Efficacy and Safety of Lenalidomide in HIV-associated Cryptococcal Meningitis (HIV-CM) Patients with Persistent Intracranial Inflammation： An Open-label, Single-arm Prospective Cohort Study

Background Several HIV-associated cryptococcal meningitis (HIV-CM) patients were found to have persistent intracranial inflammation despite negative Cerebrospinal fluid (CSF) fungal cultures after being optimally treated for CM, which could be devastating for the central nervous system. However, there is no definitive treatment strategy for this condition. Method We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24 weeks, prospective cohort study. All participants received oral lenalidomide 25 mg on days 1 to 21 of a 28-day cycle. The follow-up lasted for 24 weeks with visits performed at the baseline, week 4,8,12,24. The primary endpoint was the efficacy of lenalidomide therapy which was determined by the clinical manifestations, the changes in routine CSF parameters, and radiological findings within 24 weeks post-treatment. In addition, an exploratory analysis was made on the changes of CSF cytokine. Safety and efficacy analysis was performed in patients who received at least one dose of lenalidomide. Results Of the 14 participants, 11 patients completed the 24 weeks of follow-up. it was observed that rapid clinical remission followed lenalidomide therapy, clinical presentation such as fever, headache, and cognitive impairment was fully recovered at week 4 and remained stable during follow-up. And a significant reduction of CSF white blood cell (WBC) count occurred at week 4 [Median count 3.00×10 6 /L (IQR 0-45.00 P=0.009)] from baseline [35×10 6 /L (IQR 4.50 to 90.00)]. Median CSF protein concentration decreased from 1.39 g/L (IQR 0.74-3.23) at baseline to 0.91 g/L (IQR 0.63-1.41) at week 4 (P=0.004). CSF WBC count, CSF protein remained stable and approached the normal range through week 24. And after the 24‐week lenalidomide therapy, CSF IgG levels were also decreased, though not statistically significant. Brain MRI demonstrated that the multiple lesions were also absorbed post-therapy. In addition, it was observed that TNF-α G-CSF, IL-6, IL-17A decreased significantly during the 24-week follow-up. 2(14.3%) patients had a mild skin rash, which resolved spontaneously without drug interruption. No study drug-related serious adverse events were observed and no patient withdrew from therapy because of unacceptable toxicity. Conclusion Our study found that lenalidomide can significantly improve persistent intracranial inflammation of HIV-CM patients and have well tolerance and without notable side effects.