Lymphoproliferative Disorder
Conditions
Keywords
post-transplant lymphoproliferative disorder
Brief summary
RATIONALE: Drugs used in chemotherapy such as cyclophosphamide, prednisone, and methylprednisolone use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining cyclophosphamide and either prednisone or methylprednisolone with rituximab may be effective in treating lymphoproliferative disease following organ transplantation. PURPOSE: Phase II trial to study the effectiveness of combining cyclophosphamide and either prednisone or methylprednisolone with rituximab in treating patients who have Epstein-Barr virus-positive lymphoproliferative disease following organ transplantation.
Detailed description
OBJECTIVES: * Determine the safety and toxicity of cyclophosphamide, rituximab, and prednisone or methylprednisolone in patients with CD20-positive and Epstein-Barr virus-positive post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation. * Determine the 2-year event-free survival, defined as alive and in continuous complete remission with a functioning original allograft, of patients treated with this regimen. * Determine the response rate in patients treated with this regimen. * Determine the PTLD gene expression profile by microarray analysis and fluorescent in situ hybridization in patients treated with this regimen. * Determine the accrual rate of patients to this study. OUTLINE: This is a multicenter study. Patients receive cyclophosphamide IV over 30-60 minutes on day 1 and oral prednisone or methylprednisolone IV twice daily on days 1-5. During courses 1 and 2 only, patients also receive rituximab IV over 2-5 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression, a new primary or secondary malignancy, or unrelated disease. After finishing study treatment, patients are followed periodically for at least 5 years. PROJECTED ACCRUAL: A total of 60 patients (50 with non-fulminant post-transplant lymphoproliferative disease \[PTLD\] and 10 fulminant PTLD) will be accrued for this study within 2.5-3 years.
Interventions
BIOLOGICALrituximab
Cycles 1 and 2 only: Given IV Incremental: First dosage: \< 21 years of age: 0.5mg/kg/hr (maximum of 50 mg/hr) for the 1st hour ≥ 21 years of age: 50 mg/hr for the 1st hour. Subsequent dosages: \< 21 years of age: 1.0mg/kg/hr (maximum of 50 mg/hr) for the 1st hour ≥ 21 years of age: 100 mg/hr for the 1st hour. Days 1, 8 and 15.
DRUGcyclophosphamide
Given IV over 30-60 minutes Dose 600 mg/m2 in 50-250 mL of normal saline (NS) or Dextrose-Water 5%(D5W) (at a maximum concentration of 20 mg/ml) over 30-60 minutes on day 1 of each cycle
DRUGmethylprednisolone
Methylprednisolone 0.8 mg/kg IV over 12 hours on days 1,2,3,4 and 5 of each cycle.
DRUGprednisone
Dosage 1 mg/kg orally every 12 hours on days 1,2,3,4 and 5 of each cycle. Oral prednisone may be rounded up to the nearest 2.5 mg as necessary for tablet size
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed post-transplant lymphoproliferative disease (PTLD) * Presents with 1 of the following: * Fulminant PTLD (F-PTLD) * Fever greater than 38°C * Hypotensive (for age) * Evidence of multiple organ involvement/failure, including at least 2 of the following: * Marrow (including pancytopenia without detectable B-cell proliferation) * Liver (coagulopathy, transaminitis, and/or hyperbilirubinemia) * Lungs (interstitial pneumonitis with or without pleural effusions) * Gastrointestinal tract hemorrhage * Non-fulminant PTLD (NF-PTLD) * Does not meet the above F-PTLD criteria * Considered medically refractory to reduced immune suppression (50% or more reduction of immunosuppression) for at least 1 week * CD20 positive AND Epstein-Barr virus positive * Must have received prior solid organ transplantation * Must have residual disease after biopsy and/or surgery * No PTLD central nervous system (CNS) disease, defined as positive cytology and/or radiographic evidence PATIENT CHARACTERISTICS: Age * Under 31 Performance status * Not specified Life expectancy * NF-PTLD patients: * At least 8 weeks Hematopoietic * See Disease Characteristics Hepatic * See Disease Characteristics Renal * Not specified Pulmonary * See Disease Characteristics Other * Not pregnant or nursing * Fertile patients must use effective contraception * HIV negative PRIOR CONCURRENT THERAPY: Biologic therapy * More than 1 month since prior rituximab Chemotherapy * More than 4 weeks since prior chemotherapy and recovered Endocrine therapy * Not specified Radiotherapy * Not specified Surgery * See Disease Characteristics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | 2 years | Alive in continuous complete remission with functioning original allograft. The Event Free Survival (EFS) will be estimated by the Kaplan-Meier method. |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide, Prednisone, Rituximab Patients receive cyclophosphamide IV over 30-60 minutes on day 1 and oral prednisone or methylprednisolone IV twice daily on days 1-5. During courses 1 and 2 only, patients also receive rituximab IV over 2-5 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression, a new primary or secondary malignancy, or unrelated disease. | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | ineligible | 1 |
| Overall Study | Lack of Efficacy | 9 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Cyclophosphamide, Prednisone, Rituximab |
|---|---|
| Age, Categorical <=18 years | 54 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) White | 38 Participants |
| Region of Enrollment Australia | 2 participants |
| Region of Enrollment Canada | 7 participants |
| Region of Enrollment United States | 46 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 54 |
| serious Total, serious adverse events | 2 / 54 |
Outcome results
Primary
Event-free Survival
Alive in continuous complete remission with functioning original allograft. The Event Free Survival (EFS) will be estimated by the Kaplan-Meier method.
Time frame: 2 years
Population: One patient out of the 55 patients enrolled was ineligible for study and therefore was excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclophosphamide, Prednisone, Rituximab | Event-free Survival | 71 percentage of participants analyzed |