Frontline Therapy for Patients With CLL: Testing and Risk Classification


A review of how frontline therapy selection for patients with CLL is informed by molecular testing, staging, and risk stratification amidst a multitude of other disease factors.

Anna Schuh, MD, PhD: The ESMO [European Society for Medical Oncology] Clinical Practice Guidelines from 2021 that just came out recommend both testing for the immunoglobulin status and for the TP53 mutation and 17p deletion. The immunoglobulin status, of course, never changes with subsequent lines of treatment, so that test needs to be done only once, but the TP53 and del17q testing has to be done with each line of therapy. One might ask, “Why is this required in the year of targeted agents? I’m going to give targeted agents to everybody anyway, irrespective of their TP53 status.” The counterargument is that patients with this abnormality still belong to a high-risk group, even in the year of targeted therapies.

We can see that progression-free survival, whether it’s with ibrutinib or a fixed duration of venetoclax-obinutuzumab, is not as good as patients with wild-type TP53. I recommend that those patients enter into clinical trials, particularly in the relapsed situation, once they’re relapsing from their frontline targeted agent. And if they’re transplant eligible, they should be considered for cellular therapies if they’re young and eligible for these types of therapies. There’s definitely a role to still do the TP53 analysis on all patients and to do it with each line of therapy.

Why the immunoglobulin status? We’ve known for a long time that the immunoglobulin mutation status predicts the time to first treatment. Although that might be a useful marker in some patients when it comes to deciding whether people need regular follow up, it’s most useful in the pretreatment situation. Rather than using it as a prognostic marker, it’s more a predictive marker of who responds better to what treatment. There’s a portion of patients who are hypermutated in the immunoglobulin locus who will do exceedingly well with chemoimmunotherapy. I’m not saying that those patients should receive chemoimmunotherapy. What I’m saying is that it should be at least considered in those patients and discussed with those patients. Clearly, they also do well with the targeted agents, but chemoimmunotherapy is a fixed-duration regimen, so it might be something that’s preferred by some patients. When we’re writing guidelines, we always have to consider that targeted agents are not available in all health care systems, so this type of analysis might help you identify patients who are doing quite well with chemotherapy. And if targeted agents aren’t available, then for those patients they should really be considered for chemotherapy in that setting.

John C. Byrd, MD: How we approach restratification of CLL [chronic lymphocytic leukemia] is evolving, and it’s still a moving piece. The big study that was performed by looking across different targeted trial groups with ibrutinib, and then validated by the NHLBI [National Heart, Lung, and Blood Institute] group, showed that probably 4 things most greatly impact how your response to BTK [Bruton tyrosine kinase] inhibitors is going to be influenced. Those things are beta-2-microglobulin over 5, something that comes from the chemo-immunotherapy error; the presence or absence of TP53; prior therapy for CLL; and an elevated LDH [lactate dehydrogenase]. Those factors are incredibly predictive of being able to stay on a BTK inhibitor for an extended period of time or having a remission as short as 3 years based on, say, 0.4 point, because each of those criteria is worth a point.

That group of patients who develop Richter’s syndrome almost always falls into the higher groups, those who have 3 or 4 of those things. If you have none of them, your incidence of developing Richter’s is pretty close to 0. We’ll see evolution as we identify additional small biomarker groups that put patients at higher risk. Tetraploidy is 1 where we saw that there was an immense risk of patients who develop Richter’s. A complex karyotype is 1 that really hasn’t fit into this prognostic marker. And how we use these is going to evolve over time. They’re probably going to end up being most impactful in patients who’ve had prior therapy. For the irreversible inhibitors zanubrutinib, ibrutinib, and acalabrutinib, I wouldn’t expect—because most of these are derived from ibrutinib, which has been around the longest—to see a big difference with the other BTK inhibitors. With the reversible inhibitors in clinical trials, the story has to be told, even if those will be as good when you move them to up-front disease.

Paolo Ghia, MD, PhD: For systemic therapies, until you can use therapies in CLL, I use the iwCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria. But for me, the most important ones are when there’s so-called damage from the leukemia on the bone marrow or the lymph nodes. The main criteria to start treating this patient can be unlimited, and I wait until below 10 g/dL, or in thrombocytopenia. We know that from experience, thanks to the iwCLL guidelines that the 100,000 threshold is not relevant anymore. Below 100,000, patients do not lead, and we can wait safely to lower accounts. In my practice, I tend to wait until below 50,000, because that’s the threshold that surgeons are requiring for any surgical intervention. You may want to be prepared even for an emergency.

The third criteria for me is the size of lymph nodes, and I wait until what’s stated in the iwCLL guidelines: 10 cm of size. In some patients, I had to admit that when they reach 10 cm, they’re still feeling very well, in particular if there are cervical nodes. Therefore, it becomes difficult to start out or to convince the patient that he needs therapy if not for an aesthetic reason. Of course, when patients are becoming anemic or thrombocytopenic or have large lymph nodes, it’s typical that they…feel fatigue, may experience low-grade fever, may lose weight, and start sweating at night. This is somehow reassuring.

Transcript Edited for Clarity

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