Lymphoma, Non-Hodgkin
Conditions
Keywords
Follicular Non-Hodgkin's Lymphoma, Hematopoietic Stem Cell Transplant (HSCT), Non-Myeloablative Transplant (NST)
Brief summary
Blood stem cell transplants are one treatment option for people with lymphoma or other types of blood cancers. For this type of treatment, family members or unrelated donors with a similar tissue type usually donate their blood stem cells to the transplant patients. This study will evaluate the effectiveness of a type of blood stem cell transplant that uses lower doses of chemotherapy in people with relapsed follicular non-Hodgkin's lymphoma (NHL).
Detailed description
Follicular NHL, a type of blood cancer, is the second most common type of non-Hodgkin's lymphoma, with approximately 15,000 new cases being diagnosed each year in the United States. Chemotherapy is a common treatment option for people with NHL, and at first most people achieve cancer remission with initial chemotherapy. However, after the initial chemotherapy, people with this disease typically experience a continuous pattern of relapse that results in progressively shorter remission durations. A blood stem cell transplant is another treatment option for people with follicular NHL. In a blood stem cell transplant procedure, healthy blood stem cells are taken from a donor and transplanted into the patient. The cells can be donated by a family member or an unrelated donor who has a similar tissue type. Typically, people who are undergoing a blood stem cell transplant receive high doses of chemotherapy before the transplant to prepare their bodies to accept the donor stem cells. In this study, participants will undergo a type of stem cell transplant called a nonmyeloablative transplant, which involves a reduced intensity method of transplantation that does not require high doses of chemotherapy. The purpose of the study is to examine the effectiveness of a nonmyeloablative allogeneic blood stem cell transplant at improving survival rates in people with relapsed follicular NHL. This study will enroll people with relapsed follicular NHL. At a baseline study visit, participants will undergo a medical history review, physical examination, blood collection, lung function testing, computed tomography (CT) scans, a bone marrow biopsy, and questionnaires to assess quality of life. Participants will be admitted to the hospital and on various days in the 2 weeks before the transplant, they will receive fludarabine, cyclophosphamide, rituximab, which are cancer medications, and tacrolimus, a medication that will help prevent graft-versus-host disease (GVHD), which is an attack by the donor cells on the body's normal tissues. Participants will then undergo the blood stem cell transplant. At various times during the 2 weeks after the transplant, participants will receive rituximab and methotrexate, which is another medication to prevent GVHD. They will also receive tacrolimus for at least 6 months to help prevent GVHD. Participants will remain in the hospital for as long as necessary to recover from the transplant. Follow-up study visits will occur weekly for Weeks 1 to 14, and then at Months 6, 12, 18, and 24. At each study visit, select baseline procedures will be repeated.
Interventions
BIOLOGICALHematopoietic Stem Cell Transplant
NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant. The conditioning regimen will consist of the following: * Rituxan 375 mg/m\^2 on Day -13 * Rituxan 1000 mg/m\^2 on Days -6, +1, and +8 * Fludarabine 30 mg/m\^2 on Days -5 to -3 * Cyclophosphamide 750 mg/m\^2 on Days -5, -4, -3 Day 0 will be the day of the transplant. The GVHD prophylaxis will consist of the following: * Tacrolimus .09 mg/kg/po (Day -2 thru Day +180). Doses will be adjusted to maintain blood levels of 5-15 ng/mL. * Methotrexate 5 mg/m\^2 (Days +1, +3, and +6). Unrelated donor recipients will receive a fourth dose on Day +11.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Medical College of Wisconsin
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
* Must have confirmed CD20+ follicle center lymphoma that meets one of the following: 1. Histologically confirmed recurrent Revised European American Lymphoma (REAL) Classification CD20+ follicle center lymphoma, follicular grades I and II 2. Histologically confirmed World Health Organization (WHO) classification CD20+ follicular lymphoma grades 1, 2, or 3a. For either classification, the diffuse component of large cleaved cells (if present) cannot be greater than 50% of cellularity. Patients do not have to express t(14;18) to be eligible. * Any number of prior regimens (including autologous hematopoietic cell transplantation \[HCT\]); the most recent prior regimen must have occurred more than 28 days before study entry * Must demonstrate chemosensitive or radiosensitive disease to most recent prior regimen and meet one of the following criteria: 1. Patients in second or subsequent complete remission (CR) 2. Patients in first or subsequent partial remission (PR) 3. Patients experiencing a relapse that demonstrates a response, as defined as largest nodal mass less than or equal to 3 cm or greater than or equal to 50% reduction in estimated lymph node volume measured as a product of bi-dimensional measurements (see protocol for detailed definition). 4. Patients with stable follicular lymphoma are eligible if all lymph node masses are less than or equal to 3 cm and are smaller or unchanged in size to the most recent salvage regimen. * Patients with human leukocyte antigen (HLA)-matched donors that meet the following criteria: 1. 6/6 HLA-matched related donor. HLA typing must be performed by DNA methods for HLA-A and B at intermediate (or higher) resolution, and DRB1 at high resolution. The donor must be willing to donate peripheral blood stem cells and meet institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to individual transplant center criteria; or, 2. 8/8 HLA-matched unrelated donor. HLA typing must be performed by DNA methods for HLA-A, B, C, and DRB1 at high resolution. The donor must be willing to donate peripheral blood stem cells and meet National Marrow Donor Program (NMDP) criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to NMDP criteria. * Patients with adequate organ function, as measured by the following: 1. Heart: Left ventricular ejection fraction at rest greater than 45% 2. Lungs: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50% of predicted (corrected for hemoglobin). For patients in whom pulse oximetry is performed, baseline O2 saturation greater than 85% (when lung function testing cannot be performed due to age restrictions) 3. Liver: Bilirubin less than two times the upper limit of normal for age as per local laboratory; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than three times the upper limit of normal as per local laboratory 4. Kidney: Calculated or measured creatinine clearance greater than or equal to 40 mL/min; if creatinine is greater than or equal to 1.5 mg/dL then 24-hour urine for measured creatinine clearance should be performed.
Exclusion criteria
* Patients in first CR * Karnofsky performance score less than 70% * Patients with follicular lymphoma that demonstrates evidence of histologic transformation. In the presence of B symptoms, rapid growth of a single dominant site, or prolonged (\> 2 yrs) interval since last tissue diagnosis, investigators are encouraged to consider re-biopsy of nodes prior to enrollment. * Uncontrolled hypertension * Uncontrolled bacterial, viral, or fungal infection (i.e., currently taking medication and progression of clinical symptoms) * Prior cancer, other than resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent less than 5 years will not be allowed unless approved by the medical monitor or protocol chair. Cancer treated with curative intent greater than 5 years will be allowed. * Pregnant or breastfeeding * Seropositive for human immunodeficiency virus (HIV) * Fertile men or women unwilling to use contraception from the time of initiation of conditioning until 6 months post-transplant * Prior allogeneic HSCT * Known anaphylactic reaction to rituximab * Seropositive for any of the following: HIV ab, hepatitis B sAg or polymerase chain reaction (PCR)+, or hepatitis C ab or PCR+
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Year 2 | Patients are considered a failure for this endpoint if they die, or if they relapse/progress or receive anti-lymphoma therapy not including planned post-transplant radiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Graft Failure | Day 30 | Primary graft failure is defined as a donor peripheral blood T cell chimerism \< 5% at Day +30 post-transplant. Secondary Graft Failure is defined as documented engraftment followed by loss of graft as defined by donor peripheral blood T cell chimerism \< 5%. |
| Donor Cell Engraftment | Days 30 and 100 | Donor engraftment is defined as \> 5% donor peripheral blood T cell chimerism by Day +30 post-transplant in the setting of Absolute Neutrophil Count (ANC) recovery (ANC \>500/mm\^3 for 3 consecutive days). |
| Time to Neutrophil Recovery | Day 60 | Neutrophil Recovery is defined as ANC \> 500/mm\^3 for 3 consecutive days. |
| Acute Graft-versus-Host Disease (GVHD) | Day 100 | The event is the incidence of grades II-IV acute GVHD from day of transplant, where grade IV is worst. The first day of acute GVHD onset at a certain grade will be used to calculate a cumulative incidence curve for that acute GVHD grade. GVHD should be monitored in accordance with BMT CTN manual of procedures guidelines. Acute GVHD grading was based on the consensus conference criteria (Przepiorka, et. al., 1994) and the Center for International Blood and Marrow Transplant Research (CIBMTR) grading criteria. |
| Chronic GVHD | Year 2 | The event is the incidence and severity of chronic GVHD from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval at two years post-transplant. Death prior to occurrence of chronic GVHD will be considered as a competing risk. |
| Overall Survival | Years 2 and 3 | The event is death from any cause. |
| Infections | Year 2 | — |
| Quality of Life | Year 2 | — |
| Immunologic Reconstitution | Year 1 | Quantitative immunoglobulins (IgG) |
| Incidence of Toxicities | Year 2 | Number of participants that experiences at least one grade 3 - 5 toxicity during the first two years, where grade 5 is worst. Toxicity grades are based on the NCI CTCAE Version 3.0. |
| Serum Rituximab (RTX) Levels | Baseline, Days 28 and 365 | RTX concentration levels within participants |
| Treatment-related Mortality (TRM) | Year 3 | The event is death occurring in patients in continuous complete remission. The TRM distribution will be estimated by the Kaplan-Meier curve. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between April 2009 and November 2012 from 21 different transplant centers.
Participants by arm
| Arm | Count |
|---|---|
| Hematopoietic Stem Cell Transplant Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant. | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Not transplanted | 1 |
| Overall Study | Transformed disease | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Hematopoietic Stem Cell Transplant |
|---|---|
| Age, Continuous | 55 years |
| Comorbidity Index Score 0 | 31 participants |
| Comorbidity Index Score 1-2 | 16 participants |
| Comorbidity Index Score >3 | 15 participants |
| Disease Status CR2 | 32 participants |
| Disease Status PR1 | 6 participants |
| Disease Status ≥ PR2 | 16 participants |
| Disease Status Stable Disease | 2 participants |
| Disease Status Unknown | 6 participants |
| Donor Type (HLA match) Matched Related Donor (6/6 allele) | 33 participants |
| Donor Type (HLA match) Matched Unrelated Donor (8/8 allele) | 29 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 58 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Karnofsky Performance Score 100 | 29 participants |
| Karnofsky Performance Score 80 | 5 participants |
| Karnofsky Performance Score 90 | 28 participants |
| Number of Prior Chemotherapy Regimens 2 | 14 participants |
| Number of Prior Chemotherapy Regimens 3 | 16 participants |
| Number of Prior Chemotherapy Regimens 4 | 12 participants |
| Number of Prior Chemotherapy Regimens ≥ 5 | 20 participants |
| Recipient Cytomegalovirus Status Negative | 27 participants |
| Recipient Cytomegalovirus Status Positive | 35 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 62 |
| serious Total, serious adverse events | 2 / 62 |
Outcome results
Primary
Progression-Free Survival (PFS)
Patients are considered a failure for this endpoint if they die, or if they relapse/progress or receive anti-lymphoma therapy not including planned post-transplant radiation.
Time frame: Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Progression-Free Survival (PFS) | 73 percentage of participants |
Secondary
Acute Graft-versus-Host Disease (GVHD)
The event is the incidence of grades II-IV acute GVHD from day of transplant, where grade IV is worst. The first day of acute GVHD onset at a certain grade will be used to calculate a cumulative incidence curve for that acute GVHD grade. GVHD should be monitored in accordance with BMT CTN manual of procedures guidelines. Acute GVHD grading was based on the consensus conference criteria (Przepiorka, et. al., 1994) and the Center for International Blood and Marrow Transplant Research (CIBMTR) grading criteria.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Acute Graft-versus-Host Disease (GVHD) | 27 percentage of participants |
Secondary
Chronic GVHD
The event is the incidence and severity of chronic GVHD from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval at two years post-transplant. Death prior to occurrence of chronic GVHD will be considered as a competing risk.
Time frame: Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Chronic GVHD | 61 percentage of participants |
Secondary
Donor Cell Engraftment
Donor engraftment is defined as \> 5% donor peripheral blood T cell chimerism by Day +30 post-transplant in the setting of Absolute Neutrophil Count (ANC) recovery (ANC \>500/mm\^3 for 3 consecutive days).
Time frame: Days 30 and 100
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hematopoietic Stem Cell Transplant | Donor Cell Engraftment | Day 30 | 94 percentage of donor T-cell chimerism |
| Hematopoietic Stem Cell Transplant | Donor Cell Engraftment | Day 100 | 96 percentage of donor T-cell chimerism |
Secondary
Graft Failure
Primary graft failure is defined as a donor peripheral blood T cell chimerism \< 5% at Day +30 post-transplant. Secondary Graft Failure is defined as documented engraftment followed by loss of graft as defined by donor peripheral blood T cell chimerism \< 5%.
Time frame: Day 30
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hematopoietic Stem Cell Transplant | Graft Failure | Primary Graft Failure | 0 participants |
| Hematopoietic Stem Cell Transplant | Graft Failure | Secondary Graft Failure | 0 participants |
Secondary
Immunologic Reconstitution
Quantitative immunoglobulins (IgG)
Time frame: Year 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Immunologic Reconstitution | 431 mg/dL |
Secondary
Incidence of Toxicities
Number of participants that experiences at least one grade 3 - 5 toxicity during the first two years, where grade 5 is worst. Toxicity grades are based on the NCI CTCAE Version 3.0.
Time frame: Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Incidence of Toxicities | 50 participants |
Secondary
Infections
Time frame: Year 2
Population: no data collected
Secondary
Overall Survival
The event is death from any cause.
Time frame: Years 2 and 3
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hematopoietic Stem Cell Transplant | Overall Survival | 2 years | 84 percentage of participants |
| Hematopoietic Stem Cell Transplant | Overall Survival | 3 years | 82 percentage of participants |
Secondary
Quality of Life
Time frame: Year 2
Population: No data collected
Secondary
Serum Rituximab (RTX) Levels
RTX concentration levels within participants
Time frame: Baseline, Days 28 and 365
Population: Serum RTX concentrations were collected at baseline (n=57), day +28 (n=56), and day +365 (n=44) for a compliance rate of 92%, 90%, and 80% at the assigned time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hematopoietic Stem Cell Transplant | Serum Rituximab (RTX) Levels | Baseline | 42100 ng/mL |
| Hematopoietic Stem Cell Transplant | Serum Rituximab (RTX) Levels | Day 28 | 341000 ng/mL |
| Hematopoietic Stem Cell Transplant | Serum Rituximab (RTX) Levels | Day 365 | 920 ng/mL |
Secondary
Time to Neutrophil Recovery
Neutrophil Recovery is defined as ANC \> 500/mm\^3 for 3 consecutive days.
Time frame: Day 60
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Time to Neutrophil Recovery | 13 days |
Secondary
Treatment-related Mortality (TRM)
The event is death occurring in patients in continuous complete remission. The TRM distribution will be estimated by the Kaplan-Meier curve.
Time frame: Year 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Treatment-related Mortality (TRM) | 16 percentage of participants |