Leukemia
Conditions
Keywords
recurrent childhood acute myeloid leukemia, childhood myelodysplastic syndromes
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.
Interventions
BIOLOGICALanti-thymocyte globulin
Given IV
DRUGbusulfan
Given IV
DRUGcyclophosphamide
Given IV
DRUGcyclosporine
Given IV or orally
DRUGmethotrexate
Given IV
DRUGmethylprednisolone
Given IV
DRUGtacrolimus
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
PROCEDUREallogeneic bone marrow transplantation
allogeneic bone marrow transplantation
PROCEDUREallogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic SCT
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | At 5 years from HSCT date | OS - Time from HSCT until death |
| Cumulative Incidence of NK Cell Reconstitution | At 5 years from HSCT date | Cumulative incidence of successful reconstitution to donor level is calculated. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | From the date of SCT to the date of relapse, the date of death, or the date of last follow-up, whichever occurs first | 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 | Up to 5 years | Acute and chronic GVHD will be summarized. |
| Time to the Donor-specific NK-cell Receptor Expression | Up to 42 days after SCT | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy and Allogeneic SCT) All Patients | 158 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 16 |
| Overall Study | Fails to meet organ function | 6 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | No donor identified | 16 |
| Overall Study | Physician Decision | 28 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy and Allogeneic SCT) |
|---|---|
| Age, Categorical <=18 years | 149 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 3215.34 Days STANDARD_DEVIATION 2240.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Race (NIH/OMB) White | 128 Participants |
| Region of Enrollment Canada | 11 participants |
| Region of Enrollment United States | 147 participants |
| Sex: Female, Male Female | 75 Participants |
| Sex: Female, Male Male | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 32 / 90 |
| serious Total, serious adverse events | 7 / 90 |
Outcome results
Primary
Cumulative Incidence of NK Cell Reconstitution
Cumulative incidence of successful reconstitution to donor level is calculated.
Time frame: At 5 years from HSCT date
Population: Patients without completion of planned therapy (n=68) or without NK cell status (n=38) are excluded from analyses of TExp
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Chemotherapy and Allogeneic SCT) | Cumulative Incidence of NK Cell Reconstitution | 48.1 Percentage of participants |
Primary
Overall Survival (OS)
OS - Time from HSCT until death
Time frame: At 5 years from HSCT date
Population: Patients without completion of planned therapy (n=68) are excluded from analyses of OS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Chemotherapy and Allogeneic SCT) | Overall Survival (OS) | 45.9 Percentage of participants |
Other Pre-specified
Acute and Chronic Graft-versus-host Disease
Acute and chronic GVHD will be summarized.
Time frame: Up to 5 years
Other Pre-specified
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.
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
Other Pre-specified
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.
Time frame: Up to 42 days after SCT