On point in primary CNS lymphoma

Abstract

Primary CNS lymphoma (PCNSL) is an aggressive brain tumor that represents a significant challenge both to elucidate its biological pathogenesis as well as to develop definitive precision medicines with minimal collateral toxicity. We highlight the key issues in diagnosis and treatment and focus on emerging technologies, current options among consolidation strategies, and biological agents. We anticipate that further development of molecular diagnostics and molecular imaging approaches that elucidate minimal residual disease in brain parenchyma, leptomeninges, intraocular compartments and even bone marrow will greatly impact the delivery and timing of cytotoxic and biological therapies. Implementation of these approaches is likely essential to clarify ongoing discrepancies in the interpretation of clinical trial results that currently are based on relatively unrefined definitions of response. While the results of early phase investigations involving ibrutinib and the IMiD agents, lenalidomide, pomalidomide, as well as avadomide, strongly support the hypothesis that the B-cell receptor (BCR) pathway, involving MYD88 and CD79B and NF-kB activation, is critical to the pathogenesis of PCNSL, much work is needed to elucidate mechanisms of resistance. Similarly, development of strategies to overcome immunosuppressive mechanisms that are upregulated in the tumor microenvironment is a high priority. Finally, ongoing evidence supports the hypothesis that the blood-brain barrier represents a significant impediment to efficient brain tumor penetration of novel therapeutic agents and innovative strategies of drug delivery remain essential to further improve outcomes.

Keywords: NFkB; high dose chemotherapy; immunotherapy; minimal residual disease; primary CNS lymphoma.

FIGURE 1

Incomplete resolution of contrast enhancement after induction therapy in PCNSL. A, A 65 year-old women presented on MRI with large enhancing and infiltrative masses in the left frontal lobe, crossing midline and with a right interior parietal lobule with marked mass effect resulting in sulcal effacement and nearly 1 cm rightward midline shift. B, After eight cycles of methotrexate-based therapy in combination with temozolomide plus rituximab (MT-R) there was marked resolution of mass effect and enhancing infiltrating masses. However, a residual focus of enhancement persisted within a focus of cystic encephalomalacia in the left medial orbital frontal gyrus and gyrus rectus, concerning for persistent disease. There were no foci of reduced diffusion to suggest progressive CNS lymphoma. This study illustrates one of the important limitations of conventional MRI-based evaluation of response in PCNSL: it is unclear whether residual enhancement reflects active lymphoma after an aggressive course of methotrexate-based induction, or whether the remaining enhancement is a consequence of incomplete repair of areas of disrupted blood-brain barrier, within a dead or dying tumor bed

FIGURE 2

Treatment-related neurotoxicity: contrasting brain MRI’s of patients with CNS lymphoma after WBRT vs after high-dose chemotherapy and autologous stem cell transplant. MRI on the left is from a 52 year-old female patient diagnosed with CNS lymphoma with concomitant minimal bone marrow involvement who was treated with methotrexate plus R-CHOP (rituximab and cyclophosphamide, doxorubicin and vincristine) chemotherapy; because of primary refractory disease, the patient was then treated with lenalidomide followed by whole brain irradiation. The MRI on the right is from a 64 year-old female patient also diagnosed with CNS lymphoma and concomitant minimal bone marrow involvement who was also treated with methotrexate plus R-CHOP followed by consolidative myeloablative therapy with carmustine/thiotepa and autologous stem cell transplant, followed by 1 year of lenalidomide maintenance. The brain MRI from the patient treated with WBRT demonstrates far greater volume loss and white matter disease compared to the brain MRI of the patient treated with dose-intensive consolidation chemotherapy. The patient on the left exhibits the archetypical late manifestations of WBRT: encephalopathy, memory deficits, apathy, decreased concentration, urinary incontinence and gait instability. She requires full-time custodial care. The patient on the right exhibits a normal performance status without neurologic deficits

FIGURE 3

Response to the novel cereblon modulator avadomide (CC-122) in methotrexate-resistant PCNSL. Restaging after 3 months of treatment with CC-122 (4 mg/day) resulted in time-dependent regression of tumor-associated contrast enhancement on axial (upper panels) and coronal (lower panels) on T1 sequences of brain MRI. Left panel: baseline, pre-CC-122; middle panel, after 2 months of CC-122 therapy; right panel, after 3 months of CC-122 therapy