Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia in remission, childhood acute myeloid leukemia in remission, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent adult acute myeloid leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, secondary myelodysplastic syndromes
Brief 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.
Detailed 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.
Interventions
BIOLOGICALanti-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.
DRUGfludarabine 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).
DRUGthiotepa
Thiotepa 5 mg/kg/day intravenously (IV) over 4 hours on days -8, -7 (total dose 10 mg/kg).
PROCEDUREperipheral 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.
RADIATIONtotal-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.
Sponsors
Center for International Blood and Marrow Transplant Research
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Disease-free Survival | 1 Year | Number of patients alive and without disease at 1 year after transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade II-IV Acute Graft-vs-host Disease (GVHD) | Day 100 | 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. |
| Incidence of Chronic Graft-versus-host Disease (GVHD) | 1 Year | 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. |
| Incidence of Disease Relapse | 1 Year | Number of patients with disease at 1 year. |
| Transplant-related Mortality | 1 Year | Number of patients with treatment related death at 1 year post transplant. |
| Overall Survival | 1 Year | Number of patients who were deceased at 1 year post transplant. |
| Incidence of Graft Failure | Day 100 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Treated Patients Includes patients with partial matched unrelated donor transplants and treated with: 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.
Patients undergo filgrastim (G-CSF)-mobilized, T-cell-depleted, CD34+-selected allogeneic PBSC transplantation on day 0. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | All Treated Patients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age, Continuous | 41.1 years STANDARD_DEVIATION 12.9 |
| Disease Acute Myeloid Leukemia - CR1 | 10 Participants |
| Disease Acute Myeloid Leukemia - CR2 | 7 Participants |
| Disease Chronic Myeloid Leukemia | 4 Participants |
| Disease Myelodysplastic Syndrome - NOS | 1 Participants |
| Disease Myelodysplastic Syndrome - RAEB2 | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 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 | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 24 |
| serious Total, serious adverse events | 23 / 24 |
Outcome results
Primary
Incidence of Disease-free Survival
Number of patients alive and without disease at 1 year after transplant.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Incidence of Disease-free Survival | 18 Participants |
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.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Incidence of Chronic Graft-versus-host Disease (GVHD) | 4 Participants |
Secondary
Incidence of Disease Relapse
Number of patients with disease at 1 year.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Incidence of Disease Relapse | 6 Participants |
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.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Incidence of Grade II-IV Acute Graft-vs-host Disease (GVHD) | 6 Participants |
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.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Incidence of Graft Failure | 1 Participants |
Secondary
Overall Survival
Number of patients who were deceased at 1 year post transplant.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Overall Survival | 10 Participants |
Secondary
Transplant-related Mortality
Number of patients with treatment related death at 1 year post transplant.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Treated Patients | Transplant-related Mortality | 8 Participants |