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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00553202
First received: November 2, 2007
Last updated: May 29, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Leukemia
Biological: anti-thymocyte globulin
Drug: busulfan
Drug: cyclophosphamide
Drug: cyclosporine
Drug: methotrexate
Drug: methylprednisolone
Drug: tacrolimus
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: allogeneic bone marrow transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Overall survival [ Time Frame: Up to 5 years after SCT ] [ Designated as safety issue: No ]
    OS will be estimated using Kaplan-Meier methods. For the primary endpoint of overall survival, there should be similar power for other covariates including recovery of NK cell number, acquisition of donor pattern of KIR expression, and acquisition of activating receptors and co-receptors, because the distribution of patients in each risk category is similar (assume ~50% of the patients reconstitute by 6 months after SCT)

  • Time to NK cell reconstitution [ Time Frame: At baseline (donor pre-SCT) and up to 12 months post-SCT (recipient) ] [ Designated as safety issue: No ]
    Cumulative incidence of successful reconstitution to donor level will be calculated.


Other Outcome Measures:
  • Disease-free survival [ Time Frame: From the date of SCT to the date of relapse, the date of death, or the date of last follow-up, whichever occurs first ] [ Designated as safety issue: No ]
    The cumulative incidence of relapse or death after SCT will be calculated by considering relapse and death due to other causes as competing events.

  • Acute and chronic graft-versus-host disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Acute and chronic GVHD will be summarized.

  • Time to the donor-specific NK-cell receptor expression [ Time Frame: Up to 42 days after SCT ] [ Designated as safety issue: No ]
    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.


Enrollment: 158
Study Start Date: January 2008
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy and allogeneic 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.

Patients undergo allogeneic hematopoietic stem cell transplantation (SCT) or allogeneic bone marrow transplantation (BMT) on day 0.

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 pharmacological study objectives

Biological: anti-thymocyte globulin
Given IV
Other Names:
  • Rabbit ATG
  • RATG-Rabbit
  • Antithymocyte Globulin
  • Thymoglobulin
  • NSC #720095
Drug: busulfan
Given IV
Other Names:
  • Busulfex
  • NSC #750
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271
Drug: cyclosporine
Given IV or orally
Other Names:
  • Cyclosporine
  • CYA
  • Sandimmune
  • Neoral
  • Gengraf
  • NSC #290193
Drug: methotrexate
Given IV
Other Names:
  • MTX
  • amethopterin
  • NSC #000740
Drug: methylprednisolone
Given IV
Other Names:
  • Solu-Medrol
  • A-Methapred
  • Medrol
  • NSC #19987
Drug: tacrolimus
Given IV
Other Names:
  • FK-506
  • Prograf
  • NSC #717865
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Procedure: allogeneic bone marrow transplantation
allogeneic bone marrow transplantation
Other Names:
  • bone marrow therapy
  • allogeneic
  • allogenic
  • transplantation
  • allogeneic bone marrow
  • allogenic bone marrow
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic SCT

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

Ages Eligible for Study:   up to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00553202

  Show 52 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Stella M. Davies, MBBS, PhD Children's Hospital Medical Center, Cincinnati
  More Information

Additional Information:
No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00553202     History of Changes
Other Study ID Numbers: AAML05P1, COG-AAML05P1, CDR0000572744
Study First Received: November 2, 2007
Last Updated: May 29, 2014
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
recurrent childhood acute myeloid leukemia
childhood myelodysplastic syndromes

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Monosomy
Neoplasms by Histologic Type
Neoplasms
Aneuploidy
Chromosome Aberrations
Pathologic Processes
Antilymphocyte Serum
Busulfan
Cyclophosphamide
Cyclosporins
Cyclosporine
Methotrexate
Tacrolimus
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on August 28, 2014