1211 - Venetoclax as an Alternative and Effective Treatment in Central Nervous System Involvement of Chronic Lymphocytic Leukemia: Monocentric Experience

Introduction: Central nervous system (CSN) involvement in chronic lymphocytic leukemia (CLL) is rare, making diagnosis challenging. Presence of CLL-type cells in the cerebrospinal fluid (CSF) alone is insufficient for diagnosis, and CLL is rarely the cause of neurological symptoms. Differential diagnosis includes other inflammatory neurological disorders, agressive lymphoma among others. The optimal treatment for CLL patients with CNS involvement is yet to be standardized. However, ibrutinib is commonly used in this context. Recent research has highlighted the penetration of venetoclax into the cerebral compartment. Here, we report two cases of CLL patients with CNS involvement who were treated with a venetoclax-based regimen in our center
Case 1: A 57-year-old male had an history of visual loss starting in July 2019. Cerebral MRI confirmed optic neuropathy, ruling out autoimmune and infectious causes. CSF analysis were unremarkable. Corticosteroid therapy resulted in a partial response. Subsequently, CLL monoclonal B lymphocytosis was diagnosed, and a PET scan showed normal results. The patient developed progressive paresthesia in both legs starting in February 2021. Cerebrospinal and medullary MRI showed features of multilevel myelitis. Lumbar puncture revealed 100 white blood cells (80% CLL-type cells). Further laboratory investigations showed normal white blood cell count with 5.5 G/l lymphocytes, as well as normal LDH and B2M levels. CLL characteristics included unmutated IGHV gene, del 13q, absence of TP53 dysfunction, and no pathogenic mutations in NGS analysis. Ibrutinib treatment was initiated, but after 1 month, the patient experienced worsening paresthesia despite decreased lymphocytes in the CSF. A subsequent spinal MRI showed partial regression of the myelitis lesions, and ibrutinib was pursued. In September 2021, the patient presented a complete sensory-motor deficit in the legs. Cerebral and spinal MRI revealed new lesions. A cord spinal biopsy confirmed CLL cells infiltration. The patient received one cycle of high-dose methotrexate, followed by the administration of venetoclax plus rituximab (according to the Murano study). Venetoclax was rapidly escalated over 10 days without toxicity. After three months of treatment, significant neurological improvement was observed, with recovery of the walk. CSF analysis at month 9 showed few CLL-type elements, while the concentration of venetoclax in the CSF was 24.7 ng/ml consistent with literature findings. At month 12, MRI did not show any lesions left. The patient is currently in his 21st month of venetoclax treatment, with complete regression of all neurological symptoms.
Case 2: A 77-year-old male was diagnosed with Binet stage A CLL in 2005 and initially opted for therapeutic abstention. FISH analysis at the time did not show any dismal prognostic features.
After three years, the patient progressed to stage B disease and the patients received four cycles of FCR achieving complete remission.
In 2014, treatment with ibrutinib was initiated after progression stage B disease with del17p deletion. In 2019 patient progressed and was given 3rd line treatment with venetoclax-rituximab, which was discontinued after 21 months due to hepatic cytolysis. However, the patient showed negative MRD at the end of treatment. After 16 moths the patient experienced numb chin syndrome, and the CSF analysis confirmed presence of CLL cells , with normal blood counts, MRD positive at 1.3%, and normal total body scan and cerebral MRI results. Genetic analysis of CSF revealed pathogenic variations in the TP53 gene, while no acquired Bcl2 mutations were found. The patient promptly resumed treatment with venetoclax-rituximab, with rapid dose escalation over 10 days, and demonstrated good tolerance. Currently, the patient is in the 10th month of venetoclax treatment and showing a complete neurological clinical response

Conclusion: This report highlights the successful use of a venetoclax-based regimen in CLL patients with CNS involvement. It presents a case of primary ibrutinib-resistant CNS involvement in CLL, responding to second-line therapy with venetoclax-rituximab. Additionally, it discusses a case of CNS relapse after venetoclax treatment discontinuation, with a response to resuming venetoclax. Based on these results and other reported cases, venetoclax-based regimens should be considered as a therapeutic alternative for CLL patients with CNS involvement and as a treatment option for those progressing after BTK inhibitor therapy. Rapid ramp-up is considered a safe and potentially effective approach to attain therapeutic concentrations of venetoclax in CSF, but the optimal treatment duration and combination with monoclonal antibodies remain subjects of debate.