A Retired Teacher With a Constant Headache and Vomiting

Amanda L. Blackmon, DO, MS; Lauren Pinter-Brown, MD


January 05, 2022

CNS involvement in mantle cell lymphoma usually presents in patients with relapse, leading to the question of which patients require CNS prophylaxis. No guidelines regarding patients who should receive prophylaxis have been established. However, blastoid histology, high Ki-67 percentage, high LDH level, and high risk score may suggest the need to consider prophylactic CNS treatment.[13] Once patients have a CNS relapse, it usually accompanies a systemic relapse. Of note, mantle cell lymphoma has more of a predilection for leptomeningeal disease, compared with diffuse large B-cell lymphoma, in which parenchymal relapse is more frequent.

In a study by Cheah and colleagues,[2] the incidence of CNS involvement was 0.9% at diagnosis and 4.1% overall. The median overall survival at the time of CNS involvement was 3.7 months.

CNS involvement can be treated several ways, including certain chemotherapy that crosses the blood-brain barrier; intrathecal chemotherapy; and radiation for patients with refractory disease, usually parenchymal disease. Systemic chemotherapy often includes high-dose methotrexate or cytarabine, which can be used as monotherapy or in conjunction with R-CHOP. Intrathecal chemotherapy can consist of triple therapy with methotrexate, cytarabine, and hydrocortisone; however, methotrexate and liposomal cytarabine can be used, as well as methotrexate alone. Triple therapy rapidly clears from the CSF and thus requires administration two or three times per week until the CSF is cleared. This is generally the approach used by the authors of this case. Liposomal cytarabine has a longer half-life and has been associated with more case reports of adverse events.

HSCT has been used as consolidation therapy in patients with CNS involvement, which has shown longer rates of remission (>12 mo) in the small subset of patients who are eligible for HSCT.[2] Ibrutinib has been discussed in case reports, inducing a rapid, dramatic, and sustained response in a patient with mantle cell lymphoma who had symptomatic CNS relapse.[14] Whether patients with high-risk disease should be given CNS prophylaxis given the rarity of CNS involvement is unclear; however, it should be considered in patients with high-risk disease who receive regimens that do not cross the blood-brain barrier.

The patient in this case received intrathecal chemotherapy with methotrexate/cytarabine/hydrocortisone three times weekly followed by leucovorin for 3 weeks when his CSF had cleared by cell count and cytology. After clearance, he received weekly intrathecal triple therapy for 4 weeks and then tapered to every 2 weeks for 1 month. He developed diarrhea and gait imbalance. MRI of the brain and spine was performed, given that his CSF remained clear (Figure 2).

Figure 2.

The spinal MRI was unremarkable. MRI of the brain revealed periventricular white matter changes consistent with leukoencephalopathy. He has also demonstrated mild bilateral weakness and reserved deep tendon reflexes.

Neurotoxicity associated with various intrathecal chemotherapies has been described in a limited number of case reports. Whether the specific agent used has a causative effect is unclear; intrathecal chemotherapy often consists of more than one agent or is given in combination with systemic chemotherapy, which may cause heightened toxicity.[15] Another question is whether the vehicle used to carry the chemotherapy could have an independent association with neurologic toxicity.[16] The disease being treated may also alter the toxicity profile.

A series of case reports describe treatment with liposomal cytarabine, especially when used in combination with systemic chemotherapy that crosses the blood-brain barrier (ie, methotrexate); this causes significant neurotoxicity that is not always reversible and can lead to death in rare cases.[17] Intrathecal methotrexate has been associated with leukoencephalopathy/neurotoxicity leading to seizures, confusion, and headache, as well as posterior reversible leukoencephalopathy syndrome.[18,19,20]

The amount of intrathecal chemotherapy needed to ensure that lymphoma is adequately treated and avoid detrimental side effects remains unknown. The accumulated dose may not be the only factor associated with toxicity. This toxicity can be reversible, as in this patient's case, and may not occur with rechallenge.


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