Progressive Multifocal Leukoencephalopathy Among Ibrutinib Treatment In Chronic Lymphocytic Leukemia

Abstract

Introduction: Both chronic lymphocytic leukemia (CLL) itself and the drugs used for its treatment, pose a risk for progressive multifocal leukoencephalopathy (PML). Although the relationship between Rituximab and PML is well known, case reports that have been recently published, suggest that ibrutinib; which is used in the treatment of CLL, may increase the risk of PML. Case report: Here, we report a case of 64 year-old female patient with CLL who was previously treated with rituximab, fludarabine and bendamustin but developed PML after receiving monotherapy with ibrutinib. According to Naranjo’s algorithm, the causality relationship with the drug is possible with a score of 3. The patient initially exhibited neurological symptoms. Magnetic resonance of the brain revealed a bilateral asymmetric hyperintensity in the white matter involving the parietal and occipital lobules, and there was no mass effect, edema, hemorrhagic or iscemic lesions. No enhancement of contrast media was observed. The findings were consistent with demyelination and suggestive of PML. Management and outcome: Mirtazapine treatment was initiated. However, neurological sympthoms continuously progressed over the following weeks and the patient, aged 64, died six weeks after diagnosis of PML. Discussion: PML is a rare and often fatal demyelinating disease of the central nervous system (CNS) that is exclusively seen in immunocompromised patients and there is no specific agent to treat PML. The case discussed here, highlights that the use of ibrutinib in chronic lymphocytic leukemia (CLL) therapy may result in PML.

John Cunningham Virus and Progressive Multifocal Leukoencephalopathy: A Falsely Played Diagnosis

“…In fact, PML-IRIS lesion neuroimaging demonstrates contrast enhancement, mass effect, and interstitial edema [32]. But even in cases of hematological malignancies, these findings may differ across possible other prior medical conditions and the drugs that may be used to treat them [38][39][40].…”

“…Concerning CSF, apart from the viral DNA, in HIV-infected PML patients, pleocytosis was not common but increased protein levels could be possible in almost half of the patients, yet abnormal decreases in glycose level may not be observed [88]. For the IRIS-PML cases, a study reported that the total leukocyte count median was 1 cell/mm 3 (0-2), while the median glucose and protein levels were 61 mg/dL (50-69) and 36 mg/dL (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41), respectively [89]. A study on CSF analysis in 108 patients with PML demonstrated that compared to the routine CSF parameters, 22% had an elevated cell count and 35% showed an increased Qalbumin indicating a disturbed blood-CSF-barrier; the mean lactate content was 1.64 mmol/L, whereby 6% presented with elevated lactate levels; PML patients showed an increased cell count-mainly driven by HIV-PML cases, among whom a significantly higher proportion had a disturbed blood-CSF-barrier function [99].…”

A krónikus limfocitás leukémia terápiájában alkalmazott célzott hatásmechanizmusú szerek okozta mellékhatások megelőzése és kezelése, fókuszban a Bruton-féle tirozin-kinázok okozta kardiovaszkuláris toxicitás

“…A fertőző betegségek körébe tartozik a súlyos, sokszor halálos neurológiai tünetekkel járó progresszív multifokális leukoenkefalopátia, melyet a John Cunningham vírus reaktivációja okoz. Előfordulása extrém ritka, melyről pontos statisztikai adatok nem állnak rendelkezésre, esetleírások anti-CD20-kezelések nélkül, modern terápiák mellett is előfordulnak [44]. A CLL11 tanulmányban a citopéniák előfordulása nagyobb volt obinutuzumab mellett, de ez nem társult egyéb súlyos mellékhatások fokozott gyakoriságával [43].…”