How I Treat: An Older Patient With High-Risk CLL With Deletion 17p

John Allan, MD, Weill Cornell Medicine, New York, New York, discusses the treatment plan he recommends for an elderly patient with high-risk, deletion 17p chronic lymphocytic leukemia (CLL) who also has chronic medical problems such as atrial fibrillation and diabetes.

Transcript:

Hello everyone, I'm John Allan. I am an associate professor of medicine here in New York City at Weill Cornell [Medicine], where I'm a CLL and lymphoma specialist. I've been asked to present a case that presents kind of a clinical scenario that we frequently are faced with when managing our patients with CLL. I chose this case because it hits on a few facets that make decision-making somewhat complicated and difficult in this specific patient population.

This is a patient I'm currently treating and recently just started on therapy. [This] is a 75 -year -old patient who's otherwise pretty fit for his age, has some chronic medical problems, including atrial fibrillation, but is well-controlled on beta blockers and is currently on [apixaban] Eliquis. It's a paroxysmal atrial fibrillation, and for the most part remains in normal sinus rhythm and is otherwise asymptomatic from it and is [currently] well-controlled. The patient also has diabetes and again is well-controlled on diabetic regimen and is working closely with an endocrinologist.

This patient was initially diagnosed in December of 2021, where he was found to have an asymptomatic lymphocytosis picked up by the primary care physician for his medical problems, [and was] referred to a local hematologist. At that point in time, with an (absolute lymphocyte count) ALC of 18,000, [the patient] was diagnosed with CLL. Upon the workup by the local hematologist, the patient was found to have relatively high-risk disease with an unmutated (immunoglobulin heavy chain variable region) IGHV, a deletion 17P, and a trisomy 12 (+12) coexisting together, and on sequencing a P53 mutation.

So, [this is] a classic high-risk patient that we are concerned about, and as stated at the time of diagnosis, [the] diagnosis was [at] about 73 years of age and [the patient] is now 75. The patient was recommended for observation which was appropriate, and [he] started to have progression late in 2023. At that point, the physician who they were following up with was retiring and the patient sought consultation with me. I repeated the workup earlier this year and identified, again, these high-risk features with deletion 17p present. Also, we identified the trisomy 12. We also identified the P53 mutation and in this 3-year period, there [were] no new mutations or additional clonal evolution notice.

We identified the unmutated IGHV and we did the extra step that isn't commonly done in community settings, which is where we karyotyped the CLL cells and did not identify a high complex karyotype. That was a good thing there. But with those pieces, clearly the patient was confirmed to have high-risk disease, and now the white count was pushing up to about 60,000. And while there wasn't a lot of lymphadenopathy palpable, there was a clear trend in the hemoglobin dropping, with the hemoglobin approaching 11 and platelets around 110, 115 from normal the few years earlier.

This patient is of interest for a few reasons. [First], his age. [Second], some chronic medical problems that the patient has like atrial fibrillation and diabetes. And [third], due to high-risk molecular features now getting close or meeting indications for therapy. Right now, we have 2 standards of care: continuous therapy (Bruton tyrosine kinase) BTK inhibitors or a fixed duration approach with venetoclax obinutuzumab. Each of these approaches have pros and cons. One thing we know is that with BTK inhibitors, some of the patient's comorbidities might want to steer us away from using a BTK inhibitor due to the atrial fibrillation, being on a blood thinner, [and] having increased risks of potential bleeding. Alternatively, the high-risk molecular features sometimes steer us away from using a fixed duration approach with venetoclax obinutuzumab.

We know at [the American Society of Hematology meeting] ASH 2023, there was some data that was presented looking at deletion 17p patients treated with front-line ibrutinib and now have 10 years of follow up. What is wonderful to see is that the median progression-free survival (PFS) was a little over 7 years, approaching 8 years. The overall survival median was not met. In fact, close to 70% of patients were still alive at 10 years, treated with frontline BTK inhibitor ibrutinib. We have also seen other BTK inhibitors like acalabrutinib as well as zanubrutinib perform very well in patients with deletion 17p and tracking historically along those lines that ibrutinib and the benchmark that ibrutinib has set.

In this scenario, BTK inhibitors appear to have overcome in partial the high-risk features because these similar outcomes are seen in patients without deletion 17p. Therefore, [for hematologists] who treat CLL patients with deletion 17p, BTK inhibitors and continuous therapy is typically a go-to [treatment] and something we reach for. In this scenario, the [atrial fibrillation] and the eliquis might make us think twice about that.

Venetoclax obinutuzumab is also a great approach, and if this patient was maybe a little bit younger in their late '50s or early '60s, I might consider it a little bit more strongly. But the caveat there is that we know with the CLL14 study, which was the venetoclax obinutuzumab for 1 year in front-line treated patients, that those patients with deletion 17p—a small number of them were included into the study—actually did have inferior [PFS] with a PFS of about 4 years noted from that study. Now the overall survival still seems similar to those patients with low-risk disease features, and we have not identified that they've had inferior overall survival due to stopping these types of patients compared to those who continue on a BTK inhibitor, so to speak, because we have no head-to-head data to look at that. Therefore, a fixed duration approach is still reasonable. And in fact, by getting to a [minimal residual disease] MRD-negative state, you might in fact think that that might be an ideal approach for somebody with high-risk disease features. At the end of the day, both approaches are great.

We do not have head-to-head the state that 1 approach is better for this high-risk, older patient population, we do have some studies that are ongoing, and we eagerly await the results of those studies—such as the CLL17 study—which will help us answer this question, which is looking at continuous therapy ibrutinib versus venetoclax obinutuzumab fixed duration, versus the 3^rd arm ibrutinib venetoclax as a fixed duration approach as well. Since that is not an FDA-approved approach here in the [United States], it's typically difficult to use that in a frontline treated patient, but is something we can potentially consider, but right now is not a typical standard of care. That study will be important to help us differentiate this.

At the end of the day, I had a shared decision-making process with the patient. We talked about risks and benefits of these various approaches. We discussed using more selective second-generation agents [such as acalabrutinib or zanubrutinib] that have decreased atrial fibrillation [and] cardiovascular risk factors. Given the long-term data with continuous therapy BTK inhibitor, where 10 years now in this 75-year-old patient, 70% of the time he'll still be alive, and in [his] early '80s may not even have progressed yet, we opted to choose a continuous therapy BTK inhibitor approach [with zanubrutinib], a second-generation, more selective agent, used as monotherapy.

The patient just recently started on therapy, we're just a few months into treatment. The patient's tolerating it well. There's minimal bleeding [and] bruising side effects. No atrial fibrillation has been noted or worsening atrial fibrillation from his baseline. The patient is clearly responding in his blood counts, and I expect the patient to have an excellent long-term outcome.

That's how I thought through this case, and I appreciate the time and attention to be in this session with me today.

Learn More About This Case Here: 

How I Treat: Chronic Lymphocytic Leukemia