Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Complicating Biologic and Small-Molecule Therapies for Cancer.

Background: RPLS while historically uncommon and not well understood, is an important entity for hematology-oncology clinicians since this syndrome is being encountered more frequently and prompt recognition and management can allow full recovery for most patients. RPLS is considered a capillary leak syndrome affecting the brain and is associated with hypertension and fluid retention. RPLS is distinct from hypertensive encephalopathy. Antecedent blood pressure increases are not always abrupt or dramatic. RPLS should be considered when patients who are receiving various classes or regimens of cancer treatments report acute onset of headache and visual impairment, lethargy, confusion, seizure, or other neurologic disturbances. The complication occurred in less than 0.1% of patients receiving bevacizumab in clinical studies. The most important physical examination findings are a distinct increase in blood pressure as compared to the patient’s usual range, along with visual impairment. The diagnosis is usually confirmed by the MRI finding of bilateral posterior cerebral white matter edema.

Methods: We searched the FDA Adverse Event Reporting System (AERS) database of post-marketing safety reports for the 10 year period 1997 through July 2007 for all submitted reports identified by the MedDRA preferred term “reversible posterior leukoencephalopathy syndrome” or similar terms for diagnosis in association with cancer therapy. We excluded reports involving use of an anti-neoplastic agent for a non-cancer diagnosis and reports involving the concomitant use of an immunosuppressive agent.

Results: Among 109 cases reported in the 10 year interval, 64% (70/109) of the reports were received in the last 18 months of the time interval. The age range was 3 – 84 years; 30% of patients were male and 70% were female. Among 10 fatal outcomes, four appeared temporally associated with RPLS. Colorectal cancer was the most common underlying disease in 17% of the cases (19/109); the next two most common cancer settings were lymphoma 13% (14/109) and acute lymphocytic leukemia 11% (12/109). Bevacizumab (33) was the most commonly reported drug, followed by vincristine (31), cyclophosphamide (20) prednisone (20), oxaliplatin (18), fluorouracil (18), and dexamethasone (17). Regimens of CHOP or CVP were reported in 13 cases and vincristine plus steroid plus asparaginase in 9 cases.

Conclusions: Recognition and reporting of RPLS in association with chemotherapy is increasing, in part due to increasing use of anti-angiogenic therapies which raise blood pressure. Causality is not implied by association. Close monitoring of blood pressure is important, especially for agents inhibiting the VEGF pathway and for protocols mandating high fluid infusion volumes. Prompt control of blood pressure, correction of fluid and sodium overload, and cessation of the anti-cancer agent are usually successful in allowing recovery. No therapies for RPLS have been studied prospectively. High dose steroids may not be appropriate in view of their known effects to elevate blood pressure, to expand plasma and total body fluid volumes, and their association above. The risk of reinitiating therapy in patients previously experiencing RPLS is not known.