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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00553202
• Other study ID #: AAML05P1
• Secondary ID: COG-AAML05P1NCI-
• Status: Completed
• Phase: Phase 2
• Start date: January 2008
• Est. completion date: March 31, 2020

Study information

• Verified date: July 2016
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 158
• Est. completion date: March 31, 2020
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

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 CEBPa 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 CEPBa 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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Biological:
• anti-thymocyte globulin
Given IV

Drug:
• busulfan
Given IV
• cyclophosphamide
Given IV
• cyclosporine
Given IV or orally
• methotrexate
Given IV
• methylprednisolone
Given IV
• tacrolimus
Given IV

Other:
• laboratory biomarker analysis
Correlative studies
• pharmacological study
Correlative studies

Procedure:
• allogeneic bone marrow transplantation
allogeneic bone marrow transplantation
• allogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic SCT

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Children's and Women's Hospital of British Columbia	Vancouver	British Columbia
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Dayton Children's - Dayton	Dayton	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Riley's Children Cancer Center at Riley Hospital for Children	Indianapolis	Indiana
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	University of Mississippi Cancer Clinic	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Children's Hospital	Knoxville	Tennessee
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky
United States	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Children's Hospital Central California	Madera	California
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	CCOP - Scott and White Hospital	Temple	Texas
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Disease-free Survival	The cumulative incidence of relapse or death after SCT will be calculated by considering relapse and death due to other causes as competing events.	From the date of SCT to the date of relapse, the date of death, or the date of last follow-up, whichever occurs first
Other	Acute and Chronic Graft-versus-host Disease	Acute and chronic GVHD will be summarized.	Up to 5 years
Other	Time to the Donor-specific NK-cell Receptor Expression	The presence of donor cells is demonstrated by the detection of informative variable-number tandem-repeat polymorphisms or by fluorescent in situ hybridization with a Y-chromosome-specific probe in cases of sex-mismatched transplants. Independent variables that will be examined include donor-recipient KIR mismatch, taking into consideration the interactions with donor-recipient human leukocyte antigen (HLA) compatibility, and the numbers of CD34+ cells and CD3+ cells in the graft.	Up to 42 days after SCT
Primary	Overall Survival (OS)	OS - Time from HSCT until death	At 5 years from HSCT date
Primary	Cumulative Incidence of NK Cell Reconstitution	Cumulative incidence of successful reconstitution to donor level is calculated.	At 5 years from HSCT date