Reversible Posterior Leukoencephalopathy Syndrome due to Carfilzomib

Abstract

Carfilzomib is a proteasome inhibitor used in the treatment of relapsed and refractory plasma cell myeloma. We present here a case of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) attributable to Carfilzomib, an adverse side effect that was not reported in studies prior to the approval of this drug for routine clinical use. The patient was a 67 year- old male with relapsed myeloma who received ten total doses of carfilzomib as part of CCyd, 8 of which were at a dose of 36 mg/m2. He subsequently developed a severe headache with neurological deficits that progressed to a profoundly depressed mental status and seizures. His radiologic findings, clinical course and subsequent recovery supported a diagnosis of RPLS. This follows the first reported case in early 2014 associated with carfilzomib, and follows several reported instances with the use of the earlier approved proteasome inhibitor bortezomib. Our observations may serve as a reference point for future examination of the dose-related toxicities of carfilzomib, both alone and in combination with other therapeutic agents in various therapy regimens. We believe this is an important consideration that should be brought to the attention of all physicians and researchers that use this drug.

Keywords: Myeloma; Proteasome inhibitor; Reversible posterior leukoencephalopathy syndrome; Carfilzomib; Bortezomib

Introduction

The use of novel antineoplastic agents has been a mainstay in the treatment of plasma cell myeloma and has had significant positive impact on the course of this disease [1]. In particular, the use of Proteasome Inhibitors (PIs) such as bortezomib (initially approved by the US Food & Drug Administration [FDA] in 2003 for treatment of relapsed plasma cell myeloma, with further approval in 2008 and 2014 for additional indications) and carfilzomib (approved in 2012 for the treatment of relapsed and refractory myeloma previously treated with bortezomib and an immunomodulatory therapy) has further advanced our ability to treat this incurable disease. Despite their therapeutic potential, these agents are not without significant side effects. We have found in a retrospective analysis across multiple institutions that treatment- related complications have become more common over the same period that novel therapies have become more prevalent [2]. Common adverse effects noted in prospective studies of patients treated with bortezomib included gastrointestinal toxicities, reactivation of herpes zoster virus, bone marrow suppression, and dose-limiting peripheral neuropathy that is frequently irreversible [3- 5]. Second generation PIs such as carfilzomib have been shown to be better tolerated, with fewer adverse effects even in those with heavily pretreated disease [6]. There were no apparent adverse effects noted in the central nervous system with the use of either of these PIs in studies conducted prior to their FDA approval.

Reversible posterior leukoencephalopathy syndrome (RPLS, also referred to in the literature as posterior reversible encephalopathy syndrome or PRES) is best described as a clinical syndrome with supportive radiologic findings. Clinical manifestations can range from headache to seizure activity, and corresponding MRI of the brain most commonly reveals a relatively symmetric distribution of edema in the parietal and occipital lobes. It was first recognized by Hinchey and colleagues as a potentially fatal syndrome related to severe hypertension and immunosuppression [7]. It has been welldocumented as a potential adverse event due to many medications, and was recently reported for the first time in the setting of treatment with carfilzomib [8]. We recently took care of a gentleman who developed RPLS within three days of his tenth overall dose of carfilzomib.

Case Presentation

The patient was a 67 year-old white male with hyposecretory IgG plasma cell myeloma with high risk features (TP53 gene deletion by fluorescence in situ hybridization). At the time of diagnosis he had 30-40% plasma cells in the bone marrow, a syndrome of renal failure (eGFR of less than 10), anemia, and lytic bone lesions. His other comorbidities at the time of diagnosis were minimal, except for a diagnosis of hypertension and a remote history of colon cancer (early stage; resected to cure without any adjuvant chemotherapy). He was treated with a single cycle of lenalidomide, bortezomib, and dexamethasone (RVD) in combination at an outside institution. He then transferred care to our institution, and was then treated with a combination of bortezomib and dexamethasone (VD) for three additional cycles, with several doses of bortezomib being omitted due to symptoms of peripheral neuropathy. His renal function normalized. Repeat bone marrow examination indicated complete remission as defined by the International Myeloma Working Group; however, due to his performance status at that time autologous Hematopoietic Cell Transplantation (HCT) was deferred, and he began maintenance lenalidomide. He completed four cycles and was again considered for HCT, but unfortunately had relapse of his disease as noted by 25% plasma cells in the marrow. He then began treatment with a combination of Carfilzomib (20 mg/m2 on days 1 & 2; 36 mg/ m2 on days 8, 9, 15, 16), cyclophosphamide (300 mg/m2 on days 1, 8, 15), and dexamethasone 40 mg weekly (CCyd) on a 28-day cycle [9]. Throughout his treatment courses, he received standard prophylaxis and initially bisphosphonates, which were changed to denosumab due to intolerable side effects, six months prior to beginning CCyd.

His first cycle of CCyd was complicated by otitis media successfully treated with antibiotics. He was without symptoms at the beginning of his second cycle (seventh overall infusion of carfilzomib, the fifth at 36 mg/m2), and the cyclophosphamide dose was reduced to 250 mg/ m2 given his prior otitis. Three days after his eighth overall infusion of Carfilzomib, he developed a severe headache that progressed over several hours to include nausea, emesis, and altered mentation. He eventually became unresponsive to verbal stimuli and was taken to a local emergency department. There, he suffered a tonic-clonic seizure treated successfully with lorazepam. He had no history of prior seizures. His vital signs included a blood pressure of 182/80, heart rate of 49 (which was his baseline bradycardia) and oxygen saturation of 91% by pulse oximetry. Complete blood count, comprehensive metabolic panel with electrolytes, and ammonia were within normal limits. There was no evidence of stroke or intracranial bleeding on a head CT, which revealed only known calvarial changes attributed to his myeloma. He was given hydralazine and fosphenytoin, and later started on levetiracetam. On transfer to our institution, his vital signs were significant for a blood pressure of 159/62. He was somnolent but opened his eyes in response to his name. He could only repeat his first name when asked location and date. He could not participate with a full neurological exam but did withdraw to pain in all four extremities. He also was found to have hyporeflexia throughout his extremities.

MRI of the brain showed hyperintense signal on T2-weighted FLAIR imaging in the cortex and sub cortical white matter of bilateral occipital lobes, which was new when compared to a prior study of approximately 6 months (Figure). Tissue did not have restricted diffusion on Diffusion Weighted Imaging (DWI). Given the pattern of edema, which was posterior and involved both cortex and sub cortical white matter in a non-vascular territory, findings was most consistent with RPLS. RPLS most commonly affects the parietal and occipital lobes with a somewhat symmetric pattern of distribution, as was present in this case, but frontal lobe, inferior temporal-occipital junction, and cerebellum can be involved, in that order. Edema may also be seen in the basal ganglia, brain stem, and deep white matter. The majority of cases do not demonstrate restricted diffusion, indicating that the edema is vasogenic rather than cytotoxic. In a significant minority of cases, between 11-26%, concomitant foci of restricted diffusion may be present representing focal areas of tissue injury [10].

    

    

    Figure 1:  Image on the right represents the current MRI study with patchy
areas of abnormal T2 FLAIR signal in the occipital lobes, new since the prior
exam shown on the left.