VIDEO: ‘Plenty of options out there’ for relapsed/refractory CLL treatment

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Relapsed/refractory CLL, I do kind of differentiate them. So for truly refractory CLL, if you're going through active treatments, so say you're on, say acalabrutinib and you're actively growing large lymph nodes and the ALC is going up, you confirm a relapse by flow cytometry. I typically would repeat the molecular testing, at least for cytogenetics and sequencing for TP53 to a degree. IGHV doesn't typically change frankly, but I look for resistance mutations for one.

So for those folks who are actively going through treatment, I will deploy some sequencing tests, and we are blessed at Roswell Park to have a very comprehensive NGS panel, and oftentimes we'll find a mechanism of refractoriness or recurrence. And if I find a targetable mutation that I know the drug will still work against, for example, like pirtobrutinib, which is now approved, for double refractory patients and for kind of intolerance, that can still work for some of these resistance mutations like C481S and BTK for example. If you don't have that kind of testing available, which is most places, frankly, certainly you wanna look for a class that they've not seen before. So if they're relapsing on a covalent BTK inhibitor, and never seen venetoclax-based treatment, oftentimes I'll go to the venetoclax-based approach, but there's certainly gonna be a controversy.

There's preferences certainly on the provider side and on the patient side. For some folks say you live four hours from a laboratory or a hospital for example, that can monitor for tumorlysis. For some of these folks, people will reach for the pill just kind of go hop pill to pill for an indefinite, say, non-covalent BTK inhibitor therapy. So it really is logistical, it's molecular, and it's comorbidity-driven as well. But oftentimes I will be very comfortable switching between those classes, those major classes of the covalent BTK inhibitors and the BCL2 inhibitors with the venetoclax. And then if you're multiply relapsed or refractory, certainly if you're double refractory, pirtobrutinib is FDA approved in this setting as is now Liso-Cell (Breyanzi,Bristol Myers Squibb).

So CAR T-cell therapy was just recently approved. So oftentimes I would consider and start pirtobrutinib (Jaypirca, Eli Lilly & Co.) if there are no strong contraindications from a cardiovascular perspective, for example and so forth with a referral for a CAR T-cell evaluation, and oftentimes I would treat the best response with pirtobrutinib and then kind of get people ready mentally, physically, logistically, financially for something like a CAR T-cell therapy, either trial, I would always encourage clinical trial participation. We have multiple of them at Roswell Park as other centers do as well, including BTK inhibitors.

You've got a MALT1 inhibitor, several CAR T-cell trials that are available. So clinical trials are always an excellent option in this space, but we also have good standard of care options as well. But there are other treatments as well. So divarasib is still on the list. Lenalidomide is still on the list. These are things that typically I would use as a bridge to something more definitive like a CAR T-cell trial or BTK degrader trial for example. Certainly if pirtobrutinib doesn't work, those would be the other options to consider as well. High dose steroids with rituximab or obinutuzumab re-treatment can also be a temporizing measure. There are plenty of options out there, but always would talk to one of us, specialists, honestly refer folks to our large centers where we have some really nice looking trials to offer folks for some of the folks who have gone through and exhausted all the similar care options.