Graft Versus Host Disease, Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
graft versus host disease, adult acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia in remission, recurrent childhood acute lymphoblastic leukemia, adult acute myeloid leukemia in remission, recurrent adult acute myeloid leukemia, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, 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), childhood acute myeloid leukemia in remission, recurrent childhood acute myeloid leukemia, childhood myelodysplastic syndromes, previously treated myelodysplastic syndromes, refractory anemia with excess blasts, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes
Brief summary
RATIONALE: Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment that can cure acute leukemia and myelodysplasia. After giving the patient chemotherapy and total body irradiation to stop the growth of cancer and remove the patient's diseased bone marrow, healthy stem cells from a donor are infused into the patient to replace the patient's bone marrow and make red and white blood cells and platelets. Unfortunately HSCT is often complicated by 'graft versus host disease' (GVHD) in which the transplanted cells from a donor can make an immune response against the body's normal cells and cause tissue damage and severe symptoms. Removing a subset of the donor T cells, called 'naive T cells', before transplant may reduce the frequency and intensity of GVHD. PURPOSE: This phase II trial will determine whether the removal of the naive T cells from donor cells can decrease the rate and severity of graft-vs-host disease while preserving specific immunity against infections in patients with acute leukemia or advanced myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * Estimate the probability of grades II-IV acute graft-vs-host disease (GVHD) in patients with acute leukemia or advanced myelodysplastic syndromes treated with CD45RA+ T-cell-depleted allogeneic peripheral blood stem cell transplantation and compare this to relevant historical experience. * Estimate the probability of graft failure in these patients. Secondary * Evaluate immune reconstitution and pathogen-specific T-cell reconstitution in these patients. * Estimate the probability of transplant-related mortality by day 100 in these patients. * Estimate the probability of relapse in these patients. * Estimate the probability and severity of chronic GVHD in these patients. OUTLINE: This is a multicenter study. * Myeloablative conditioning regimen: Patients undergo total body irradiation twice daily for 4 days (Days -10 to -7) Patients also receive thiotepa IV over 4 hours for 2 days (Days -6 and -5) and fludarabine phosphate IV over 30 minutes for 5 days (Days -6 to -2.) * Transplantation: Patients receive a CD34+ enriched allogeneic peripheral blood stem cell (PBSC) product followed by a CD45RA+ T-cell-depleted allogeneic PBSC product on day 0. * Graft-vs-host disease (GVHD) prophylaxis: Patients will receive Tacrolimus as per cohort 1. If the rate of grade II-IV acute GVHD in the first 35 patients is significantly reduced (compared to historical controls), subsequent patients are enrolled in cohort 2. * Cohort 1: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50, followed by a standard taper in the absence of grade II-IV acute GVHD. * Cohort 2: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30, followed by a rapid taper in the absence of grade II-IV acute GVHD. Patients are followed actively for at least 1 year post transplant.
Interventions
DRUGFludarabine Phosphate
Fludarabine will be administered in a dose of 25 mg/m2/day IV over approximately 30 minutes for 5 consecutive days (day -6 to -2). The total dose of fludarabine will be 125 mg/m2.
DRUGTacrolimus
Tacrolimus will be administered beginning on day -1 at a dose of 0.03 mg/kg/day by continuous IV infusion. For the first cohort of 35 patients, if there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus should then be tapered at the rate of approximately 5% of the day 50 dose each week for liquid, and 20% of the day 50 dose per month for capsules. In the second cohort of 25 patients if there is no evidence of grade II GVHD on or prior to day 30, tacrolimus should then be tapered at the rate of approximately 8% of the day 30 dose each week for liquid, and 33% of the day 30 dose per month for capsules.
DRUGThiotepa
Thiotepa will be administered in a dose of 5 mg/kg/day (adjusted body weight) IV over approximately 4 hours for 2 consecutive days (day -6 and day -5).
RADIATIONTotal-Body Irradiation (TBI)
TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).
OTHERMagnetic Affinity Cell Sorting
Device
PROCEDUREPeripheral Blood Stem Cell Transplantation
Patient will undergo a PBSC transplantation
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation
Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of 1 of the following: * Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or subsequent remission * ALL or AML in relapse or primary refractory ALL or AML with a circulating blast count ≤ 10,000/mm\^3 * Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has received induction chemotherapy within the past 60 days * Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT) * No CNS involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy PATIENT CHARACTERISTICS: * Age 14-55 * Creatinine \< 1.5 mg/dL * Cardiac ejection fraction \> 45% * DLCO corrected \> 60% of predicted * Total bilirubin \< 2 times upper limit of normal (ULN) (unless attributed to Gilbert syndrome) * AST and ALT \< 2 times ULN * Not pregnant or nursing * Fertile patients must use effective contraception during and for 12 months after transplantation * HIV negative * No co-existing disease (other than leukemia or RAEB) that would limit life expectancy to \< 3 months * No uncontrolled infection that, in the opinion of the consulting infectious disease physician, would contraindicate myeloablative HSCT * No other medical condition that would contraindicate HSCT * No known hypersensitivity to tacrolimus PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior HSCT * No concurrent participation in other experimental studies for the prevention of graft-vs-host disease DONOR CHARACTERISTICS: * Genotypic or phenotypic HLA-identical related donor * Able to donate peripheral blood stem cells * Age \> 14 years * Applicable to male patients only: No female donors who have previously given birth to a male child or have had a pregnancy beyond the first trimester miscarriage or termination of pregnancy or nursing * No donors who have received blood transfusions * No CD45 Mutation with aberrant CD45RA isoform expression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | Within 360 days of transplant | Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening. |
| Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant | Up to 5 years post transplant | Graft failure is defined as either a failure to reach an ANC of \>500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC \<100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transplant-related Mortality by Day 100 | Transplant to day 100 | Number of participants who died due to transplant-related issues within the first 100 days of transplant |
| Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant | Up to 5 years post transplant | Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse. |
| Number of Participants With Chronic GVHD | Up to 5 years post transplant | Chronic GVHD measured by meeting NIH criteria and treated with immune suppression |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 2 academic medical centers between Dec 2009 and Oct 2014. The first patient was enrolled on December 17, 2009 and the last participant was enrolled in October 2014
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Participants CONDITIONING: Patients receive TBI twice per day on days -10 to -7, then thiotepa IV administered over approximately 4 hours on days -6 and -5, and fludarabine IV administered over 30 minutes on days -6 to -2.
DONOR BONE MARROW TRANSPLANTATION: GCSF-mobilized CD34 enriched PBSC and CD45RA depleted cells infused on day 0.
POST-TRANSPLANT IMMUNOSUPPRESSION: Ptients receive tacrolimus beginning on day -1 by continuous IV infusion, converting to oral formulation when oral feeding is established. If there is no evidence of grade II-IV acute GVHD prior to day 50, tacrolimus is then tapered. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 2 Years to 5 Years Post-transplant | Death | 3 |
| D0 to D100 Post-transplant | Death | 2 |
| D101 to 2 Years Post-transplant | Death | 8 |
Baseline characteristics
| Characteristic | Overall Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants |
| Age, Continuous | 37.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment United States | 41 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 41 |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 39 / 41 |
Outcome results
Primary
Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant
Graft failure is defined as either a failure to reach an ANC of \>500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC \<100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.
Time frame: Up to 5 years post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Participants | Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant | 0 Participants |
Primary
Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD
Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.
Time frame: Within 360 days of transplant
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall Study Participants | Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | No acute GVHD | 11 Participants |
| Overall Study Participants | Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | Grade I acute GVHD | 2 Participants |
| Overall Study Participants | Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | Grade II acute GVHD | 25 Participants |
| Overall Study Participants | Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | Grade III acute GVHD | 3 Participants |
| Overall Study Participants | Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | Grade IV acute GVHD | 0 Participants |
| Overall Study Participants | Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | Steroid refractory acute GVHD | 0 Participants |
Secondary
Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant
Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse.
Time frame: Up to 5 years post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Participants | Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant | 10 Participants |
Secondary
Number of Participants With Chronic GVHD
Chronic GVHD measured by meeting NIH criteria and treated with immune suppression
Time frame: Up to 5 years post transplant
Population: Participants alive and without relapse at D100
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall Study Participants | Number of Participants With Chronic GVHD | Chronic GVHD that meets NIH criteria | 3 Participants |
| Overall Study Participants | Number of Participants With Chronic GVHD | No documented chronic GVHD | 35 Participants |
Secondary
Transplant-related Mortality by Day 100
Number of participants who died due to transplant-related issues within the first 100 days of transplant
Time frame: Transplant to day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Participants | Transplant-related Mortality by Day 100 | 2 Participants |