Follicular Lymphoma
Conditions
Keywords
follicular lymphoma, rituximab, immunochemotherapy, peripheral blood stem cells (PBSC) mobilization, in vivo purging, autotransplant, bcl-2 rearrangement, molecular response
Brief summary
The purpose of this study is to determine the rate and duration of complete remission and molecular response in patients with relapsed/refractory follicular lymphoma, using a combined treatment with rituximab plus chemotherapy followed by in vivo purged peripheral blood stem cells (PBSC) mobilization and autotransplant.
Detailed description
Autologous stem cell transplantation has been shown effective in the long-term control of follicular lymphoma. Lymphoma, however, can progress after high-dose treatments. Lymphoma cells have been proved to contaminate bone marrow and peripheral blood stem cells (PBSC) collections and may contribute to relapse after autotransplant. The presence in peripheral blood and marrow of PCR-detectable cells bearing the bcl-2 rearrangement appeared to be a surrogate marker of disease and the achievement of a bcl-2 negative status is associated with a lower risk of recurrence. Several methods have been attempted to abolish graft contamination: in vitro treatment with cytotoxic agents, in vitro treatment with anti-B-cell monoclonal antibodies and complement, immunomagnetic beads, positive selection of CD34+ cells. All these techniques usually produce loss of cells, are time-consuming and expensive, and neoplastic depletion is often partial with residual polymerase chain reaction (PCR)-positive cells in the graft. In the last years the chimeric anti-CD20 monoclonal antibody Rituximab has been shown to be an effective therapeutic option for low-grade lymphoma. Owing to the different mechanism of action, the synergism with cytotoxic agents, and the non-overlapping toxicity, Rituximab is an ideal drug for combination with chemotherapy. On this basis, Rituximab has been used during mobilisation procedures as a tool to obtain in vivo purging and collection of lymphoma-free progenitor cells. In addition, several studies have demonstrated that the efficiency of peripheral blood stem cells (PBSC) harvested is not adversely affected by Rituximab and that engraftment and all parameters of hematopoietic recovery are not compromised. The incorporation of Rituximab into sequential high-dose therapy programs produced high rates of clinical and molecular remission in patients with indolent lymphoma, indicating that the antibody has an additive effect on chemotherapy.
Interventions
PROCEDUREImmunochemotherapy, in vivo purging and autrotransplant
2-4 courses every 3 weeks with rituximab 375 mg/m\^2 on day 1, vincristine 1.4 mg/m\^2 on day 2 and cyclophosphamide 400 mg/m\^2 on days 2-6. Courses were started if granulocytes \>1.5 · 10\^9/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m\^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m\^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day subcutaneously) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM \[carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan\] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m\^2 on days +14 and +21 after autotransplant.
Sponsors
Fondazione IRCCS Policlinico San Matteo di Pavia
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Patients with relapsed or refractory follicular lymphoma after chemotherapy * Patients with relapsed or refractory follicular lymphoma after rituximab as single agent or with chemotherapy * Patients with transformed follicular lymphoma * CD20-positivity * Age between 18 and 60 years * Advanced Ann Arbor stage * Normal cardiac, renal and hepatic functions * Negativity for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) * Total amount of anthracycline previously received \< 300 mg/m\^2
Exclusion criteria
* Creatinine \> 2 mg/dl * Alanine transaminase (ALT) and alkaline phosphatase \> 2N * Cardiac or pulmonary disease * Severe organic or psychiatric disease * Positivity for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) * Pregnancy, breastfeeding * Cancer diagnosis in the 5 years before lymphoma diagnosis, except of non-melanoma skin cancer and Cervical Intraepithelial Neoplasia (CIN)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | every 3 months for the first year after autotransplant and every 6 months after the first year of follow up | PFS is calculated according to the Kaplan-Meier estimator. The observation time of each subject is defined as the time from entry into the study until lymphoma progression or death as a result of any cause whichever occurs first. The 5-year PFS is the estimated cumulative probability of surviving at least 5 years without progression. |
Countries
Italy
Participant flow
Recruitment details
Between January 2002 and September 2007, 64 patients with relapsed or refractory follicular lymphoma were enrolled in the trial
Participants by arm
| Arm | Count |
|---|---|
| Immunochemotherapy, in Vivo Purging and Autotransplant 2-4 courses every 3 weeks with rituximab 375 mg/m\^2 on day 1, vincristine 1.4 mg/m\^2 on day 2 and cyclophosphamide 400 mg/m\^2 on days 2-6. Courses were started if granulocytes \>1.5 · 109/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m\^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m\^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day s.c.) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM \[carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan\] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m\^2 on days +14 and +21 after autotransplant. | 64 |
| Total | 64 |
Baseline characteristics
| Characteristic | Immunochemotherapy, in Vivo Purging and Autotransplant |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants |
| Age Continuous | 50 years |
| Region of Enrollment Italy | 64 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 54 / 64 |
| serious Total, serious adverse events | 2 / 64 |
Outcome results
Primary
Progression-free Survival
PFS is calculated according to the Kaplan-Meier estimator. The observation time of each subject is defined as the time from entry into the study until lymphoma progression or death as a result of any cause whichever occurs first. The 5-year PFS is the estimated cumulative probability of surviving at least 5 years without progression.
Time frame: every 3 months for the first year after autotransplant and every 6 months after the first year of follow up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunochemotherapy, in Vivo Purging and Autotransplant | Progression-free Survival | 59 percent chance of PFS at 5 years |