Diffuse Large B-Cell Lymphoma
Conditions
Keywords
DLBCL, R-HDS, R-CHOP14
Brief summary
Multicentric randomized phase III study comparing high doses of chemotherapy with Rituximab followed by auto-transplant HPC versus CHOP plus Rituximab as first line therapy in high risk patients with DLBCL Non-Hodgkin's lymphomas.
Detailed description
Diffuse large B cells Non-Hodgkin's lymphomas represents one of the most frequent form of lymphoma. Its clinical development progresses rapidly and is characterized by a biphasic survival curve with patients in complete remission (which can be considered cured) and patients that relapse. This last group of subjects have only 25%-33% chance of long free disease survival if treated with a second line therapy with high dose chemotherapy plus autologous transplant of PBPC. Therefore in order to achieve an improvement of the overall survival in patient with DLBCL, it is necessary to increase the number of complete remission after first line therapy. The aim of R-HDS study, multicentre randomized phase III trial, is to evaluate and compare the efficacy and safety of an intensive conditioning regimen with high intensity chemo-immunotherapy (R-HDS) plus autologous transplantation versus CHOP conditioning regimen plus Rituximab in patients with unfavorable prognosis at diagnosis.
Interventions
DRUGRituximab-HDS
Rituximab-HDS
DRUGRituximab-CHOP
Rituximab-CHOP
Sponsors
Gruppo Italiano Terapie Innovative nei Linfomi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of DLBCL CD20+. * Patients with Ann Arbor classification B-bulk \>= II * Patients of age between 18-65 with age-adjusted IPI 2-3 and ECOG performance status 0-3 or patients of age 61-65 with IPI 3, 4, 5 and ECOG performance status 0-2. The disease stage criteria must be documented with instrumental examinations and bone marrow biopsy. * Hematology parameters one week before starting study as follows: Hb \>= 9 g/dl, WBC \>= 3 x 10exp9/l, neutrophils \>= 1.5 x 10exp9/l, PLT \>= 100 x 10exp9/l. * Patients with pulmonary DLCO \>= 50% and cardiac EF \>= 40%. * Voluntary written informed consent must be signed before recruitment, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Patients must to be informed on the risk of sterility and they must agree to use contraception for the duration of the study. Male subject have to the opportunity of freezing seminal fluid.
Exclusion criteria
* Diagnosis different from that describe above. * Patients with concomitant, serious and uncontrolled illnesses such as cardiopathies (i.e. congestive cardiopathy, ischemic hearth disease, cardiac arrhythmia not controlled by therapy, IMA in the last six months, hearth disease NYHA class III or IV), hepatopathy not related to the lymphoma (bilirubin \>= 2 mg/dl, ALT \>= 2.5 times the normal value, alkaline phosphatase \>=2.5 times the upper limit), kidneys insufficiency not related to the lymphoma (creatinine \>=2 mg/dl). * Patients affected by opportunistic infections or with positive serology for HIV, HCV, HbsAg (cases with normal levels of hepatic enzymes and not showing active viral replication documented with HBV-DNA are not excluded from randomization; patients with HBV+ can be enrolled after receiving prophylaxis with lamivudina one week before starting chemotherapy. These patients should be monitored twice a month for HbsAg, HBCab, HBV-DNA). * Patients which have or have had another type of cancer exception made for skin cancers (melanoma and in situ cervical cancer not included). * Patient with a history of anaphylaxes or more generally patients which have had any serious allergic reaction after serum infusion. * Patient with uncontrolled epilepsy, CNS disorders or psychiatric problems which, according to the investigator, is likely to interfere with participation in this clinical study (i.e. the signing of the informed consent, therapy compliance). * Inability to attend follow-up visits.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | 36 months from end of therapy | EFS was defined from the time of the study entry to any treatment failure including disease progression or discontinuation of treatment for any reason or date of the last follow-up visit |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission | Through therapy completion an average of 8 months | Clinical response was assessed by complete restaging according to Cheson criteria. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-86, 2007 |
| Disease Free Survival | 36 months from end of therapy | DFS was defined from the time of documentation of CR to time to relapse or death as a result of lymphoma or acute toxicity of treatment or date of the last follow-up visit |
| Overall Survival | 36 months from end of therapy | OS was defined from the time of the study entry to death as a result of any cause or date of the last follow-up visit |
| Toxicity | Through therapy completion an average of 8 months | Percentage of participants with at least one reported episode of CTC grade III or IV toxic events |
| Efficacy of R-HDS Conditioning as Salvage Therapy in Patients Non-responders After Four Cycles of R-CHOP 14 | Through completion of salvage therapy | — |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| R-HDS R-HDS : Rituximab supplemented high-dose (Cyclophosphamide,Ara-C, Methotrexate, Etoposide, Cis-Platin) sequential chemotherapy with autografting.
Rituximab-HDS: Rituximab-HDS | 113 |
| R-CHOP Rituximab-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone).
Rituximab-CHOP: Rituximab-CHOP | 122 |
| Total | 235 |
Baseline characteristics
| Characteristic | R-HDS | R-CHOP | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 113 Participants | 120 Participants | 233 Participants |
| Region of Enrollment Italy | 113 participants | 122 participants | 235 participants |
| Sex: Female, Male Female | 48 Participants | 51 Participants | 99 Participants |
| Sex: Female, Male Male | 65 Participants | 71 Participants | 136 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 30 / 113 | 35 / 122 |
| other Total, other adverse events | 0 / 113 | 0 / 122 |
| serious Total, serious adverse events | 29 / 113 | 10 / 122 |
Outcome results
Primary
Event Free Survival
EFS was defined from the time of the study entry to any treatment failure including disease progression or discontinuation of treatment for any reason or date of the last follow-up visit
Time frame: 36 months from end of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R-HDS | Event Free Survival | 65 percentage of EFS at 3 years follow-up |
| R-CHOP 14 | Event Free Survival | 62 percentage of EFS at 3 years follow-up |
p-value: <0.0595% CI: [0.66, 1.48]Regression, Cox
Secondary
Complete Remission
Clinical response was assessed by complete restaging according to Cheson criteria. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-86, 2007
Time frame: Through therapy completion an average of 8 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R-HDS | Complete Remission | 86 participants |
| R-CHOP 14 | Complete Remission | 95 participants |
Secondary
Disease Free Survival
DFS was defined from the time of documentation of CR to time to relapse or death as a result of lymphoma or acute toxicity of treatment or date of the last follow-up visit
Time frame: 36 months from end of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R-HDS | Disease Free Survival | 91 percentage of DFS at 3 years follow-up |
| R-CHOP 14 | Disease Free Survival | 79 percentage of DFS at 3 years follow-up |
p-value: <0.0595% CI: [0.29, 1.21]Regression, Cox
Secondary
Efficacy of R-HDS Conditioning as Salvage Therapy in Patients Non-responders After Four Cycles of R-CHOP 14
Time frame: Through completion of salvage therapy
Secondary
Overall Survival
OS was defined from the time of the study entry to death as a result of any cause or date of the last follow-up visit
Time frame: 36 months from end of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R-HDS | Overall Survival | 77 percentage of OS at 3 years follow-up |
| R-CHOP 14 | Overall Survival | 74 percentage of OS at 3 years follow-up |
p-value: <0.0595% CI: [0.57, 1.52]Regression, Cox
Secondary
Toxicity
Percentage of participants with at least one reported episode of CTC grade III or IV toxic events
Time frame: Through therapy completion an average of 8 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| R-HDS | Toxicity | Grade III or IV Neutropenia | 84 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Thrombocytopenia | 86 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Neurological | 0 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Anemia | 71 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Hepatic and Metabolic | 7 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Gastrointestinal | 29 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Infection | 54 percentage of participants |
| R-HDS | Toxicity | Grade III or IV Cardiac | 4 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Infection | 8 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Neutropenia | 34 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Anemia | 15 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Thrombocytopenia | 5 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Gastrointestinal | 11 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Cardiac | 7 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Neurological | 7 percentage of participants |
| R-CHOP 14 | Toxicity | Grade III or IV Hepatic and Metabolic | 6 percentage of participants |