RT actually represents a spectrum of disease. It is a more diverse condition than many people realize. RT most often involves the progression of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma, but CLL can also progress to any one of a number of other diseases. For instance, I have a patient right now whose CLL transformed to Hodgkin lymphoma. Although the progression of RT to diffuse large B-cell lymphoma is said to have a very unfavorable prognosis, even the latter clinical entity has at least 2 distinct presentations, in my experience. One presentation involves patients with CLL whom you have been treating for several years who develop some progressive adenopathy and related symptoms, but, other than that, they are clinically stable. You may discover some large cells in biopsy that confirm an RT diagnosis, but, again, they are otherwise clinically stable. The other presentation involves patients with CLL who present with rapidly progressive disease with skyrocketing white blood cell counts and lactate dehydrogenase levels, along with fevers, chills, and drenching night sweats. The latter group of patients tend to do poorly, whereas the former group often respond to therapy and can live for several years in remission.

It has been suggested that treatments for CLL can cause RT; however, recent analyses of clinical trials have reported no increased risk of RT with the new targeted drugs. The risk of RT may seem  increased, owing to the fact that patients are now living longer (ie, the longer they live, the more likely they are to develop RT). A recent study by Sinha and colleagues presented at the 60th American Society of Hematology Annual Meeting & Exposition found that PD-1, an inhibitory receptor expressed on CLL T cells, may play a role in mediating immune suppression in patients with CLL. The investigators revealed that patients with RT had an overexpression of PD-1, AKT/mTOR, and BCL-2 gene signature. However, it is unclear whether PD-1 inhibition will be effective for RT. These authors previously reported on 16 patients with relapsed CLL and 9 patients with RT who had been treated with pembrolizumab. The drug produced responses in 4 out of 9 patients with RT but in none of the individuals with CLL.

Nevertheless, the safety and efficacy of adding an AKT/mTOR inhibitor to a PD-1 inhibitor should be evaluated in a randomized clinical trial. It is important to remember that we will not know whether the combination is better than a single agent without one. We also do not know whether it is better to combine drugs or to use them sequentially. Sequencing may make more sense for patients with typical presentations of CLL, but combination therapy may be better for those with more aggressive presentations, such as RT, although a clinical trial is required to demonstrate that proposition.