Complete response of mantle cell lymphoma with central nervous system involvement at diagnosis with acalabrutinib – Case report

Abstract Central nervous system (CNS) involvement by mantle cell lymphoma (MCL) is rare and portends a poor prognosis. We describe the first patient to have a complete response with front‐line treatment with single‐agent acalabrutinib for MCL CNS.


INTRODUCTION
Central nervous system (CNS) involvement by mantle cell lymphoma (MCL) is rare, observed in < 5% of cases at relapse and in < 1% at diagnosis [1].Outcomes are poor with median overall survival (OS) as low as 3.7 months from presentation [1].Treatment outcomes with high-dose chemotherapy which penetrates the blood-brain barrier (BBB) are unsatisfactory and novel therapies with different therapeutic mechanisms are required.

DISCUSSION
a 3-month history of weight loss and generalized lymphadenopathy.
He had multiple comorbidities including ischaemic heart disease with coronary artery stenting performed 3 years prior, dyslipidemia, hypertension, type II diabetes mellitus, and chronic kidney disease with a baseline estimated glomerular filtration rate (eGFR) of 45 mL/min.Full blood count (FBC) at presentation revealed a hemoglobin of 8.2 g/dL but with a normal platelet and white cell count.
A magnetic resonance imaging (MRI) scan of the brain showed thickening of the left amygdala associated with abnormal enhancement.
A positron emission tomography (PET) scan showed fluorodeoxyglucose (FDG)-avid lymph nodes above and below the diaphragm, and a focal increase in FDG-avidity in the medial aspect of the left temporal lobe with a standardized uptake value max of 8.4 consistent with the intracranial spread of lymphoma (Figure 1).A subsequent lymph node biopsy showed a CD20, SOX11, and cyclin D1-positive  an upcoming phase II study will examine its use in relapsed primary CNS lymphoma [6].There are only two recorded cases of acalabrutinib use in CNS involvement of MCL at relapse in the literature, with one patient achieving a partial response (PR) to treatment [4] and a second patient who was intolerant of ibrutinib achieving a CR with acalabrutinib [7].

CONCLUSION
To the best of our knowledge, this is the first case where acalabrutinib has been used as first-line therapy in MCL presenting initially with CNS involvement.Our patient was unfit for a more standard intensive approach with cytarabine-containing chemoimmunotherapy and autologous transplantation as consolidation.First-line acalabrutinib monotherapy represents a valid treatment option where available for the management of CNS MCL in patients who are unsuitable for intensive BBB-penetrating chemotherapy-based approaches and may be preferable to ibrutinib in light of the well-described improvement in toxicity profile.

AUTHOR CONTRIBUTIONS
Aisling Barrett and Toby A. Eyre co-wrote the manuscript.Shaheel Bhuva reviewed the radiological images for the manuscript.
Mahmoud Aljurf, Riad El Fakih, Mohammad A. Ashshi, and Alfadel Alshaibani provided the data for the manuscript and reviewed the manuscript.

F I G U R E 1
Positron emission tomography (PET) at diagnosis.This shows metabolically active lymphoma above and below the diaphragm with a focal increase in fluorodeoxyglucose (FDG)-avidity in the medial aspect of the left temporal lobe with a standardized uptake value (SUV) max of 8.4 consistent with central nervous system (CNS) involvement by mantle cell lymphoma (MCL).

F I G U R E 2
Positron emission tomography (PET) 3 months after commencement of acalabrutinib.This shows complete resolution of intracranial changes and almost complete resolution of fluorodeoxyglucose (FDG)-avid lymphadenopathy.pleomorphic lymphoid infiltration with a Ki67 of 50% which was negative for CD10 and BCL6, consistent with MCL.TP53 analysis was not undertaken and fluorescence in situ hybridization for CCND1 rearrangement failed.Lumbar puncture was not performed due to the increased risk of bleeding at this time due to concomitant aspirin use.The patient became critically unwell during this admission, with the development of new atrial fibrillation and a non-ST elevation myocardial infarction requiring management in the intensive care unit.These were managed conservatively as he was deemed unfit for percutaneous coronary intervention due to an acute kidney injury (eGFR 12 mL/min).Conventional chemotherapy was considered inappropriate dueto the patient's background comorbidities and current clinical state.Initial steroid debulking therapy with 30 mg of oral prednisolone daily for 8 days and subsequent anti-lymphoma therapy with off-label acalabrutinib monotherapy was commenced.Therapy was well tolerated with a transient skin rash which spontaneously resolved.A 3-month PET scan showed an excellent partial metabolic response to acalabrutinib, with a complete response (CR) of the intracranial FDG avidity (Figure2).A repeat MRI of the brain at 3 months also showed complete resolution of the previous abnormal findings.Treatment continued to be well tolerated and the patient has remained an outpatient in the 6 months following his admission with complete regain of cognitive function and full symptomatic resolution.Acalabrutinib is a highly selective second-generation covalent Bruton tyrosine kinase inhibitor (BTKi), with an improved cardiac and noncardiac adverse event profile in comparison to the first-in-class agent ibrutinib[2].It is Food and Drug Administration-approved for the treatment of relapsed or refractory MCL on the basis of the phase II trial ACE-LY-004, which demonstrated an overall response rate (ORR) of 81% in this setting with a median duration of response of 26 months[3].CNS involvement by MCL is more common in patients with advanced-stage disease, blastoid histological variant, and aggressive biological features[4].Median OS from diagnosis of CNS disease either at initial diagnosis or at relapse strikingly varies in analyses, from 3.7 months in a historical cohort[1] to 50.3 months in the aforementioned study where 11% of patients were treated with a BTK inhibitor.The first-generation BTKi ibrutinib has been shown to improve OS in CNS relapse of MCL, with a median OS of 16.8 versus 4.4 months (p = 0.007) in a large retrospective study of 88 patients treated with either ibrutinib or standard BBB penetrating chemotherapy [5]; randomised trials have not been performed.Data on acalabrutinib use for CNS MCL are lacking.Acalabrutinib is pharmacologically expected to cross the BBB similarly to ibrutinib, and