Durable remission with Bruton’s tyrosine kinase inhibitor therapy in a patient with leptomeningeal disease secondary to relapsed mantle cell lymphoma

Background

Mantle cell lymphoma (MCL) is a rare, aggressive B cell malignancy that accounts for 5%–7% of cases of non-Hodgkin’s lymphomas (NHLs).1 MCL predominates in men, and the median age at diagnosis is 60–70 years.1 The distinctive feature of MCL is cyclin D1 overexpression secondary to (11; 14) (q13; q32) translocation.2 Unfortunately, MCL remains incurable with standard chemoimmunotherapy, and long-term survival is poor.3 MCL is usually diagnosed at an advanced stage; extranodal involvement of the bone marrow and gastrointestinal tract are common. Central nervous system (CNS) disease is a dreaded complication of MCL that is associated with dismal outcomes. Fortunately, this is rare and is seen in <5% of cases.4 5 We report a case of a man with MCL who was in complete remission (CR) after initial treatment with rituximab and bendamustine. Four years later, his disease relapsed and he developed leptomeningeal disease. He was successfully treated with a single-agent Bruton’s tyrosine kinase (BTK) inhibitor, remaining in CR 3 years later.

Case presentation

A man in his 50s with a remote history of hiatal hernia and open Nissen fundoplication underwent evaluation for gastro-oesophageal reflux disease. Surveillance CT of the abdomen revealed a large mass in the hepatic flexure and enlarged intra-abdominal lymph nodes. He denied fever, chills, night sweats, weight loss, abdominal pain, melena or haematochezia. His other medical comorbidities included diabetes, hypertension and hyperlipidaemia. The family history was unremarkable. He had a 50 pack-year smoking history and denied any history of alcohol abuse or illicit drug use. Physical examination was unremarkable, and he had no evidence of generalised lymphadenopathy.

Investigations

The patient underwent colonoscopy and biopsy of the mass that confirmed a diagnosis of MCL. The tumour had a relatively low Ki-67 index (15%). A staging positron emission tomography (PET)-CT scan revealed a 7.5 cm fluorodeoxyglucose (FDG)-avid mass in the ascending colon at the hepatic flexure with amaximum standardized uptake value (SUV)_max of 8.0. He also had an FDG-avid conglomeration of portal lymph nodes measuring 3.4 cm in diameter with an SUV_max of 5.2. Overall, the clinical picture was consistent with stage IV lymphoma (figure 1A). Complete blood counts, metabolic parameters and coagulation profile were normal. The serum lactate dehydrogenase (LDH) was 165 U/L, and the beta-2 microglobulin level was 2. Immunophenotyping of bone marrow biopsy aspirate by flow cytometry showed an abnormal B cell population (84%) positive for CD5, CD19, CD20, CD22, FMC7 and surface lambda light-chain restriction. The lymphoma cells were positive for cyclin D1 (BCL1) immunostains, which confirmed MCL involvement of the bone marrow. The morphology and immunophenotype were consistent with classic MCL. The MCL International Prognostic Index (MIPI) score was 5.8, indicating intermediate-risk disease.

Differential diagnosis of CNS disease

The differential diagnosis of leptomeningeal metastasis from NHL is broad and includes infection, autoimmune, inflammatory processes, and sequelae of prior therapy. Contrast-enhanced MRI is the most sensitive imaging modality and often shows leptomeningeal and cranial nerve root enhancement. Cerebrospinal fluid (CSF) findings may mimic an infectious aetiology, and classic findings include high opening pressure, low glucose, high protein, lymphocytic pleocytosis and positive cytology for malignancy cells. In patients with an underlying malignancy, there should be a high index of clinical suspicion for leptomeningeal disease in those with typical imaging and CSF findings. Acute bacterial meningitis or viral encephalitis usually has a more acute presentation, and patients are febrile and sick. A CSF sample should be sent for gram stain, culture, virus detection assays, acid fast bacilli smear and cryptococcal antigen. Non-infectious conditions such as autoimmune and granulomatous diseases should also be considered in the differential diagnosis. In patients who had prior radiotherapy to the brain, radiation-induced nerve root thickening can also mimic leptomeningeal disease. Our patient had the classic MRI findings and positive CSF cytology that verified the diagnosis of leptomeningeal relapse of MCL.

Upfront treatment

The patient was treated with six cycles of rituximab and bendamustine, and a follow-up PET showed CR in the ascending colon mass and FDG-avid lymph nodes (figure 1B). The bowel uptake seen on PET was considered physiological in nature. The option of an autologous stem cell transplant (ASCT) was discussed; however, the patient decided against this. Therefore, he was placed on rituximab maintenance and completed 12 courses. He was placed on regular surveillance every 6–8 months with all subsequent PET scans confirming CR.

Outcome and CNS relapse

Four years after his initial diagnosis, the patient was hospitalised with a 6-week history of persistent bitemporal headache, short-term memory loss, difficulty walking and occasional left arm tremor. He has also had several syncopal episodes but denied any seizure activity. On examination, he was alert, awake, and oriented to place, person, and time. Cranial nerves were intact. Muscle bulk and tone were normal. Sensations, coordination and deep tendon reflexes were intact. He had intentional tremor of the left arm and a short, shuffling gait. Brain MRI showed evidence of leptomeningeal disease (figure 2A). CSF analysis confirmed atypical lymphoid cells suspicious for malignancy. Cell blocks were prepared that showed small-sized to intermediate-sized lymphocytes, and immunostains showed lymphocytes that were positive for PAX-5, ~50% for cyclin D1, and the Ki-67 proliferation index was ~20%–30%. He had a late relapse (>24 months) and presented with CNS disease 45 months after his initial diagnosis. He was treated with dexamethasone, ibrutinib (420 mg daily) and six doses of intrathecal cytarabine (100 mg/dose). Ibrutinib therapy was not interrupted for intrathecal therapy, and he tolerated the treatment without any bleeding events. The patient’s neurological symptoms improved rapidly. One week after the initiation of intrathecal cytarabine, the CSF cytology became negative. CSF flow cytometry was attempted; however, there were insufficient cells for analysis. Two months later, a restaging brain MRI showed no leptomeningeal enhancement (figure 2B). However, he started developing shortness of breath. A subsequent CT of the chest showed mild diffuse interlobular septal thickening associated with diffuse ground-glass opacities suggestive of ibrutinib-associated pneumonitis. The drug was discontinued immediately. The patient received oral prednisone 60 mg daily that was gradually tapered over the next 3 weeks with complete resolution of the symptoms.

Given the remarkable improvement in the patient’s leptomeningeal disease with ibrutinib, he was rechallenged with ibrutinib 560 mg daily with oral dexamethasone 2 mg daily. Restaging PET-CT scan and brain MRI done 6 months after initiation of ibrutinib demonstrated CR. Treatment was temporarily discontinued for 1 month due to extreme fatigue and intolerance to ibrutinib. The patient had no evidence of disease progression when ibrutinib was held. Therapy was switched to acalabrutinib 100 mg every 12 hours which the patient has tolerated well. Six months after diagnosis of CNS relapse, a repeat CSF cytology showed degenerated atypical lymphoid cells suspicious for lymphoma; however, the patient was asymptomatic, and MRI of the brain and spine were negative. The patient received one additional dose of intrathecal cytarabine. His last brain and spine MRI, done 1 year previously, was negative. Given the excellent response to treatment and his reluctance to undergo consolidation ASCT, we decided to continue with the BTK inhibitor. At the time of this publication, the patient continues to be in CR 3 years after the initiation of BTK inhibitor therapy. Both ibrutinib and acalabrutinib have good CNS penetration. We believe that switching to acalabrutinib has played a role in the 3-year durability of the response.