Leukemia, Lymphoma, Myelodysplastic Syndromes
Conditions
Keywords
refractory chronic lymphocytic 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), adult acute lymphoblastic leukemia in remission, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult grade III lymphomatoid granulomatosis, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, relapsing chronic myelogenous leukemia, recurrent cutaneous T-cell non-Hodgkin lymphoma, secondary acute myeloid leukemia
Brief summary
RATIONALE: Giving chemotherapy with or without total-body irradiation before a donor umbilical cord blood 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 the 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 cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening. PURPOSE: This clinical trial is studying how well four different chemotherapy regimens given with or without total-body irradiation before umbilical cord blood transplant work in treating patients with relapsed or refractory hematologic cancer.
Detailed description
OBJECTIVES: Primary * To determine the survival at day 100 of patients with relapsed, refractory, or poor-risk hematological malignancies treated with four different preparative regimens followed by allogeneic hematopoietic stem cell transplantation (HSCT) using two unrelated umbilical cord blood (UCB) units. Secondary * To determine the incidence and timing of neutrophil engraftment in patients treated with these regimens. * To determine the incidence and timing of platelet engraftment in patients treated with these regimens. * To determine the incidence and severity of acute and chronic graft-versus-host-disease (GVHD) in patients treated with these regimens. * To determine the survival at day 180 in patients treated with these regimens. * To determine the disease-free survival in patients treated with these regimens. * To determine the incidence of primary and secondary engraftment failure in patients treated with these regimens. * To determine the incidence of transplantation-related complications (e.g., infection, veno-occlusive disease of the liver, or organ toxicity) in these patients. * To determine the incidence of post-transplantation-related lymphoproliferative disease, secondary myelodysplastic syndromes, or other secondary malignancies in these patients. * To determine the incidence of relapse in patients treated with these regimens. * To determine post-transplantation chimerism in patients treated with these regimens. * To determine immune reconstitution in patients treated with these regimens. OUTLINE: This is a multicenter study. * Preparative regimens: Patients are assigned to 1 of 4 preparative regimens. * Regimen 1 (for patients \< 50 years of age and no contraindication to fractionated total-body irradiation (FTBI): Patients undergo FTBI 2-3 times a day on days -9 to -6 for a total of 11 fractions. Patients also receive cyclophosphamide IV over 2 hours on days -5 and -4 and fludarabine phosphate IV on days -5 to -2. * Regimen 2 (for patients \< 50 years of age and unable to tolerate FTBI due to prior dose-limiting radiotherapy or significant cardiotoxicity): Patients receive a test dose of busulfan on day -10 and then dose adjusted busulfan IV 3-4 times daily on days -9 to -6, melphalan IV on days -5 and -4, and fludarabine phosphate IV on days -5 to -2. * Regimen 3\* (for patients unable to tolerate regimen 1 or 2; no age exclusion): Patients receive fludarabine phosphate IV on days -8 to -4 and cyclophosphamide IV over 2 hours on day -3 and undergo TBI (single dose) on day -2. * Regimen 4\* (for patients unable to tolerate regimen 1 or 2): Patients receive fludarabine phosphate IV on days -7 to -3 and melphalan IV on day -2. NOTE: \*Treating physician decides the choice between regimen 3 and 4 * Umbilical cord blood (UCB) transplantation: Patients receive 2 combined units of UCB IV on day 0. Patients also receive G-CSF IV or subcutaneously beginning on day 5 (or later) and continuing until blood counts recover. * Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV twice daily beginning on day -1 followed by a taper according to institutional guidelines. Patients also receive mycophenolate mofetil orally or IV beginning on day 0 and continuing until day 27 (or as clinically indicated). After completion of study therapy, patients are followed periodically.
Interventions
BIOLOGICALfilgrastim
DRUGBusulfan
DRUGCyclophosphamide
DRUGCyclosporine
DRUGFludarabine phosphate
DRUGMelphalan
DRUGMycophenolate Mofetil
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREumbilical cord blood transplantation
RADIATIONtotal-body irradiation
RADIATIONFractionated total body irradiation
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed hematological or lymphatic malignancy, including any of the following: * Acute myeloid leukemia * Relapsed or primary refractory disease with \< 10% blasts on peripheral blood smear * In first remission with poor risk factors and molecular prognosis \[i.e., AML with -5, -7, t(6;9), tri8, -11\] (preparative regimen 3 or 4) * Acute lymphocytic leukemia * In second complete remission or higher OR in first remission with poor risk factors, including any of the following (preparative regimen 1 or 2): * BCR/ABL by fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction * t(9;22)(q34;q11) detected by cytogenetics * Chromosomes \< 44 by cytogenetics * DNA index \< 0.81 by flow cytometry * Any rearrangement of chromosome 11 that results in disruption of MLL gene (11q23) by cytogenetics and SER * In first remission with poor risk factors and molecular prognosis \[ALL with Philadelphia chromosome-positive t(9;22), t(4;22), (q34;q11)\] (preparative regimen 3 or 4) * Chronic myelogenous leukemia * In accelerated phase or greater (preparative regimen 1 or 2) * In accelerated or second chronic phase (preparative regimen 3 or 4) * Myelodysplastic syndromes * With deletion of chromosome 7 or short arm of chromosome 5 (preparative regimen 1 or 2) * In high and high-intermediate risk categories (preparative regimen 3 or 4) * Non-Hodgkin lymphoma in relapse with marrow involvement * Refractory chronic lymphocytic leukemia * Patients deemed ineligible for conventional high-dose chemotherapy programs (i.e., regimens 1 or 2) due to any of the following concurrent medical conditions may be eligible for regimens 3 or 4 at the discretion of the treating physician and principal investigator (preparative regimen 3 or 4): * LVEF \< 50% and \> 40% * FEV1, FVC, or DLCO \< 50% * Bilirubin \> 3 mg/dL * Creatinine \> 2 mg/dL * Two partially HLA-matched umbilical cord blood (UCB) units available * HLA-matched minimally at 4 of 6 HLA-A, HLA-B, and -DRB1 loci with the patient * DRB1 matched by high resolution DNA typing * HLA-A and HLA-B matched by low resolution at the serological match level * Two pooled units with a nucleated cell number \> 2.5 x 10\^7/kg * No available HLA-identical sibling or 1 antigen-mismatched related donor * No available HLA-matched unrelated bone marrow donor PATIENT CHARACTERISTICS: * See Disease Characteristics * Karnofsky performance status (PS) 60-100% OR Lansky PS 60-100% OR Zubrod PS 0-1 * Physiological age 60 or less (at any chronological age) * Weight \> 50 kg * Creatinine normal for age OR creatinine clearance by 24-hour urine collection or glomerular filtration rate \> 60 mL/min * Bilirubin ≤ 1.5 mg/dL * LVEF ≥ 50% * DLCO ≥ 60% of predicted * No HIV-1 infection * No active uncontrolled infection * Not pregnant * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * Recovered from prior intensive chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival Rate at Day 100 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | From transplant to Day 100 post-transplant | Number of surviving patients at Day 100 post-transplant divided by number of patients undergone transplantation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival Rate at Day 180 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | From transplant up to Day 180 post-transplant | Number of surviving patients at Day 180 post-transplant divided by number of patients undergone transplantation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen I (FTBI, Cyclophosphamide, Fludarabine) Patients undergo FTBI 2-3 times a day on days -9 to -6 for a total of 11 fractions. Patients also receive cyclophosphamide IV over 2 hours on days -5 and -4 and fludarabine phosphate IV on days -5 to -2. UCB transplantation: Patients receive 2 combined units of UCB IV on day 0. Patients also receive G-CSF IV or subcutaneously beginning on day 5 (or later) and continuing until blood counts recover. GVHD prophylaxis: Patients receive cyclosporine IV twice daily beginning on day -1 followed by a taper according to institutional guidelines. Patients also receive mycophenolate mofetil orally or IV beginning on day 0 and continuing until day 27 (or as clinically indicated).
filgrastim
Cyclophosphamide
Cyclosporine
Fludarabine phosphate
Mycophenolate Mofetil
allogeneic hematopoietic stem cell transplantation
umbilical cord blood transplantation
Fractionated total body irradiation | 5 |
| Regimen II (Busulfan, Fludarabine, Melphalan) Patients receive a test dose of busulfan on day -10 and then dose adjusted busulfan IV 3-4 times daily on days -9 to -6, melphalan IV on days -5 and -4, and fludarabine phosphate IV on days -5 to -2. UCB transplantation: Patients receive 2 combined units of UCB IV on day 0. Patients also receive G-CSF IV or subcutaneously beginning on day 5 (or later) and continuing until blood counts recover. GVHD prophylaxis: Patients receive cyclosporine IV twice daily beginning on day -1 followed by a taper according to institutional guidelines. Patients also receive mycophenolate mofetil orally or IV beginning on day 0 and continuing until day 27 (or as clinically indicated).
filgrastim
Busulfan
Cyclosporine
Fludarabine phosphate
Melphalan
Mycophenolate Mofetil
allogeneic hematopoietic stem cell transplantation
umbilical cord blood transplantation | 0 |
| Regimen III (TBI, Cyclophosphamide, Fludarabine) Patients receive fludarabine phosphate IV on days -8 to -4 and cyclophosphamide IV over 2 hours on day -3 and undergo TBI (single dose) on day -2. UCB transplantation: Patients receive 2 combined units of UCB IV on day 0. Patients also receive G-CSF IV or subcutaneously beginning on day 5 (or later) and continuing until blood counts recover. GVHD prophylaxis: Patients receive cyclosporine IV twice daily beginning on day -1 followed by a taper according to institutional guidelines. Patients also receive mycophenolate mofetil orally or IV beginning on day 0 and continuing until day 27 (or as clinically indicated).
filgrastim
Cyclophosphamide
Cyclosporine
Fludarabine phosphate
Mycophenolate Mofetil
allogeneic hematopoietic stem cell transplantation
umbilical cord blood transplantation
total-body irradiation | 1 |
| Regimen IV (Fludarabine, Melphalan) Patients receive fludarabine phosphate IV on days -7 to -3 and melphalan IV on day -2. UCB transplantation: Patients receive 2 combined units of UCB IV on day 0. Patients also receive G-CSF IV or subcutaneously beginning on day 5 (or later) and continuing until blood counts recover. GVHD prophylaxis: Patients receive cyclosporine IV twice daily beginning on day -1 followed by a taper according to institutional guidelines. Patients also receive mycophenolate mofetil orally or IV beginning on day 0 and continuing until day 27 (or as clinically indicated).
filgrastim
Cyclosporine
Fludarabine phosphate
Melphalan
Mycophenolate Mofetil
allogeneic hematopoietic stem cell transplantation
umbilical cord blood transplantation | 2 |
| Unassigned Patients consented but were not eligible for the treatment after screening. | 2 |
| Total | 10 |
Baseline characteristics
| Characteristic | Regimen I (FTBI, Cyclophosphamide, Fludarabine) | Total | Unassigned | Regimen IV (Fludarabine, Melphalan) | Regimen III (TBI, Cyclophosphamide, Fludarabine) |
|---|---|---|---|---|---|
| Age, Continuous | 14 years | 15 years | 18.5 years | 35 years | 58 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 6 Participants | 1 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 5 participants | 10 participants | 2 participants | 2 participants | 1 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 2 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 0 / 0 | 1 / 1 | 2 / 2 |
| other Total, other adverse events | 3 / 5 | 0 / 0 | 1 / 1 | 1 / 2 |
| serious Total, serious adverse events | 2 / 5 | 0 / 0 | 1 / 1 | 1 / 2 |
Outcome results
Primary
Survival Rate at Day 100 After Allogeneic Transplant From Umbilical Cord Blood (UCB)
Number of surviving patients at Day 100 post-transplant divided by number of patients undergone transplantation.
Time frame: From transplant to Day 100 post-transplant
Population: No subject in the Regimen II arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen I (FTBI, Cyclophosphamide, Fludarabine) | Survival Rate at Day 100 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | 100 percentage of surviving patients |
| Regimen III (TBI, Cyclophosphamide, Fludarabine) | Survival Rate at Day 100 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | 100 percentage of surviving patients |
| Regimen IV (Fludarabine, Melphalan) | Survival Rate at Day 100 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | 100 percentage of surviving patients |
Secondary
Survival Rate at Day 180 After Allogeneic Transplant From Umbilical Cord Blood (UCB)
Number of surviving patients at Day 180 post-transplant divided by number of patients undergone transplantation.
Time frame: From transplant up to Day 180 post-transplant
Population: No subject in the Regimen II arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen I (FTBI, Cyclophosphamide, Fludarabine) | Survival Rate at Day 180 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | 60 percentage of surviving patients |
| Regimen III (TBI, Cyclophosphamide, Fludarabine) | Survival Rate at Day 180 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | 100 percentage of surviving patients |
| Regimen IV (Fludarabine, Melphalan) | Survival Rate at Day 180 After Allogeneic Transplant From Umbilical Cord Blood (UCB) | 50 percentage of surviving patients |