While we do not understand as much about the biology of RS as we do about CLL itself, we are learning more about RS from both genomic and functional studies. The treatment of RS has historically been chemotherapy, which induces remission in some patients, but the responses are not typically durable. Thus, we have generally used chemotherapy as a bridge to allogeneic stem cell transplantation, which does have curative potential; however, most patients do not achieve sufficient response with chemotherapy to make it to transplant.

Therapeutically, the focus more recently has been on trying to develop strategies to induce higher rates of complete remission in RS and then moving patients onto a consolidative transplant. We presented an analysis of 27 patients with RS showing that venetoclax plus R-EPOCH (rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride) was associated with an objective response rate of 59%, while 48% of patients experienced complete response, all of whom also achieved undetectable bone marrow minimal residual disease for CLL. This response rate compares favorably with the approximate 20% response rate that we have seen in this setting with chemotherapy alone, and it shows that using venetoclax may be promising as a chemosensitization strategy.

Immunotherapy-based regimens have also been of interest in RS. One approach that appears promising is the use of the PD-1 inhibitors (eg, nivolumab) in combination with Bruton tyrosine kinase inhibitors. CAR T-cell therapy is another interesting approach. In a retrospective study by Kittai et al from the Ohio State University involving 9 patients with RS, axicabtagene ciloleucel was associated with complete response in 5 patients and partial response in the other 3. Cytokine release syndrome occurred in all patients, but it was grade 2 or lower in all cases. A total of 7 out of 8 responding patients remained in remission at a median follow-up of 6 months. Although the duration of follow-up was short, these promising results warrant the further investigation of CAR T-cell therapy, which has some of the benefits of allogeneic transplantation because it relies on an immune effect. One challenge with allogeneic transplantation is that patients need to be in a good remission to benefit from it. With CAR T-cell therapy, we have some preliminary evidence that even patients who are not in remission can benefit from this immune-based approach.

There are also some compelling preclinical data on the combination of duvelisib with venetoclax in models of RS, and we are actively accruing a trial evaluating this combination in relapsed/refractory CLL and in a dedicated cohort of patients with RS in an attempt to learn whether the preclinical results will translate into the clinic.

Overall, although RS is relatively uncommon, it is increasingly becoming a reason why patients with CLL are dying. We have gotten much better at treating CLL, so individuals are living longer, and there is more opportunity for the disease to escape with RS. The prognosis for patients with RS is still quite poor, so it is encouraging that more research is being done now in this area.