Two Distinct Clinical Patterns of Ibrutinib-to-Venetoclax Transition in Relapsed Chronic Lymphocytic Leukemia Patients

Abstract

Patients with chronic lymphocytic leukemia (CLL) relapsing on ibrutinib are often treated with the Bcl-2 inhibitor venetoclax. However, the transition from one agent to another poses some clinical challenges due to disease flares sometimes occurring right after ibrutinib interruption. Here, we describe three clinical vignettes highlighting two distinct patterns of ibrutinib-to-venetoclax transition. While patients following the favorable pattern transited to venetoclax without experiencing disease flare, the one patient who took the unfavorable path showed rapid disease rebound, with large-cell transformation occurring one week after ibrutinib interruption. A high burden of BTK and PLCG2 mutations was found only in patients with the favorable transition pattern, suggesting that removing BTK inhibition might be particularly harmful if CLL cells are progressing through mechanisms external to the BTK axis.

Switching from ibrutinib to venetoclax in chronic lymphocytic leukemia: a management protocol based on clinical cases avoiding rapid disease progression

“…A high burden of BTK and PLCG2 mutations was found only in patients with a favorable transition pattern while the majority of CLL cells of the patient with rapid DP after the transition did not harbor BTK or PLCG2 mutations and likely progressed through resistance mechanisms not involving the BTK signaling pathway. Hence, they suggest that removing BTK inhibition might be particularly harmful if CLL cells are progressing through mechanisms external to the BTK axis 15 . Without this being the scope of our work, this suggests that further investigating the role of these resistance mechanisms could help tailor the transition strategy.…”

Cambio de ibrutinib a venetoclax en la leucemia linfocítica crónica para evitar la progresión rápida de la enfermedad: un protocolo de transición basado en casos clínicos

“…Se observó una carga alta de mutaciones en los genes BTK y PLCG2 solo en pacientes con patrones favorables de transición, si bien la mayoría de las células de la LLC de pacientes con avance rápido de la enfermedad tras la transición carecían de mutaciones de los genes BTK o PLCG2 y, probablemente, progresaron mediante mecanismos de resistencias que nada tenían que ver con la vía de señalización del BTK. Por eso retirar la inhibición del BTG podría ser especialmente perjudicial si las células de la LLC avanzan por mecanismos externos al eje del BTK 15 . Aunque este no fue el objetivo de nuestro trabajo, sugiere que seguir investigando el papel que juegan estos mecanismos de resistencia puede ayudarnos a diseñar estrategias de transición.…”