VIDEO: Tailoring initial treatment approach for CLL to patients’ molecular features

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My overall approach really individualizes patients, and specifically, I look for molecular characteristics, specifically fluorescent insight to hybridization or fish results, specifically looking for deletion of 17-P. Or we also do MGS testing for TP-53 mutations, and that will really inform our overall approach as well as the nature of a patient's CLL.

For those with a deletion of 17-P by fish or mutation of TP-53 by sequencing or unmutated IGHV mutation status, those folks, we really would strongly avoid chemotherapy. And in fact, in my practice overall, we avoid chemotherapy for the vast majority of patients. Nowadays with targeted therapies, especially second generation covalent BTK inhibitors like Acalabrutinib (Calquence, AstraZeneca Pharmaceuticals) and Zanubrutinib (Brukinsa,BeiGene USA). And to a lesser degree, Ibrutinib (Imbruvica, Janssen Biotech, Inc., which is the old workhorse from 2013 when it was initially approved, was a game changer at the time.

But the newer ones have less toxicities. And then of course, Venetoclax based BCL two inhibitors are the standard frontline treatment options, and these are with or without, and typically with anti-CD 20 monoclonal antibodies like obinutuzumab. So specifically for me, for patients with CLL I first look and see how fit are they, what are their preferences? You know, fixed duration therapies, generally speaking are preferred. This is with my colleagues on the NCCN guidelines more widely. But there's certainly debate within the fields, particularly with those folks with adverse molecular features, especially loss of 17-P or TP-53 mutations. Some folks prefer covalent PTK inhibitors indefinitely. Second generation preferred and others, including myself, are still comfortable even with those features of time limited therapies using Venetoclax based approaches. I also look for comorbidities specifically.

So for patients with known atrial fibrillation patients on antiplatelet therapies or anticoagulation or prior bleeding issues, those are folks I generally would try to shy away from the BTK inhibitors if given a choice in favor of Venetoclax based treatments. Venetoclax based treatments are concerning for some because of the risk for tumor lysis syndrome when you start those medications. And certainly as an investment in time, certainly, you know, a lot of work kind of goes into monitoring for tumor lysis syndrome, which is when CLL cells of course break apart very quickly.

You know, six to 24 hours later you'll see chemical changes that can be very substantial. In my practice, I try to debulk for those folks who I'm not too concerned about infusional reactions. So patients over 80 with bulky disease, high lymphocyte counts, especially with cardiovascular or prior stroke risk factors. I try to avoid initial CD-20 therapy or heavily pre-medicate them, but for all of their I typically will try to debulk with obinutuzumab based treatments and then decrease their risk for tumor lysis syndrome for Venetoclax. And that works incredibly well.

And in fact, we start Venetoclax as an outpatient for a lot of folks. There are newer approaches, newer trials, like our magic study that we had accrued to, which is ongoing as far as data using BTK inhibitors with Venetoclax for time-limited approaches, and those are under investigation and so far look very, very promising. And Ibrutinib Venetoclax is lots of data behind that, you know, for time limited therapies and is being considered for national guidelines as well. Despite the Ibrutinib, you know, known toxicities, especially for age over 65, cardiovascular disease, hypertension, bleeding, et cetera. It's nuanced, I look for comorbidities, I look for preferences, I use targeted therapies and I try to tailor to the patients and their molecular features kind of together.