Paolo Ghia, MD, PhD, Professor of Medical Oncology at Università Vita-Salute San Raffaele in Milan, Italy, discusses results from clinical trial testing ibrutinib plus venetoclax in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL).
CLL/SLL are rare cancers that affect the white blood cells, specifically B cells. The conditions are similar but differ primarily in location of the disease. In patients with CLL, the cancer mainly manifests in the bloodstream, while in patients with SLL, the cancer manifests mainly in the lymph nodes and lymphoid tissue. Early signs and symptoms may include swollen lymph nodes, fatigue, weight loss, fever, night sweats and/or frequent infections. The underlying cause is thought to be a combination of genetic and other unknown factors.
Ibrutinib is a tyrosine kinase inhibitor and venetoclax is a B-cell lymphoma 2 protein inhibitor, both approved for the treatment of CLL. The combination Ibr+Ven is an oral, once-daily, chemotherapy-free first-line treatment for CLL/SLL. The CAPTIVATE clinical trial (NCT02910583) was a phase 2, multicenter, 2-cohort study evaluating ibrutinib plus venetoclax (Ibr+Ven) for the treatment of treatment-naïve patients with CLL/SLL. The trial specifically looked at minimal residual disease (MRD)-guided discontinuation and fixed duration therapy.
CAPTIVATE Clinical Trial Results
A total of 202 patients enrolled in this clinical trial and completed dosing with Ibr+Ven with a median follow-up of 68.9 months. The 5.5-year progression-free survival (PFS) rate was 66% and the overall survival (OS) rate was 97%. The 5.5-year PFS rates in patients without and with del(17p)/mutated TP53 were 70% and 36%, respectively. In patients with unmutated IGHV, 5.5-year PFS was 55%; 63% in patients without, and 44% in patients with concomitant del(17p)/mutated TP53/complex karyotype.For those with mutated IGHV, PFS was 79%, 85% in patients without, and 62% in patients with concomitant del(17p)/mutated TP53/complex karyotype.
Undetactable MRD (uMRD) was achieved in peripheral blood in 54% of patients at cycle 7 and 69% at end of treatment. This was also achieved in bone marrow in 69% of patients at the end of treatment. In patients with uMRD in peripheral blood at the end of treatment, 5.5-year PFS rates were higher than in those with MRD. A total of 64 patients had progressive disease following treatment with Ibr+Ven, while freedom from next-line treatment was 73%.
Of the 40 patients with available samples at disease progression, only one was found to have an acquired subclonal mutation in BCL2, a finding of unclear clinical significance. Importantly, no acquired resistance-associated mutations were observed in BTK or PLCG2. A total of 36 patients went on to receive retreatment, with 25 receiving ibrutinib alone and 11 receiving Ibr+Ven. Among those retreated with Ibr alone, the overall response rate (ORR) was 76% following a median follow-up of 28.4 months. The two-year PFS and OS rates in this group were 91% and 96%, respectively. For those retreated with Ibr+Ven, the ORR was 82% after a median follow-up of 15.2 months. Notably, both one-year PFS and OS rates in this group were 100%, highlighting the promising activity and tolerability of Ibr-based retreatment strategies in patients with CLL who experience disease progression.
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