Sickle Cell Disease
Conditions
Keywords
sickle cell disease
Brief summary
RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the 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 sirolimus and mycophenolate mofetil after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by a donor bone marrow transplant works in treating patients with sickle cell anemia and other blood disorders.
Detailed description
OBJECTIVES: * Determine the transplant-related mortality and progression-free survival of patients with severe hemoglobinopathies receiving nonmyeloablative conditioning comprising fludarabine phosphate, cyclophosphamide, and total-body irradiation followed by partially HLA-mismatched bone marrow transplantation from first-degree relatives or HLA-matched donors. * Characterize donor hematopoietic chimerism at 30, 60, and 180 days after transplantation in these patients. * Determine the hematologic and non-hematologic toxicity of this regimen in these patients. OUTLINE: * Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients also undergo total-body irradiation on day -1. * Bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. * Graft-versus-host disease prophylaxis: Patients receive sirolimus orally daily on days 5-365 and oral mycophenolate mofetil 3 times a day on days 5-35. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
Interventions
DRUGCyclophosphamide
Cyclophosphamide (Cy) 14.5 mg/kg/day intravenously (IV) on Days -6 and -5 and 50 mg/kg/day IV on Days +3 and +4.
DRUGFludarabine
Fludarabine 30 mg/m\^2/day IV on Days -6, -5, -4, -3, and -2.
DRUGMycophenolate mofetil
Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.
DRUGSirolimus
The first dose of Sirolimus is 6 mg PO on Day +5. Further dosing is adjusted according to drug levels. Sirolimus is continued through Day +365.
PROCEDUREAllogeneic bone marrow transplant
An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.
RADIATIONTotal body irradiation - 200
200 centigray (cGy) in one fraction on Day -1.
DRUGLevetiracetam
Given at 500 mg PO twice daily from Day -6 to Day +365.
BIOLOGICALAnti-thymocyte globulin
Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.
RADIATIONTotal body irradiation - 400
400 centigray (cGy) in one fraction on Day -1.
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of 1 of the following sickle cell anemias (Hb SS): * Hb S/β° thalassemia * Hb S/β+ thalassemia * Hb SC disease * Hb SE disease * Hb SD disease * Hemoglobin SO-Arab disease * Hb S/hereditary persistence of fetal hemoglobin * Meets 1 of the following criteria: * History of invasive pneumococcal disease * Stroke or CNS event lasting \> 24 hours * MRI changes indicative of brain parenchymal damage * Evidence of cerebrovascular disease by magnetic resonance angiography * Acute chest syndrome requiring exchange transfusion or hospitalization * Recurrent vaso-occlusive pain crisis (\> 2 per year for the last 2 years) * Stage I or II sickle lung disease * Sickle retinopathy * Osteonecrosis * Red cell alloimmunization (\> 2 antibodies) during long-term transfusion * Constellation of dactylitis in the first year of life AND a baseline hemoglobin \< 7 g/dL and leukocytosis (WBC \> 13.4/mm\^3) in the absence of infection during the second year of life * Pitted RBC count \> 3.5% during the first year of life * Ineligible for or refused bone marrow transplantation from an HLA-matched sibling donor * Partially mismatched (at least haploidentical) first-degree relative donor available * No minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available PATIENT CHARACTERISTICS: * ECOG performance status (PS) 0-1 OR Karnofsky or Lansky PS 70-100% * LVEF ≥ 35% * FEV\_1 and forced vital capacity ≥ 40% predicted * Direct bilirubin \< 3.1 mg/dL * No moderate to severe pulmonary hypertension by ECHO * No debilitating medical or psychiatric illness that would preclude study participation * No HIV positivity * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * No prior transfusions from donor * No immunosuppressive agents, including steroids as antiemetics, within 24 hours after the last dose of post-transplantation cyclophosphamide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Transplant-related Mortality | Up to one year | Number of participants who died for reasons related to bone marrow transplant. |
| Progression-free Survival | 2 years | Percentage of participants who are alive without relapse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Donor Chimerism at 30 Days | 30 days | Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells. |
| Donor Chimerism at 1 Year | 1 year | Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells. |
Countries
United States
Participant flow
Pre-assignment details
One participant was a screen failure.
Participants by arm
| Arm | Count |
|---|---|
| Transplant - 200 cGy Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 200. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus. | 29 |
| Transplant - 400 cGy Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 400. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus. | 13 |
| Total | 42 |
Baseline characteristics
| Characteristic | Transplant - 200 cGy | Total | Transplant - 400 cGy |
|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 15 Participants | 6 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 27 Participants | 7 Participants |
| Age, Continuous | 19 years | 21 years | 21 years |
| Disease Sickle cell disease | 25 Participants | 32 Participants | 7 Participants |
| Disease Thalassemia | 4 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 42 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 31 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 29 Participants | 42 Participants | 13 Participants |
| Sex: Female, Male Female | 17 Participants | 25 Participants | 8 Participants |
| Sex: Female, Male Male | 12 Participants | 17 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 29 | 0 / 13 |
| other Total, other adverse events | 0 / 29 | 0 / 13 |
| serious Total, serious adverse events | 21 / 29 | 7 / 13 |
Outcome results
Primary
Progression-free Survival
Percentage of participants who are alive without relapse.
Time frame: 2 years
Population: Due to early study termination, data was not collected to assess this outcome measure
Primary
Transplant-related Mortality
Number of participants who died for reasons related to bone marrow transplant.
Time frame: Up to one year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant - 200 cGy | Transplant-related Mortality | 1 Participants |
| Transplant - 400 cGy | Transplant-related Mortality | 0 Participants |
Secondary
Donor Chimerism at 1 Year
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.
Time frame: 1 year
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Transplant - 200 cGy | Donor Chimerism at 1 Year | Whole blood | 95-100% | 6 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | Whole blood | 5-94% | 9 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | Whole blood | 0-4% | 1 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | Whole blood | Unknown or not measured | 13 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | T cells | 95-100% | 7 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | T cells | 5-94% | 9 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | T cells | 0-4% | 0 Participants |
| Transplant - 200 cGy | Donor Chimerism at 1 Year | T cells | Unknown or not measured | 13 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | T cells | Unknown or not measured | 1 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | Whole blood | 95-100% | 9 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | T cells | 95-100% | 10 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | Whole blood | 5-94% | 3 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | T cells | 0-4% | 0 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | Whole blood | 0-4% | 0 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | T cells | 5-94% | 2 Participants |
| Transplant - 400 cGy | Donor Chimerism at 1 Year | Whole blood | Unknown or not measured | 1 Participants |
Secondary
Donor Chimerism at 30 Days
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.
Time frame: 30 days
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Transplant - 200 cGy | Donor Chimerism at 30 Days | Whole blood | 95-100% | 12 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | Whole blood | 5-94% | 15 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | Whole blood | 0-4% | 1 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | Whole blood | Unknown or not measured | 1 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | T cells | 95-100% | 4 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | T cells | 5-94% | 18 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | T cells | 0-4% | 5 Participants |
| Transplant - 200 cGy | Donor Chimerism at 30 Days | T cells | Unknown or not measured | 2 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | T cells | Unknown or not measured | 1 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | Whole blood | 95-100% | 8 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | T cells | 95-100% | 4 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | Whole blood | 5-94% | 3 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | T cells | 0-4% | 0 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | Whole blood | 0-4% | 1 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | T cells | 5-94% | 8 Participants |
| Transplant - 400 cGy | Donor Chimerism at 30 Days | Whole blood | Unknown or not measured | 1 Participants |