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Risk stratification for secondary CNS involvement in non-Hodgkin lymphoma integrating histologic, clinical, and molecular factors Case 1 Presentation. A year-old retired nurse presented with hematemesis. She did not have signs or symptoms suggestive of CNS involvement.

Examination of the blood film and peripheral blood lymphocyte immunophenotyping excluded circulating lymphoma cells. The decision to offer CNS prophylaxis to this patient was straightforward. Her predicted 2-year CNS risk of In fact, for the 0.

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She achieved complete metabolic response CMR at the end of treatment, but unfortunately experienced nodal disease relapse with B symptoms and retroperitoneal and mediastinal lymphadenopathy 9 months later. Her disease was refractory to second-line chemotherapy. She was offered participation in a clinical trial and remains on study with stable disease after 4 months on the investigational agent.

A year-old female lawyer presented with a painless right breast lump and subsequently underwent a core biopsy. The contralateral breast was normal by clinical examination and ultrasound; PET-CT confirmed ipsilateral breast involvement only stage IAE or primary breast lymphoma. This is probably explained by underrepresentation of such patients from prospective studies.

For instance, many patients with epidural involvement require emergent radiotherapy to treat impending spinal cord compression precluding clinical trial participation, and patients with stage IE lymphomas are excluded from many protocols. The propensity for primary testicular lymphoma to disseminate to the CNS is well described 18 , 35 , 36 ; a specific treatment protocol was shown in a prospective phase 2 study to result in an apparent reduction in CNS risk relative to historic controls.

Consolidative radiotherapy was delivered to the ipsilateral breast and she remains in ongoing remission 4 years from initial presentation. PET-CT identified widespread lymphadenopathy with bone marrow the only apparent site of extranodal involvement. He had no antecedent history of indolent lymphoma. After the fourth cycle, he developed severe post—lumbar puncture headache unresponsive to simple analgesia and caffeine. The node remains unchanged in size and avidity 3 months later and he remains in clinical remission at 8 months follow-up.

A year-old male office worker presented with abdominal discomfort, night sweats, and hypercalcemia. MYC—fluorescence in situ hybridization was negative. PET-CT revealed extensive nodal disease and involvement of the liver, multiple bone lesions, and muscle. CSF analysis was negative. However, by multivariate analysis, only DE status hazard ratio, 3.

A year-old engineer presented with widespread lymphadenopathy and fevers. PET-CT identified involvement of the liver, spleen, and multifocal bone lesions. Treatment with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone CHOEP was commenced at another institution. He attended our institution for a second opinion after completing the first cycle of therapy.

Ellin et al reported that 28 of patients with PTCL 4. Mantle cell lymphoma MCL is another aggressive histologic subtype where the role of CNS prophylaxis remains controversial. Outside of clinical trials, in transplant-eligible patients we use high-dose cytarabine-based induction followed by autologous stem cell transplant; in elderly patients, we use bendamustine-rituximab, but we do not specifically add CNS-directed prophylaxis in either setting.

However, most patients with MCL at our institution are offered participation in investigational protocols incorporating Bruton tyrosine kinase inhibitors; there are data suggesting the first-in-class agent, ibrutinib, penetrates the CNS 66 and may be effective in MCL with CNS involvement.

However, larger datasets are required to confirm this observation. This patient achieved a CMR at the completion of therapy and remains in remission at 12 months follow-up. Even among high-risk patients, only a minority develop CNS recurrence, making adequately powered prospective randomized studies to address this question challenging.

Three to 4 weeks after the completion of chemoimmunotherapy, 2 cycles of systemic MTX are administered, 2 to 3 weeks apart. We discontinue medications that may interfere with MTX clearance eg, cotrimoxazole, proton pump inhibitors at least 3 days prior to admission for IV MTX. We admit patients the afternoon before scheduled MTX and alkalinize the urine with IV fluids containing sodium bicarbonate, with careful attention to clinical assessment of fluid status weighing patients twice daily and using diuretics as needed to prevent fluid overload.

In contrast, CNS relapse in DLBCL usually has a parenchymal component 4 and the limited ability of cytotoxic drugs administered by IT injection to penetrate into deep brain tissue is problematic, with data suggesting minimal impact on CNS progression. Several subsequent retrospective 68 , 76 , 77 and 2 prospective studies also support a potential benefit for high-dose systemic MTX in this setting.

There remains lack of consensus regarding a systemic MTX-dosing regimen, number of cycles, and whether IT prophylaxis has any role or not. No randomized study exists to show that IT prophylaxis is effective, with only small retrospective, single-arm, or nonrandomized studies in combination with systemic therapy providing limited evidence for a reduction in CNS risk.

Accordingly, some groups are using systemic MTX either before chemoimmunotherapy or intercalated between cycles. It is noteworthy that several groups have explored dose-intensified regimens for younger patients with DLBCL and poor prognostic features in nonrandomized studies.

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Dunleavy, George Washington University, e-mail, March The numbers of patients treated remain relatively small, though the CNS progression rate in the phase 2 study using the same regimen in low-risk Burkitt lymphoma appeared to prevent CNS relapse. This shares some similarities with the Nordic approach. Holte et al used dose-dense rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone delivered in day cycles, followed by intensification with high-dose cytarabine and HD-MTX in patients with DLBCL aged 18 to 65 years with age-adjusted IPI CNS relapses occurred in 7 patients 4.

Finally, Phillips et al reported CNS outcomes from the UK National Cancer Research Institute phase 2 study of rituximab, cyclophosphamide, doxorubicin, vincristine, high-dose methotrexate, followed by ifosfamide, etoposide, high-dose cytarabine, rituximab with intrathecal methotrexate and cytarabine in intermediate-high risk DLBCL. This observation suggests a potential benefit from the early inclusion of HD-MTX used in this regimen, however, confirmation of this finding in larger, randomized studies is needed.

Conclusion and future directions Although the case vignettes detailing our approach to CNS prophylaxis have been successful, it is important to acknowledge that failures may still occur. This highlights the need for further studies to better identify high-risk patients; better prophylactic strategies are needed as well.

Until then, we suggest that careful assessment for CNS recurrence be integrated into routine therapeutic decision-making for patients with aggressive lymphomas.

Submitted March 16,