Unraveling the Enigma: A Case Study on Primary CNS Lymphoma

Case Presentation

A 62-year-old male with a history of gastrointestinal stromal tumor of the stomach, post-treatment with chemotherapy/adjunctive immunotherapy with imatinib on active surveillance, presented to the emergency department with headache, hyperemesis, blurred vision, and weakness for 2 weeks. Brain MRI demonstrated multifocal mainly right hemispheric contrast-enhancing lesions with vasogenic edema with right shift. Lab findings demonstrated significant anemia (hemoglobin 11 g/dL), creatinine clearance 45 mg/dL, and serum lactate dehydrogenase 630 U/L. Cerebral spinal fluid (CSF) revealed high protein level, cytology, and flow cytometry positive. The patient underwent a stereotactic-guided biopsy of the right frontal tumor mass, which demonstrated primary central nervous system lymphoma (PCNSL), diffuse large B-cell lymphoma (DLBCL) with non-germinal B-cell (non-GCB) subtype, positive for CD20, and Epstein-Barr virus. PET/CT scan and testicular ultrasound were negative. An ophthalmologist performed an exam, which demonstrated bilateral vitritis and right optic neuropathy. Due to the known diagnosis of PCNSL, a vitrectomy was not performed.

The patient was initiated on a MATRix (methotrexate [MTX], cytarabine, thiotepa, rituximab) regimen with MTX renally dosed. Toxicities included pancytopenia, which led to dose reductions and delay after cycles 2 and 3, as well as febrile neutropenia and mucositis. Restaging MRIs after the second and fourth cycles were negative. With supportive care, he completed 4 cycles and achieved complete remission (CR) followed by autologous stem cell transplant (ASCT) consolidation with thiotepa and carmustine. The patient remains in remission at 18 months post-ASCT.

Discussion

PCNSL Presentation and Diagnosis

PCNSL is rare aggressive extranodal non-Hodgkin’s lymphoma, which accounts for 3% of brain tumors, and 95% of cases are non-GCB DLBCL, with less common histologies such as Burkitt’s, peripheral T-cell, and marginal zone lymphomas.¹ The most common cause is acquired or congenital immunodeficiency. PCNSL, which is prevalent in the brain, spinal cord, eyes, and leptomeninges, is often misdiagnosed due to an unspecific presentation or unavailable biopsy.¹ The procedure of choice to establish the diagnosis is a stereotactic biopsy, or, if ocular or CSF involvement is evident, vitrectomy or CSF cytology is sufficient. Depending on the patient, the risk versus benefit must be considered in obtaining the biopsy.²

Patients with PCNSL develop neurologic signs over weeks, including focal neurologic deficits (56%-70%), mental status and behavioral changes (32%-43%), symptoms of increased intracranial pressure (e.g., headaches, nausea, vomiting, papilledema; 32%-33%), seizures (11%-14%), and eye damage characterized by blurred vision or floating objects (10%-20%).^3,4

MRI or contrast enhanced CT classically shows multiple ring-enhancing lesions in the deep white matter. The International PCNSL Collaborative Group recommends baseline staging, including MRI of the brain (and spine, if spinal symptoms are present), ophthalmologic evaluation, and CSF evaluation. To detect the presence of non-CNS disease, PET/CT scan and bone marrow biopsy should be performed. Testicular ultrasound is recommended especially in elderly men due to frequency of CNS involvement in testicular lymphomas. PET/CT evaluates for concomitant systemic lymphoma, which affects 7% of patients with PCNSL.^1,5

 sPCNSL Treatment

The approach to treatment is a two-step strategy encompassing induction for remission and consolidation to forestall disease recurrence. Induction treatment should be initiated as soon as diagnosis is confirmed to ameliorate neurologic deficits. Corticosteroids are lymphocytotoxic and can obscure pathologic diagnosis; therefore, it is recommended, if possible, that empiric administration of steroids be delayed until diagnosis is established. There is no consensus regarding the role of intraventricular or intrathecal chemotherapy, as well as no data to suggest that newly diagnosed PCNSL with or without CSF or ocular disease should be treated differently.²

Surgery is not effective for PCNSL outside of obtaining biopsy. An induction treatment regimen containing high-dose methotrexate (HD-MTX)–based chemotherapy is the first-line treatment, with or without consolidation whole-brain radiation (WBRT) or ASCT. Unlike other brain tumors, PCNSL has a good response to chemotherapy and/or radiation therapy, compared with other lymphomas, and overall survival (OS) is poorer.²

The optimal dose of HD-MTX remains unclear. Doses between 3 and 8 g/m² have been shown to be effective . A real-world review of 73 patients demonstrated that for those who received HD-MTX at 8 g/m² vs 3.5 g/m², the CR rates were 68.29% vs 43.75% (p = .03), and the median progression-free survival (PFS) was 17.7 months vs 9.05 months (HR 0.455 [95% CI: 0.239–0.865]; p = .016), respectively. There was no significant difference in OS between the two groups. Reducing the initial HD-MTX dose improved tolerability and completion of induction therapy, especially in patients with comorbidities or older age who have poorer outcomes.^7-9

The patient in this case received the MATRix regimen based on the randomized International Extranodal Lymphoma Study Group trial (IELSG32) phase 2 trial for newly diagnosed PCNSL (219 patients) in three arms: MTX plus cytarabine; MTX, cytarabine, and rituximab; and MATRix. CR was achieved in the MATRix arm (49% [95% CI: 38%-60%]) compared with MTX, cytarabine and rituximab (30% [95% CI: 21%-42%]) and MTX plus cytarabine (23% [95% CI: 14%-31%]).^8,9

Approximately 10% to 15% of newly diagnosed PCNSL is refractory to HD-MTX regimens, and half relapse within 2 years. Treatment following induction HD-MTX therapy depends on disease response, and patients who are transplant-eligible should undergo consolidation ASCT.¹⁰  

The IELSG32 trial also examined long-term outcomes of MATRix followed by consolidation therapy with either ASCT or WBRT in patients with PCNSL. Addition of thiotepa to MATRix prolonged both OS and PFS, producing sustained improved outcomes with a 7-year PFS of 50% and OS of 70%. The IELSG32 trial population was young and fit, with a median age of 57 years, and 67% of patients had Eastern Cooperative Oncology Group performance status 0-1.⁷

In a real-world setting, Suleman et al. evaluated 37 patients with PCNSL, median age 58 years, and found dose reductions of any degree in 25 patients (68%) during any cycle of MATRix. Treatment was delayed in 18 patients (49%), the majority experienced hematologic toxicity, and 65% developed grade 3/4 infectious complications. Thirty patients (81%) completed all 4 cycles, and 22 patients went on to ASCT. Of the 7 patients who did not complete all cycles, 2 (29%) died and 5 discontinued treatment due to toxicity or disease progression.¹¹

A total of 35 patients (95%) were alive at the end of treatment. A CR was seen in 7 patients (23%) and a partial response in 18 patients (60%). One patient had stable disease, and 4 patients had progressive disease. Of the 25 patients who responded to treatment, 21 went on to have consolidation therapy with ASCT with thiotepa and carmustine conditioning, and 4 had consolidation with WBRT. Consolidation was not administered to 10 patients because of disease progression, worsening performance status, or ineligibility as determined by the treating physician.¹¹

The 2-year OS for all patients was 74%, and the median OS was not reached. Two-year OS was 100% for patients who received ASCT and 49% for patients who did not (p < .01). The 2-year PFS was 54%, and the median PFS was not reached. The 2-year PFS was 78% for ASCT patients and 21% for non-ASCT patients (p < .01). The median PFS was not reached for the 21 ASCT patients and was 10 months (95% CI: 2.2-17.9 months) for non-ASCT patients. ¹¹

In a meta-analysis, PFS and OS showed that post-remission consolidation with ASCT was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Another analysis demonstrated WBRT plus chemotherapy showed a 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. Based on these analyses, high-dose chemotherapy followed by ASCT is an efficacious approach for consolidation, and WBRT plus chemotherapy is another feasible approach.¹²

Role of the AP and Follow-Up Care

Advanced practitioners are integral members of the healthcare team involved in diagnosis and assessment, collaborative treatment and medication management, symptom and supportive care, patient and caregiver education, and long-term follow-up care. The National Comprehensive Cancer Network recommends brain MRI every 3 months for 2 years, then every 6 months for 5 years, and then annually indefinitely. Patients with prior ocular involvement must undergo ophthalmologic follow-up.¹³

References

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2. Zhao H, Ma M, Zhang L, et al. Diagnosis of central nervous system lymphoma via cerebrospinal fluid cytology: a case report. BMC Neurol. 2019;19:90.
3. Yim J, Song SG, Kim S, et al. Primary peripheral gamma delta T-cell lymphoma of the central nervous system: Report of a case involving the intramedullary spinal cord and presenting with myelopathy. J Pathol Transl Med. 2019;53:57-61.
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7. Ferreri AJM, Cwynarski K, Pulczynski E, et al. Long-term efficacy, safety, and neuro tolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. 2022;36:1870-1878.
8. Wang A, Cirrone F, De Los Reyes FA, et al. High-dose methotrexate dosing strategy in primary central nervous system lymphoma. Leuk Lymphoma. 2022;63:1348-1355.
9. Li Q, Ma J, Ma Y, et al. Improvement of outcomes of an escalated high-dose methotrexate-based regimen for patients with newly diagnosed primary central nervous system lymphoma: a real-world cohort study. Cancer Manag Res. 2021;13:6115-6122.
10. Ambady P, Doolittle ND, Fox CP. Relapsed and refractory primary CNS lymphoma: Treatment approaches in routine practice. Ann Lymphoma. 2021;5:23.
11. Suleman A, Liu J, Hicks LK, et al. Methotrexate, cytarabine, thiotepa and rituximab (MATRix) chemoimmunotherapy for primary central nervous system lymphoma: A Toronto experience. 2023;108:1186-1189.
12. Yu J, Du H, Ye X, et al. High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials. Sci Rep. 2021;11:2125.
13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Central Nervous Systems Cancers. V.1.2023. Updated March 24, 2023. Accessed February 26, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf