In an interview with OncLive®, Andrew Kuykendall, MD, discussed the potential effects of emerging treatments, such as BCL2 inhibitors and CD19 CAR T-cell therapies, on treatment sequencing in chronic lymphocytic leukemia (CLL), as well as excitement around disease-modifying and combination targeted therapies, and the importance of understanding toxicity profiles and the potential for treatment-free remission when approaching treatment sequencing.
“One of the key questions when we have all these agents approved is: how do we get them onto the [treatment] menu? In what order? What’s the appetizer, what’s the entrée, and what do we combine to serve at the same time?” Kuykendall said regarding a State of the Science Summit™ on hematologic malignancies, which he chaired.
Kuykendall also expanded on limitations with current clinical trial end points in myeloproliferative neoplasms (MPN) and the need for molecularly-informed drug development for myelofibrosis and polycythemia vera in another article.
Kuykendall is an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.
OncLive: With pirtobrutinib and other noncovalent agents coming onto the scene in CLL, how could standard covalent BTK inhibitors be replaced in earlier lines?
Kuykendall: From my perspective, as someone who mostly [treats patients with] myeloid diseases, and some patients with lymphoid diseases as well, following the progress of BTK inhibitors has been quite interesting. [We’ve been] sticking with these covalent, very effective agents, but still [have] some concerns regarding toxicity. That is where a lot of the effort in optimizing these therapies lies.
As we get pirtobrutinib [Jaypirca] on the scene, ongoing trials need to be [conducted]to determine exactly how best to leverage this agent. I was very impressed with the toxicity profile, which seems to be perhaps more manageable and with fewer of the concerns seen with earlier BTK inhibitors, without sacrificing much efficacy. Whether covalent or noncovalent, we certainly see a path forward for an agent that may improve upon the toxicity profile while building on a very efficacious backbone.
How does a comprehensive understanding of tolerability contribute to the selection of covalent vs noncovalent BTK inhibitors and management of associated toxicities?
We certainly rely on our lymphoma colleagues. These [agents] certainly were game changers when they were brought into the clinic. [When considering their use], understanding the different experiences that different folks have had, getting a sense for where these can fit [into the paradigm], and not exacerbating other preexisting comorbidities is important.
What additional treatment modalities are of interest in CLL, and how could these emerging therapies affect treatment sequencing?
Watching from the myeloid side of things and seeing these disease-modifying therapies and understanding the mechanisms that allow these cells to proliferate and survive is remarkable. There’s almost an abundance of riches. The excitement in developing BCL-2 inhibitors, BTK inhibitors, or targeted therapies with CD20-, CD19-[directed] CAR T-cell therapies, bispecifics, and similar approaches is clear.
The interesting thing will be figuring out what we can sequence, what we can combine, and how to do so safely. CLL is a disease in which patients can live without treatment for a long time. However, what is the trigger to start treatment? How can we give the safest, most effective treatment upfront and achieve the longest period of time for patients to live with a normal quality of life, or maybe even discontinue therapy and have treatment-free remissions? I’m fascinated by [these developments].