Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia in Remission, Aggressive Non-Hodgkin Lymphoma, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Diffuse Large B-Cell Lymphoma, Hematopoietic and Lymphoid Cell Neoplasm, Indolent Non-Hodgkin Lymphoma, Mantle Cell Lymphoma, Myelodysplastic/Myeloproliferative Neoplasm, Plasma Cell Myeloma, Refractory Chronic Lymphocytic Leukemia, Refractory Hodgkin Lymphoma, Waldenstrom Macroglobulinemia
Conditions
Brief summary
This randomized phase III trial is studying total-body irradiation (TBI) and fludarabine phosphate to see how it works compared with TBI alone followed by donor stem cell transplant in treating patients with hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, and radiation therapy before a donor stem cell transplant 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 system 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 cyclosporine and mycophenolate mofetil after transplant may stop this from happening. It is not yet known whether TBI followed by donor stem cell transplant is more effective with or without fludarabine phosphate in treating hematologic cancer.
Detailed description
PRIMARY OBJECTIVES: I. To compare overall survival at 3 years after conditioning with 200 cGy TBI alone vs. fludarabine (fludarabine phosphate)/200 cGy TBI in heavily pretreated patients with hematologic malignancies at low/moderate risk for graft rejection. SECONDARY OBJECTIVES: I. To compare the non-relapse mortality 1-year after conditioning in patients who received TBI alone vs. fludarabine/TBI. II. To compare the incidences of graft rejection in patients who received TBI alone vs. fludarabine/TBI. III. To compare the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD. IV. To compare rates of disease progression and/or relapse-related mortality. V. To compare the immune reconstitution and the risks of infections. OUTLINE: NONMYELOABLATIVE CONDITIONING REGIMEN: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2. Patients then undergo low-dose TBI on day 0. ARM II: Patients undergo low-dose TBI on day 0. ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): After TBI, patients undergo PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive mycophenolate mofetil (MMF) PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins. Patients are followed up periodically for 1.5 years and then annually for 5 years post-transplantation.
Interventions
PROCEDURETotal-Body Irradiation
Undergo TBI
DRUGFludarabine Phosphate
Given IV
DRUGMycophenolate Mofetil
Given PO
DRUGCyclosporine
Given PO
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo transplantation
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be not eligible for conventional allogeneic hematopoietic cell transplantation (HCT) and must have disease expected to be stable for at least 100 days without chemotherapy * An autograft immediately prior (less than 6 months) to nonmyeloablative HCT (tandem approach) is not permitted * Patients with hematologic malignancies treatable with HCT or with a B cell malignancy except those curable with autologous transplant will be included * Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B cell NHL: patients are eligible IF they are not eligible for autologous hematopoietic stem cell transplantation (HSCT), not eligible for conventional myeloablative HSCT, or have failed an autologous HSCT * Low grade NHL with \< 6 month duration of complete remission (CR) between courses of conventional therapy * Mantle cell NHL; may be treated in first CR * Chronic lymphocytic leukemia (CLL) must have either: * Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog, e.g. cladribine \[2-CDA\], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog) * Failed FLU-cyclophosphamide \[CY\]-rituximab (FCR) combination chemotherapy at any time point * Have 17p deletion cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR * Or patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL * Hodgkin lymphoma (HL): must have received and failed frontline therapy; patients must have failed or were not eligible for autologous transplant * Multiple myeloma (MM): must have chemosensitive disease after failed autografting (an autografting immediately prior \[within 6 months\] to nonmyeloablative HCT \[tandem approach\] is not permitted) * Acute myeloid leukemia (AML): must have \< 5% marrow blasts at the time of transplant and be beyond first CR * Acute lymphocytic leukemia (ALL): must have \< 5% marrow blasts at the time of transplant and be beyond first CR * Chronic myelogenous leukemia (CML): patients will be accepted in chronic phase (CP) beyond CP1 if they have received previous myelosuppressive chemotherapy or HCT, \< 5% marrow blasts at time of transplant * Myelodysplastic syndromes (MDS)/myeloproliferative disorders (MPD): must have received previous myelosuppressive chemotherapy or HCT, \< 5% marrow blasts at time of transplant * Waldenstroms Macroglobulinemia: must have failed 2 courses of therapy * Patients will not be allowed to receive myelosuppressive chemotherapy for three weeks prior to conditioning * Patients \< 12 years old must be approved by both the participating institutions' patient review committee such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and the FHCRC principal investigator * Patients who refused to be treated on a conventional HCT protocol; for this inclusion criterion, transplants must be approved by both the participating institution's patient review committee such as the Patient Care Conference (PCC) at the FHCRC and the FHCRC principal investigator * Patients with human leukocyte antigen (HLA)-matched related donors * DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1 * DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis * DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) * DONOR: For females of child bearing age, serum pregnancy qualitative (PGSTAT) within 72 hours prior to initial dose of filgrastim (G-CSF); results must be available prior to filgrastim
Exclusion criteria
* Eligible for a high priority curative autologous transplant * Patients with rapidly progressive, aggressive NHL unless in minimal disease state * Patients with chronic myelomonocytic leukemia * Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML * Life expectancy severely limited by diseases other than malignancy * Any current central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy * Fertile men or women unwilling to use contraceptives during and for up to 12 months post treatment * Female patients who are pregnant or breastfeeding * Human immunodeficiency virus (HIV) positive patients * Patients with active non-hematological malignancies (except localized non-melanoma skin malignancies) * Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \> 20% risk of disease recurrence * Fungal infections with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month * Patients with active bacterial or fungal infections unresponsive to medical therapy * Karnofsky score \< 50 for adult patients * Lansky-Play performance score \< 50 for pediatric patients * The addition of cytotoxic agents for cytoreduction with the exception of tyrosine kinase inhibitors (imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning * Patients with the following organ dysfunction: * Symptomatic coronary artery disease or ejection fraction \< 35% or other cardiac failure requiring therapy (required for patients with history of cardiac disease or anthracycline use); ejection fraction is required if age \> 50 years or there is a history of anthracycline exposure or history of cardiac disease * Poorly controlled hypertension on multiple antihypertensives * Pulmonary: diffusion capacity of carbon monoxide (DLCO) \< 30%, total lung capacity (TLC) \< 30%, forced expiratory volume in one second (FEV1) \< 30% and/or receiving supplementary continuous oxygen; the FHCRC study principal investigator (PI) must approve enrollment of all patients with pulmonary nodules * Liver function abnormalities: patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, and symptomatic biliary disease * DONOR: Age less than 12 years * DONOR: Identical twin * DONOR: Pregnancy * DONOR: Infection with HIV * DONOR: Known allergy to filgrastim * DONOR: Current serious systemic illness that would result in increased risk for filgrastim mobilization and harvest of PBSC
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 3 years after transplant | Percentage of patients surviving as estimated by Kaplan-Meier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Relapse/Progression | 3 years after transplant | Percentage of relapse estimated by cumulative incidence methods |
| Incidence of Relapse-related Mortality | 3 years after transplant | Percentage of death following relapse/progression, estimated by cumulative incidence methods |
| Incidence of Grades II-IV Acute GVHD | 120 days after transplant | Percentage patients with grades II-IV GHVD, estimated by cumulative incidence methods |
| Incidence of Non-relapse Mortality | 3 years after transplant | Percentage of NRM as estimated by cumulative incidence methods with competing risks |
| Incidence of Graft Rejection | 1 year after transplant | Donor CD3 chimerism less than 5% |
| Progression-free Survival | 3 years after transplant | Percentage of patients with progression-free survival, estimated by cumulative incidence methods |
| Incidence of Chronic Extensive GVHD | 3 years after transplant | Percentage patients with chronic extensive GVHD, estimated by cumulative incidence methods |
Countries
Germany, Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) Patients receive fludarabine phosphate IV on days -4 to -2. Patients then undergo low-dose TBI on day 0. After TBI, patients undergo PBSCT on day 0. Patients receive cyclosporine PO BID on days -3 to 56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive MMF PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.
total-body irradiation: Undergo TBI
fludarabine phosphate: Given IV
mycophenolate mofetil: Given PO
cyclosporine: Given PO
peripheral blood stem cell transplantation: Undergo transplantation | 41 |
| Arm II (TBI, Transplant, GVHD Prophylaxis) Patients undergo low-dose TBI on day 0. After TBI, patients undergo PBSCT on day 0. Patients receive cyclosporine PO BID on days -3 to 56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive MMF PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.
total-body irradiation: Undergo TBI
mycophenolate mofetil: Given PO
cyclosporine: Given PO
peripheral blood stem cell transplantation: Undergo transplantation | 44 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | not eligible | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Arm II (TBI, Transplant, GVHD Prophylaxis) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 4 Participants | 6 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 37 Participants | 73 Participants |
| Age, Continuous | 57 years | 54.5 years | 56 years |
| Region of Enrollment Germany | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Italy | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 33 participants | 37 participants | 70 participants |
| Sex: Female, Male Female | 16 Participants | 11 Participants | 27 Participants |
| Sex: Female, Male Male | 25 Participants | 33 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 41 | 20 / 44 |
| serious Total, serious adverse events | 8 / 41 | 5 / 44 |
Outcome results
Primary
Overall Survival
Percentage of patients surviving as estimated by Kaplan-Meier.
Time frame: 3 years after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Overall Survival | 65 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Overall Survival | 54 percentage of participants |
Comparison: Reference arm is Arm 2.p-value: 0.0995% CI: [0.3, 1.1]Regression, Cox
Secondary
Incidence of Chronic Extensive GVHD
Percentage patients with chronic extensive GVHD, estimated by cumulative incidence methods
Time frame: 3 years after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Incidence of Chronic Extensive GVHD | 72 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Incidence of Chronic Extensive GVHD | 48 percentage of participants |
p-value: 0.1495% CI: [0.9, 2.7]Regression, Cox
Secondary
Incidence of Grades II-IV Acute GVHD
Percentage patients with grades II-IV GHVD, estimated by cumulative incidence methods
Time frame: 120 days after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Incidence of Grades II-IV Acute GVHD | 46 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Incidence of Grades II-IV Acute GVHD | 32 percentage of participants |
p-value: 0.1695% CI: [0.8, 3.1]Regression, Cox
Secondary
Incidence of Graft Rejection
Donor CD3 chimerism less than 5%
Time frame: 1 year after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Incidence of Graft Rejection | 0 participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Incidence of Graft Rejection | 2 participants |
Secondary
Incidence of Non-relapse Mortality
Percentage of NRM as estimated by cumulative incidence methods with competing risks
Time frame: 3 years after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Incidence of Non-relapse Mortality | 7 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Incidence of Non-relapse Mortality | 9 percentage of participants |
p-value: 0.5995% CI: [0.1, 3]Regression, Cox
Secondary
Incidence of Relapse/Progression
Percentage of relapse estimated by cumulative incidence methods
Time frame: 3 years after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Incidence of Relapse/Progression | 40 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Incidence of Relapse/Progression | 55 percentage of participants |
p-value: 0.0695% CI: [0.3, 1]Regression, Cox
Secondary
Incidence of Relapse-related Mortality
Percentage of death following relapse/progression, estimated by cumulative incidence methods
Time frame: 3 years after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Incidence of Relapse-related Mortality | 28 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Incidence of Relapse-related Mortality | 37 percentage of participants |
p-value: 0.0995% CI: [0.3, 1.1]Regression, Cox
Secondary
Progression-free Survival
Percentage of patients with progression-free survival, estimated by cumulative incidence methods
Time frame: 3 years after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, TBI, Transplant, GVHD Prophylaxis) | Progression-free Survival | 53 percentage of participants |
| Arm II (TBI, Transplant, GVHD Prophylaxis) | Progression-free Survival | 36 percentage of participants |
p-value: 0.0595% CI: [0.3, 1]Regression, Cox