Lymphoma, Mucosa-Associated Lymphoid Tissue
Conditions
Brief summary
Assess the therapeutic activity and safety of the combination of Chlorambucil and Rituximab in MALT lymphomas and determine whether the addition of Rituximab to Chlorambucil will improve the outcome of MALT lymphoma in comparison to treatment with Chlorambucil alone. In April 2006, a third arm of treatment was added to compare the antitumor activity and safety of rituximab alone vs chlorambucil alone
Interventions
DRUGchlorambucil (drug)
chlorambucil 6 mg/m2 daily during the first 6 weeks of treatment, two weeks rest, chlorambucil 6 mg/m2 daily during the first two of a four weeks cycles (total of 4 cycles)
DRUGrituximab+chlorambucil
rituximab 375 mg/m2 iv, d1, 8, 15, 22, chlorambucil 6 mg/m2 os, daily during the first 6 weeks of treatment, ; two weeks rest; chlorambucil 6 mg/m2 os, daily during the first two of a four weeks cycles (total of 4 cycles) rituximab 375 mg/m2 iv at day 1 of each cycle
DRUGrituximab
rituximab 375 mg/m2 iv on days 1, 8, 15, 22, 56, 84, 112, 140
Sponsors
International Extranodal Lymphoma Study Group (IELSG)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. histologically proven diagnosis of CD20-positive marginal zone B-cell lymphoma of MALT type arisen at any extranodal site 2. any stage (Ann Arbor I-IV) 3. either de novo, or relapsed disease following local therapy (including surgery, radiotherapy and antibiotics for H. pylori-positive gastric lymphoma) 4. no evidence of histologic transformation to a high grade lymphoma 5. measurable or evaluable disease 6. age \> 18 7. life expectancy of at least 1 year 8. ECOG performance status 0-2 9. no prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer 10. no prior chemotherapy 11. no prior immunotherapy with any anti-CD20 monoclonal antibody 12. no prior radiotherapy in the last 6 weeks 13. no corticosteroids during the last 28 days, unless prednisone chronically administered at a dose \<20 mg/day for indications other than lymphoma or lymphoma-related symptoms 14. no evidence of clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months before study entry 15. no evidence of symptomatic central nervous system (CNS) disease 16. no impairment of bone marrow function (WBC \>3.0x109/L, ANC \>1.5x109/L, PLT \>100x109/L), unless due to lymphoma involvement 17. no major impairment of renal function (serum creatinine \<1,5x upper normal) or liver function (ASAT/ALAT \<2,5 upper normal, total bilirubin \<2,5x upper normal), unless due to lymphoma involvement 18. no evidence of active opportunistic infections 19. no known HIV infection 20. no active HBV and/or HCV infection 21. no pregnant or lactating status 22. appropriate contraceptive method in women of childbearing potential or men 23. absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial 24. informed consent must be given according to national/local regulations before randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free-survival (EFS) | 5 years | Percentage of patients without events (failure of treatment or Death from any cause) after 5 years from trial registration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete and Partial Remission Rate - Percentage of Patients With Complete and Partial Response at the End of Treatment | End of treatment (after 24 weeks of therapy) | Response criteria were defined according to the NCI standardized response criteria for non-Hodgkin's lymphoma. Complete response. Disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Regression of all lymph nodes and nodal masses to normal (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm before therapy and to ≤ 1 cm for nodes that were 1.1-1.5 cm. Regression by more than 75% in the sum of the products of the greatest diameters). Partial response. Decrease by at least 50% in SPD of the six largest measurable lesions. It is not necessary for all lesions to have regressed to qualify for partial response, but no lesion should have progressed and no new lesion should appear. For primary gastric sites, response was based on GELA histologic grading system. |
| Response Duration (Time to Relapse or Progression) - Percentage of Patients in Continuous Remission at Five Years From Trial Registration | 5 years | Response criteria were defined according to the NCI standardized response criteria for non-Hodgkin's lymphoma. Complete response (CR). Disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Regression of all lymph nodes and nodal masses to normal (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm before therapy and to ≤ 1 cm for nodes that were 1.1-1.5 cm. Regression by more than 75% in the sum of the products of the greatest diameters). |
| Progression-free-survival (PFS) | 5 years | Percentage of patients without disease progression after 5 years from trial registration |
| Overall Survival | 5 years | Percentage of patients alive after 5 years from trial registration |
Countries
Belgium, France, Italy, Spain, Switzerland, United Kingdom
Participant flow
Recruitment details
Subjects were enrolled from 10 January 2003 to 07 July 2010
Participants by arm
| Arm | Count |
|---|---|
| ARM A - Chlorambucil Chlorambucil 6 mg/m2 daily during the first 6 weeks of treatment; two weeks rest; chlorambucil 6 mg/m2 daily during the first two of a four weeks cycles (total of 4 cycles) | 131 |
| ARM B - Rituximab + Chlorambucil Rituximab 375 mg/m2 iv, d1, d8, d15, d22 Chlorambucil 6 mg/m2 os, daily during the first 6 weeks of treatment two weeks rest chlorambucil 6 mg/m2 os daily during the first two of a four weeks cycles (total of 4 cycles) rituximab 375 mg/m2 iv at day 1 of each cycle | 132 |
| ARM C (Since April 2006) - Rituximab Rituximab 375 mg/m2 iv on days 1, 8, 15, 22, 56, 84, 112, 140 | 138 |
| Total | 401 |
Baseline characteristics
| Characteristic | Total | ARM A - Chlorambucil | ARM B - Rituximab + Chlorambucil | ARM C (Since April 2006) - Rituximab |
|---|---|---|---|---|
| Age, Continuous | 61 years | 60 years | 59.5 years | 62.5 years |
| Ann Arbor stage Ann arbor stage ≤ 2 | 226 Participants | 78 Participants | 73 Participants | 75 Participants |
| Ann Arbor stage Ann Arbor Stage > 2 | 175 Participants | 53 Participants | 59 Participants | 63 Participants |
| B-symptoms Absence of B symptoms | 359 Participants | 125 Participants | 112 Participants | 122 Participants |
| B-symptoms Presence of B-symptoms | 42 Participants | 6 Participants | 20 Participants | 16 Participants |
| International Prognostic Index (IPI) risk High | 9 Participants | 3 Participants | 4 Participants | 2 Participants |
| International Prognostic Index (IPI) risk Intermediate-high | 68 Participants | 23 Participants | 20 Participants | 25 Participants |
| International Prognostic Index (IPI) risk Low | 229 Participants | 79 Participants | 74 Participants | 76 Participants |
| International Prognostic Index (IPI) risk Low-intermediate | 94 Participants | 25 Participants | 34 Participants | 35 Participants |
| International Prognostic Index (IPI) risk NA | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Belgium | 28 participants | 8 participants | 5 participants | 15 participants |
| Region of Enrollment France | 120 participants | 39 participants | 40 participants | 41 participants |
| Region of Enrollment Italy | 164 participants | 54 participants | 52 participants | 58 participants |
| Region of Enrollment Spain | 18 participants | 9 participants | 9 participants | 0 participants |
| Region of Enrollment Switzerland | 11 participants | 3 participants | 3 participants | 5 participants |
| Region of Enrollment United Kingdom | 60 participants | 18 participants | 23 participants | 19 participants |
| Sex: Female, Male Female | 204 Participants | 62 Participants | 68 Participants | 74 Participants |
| Sex: Female, Male Male | 197 Participants | 69 Participants | 64 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 131 | 25 / 132 | 13 / 138 |
| other Total, other adverse events | 42 / 131 | 77 / 132 | 59 / 138 |
| serious Total, serious adverse events | 4 / 131 | 20 / 132 | 13 / 138 |
Outcome results
Primary
Event-free-survival (EFS)
Percentage of patients without events (failure of treatment or Death from any cause) after 5 years from trial registration
Time frame: 5 years
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Chlorambucil | Event-free-survival (EFS) | 51 percentage of patients |
| ARM B - Rituximab + Chlorambucil | Event-free-survival (EFS) | 68 percentage of patients |
| ARM C (Since April 2006) - Rituximab | Event-free-survival (EFS) | 51 percentage of patients |
Secondary
Complete and Partial Remission Rate - Percentage of Patients With Complete and Partial Response at the End of Treatment
Response criteria were defined according to the NCI standardized response criteria for non-Hodgkin's lymphoma. Complete response. Disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Regression of all lymph nodes and nodal masses to normal (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm before therapy and to ≤ 1 cm for nodes that were 1.1-1.5 cm. Regression by more than 75% in the sum of the products of the greatest diameters). Partial response. Decrease by at least 50% in SPD of the six largest measurable lesions. It is not necessary for all lesions to have regressed to qualify for partial response, but no lesion should have progressed and no new lesion should appear. For primary gastric sites, response was based on GELA histologic grading system.
Time frame: End of treatment (after 24 weeks of therapy)
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Chlorambucil | Complete and Partial Remission Rate - Percentage of Patients With Complete and Partial Response at the End of Treatment | 85.5 percentage of patients |
| ARM B - Rituximab + Chlorambucil | Complete and Partial Remission Rate - Percentage of Patients With Complete and Partial Response at the End of Treatment | 94.7 percentage of patients |
| ARM C (Since April 2006) - Rituximab | Complete and Partial Remission Rate - Percentage of Patients With Complete and Partial Response at the End of Treatment | 78.3 percentage of patients |
Secondary
Overall Survival
Percentage of patients alive after 5 years from trial registration
Time frame: 5 years
Population: Evaluable Patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Chlorambucil | Overall Survival | 89 percentage of patients |
| ARM B - Rituximab + Chlorambucil | Overall Survival | 90 percentage of patients |
| ARM C (Since April 2006) - Rituximab | Overall Survival | 92 percentage of patients |
Secondary
Progression-free-survival (PFS)
Percentage of patients without disease progression after 5 years from trial registration
Time frame: 5 years
Population: Evaluable Patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Chlorambucil | Progression-free-survival (PFS) | 59 percentage of patients |
| ARM B - Rituximab + Chlorambucil | Progression-free-survival (PFS) | 72 percentage of patients |
| ARM C (Since April 2006) - Rituximab | Progression-free-survival (PFS) | 57 percentage of patients |
Secondary
Response Duration (Time to Relapse or Progression) - Percentage of Patients in Continuous Remission at Five Years From Trial Registration
Response criteria were defined according to the NCI standardized response criteria for non-Hodgkin's lymphoma. Complete response (CR). Disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Regression of all lymph nodes and nodal masses to normal (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm before therapy and to ≤ 1 cm for nodes that were 1.1-1.5 cm. Regression by more than 75% in the sum of the products of the greatest diameters).
Time frame: 5 years
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Chlorambucil | Response Duration (Time to Relapse or Progression) - Percentage of Patients in Continuous Remission at Five Years From Trial Registration | 70 percentage of patients |
| ARM B - Rituximab + Chlorambucil | Response Duration (Time to Relapse or Progression) - Percentage of Patients in Continuous Remission at Five Years From Trial Registration | 79 percentage of patients |
| ARM C (Since April 2006) - Rituximab | Response Duration (Time to Relapse or Progression) - Percentage of Patients in Continuous Remission at Five Years From Trial Registration | 66 percentage of patients |