primary induction failure or relapse who have already received initial therapy and who may have gone on to have additional therapy prior to receiving protocol stipulated therapy on AAML05P1
* No treatment for fungal infection within the past 30 days
* Concurrent radiotherapy to localized painful lesions allowed
* No other concurrent cancer chemotherapy or immunomodulating agents

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: At 5 years from HSCT date
measure: Cumulative Incidence of NK Cell Reconstitution
timeFrame: At 5 years from HSCT date
Secondary outcomes:
Other outcomes:
measure: Disease-free Survival
timeFrame: From the date of SCT to the date of relapse, the date of death, or the date of last follow-up, whichever occurs first
measure: Acute and Chronic Graft-versus-host Disease
timeFrame: Up to 5 years
measure: Time to the Donor-specific NK-cell Receptor Expression
timeFrame: Up to 42 days after SCT
Locations:
city: Birmingham
country: United States
facility: UAB Comprehensive Cancer Center
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Long Beach
country: United States
facility: Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Lee Cancer Care of Lee Memorial Health System
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic - Orlando
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
state: Georgia
city: Indianapolis
country: United States
facility: Riley's Children Cancer Center at Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Lexington
country: United States
facility: Lucille P. Markey Cancer Center at University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
state: Maryland
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Cancer Clinic
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: CCOP - Nevada Cancer Research Foundation
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center Cancer Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center at University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Blumenthal Cancer Center at Carolinas Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's - Dayton
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Cancer Institute
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Knoxville
country: United States
facility: East Tennessee Children's Hospital
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center at Children's Hospital of Wisconsin
state: Wisconsin
city: Vancouver
country: Canada
facility: Children's and Women's Hospital of British Columbia
state: British Columbia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Stella M. Davies, MBBS, PhD
role: STUDY_CHAIR
References: