CNS Prophylaxis in Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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Comparison of cumulative incidence of CNS relapses in patients with diffuse large B-cell lymphoma with intermediate or high risk of CNS relapse treated with CNS prophylaxis: either with 2 doses of intravenous methotrexate 3g/m2 i.v.(arm A) or 6 doses of intrathecal methotrexate 12mg (arm B) and in patients with low risk of CNS relapse without CNS prophylaxis (arm C).

Detailed Description
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Patients with diffuse large B-cell lymphoma are evaluated for risk factors of CNS relapse during initial staging (age > 60years, lactate dehydrogenase (LDH) > reference range, clinical stage III/IV, performance status according to Eastern Cooperative Oncology Group (ECOG) >1, kidney and/or adrenal gland involvement, involvement > 1 extranodal organ) including evaluation of cerebrospinal fluid. All patients with systemic DLBCL without CNS involvement are treated with systemic chemotherapy: either 6 cycles of R CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednison) +2xR (rituximab) or 6 cycles of DA EPOCH R (dose adjusted etoposide, prednison, vincristin, cyclophosphamide, doxorubicin) +2xR (rituximab). Patients with ≥ 2 risk factors for CNS relapse or with occult meningeal involvement will be randomized in 1:1 ratio either into arm A with 2 cycles of prophylactic methotrexate 3g/m2 i.v., or into arm B with prophylactic 6x intrathecal methotrexate 12mg (1x intrathecal methotrexate in each cycle of systemic chemotherapy). Patients with 0-1 risk factor will be allocated into arm C without CNS prophylaxis. Patients will be observed for CNS relapse during the follow-up of 1year after the end of the first-line treatment.

Official Title
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Study Evaluating Relapses in Central Nervous System in Patients With Diffuse Large B-Cell Lymphoma Treated With Chemotherapy With or Without CNS Prophylaxis. Multicentric, Prospective, Randomized Phase III Study

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically confirmed DLBCL age 18-72 years signed informed consent with the study first-line treatment 6 cycles of R CHOP +2x R or 6 cycles of DA EPOCH R+ 2xR Exclusion Criteria: DLBCL and concomitant initial CNS involvement PMBL (primary mediastinal B-cell lymphoma) treatment with another chemotherapy than R CHOP or DA EPOCH R HIV positive, or active hepatitis B or C other concomitant serious disease (based on the decision of the physician-investigator) non-compliance of a patient any contraindication for application of anthracycline based chemotherapy or high dose methotrexate pregnancy or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Methotrexate i.v.<br>Patients with risk factors for CNS relapse ≥ 2 or with occult meningeal involvement will receive 2 cycles of methotrexate 3g/m2 i.v. after the 3rd and 6th cycle of systemic chemotherapy (R CHOP or DA EPOCH R). | Drug: Methotrexate<br>* i.v. or intrathecal CNS prophylaxis<br>* Other names: Methotrexate, manufactured by HOSPIRA;|
| Active Comparator: Arm B - Methotrexate i.t.<br>Patients with risk factors for CNS relapse ≥ 2 or with occult meningeal involvement will receive intrathecal methotrexate 12mg in each cycle of systemic chemotherapy (6x). | Drug: Methotrexate<br>* i.v. or intrathecal CNS prophylaxis<br>* Other names: Methotrexate, manufactured by HOSPIRA;|
| No Intervention: Arm C - no Methotrexate<br>Patients with 0-1 risk factor for CNS relapse will not receive CNS prophylaxis. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of CNS relapse in patients treated either with methotrexate i.v. or methotrexate i.t. or without CNS prophylaxis |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate |  | 1 year | 
| Overall response rate |  | 1 year | 
| Overall survival |  | 2 years | 
| Progression-free survival |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, B cell, Central nervous system relapse, Methotrexate, Intrathecal chemotherapy