Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, is showing promising results when combined with ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to recent clinical findings.
The open-label, phase 1/2 Transcend CLL 004 Study evaluated this combination therapy in patients with relapsed/refractory CLL/SLL, demonstrating high overall response rates with many patients achieving complete or partial responses. The treatment approach involved administering liso-cel following a bridging therapy of ibrutinib, a Bruton tyrosine kinase inhibitor.
Promising Efficacy in Difficult-to-Treat Patient Populations
The combination therapy showed particularly encouraging results in patients with Richter transformation (RT), a condition where CLL transforms into aggressive lymphoma, typically associated with a dismal prognosis of just 5-12 months median survival after diagnosis.
A case series published in eJHaem reported outcomes from six patients with RT who received liso-cel treatment. The patients, aged 56 to 68 years, had varying prior treatment histories ranging from 0 to 9 lines of therapy before RT. All patients successfully received manufactured liso-cel with a median vein-to-vein time of 34 days.
The results were striking: an 83.3% best overall response rate was observed across the cohort. Most notably, all four patients who were still alive at study completion were receiving concurrent ibrutinib and had achieved minimal residual disease (MRD)-negative complete responses, indicating a robust response to the CAR T-cell therapy.
Mechanism of Action and Synergistic Effects
Researchers believe ibrutinib may enhance the efficacy of liso-cel through multiple mechanisms. Ibrutinib inhibits both Bruton tyrosine kinase and interleukin-2 inducible kinase (ITK), the latter playing a crucial role in T-cell activation.
"Given the significant influence of T-cell anergy on CAR T efficacy in RT, concurrent ibrutinib with CAR T-cell therapy may be an impactful strategy to overcome this challenge," the case series authors noted.
The addition of ibrutinib appears to enhance the expansion and persistence of CAR T cells, potentially improving clinical outcomes compared with standard CAR T-cell therapy alone. This is particularly significant for CLL patients, as CAR T-cell therapies have historically shown inferior outcomes in this population compared to their success in other B-cell malignancies.
Safety Profile
The safety profile of the liso-cel and ibrutinib combination was consistent with expectations based on prior studies of these agents individually. Common adverse events included cytokine release syndrome and neutropenia, both of which were manageable with appropriate interventions.
In the case series, none of the six patients experienced grade 3 or above cytokine release syndrome, though one patient did develop grade 3 immune-effector cell-associated neurotoxicity syndrome. Importantly, there was no increase in the incidence of neurotoxicity when compared with previous CAR T-cell therapy studies.
Implications for Treatment Landscape
These findings are particularly significant given the limited treatment options for patients with relapsed/refractory CLL/SLL and especially those with Richter transformation. While allogeneic stem cell transplantation is an option for patients who respond to initial chemoimmunotherapy, effective alternatives for chemoimmunotherapy-refractory RT have been lacking.
The researchers acknowledge that the small sample size of the case series limits definitive conclusions, but the results strongly support further exploration of combining ibrutinib with liso-cel to improve responses in RT.
Future Directions
The promising results from both the Transcend CLL 004 Study and the case series suggest that this combination therapy warrants additional investigation in larger clinical trials. If confirmed in larger studies, the liso-cel and ibrutinib combination could represent a significant advancement in the treatment of these challenging hematologic malignancies.
For patients with limited options and poor prognoses, particularly those with Richter transformation, this novel approach may offer new hope and potentially improved survival outcomes.
