B-cell Lymphoma, Chronic Lymphocytic Leukemia, Lymphoma, Non Hodgkin Lymphoma
Conditions
Keywords
lymphoma, non hodgkin lymphoma, allogeneic, bone marrow transplantation, nonmyeloablative, cyclophosphamide, rituximab
Brief summary
This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation and rituximab works in treating patients with B-cell lymphoma or chronic lymphocytic leukemia who are undergoing an allogeneic (donor) bone marrow transplant. The type of bone marrow transplant is a less intensive or mini transplant using a relative as the bone marrow donor. The donated bone marrow stem cells may replace the patient's immune system cells and help destroy any remaining cancer (graft-versus-tumor effect). Patients undergoing this type of transplant often have more than one relative who could be a donor. The trial is also studying a new way of choosing amongst possible donors which might improve how the rituximab works.
Detailed description
This phase II for relapsed or refractory B-cell malignancies builds on the platform of nonmyeloablative, related-donor, HLA (human leukocyte antigen)-matched or HLA-haploidentical BMT with post-transplantation high-dose cyclosphosphamide administered for prophylaxis of graft-versus-host disease and graft rejection. Rituximab is added to the transplant regimen with the goal of augmenting anti-tumor activity. In patients with B-cell lymphomas, specific polymorphisms in the immunoglobulin Fc receptor have been associated with greater sensitivity to rituximab or rituximab-based therapies, translating in some series into higher response rates and improved progression-free survival. This raises the possibility of selecting donors who carry this permissive polymorphism. This trial identifies and selects donors who have the favorable polymorphism at FcgammaR3A-158, thereby potentially conferring greater sensitivity to rituximab in the host after BMT.
Interventions
DRUGFludarabine
Days -6 through -2: 30 mg/m\^2 IV daily
DRUGCyclophosphamide
Days -6 and -5: 14.5 mg/kg IV daily; Days 3 and 4: 50 mg/kg IV daily
RADIATIONTotal body irradiation
Day -1: 200 centigray (cGy) in a single fraction
DRUGTacrolimus
Start on Day 5 through Day 180
DRUGMycophenolate Mofetil
Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)
DRUGRituximab
Day 30 and every week after for 8 total doses: 375 mg/m\^2 IV
BIOLOGICALAllogeneic Bone Marrow Transplant (BMT)
Day 0: Donor bone marrow infusion
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Poor-risk CD20+, B-cell lymphoma, as follows: * Low grade B-cell lymphoma that has failed at least two prior therapies (excluding single agent rituximab), or undergone histologic conversion (if histologic conversion, PR or CR is required): 1. Follicular grade 1 or 2 lymphoma 2. Follicular lymphoma not otherwise specified 3. Marginal zone (or MALT) lymphoma 4. Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia 5. Hairy cell leukemia 6. Small lymphocytic lymphoma / chronic lymphocytic leukemia (SLL/CLL) 7. Low grade B-cell lymphoma, unspecified 8. Nodular lymphocyte-predominant Hodgkin lymphoma * Poor-risk small lymphocytic lymphoma or chronic lymphocytic leukemia, defined by a 17p deletion, 11q deletion, or histologic conversion (if histologic conversion, PR or CR is required) * Aggressive B-cell non-Hodgkin's lymphoma that has failed at least one prior regimen of multiagent chemotherapy, is in PR (partial remission) or CR (complete remission), and patient is either ineligible for autologous hematopoietic BMT or autologous BMT is not recommended: 1. Follicular grade 3 lymphoma 2. Histoconversion of low-grade B-cell lymphoma (including SLL/CLL) to aggressive B-cell non-Hodgkin's lymphoma 3. Mantle cell lymphoma 4. Diffuse large B-cell lymphoma (excluding primary CNS \[central nervous system\] lymphoma) 5. Gray zone or composite lymphomas with combined features of primary mediastinal large B-cell and Hodgkin's lymphoma 6. Burkitt's lymphoma/leukemia 7. Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma) * Must have a related donor who is at least HLA haploidentical * Any previous BMT must have occurred at least 3 months prior * Left ventricular ejection fraction at least 35% * Bilirubin no more than 3.0 mg/dL (unless due to Gilbert's syndrome), and ALT (alanine aminotransferase) and AST (aspartate aminotransferase) no more than 5 x upper limit of normal * FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) at least 40% of predicted * Absence of uncontrolled infection
Exclusion criteria
* More than 20% involvement of bone marrow by chronic lymphocytic leukemia * Active central nervous system lymphoma * ECOG (Eastern Cooperative Oncology Group) performance status greater than 1 (2,3, and 4) * HIV positive * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 1 year post-intervention | Percentage of participants alive and without relapse or disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 1 year post intervention | Percentage of participants alive. |
| Relapse | 1 year post intervention | Percentage of participants alive with relapse or disease progression. |
| Non-relapse Mortality | 1 year post intervention | Percentage of participants who died due to BMT-related reasons. |
| Incidence of Grades II-IV Acute Graft-versus-Host-Disease (GVHD) | 1 year post intervention | Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria. |
| Progression-free Survival | 2 years post-intervention | Percentage of participants alive with and without relapse. |
| Incidence of Chronic GVHD | 1 year post intervention | Percentage of participants who experienced chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. |
| Engraftment | Day 60 | Percentage of patients who engrafted neutrophils and platelets. |
| Graft Failure | Day 60 | Percentage of participants who failed to engraft. |
| Incidence of Grades III-IV Acute GVHD | 1 year post intervention | Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria. |
Countries
United States
Participant flow
Pre-assignment details
52 participants were screen failures and did not proceed on the study.
Participants by arm
| Arm | Count |
|---|---|
| Transplant Non-myeloablative bone marrow transplant with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis. Rituximab will be given as post-transplant maintenance.
Fludarabine: Days -6 through -2: 30 mg/m\^2 IV daily
Cyclophosphamide: Days -6 and -5: 14.5 mg/kg IV daily; Days 3 and 4: 50 mg/kg IV daily
Total body irradiation: Day -1: 200 centigray (cGy) in a single fraction
Tacrolimus: Start on Day 5 through Day 180
Mycophenolate Mofetil: Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)
Rituximab: Day 30 and every week after for 8 total doses: 375 mg/m\^2 IV | 83 |
| Total | 83 |
Baseline characteristics
| Characteristic | Transplant |
|---|---|
| Age, Continuous | 59 years |
| Age, Customized >= 60 years old | 39 Participants |
| Region of Enrollment United States | 83 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 34 / 83 |
| other Total, other adverse events | 62 / 83 |
| serious Total, serious adverse events | 56 / 83 |
Outcome results
Primary
Progression-free Survival
Percentage of participants alive and without relapse or disease progression.
Time frame: 1 year post-intervention
Population: Populations were analyzed as follows:~1. All participants~2. Recipients of haploidentical donors (69 participants)~3. Recipients of VV, VF, and FF donors (17, 43, and 23 participants, respectively, totaling 83 participants)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Progression-free Survival | All participants | 71 percentage of participants |
| Transplant | Progression-free Survival | Haploidentical recipients | 70 percentage of participants |
| Transplant | Progression-free Survival | VV donor | 82 percentage of participants |
| Transplant | Progression-free Survival | VF donor | 70 percentage of participants |
| Transplant | Progression-free Survival | FF donor | 65 percentage of participants |
Secondary
Engraftment
Percentage of patients who engrafted neutrophils and platelets.
Time frame: Day 60
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Engraftment | Neutrophil engraftment | 98 percentage of participants |
| Transplant | Engraftment | Platelet engraftment | 98 percentage of participants |
Secondary
Graft Failure
Percentage of participants who failed to engraft.
Time frame: Day 60
Population: Two participants were not analyzed because they died prior to Day 60.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant | Graft Failure | 2 Participants |
Secondary
Incidence of Chronic GVHD
Percentage of participants who experienced chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria.
Time frame: 1 year post intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant | Incidence of Chronic GVHD | 11 percentage of participants |
Secondary
Incidence of Grades III-IV Acute GVHD
Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria.
Time frame: 1 year post intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant | Incidence of Grades III-IV Acute GVHD | 5 percentage of participants |
Secondary
Incidence of Grades II-IV Acute Graft-versus-Host-Disease (GVHD)
Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria.
Time frame: 1 year post intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant | Incidence of Grades II-IV Acute Graft-versus-Host-Disease (GVHD) | 41 percentage of participants |
Secondary
Non-relapse Mortality
Percentage of participants who died due to BMT-related reasons.
Time frame: 1 year post intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant | Non-relapse Mortality | 8 percentage of participants |
Secondary
Overall Survival
Percentage of participants alive.
Time frame: 2 years post intervention
Population: Populations were analyzed as follows:~All participants Recipients of haploidentical donors (69 participants) Recipients of VV, VF, and FF donors (17, 43, and 23 participants, respectively, totaling 83 participants)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Overall Survival | All participants | 76 percentage of participants |
| Transplant | Overall Survival | Haploidentical recipients | 73 percentage of participants |
| Transplant | Overall Survival | VV donor | 87 percentage of participants |
| Transplant | Overall Survival | VF donor | 76 percentage of participants |
| Transplant | Overall Survival | FF donor | 69 percentage of participants |
Secondary
Overall Survival
Percentage of participants alive.
Time frame: 1 year post intervention
Population: Populations were analyzed as follows:~All participants Recipients of haploidentical donors (69 participants) Recipients of VV, VF, and FF donors (17, 43, and 23 participants, respectively, totaling 83 participants)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Overall Survival | All participants | 86 percentage of participants |
| Transplant | Overall Survival | Haploidentical recipients | 83 percentage of participants |
| Transplant | Overall Survival | VV donor | 94 percentage of participants |
| Transplant | Overall Survival | VF donor | 86 percentage of participants |
| Transplant | Overall Survival | FF donor | 78 percentage of participants |
Secondary
Progression-free Survival
Percentage of participants alive with and without relapse.
Time frame: 2 years post-intervention
Population: Populations were analyzed as follows:~All participants Recipients of haploidentical donors (69 participants) Recipients of VV, VF, and FF donors (17, 43, and 23 participants, respectively, totaling 83 participants)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Progression-free Survival | All participants | 60 percentage of participants |
| Transplant | Progression-free Survival | Haploidentical recipients | 63 percentage of participants |
| Transplant | Progression-free Survival | VV donor | 68 percentage of participants |
| Transplant | Progression-free Survival | VF donor | 59 percentage of participants |
| Transplant | Progression-free Survival | FF donor | 56 percentage of participants |
Secondary
Relapse
Percentage of participants alive with relapse or disease progression.
Time frame: 2 years post intervention
Population: Populations were analyzed as follows:~All participants Recipients of haploidentical donors (69 participants) Recipients of VV, VF, and FF donors (17, 43, and 23 participants, respectively, totaling 83 participants)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Relapse | Haploidentical recipients | 23 percentage of participants |
| Transplant | Relapse | VV donor | 25 percentage of participants |
| Transplant | Relapse | All participants | 27 percentage of participants |
| Transplant | Relapse | VF donor | 31 percentage of participants |
| Transplant | Relapse | FF donor | 22 percentage of participants |
Secondary
Relapse
Percentage of participants alive with relapse or disease progression.
Time frame: 1 year post intervention
Population: Populations were analyzed as follows:~All participants Recipients of haploidentical donors (69 participants) Recipients of VV, VF, and FF donors (17, 43, and 23 participants, respectively, totaling 83 participants)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant | Relapse | All participants | 20 percentage of participants |
| Transplant | Relapse | Haploidentical recipients | 20 percentage of participants |
| Transplant | Relapse | VV donor | 18 percentage of participants |
| Transplant | Relapse | VF donor | 23 percentage of participants |
| Transplant | Relapse | FF donor | 17 percentage of participants |