Historically, allo-transplant, a form of cellular therapy, was considered a treatment of choice for patients with relapsed high-risk CLL, such as those with 17p deletion or TP53 mutations, because it offers the potential for cure. However, allo-transplant has become more of a last resort in recent years for a couple of reasons: (1) most patients are older and therefore do not tolerate transplant as well and it can be difficult to find an acceptable donor and (2) there are a number of new and novel targeted therapies to achieve long-term disease control, even in the high-risk setting. Regarding new agents for the long-term management of CLL, we are working on developing synergistic combinations that improve activity and outcomes. Thus, today, it is uncommon for us to recommend allo-transplant for patients with high-risk relapsed/refractory CLL, although we do still consider it for individuals with Richter’s transformation because we know that those patients can have durable remissions with this modality.

Other cell-based therapeutic strategies are emerging as very promising for relapsed/refractory CLL, including high-risk disease, particularly the CD19 chimeric antigen receptor T-cell strategy. I believe that this strategy will overtake allo-transplant for patients who otherwise would have been considered for transplant. The ongoing phase 1/2 TRANSCEND CLL 004 study is evaluating the use of lisocabtagene maraleucel (also known as liso-cel) monotherapy, combined with the Bruton tyrosine kinase inhibitor ibrutinib or combined with venetoclax for patients with relapsed/refractory CLL or small lymphocytic lymphoma. We reported the initial safety and preliminary efficacy data at the 62nd American Society of Hematology Annual Meeting and Exposition and continue to update the results. In the latest update for the cohort of liso-cel combined with ibrutinib, 23 patients received this combination. More than half (59%) of the 22 evaluable patients in the study had a complete response, and, of the 22 individuals who were evaluable for minimal residual disease (MRD) in bone marrow, 19 (86%) achieved undetectable MRD status by next-generation sequencing and 86% of the 21 patients evaluable in blood via flow cytometry achieved undetectable MRD (both assays had a sensitivity of ≤10^-4). These results suggest that chimeric antigen receptor T-cell therapy may be an effective treatment option for treatment-experienced adult patients with high-risk relapsed/refractory CLL, producing rapid and durable responses. It is a strategy that is better tolerated by older patients than transplant and therefore, in my opinion, offers more potential over stem cell transplantation. With more experience, we will likely see optimization of this treatment and evaluation in earlier lines of treatment.