Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents

Abstract

Primary central nervous system (CNS) lymphomas represent a subgroup of malignancies with specific characteristics, an aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumor burden and histological type. Despite the high sensitivity to conventional chemotherapy and radiotherapy, remissions are frequently short lasting. Treatment efficacy is limited by several factors, including the biology and microenvironment of this malignancy and the "protective" effect of the blood-brain barrier, which limits the access of most drugs to the CNS. Patients who survive are at high risk of developing treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with the control of side effects. Recent therapeutic progress and effective international cooperation have resulted in a significantly improved outcome over the past 2 decades, with a higher proportion of patients receiving treatment with curative intent. Actual front-line therapy consists of high-dose methotrexate-based polychemotherapy. Evidence supporting the addition of an alkylating agent and rituximab is growing, and a recent randomized trial demonstrated that the combination of methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) is associated with a significantly better overall survival. Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy. Different strategies such as alkylating maintenance, conservative radiotherapy, and nonmyeloablative consolidation are being addressed in large randomized trials and a more accurate knowledge of the molecular and biological characteristics of this malignancy are leading to the development of target therapies in refractory/relapsing patients, with the overall aim to incorporate new active agents as part of first-line treatment. The pros and cons of these approaches together with the best candidates for each therapy are outlined in this article.

Figure 1.

Flowchart of management of HIV-negative patients with brain masses suspected for lymphoma from presentation to therapeutic decision in ordinary clinical practice. ¹Despite a strong suspicion of PCNSL, some patients suffering from large space-occupying lesions with acute symptoms of brain herniation could be eligible for surgical resection to reduce rapidly increased intracranial pressure; biopsy of extra-CNS organs is usually prefered in patients with positive staging as this procedure is associated with lower risk of severe complications. ²Ocular examination should include slit-lamp examination, indirect ophthalmoscopy, and ophthalmic ultrasonography. ³CSF evaluation should include cell counts, protein and glucose levels, cytology, and flow cytometry. IgHV gene rearrangement studies are optional. ADC, average diffusion coefficient; CT, computed tomography; Deep regions, basal ganglia, corpus callosum, periventricular areas, brain stem, and/or cerebellum; DLBCL, diffuse large B-cell lymphoma; ¹⁸FDG, ¹⁸F-fluorodeoxyglucose; IgHV, immunoglobulin heavy chain variable region; LDH, lactate dehydrogenase serum level; MRI, magnetic resonance imaging; sym., symptoms.

Figure 2.

Flowchart of therapeutic management of HIV-negative patients with PCNSL. ¹Other clinical and biochemical parameters may be considered. An overall evaluation of an experienced multidisciplinary team is recommended. ²An undebatable cutoff to define “elderly” population does not exist. Age should not be used as an exclusive parameter to define therapeutic approach. Age, comorbidity, and ASCT feasibility should be considered together to define treatment. ³Several chemotherapy regimens for young patients are available; some examples are reported in parenthesis. The MATRix regimen is supported by the highest level of evidence as assessed in an international randomized trial. ⁴Several chemotherapy regimens for elderly patients are available; some examples are reported in parenthesis. The PRIMAIN regimen has been assessed in the largest single-arm phase 2 trial; MPV and MT have been addressed in a randomized trial performed in the pre-rituximab era. The effect of the addition of this antibody both on toxicity and efficacy remains to be assessed. ⁵Randomized trials suggest both WBRT and ASCT are effective as consolidation therapies in young patients, with a higher risk of neurotoxicity after WBRT. The discussion with selected patients about the pros and cons of the use of consolidation WBRT or ASCT is recommended. ⁶Randomized trials focused on consolidation therapies in elderly patients are not available. All consolidation options are supported by single-arm phase 2 trials. ⁷Radiation field and dose should be chosen on the basis of response to primary chemotherapy. WBRT dose reduction to 23.4 Gy is recommended in patients who achieved a complete remission after induction of chemoimmunotherapy. ⁸Encouraging data with maintenance with temozolomide or procarbazine are available. Lenalidomide maintenance seems to be an interesting experimental option. ⁹Watchful waiting is suggested only in patients in complete remission after well-documented induction chemoimmunotherapy. ASCT, myeloablative chemotherapy supported by ASCT; HD-ARAC, high-dose cytarabine; HD-MTX, high-dose methotrexate; LVEF, left ventricular ejection fraction; MPV, HD-MTX/procarbazine/vincristine; MT, HD-MTX/temozolomide; MT-R, rituximab/HD-MTX/temozolomide; NYHA, New York Hospital Association; PRIMAIN, rituximab/HD-MTX/procarbazine; R-MBVP, rituximab/HD-MTX/carmustine/etoposide/HD-ARAC; R-MPV, rituximab/HD-MTX/procarbazine/vincristine.

Figure 3.

Survival curves of PCNSL with disease responsive to MATRix chemoimmunotherapy. PFS (A) and OS (B) curves of PCNSL patients with disease responsive to a MATRix regimen and consolidated with WBRT (dotted lines) or HDC/ASCT (continuous lines) in the IELSG32 trial.