Diffuse Large B-cell Lymphoma
Conditions
Brief summary
This is an open, non comparative, multicentre phase II trial, to evaluate the efficacy and feasibility of a new sequential combination of HD-MTX-AraC-based chemoimmunotherapy, followed by R-ICE regimen, and by high-dose chemotherapy supported by ASCT.
Detailed description
Treatment includes 6 courses of chemoimmunotherapy, the first three courses with an high dose methotrexate-based combination (MATRIX) followed by other three courses of R-ICE combination and finally a BCNU-thiotepa- containing conditioning and subsequent autologous stem cell transplantation. MATRIX (courses 1, 2, 3): Rituximab 375 mg/m2, Methotrexate 3.5 g/m2, Cytarabine 2 g/m2, Folinic rescue 15 mg/m2, Thiotepa 30 mg/m2, Intrathecal liposomial cytarabine 50 mg, rHuG-CSF 2,5 g/kg s.c. R-ICE (courses 4, 5, 6): Rituximab 375 mg/m2, Etoposide 100 mg/m2/d , Ifosfamide 5 g/m2, Intrathecal liposomial cytarabine 50 mg
Interventions
DRUGMethotrexate
methotrexate 3.5 g/m2 on day 1 courses 1, 2,3 of MATRIX regimen
DRUGRituximab
Rituximab 375 mg/m2 as conventional IV infusion on day 0 courses 1, 2,3 (MATRIX regimen) and on day 1 courses 4,5,6 (R-ICE)
DRUGCytarabine
Cytarabine 2 g/m2 every 12 hours, in 3-hr infusion on days 2,3 courses 1, 2,3 (MATRIX regimen)
DRUGThiotepa
Thiotepa 30 mg/m2 in 30 minutes infusion on day 4 courses 1, 2,3 (MATRIX regimen) and 5 mg/kg in 250 ml of saline sol. in 2-hrs infusion every 12 hours on day -5 and -4 of conditioning and ASCT
DRUGliposomial cytarabine
Intrathecal liposomial cytarabine 50 mg on day 5 courses 1, 2,3 (MATRIX regimen) and on day 4 courses 4,5,6 (R-ICE)
DRUGEtoposide
Etoposide 100 mg/m2/d in 500 mL saline sol. in 30 minutes on day 1-2-3 courses 4,5,6 (R-ICE)
DRUGIfosfamide
Ifosfamide 5 g/m2 in 1.000 mL saline sol. in 24-hour infusion on day 2 courses 4,5,6 (R-ICE)
DRUGCarmustine
BCNU (carmustine) 400 mg/m2 in 500 mL glucose 5% sol. in 1-hr infusion on day-6 of conditioning and ASCT
RADIATIONwhole brain radiotherapy
whole-brain irradiation 36 Gy + tumor- bed boost 10 Gy in patients with residual disease in the parenchymal brain/cerebellum.
Sponsors
International Extranodal Lymphoma Study Group (IELSG)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed diagnosis of diffuse large B-cell lymphoma 2. CNS involvement (brain, meninges, cranial nerves, eyes and/or spinal cord) at diagnosis (concomitant to extra-CNS disease) or relapse after conventional chemo(-immuno)therapy 3. Diagnosis of CNS involvement either by brain biopsy or CSF cytology examination. Neuroimaging alone is acceptable when stereotactic biopsy is formally contraindicated or when the disease has been previously histologically documented in other areas and the CNS localization is concomitant with a diffuse progression of systemic disease. 4. No previous treatment with high-dose methotrexate-based chemotherapy and/or brain irradiation. One-two courses of R-CHOP combination as upfront therapy are admitted in patients with large amount and/or extensive extra-CNS disease that could condition prognosis in an early phase of treatment. Local investigator decides if initial R-CHOP is needed based on patient's conditions 5. Age 18-70 years 6. ECOG performance status 0-3 7. Adequate bone marrow (Platelets count ≥100.000/mm3, hemoglobin ≥9 g/dL, neutrophils count≥1.500/mm3), renal (creatinine clearance ≥60 mL/min), cardiac (LVEF ≥50%), and hepatic function (total serum bilirubine ≤3 mg/dL, AST/ALT and GGT ≤2.5 per upper normal limit value), unless the abnormality is due to lymphoma infiltration 8. Absence of HIV infection and of detectable HCV-RNA and/or HBsAg and/or HBV-DNA 9. No concurrent malignancies. Previous malignancies are accepted if surgically cured or if there was no evidence of disease in the last 3 years at a regular follow-up 10. Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule 11. Female patients must be non-pregnant and non-lactating. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation 12. No treatment with other experimental drugs within the 6 weeks previous to enrolment 13. Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice. Informed consent signed by a patient's guardian is acceptable if the patient is not able to decide inclusion in the study due to cognitive impairment
Exclusion criteria
1. Other lymphoma categories other than diffuse large B-cell lymphoma. In particular, patients with primary mediastinal lymphoma, intravascular large B-cell lymphoma or leg-type large B-cell lymphoma are excluded. 2. Patients with positive flow cytometry examination of the CSF, but negative results in CSF conventional cytology, and without any other evidence of CNS disease. 3. Patients with exclusive CNS disease at presentation (primary CNS lymphoma) are excluded 4. Previous treatment with support of autologous or allogeneic stem cells/bone marrow transplantation. 5. Symptomatic coronary artery disease, cardiac arrhythmias not well controlled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease) 6. Any other serious medical condition which could impair the ability of the patient to participate in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1 Year Progression Free Survival (PFS) | From study entry until 1 year after | Percentage of patients free from progression after 1 year from study entry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 2 Years Progression Free Survival (PFS) | From study entry until 2 years after | Percentage of patients free from progression after 2 years from study entry |
| 2 Years Overall Survival (OS) | From trial entry until 2 years after | Percentage of participants alive after 2 years from study entry |
Countries
Czechia, Italy, Netherlands, United Kingdom
Participant flow
Recruitment details
During the recruitment period 79 patients were enrolled and 75 of them were treated. Four patients were excluded after enrolment before the start of study treatment because of unrelated laboratory abnormalities (two patients), disease only at flow cytometry examination of the cerebrospinal fluid (one), and death at the same time as registration (one).
Participants by arm
| Arm | Count |
|---|---|
| MATRIX - R-ICE - Conditioning and ASCT MATRIX (courses 1,2,3): Rituximab 375 mg/m2 d0/Methotrexate 3.5 g/m2 d1/Cytarabine 2 g/m2 d2 & d3/Thiotepa 30 mg/m2 d4/Liposomial Cytarabine 50 mg\* d5
R-ICE (courses 4,5,6):Rituximab 375 mg/m2 d1/Etoposide 100 mg/m2 d1,d2, d3/Ifosfamide 5 g/m2 d2/Carboplatin 5 AUC d2/Liposomial Cytarabine 50 mg\* d4
\*If liposomal cytarabine is not available, standard intrathecal chemotherapy with methotrexate 10 mg + cytarabine 40 mg + hydrocortisone 50 mg can be administered. Oral steroids are suggested for 2-3 days after intrathecal liposomial cytarabine delivery to prevent chemical or aseptic meningitis/ arachnoiditis.
Conditioning and ASCT: BCNU (carmustine)\*\* 400 mg/m2 d-6/Thiotepa 5 mg/kg d-5 & d-4 ASCT: 5 x 106 CD34+cells/kg d0
\*\*In case of BCNU unavailability, the recommended conditioning regimen (Phase IV) is: Thiotepa 5 mg/kg d-6 & d-5/Busulfan 3.2 mg/kg d-4,d -3,d-2/Clonazepam 2 mg/d d-4,d -3,d-2 ASCT: 5 x 106 CD34+cells/kg d0 | 75 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Complete response | 4 |
| Overall Study | Death | 4 |
| Overall Study | Lack of Efficacy | 22 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Partial response | 4 |
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | MATRIX - R-ICE - Conditioning and ASCT | — |
|---|---|---|
| Advanced stage Advanced stage | 60 Participants | — |
| Advanced stage No advanced stage | 15 Participants | — |
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 25 Participants | — |
| Age, Categorical Between 18 and 65 years | 50 Participants | — |
| CNS involvement at presentation CNS involvement at presentation | 32 Participants | — |
| CNS involvement at presentation No CNS involvement at presentation | 43 Participants | — |
| CNS site of disease - Brain parenchima Brain parenchima | 34 Participants | — |
| CNS site of disease - Brain parenchima No brain parenchima | 41 Participants | — |
| CNS site of disease - Cerebrospinal fluid or meninges Cerebrospinal fluid or meninges | 8 Participants | — |
| CNS site of disease - Cerebrospinal fluid or meninges No cerebrospinal fluid or meninges | 67 Participants | — |
| CNS sites of disease - Brain and cerebrospinal fluid or meninges Brain and cerebrospinal fluid or meninges | 13 Participants | — |
| CNS sites of disease - Brain and cerebrospinal fluid or meninges No brain and cerebrospinal fluid or meninges | 62 Participants | — |
| CNS sites of disease - Brain and eyes Brain and eyes | 10 Participants | — |
| CNS sites of disease - Brain and eyes No Brain and eyes | 65 Participants | — |
| CNS sites of disease - Brain, cerebrospinal fluid and eyes Brain, cerebrospinal fluid and eyes | 6 Participants | — |
| CNS sites of disease - Brain, cerebrospinal fluid and eyes No brain, cerebrospinal fluid and eyes | 69 Participants | — |
| CNS sites of disease - Eyes Eyes | 2 Participants | — |
| CNS sites of disease - Eyes No eyes | 73 Participants | — |
| CNS sites of disease - Spinal cord No spinal cord | 73 Participants | — |
| CNS sites of disease - Spinal cord Spinal cord | 2 Participants | — |
| Concomitant CNS-systemic localisation Concomitant CNS-systemic localisation | 28 Participants | — |
| Concomitant CNS-systemic localisation No concomitant CNS-systemic localisation | 47 Participants | — |
| Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG-PS </= 1 | 47 Participants | — |
| Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG-PS > 1 | 28 Participants | — |
| HBV or HCV seropositivity HBV or HCV seropositivity | 2 Participants | — |
| HBV or HCV seropositivity No HBV or HCV seropositivity | 73 Participants | — |
| High LDH serum concentration High LDH serum concentration | 37 Participants | — |
| High LDH serum concentration No high LDH serum concentration | 38 Participants | — |
| International Prognostic Index (IPI) High-intermediate IPI risk | 26 Participants | — |
| International Prognostic Index (IPI) High IPI risk | 17 Participants | — |
| International Prognostic Index (IPI) Low-intermediate IPI risk | 18 Participants | — |
| International Prognostic Index (IPI) Low IPI risk | 14 Participants | — |
| Isolated CNS relapse Isolated CNS relapse | 15 Participants | — |
| Isolated CNS relapse No isolated CNS relapse | 60 Participants | — |
| Number of extranodal organs involved (other than CNS) Number of extranodal organs involved </=1 | 52 Participants | — |
| Number of extranodal organs involved (other than CNS) Number of extranodal organs involved >1 | 23 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Italy | 52 participants | — |
| Region of Enrollment Netherlands | 4 participants | — |
| Region of Enrollment Switzerland | 1 participants | — |
| Region of Enrollment United Kingdom | 18 participants | — |
| Sex: Female, Male Female | 37 Participants | — |
| Sex: Female, Male Male | 38 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 50 / 75 | 1 / 4 |
| other Total, other adverse events | 72 / 75 | 0 / 4 |
| serious Total, serious adverse events | 46 / 75 | 0 / 4 |
Outcome results
Primary
1 Year Progression Free Survival (PFS)
Percentage of patients free from progression after 1 year from study entry
Time frame: From study entry until 1 year after
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MATRIX - R-ICE - Conditioning and ASCT | 1 Year Progression Free Survival (PFS) | 58 Percentage of participants |
Secondary
2 Years Overall Survival (OS)
Percentage of participants alive after 2 years from study entry
Time frame: From trial entry until 2 years after
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MATRIX - R-ICE - Conditioning and ASCT | 2 Years Overall Survival (OS) | 46 percentage of participants |
Secondary
2 Years Progression Free Survival (PFS)
Percentage of patients free from progression after 2 years from study entry
Time frame: From study entry until 2 years after
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MATRIX - R-ICE - Conditioning and ASCT | 2 Years Progression Free Survival (PFS) | 46 percentage of participants |