Treatment Tips in Chronic Lymphocytic Leukemia

David Henry, MD; Anthony R. Mato, MD; Lindsey Roeker, MD


April 14, 2020

This interview was originally published as part of MDEdge's Blood & Cancer podcast series. In this episode, Anthony R. Mato, MD, and Lindsey Roeker, MD, both of Memorial Sloan Kettering Cancer Center in New York, joined podcast host David Henry, MD, of Pennsylvania Hospital in Philadelphia, at the 2019 meeting of the American Society of Hematology (ASH) to discuss strategies for treating a patient with chronic lymphocytic leukemia (CLL). This transcript has been edited for length and clarity.

David Henry, MD: It's common for a primary care doctor to see a patient—let's say he's 75 and fit—whose complete blood count (CBC) comes back from routine evaluation with a white blood cell count of 25,000 µL. Additional analysis may show that there's a lot of lymphocytes, not so many neutrophils, with the hemoglobin and platelets looking okay. Then perhaps we send out for CD5, CD19, CD20, CD23, all of which come back positive. I would say that this is CLL. But what additional aspects of the workup do you suggest we do with this new patient?

Lindsey Roeker, MD: Our initial workup is often a fluorescence in situ hybridization (FISH), looking for trisomy 12 as well as deletion of 13q, 17p, and 11q.

Anthony R. Mato, MD: We also perform next-generation sequencing specifically to look for mutations in TP53, as well as IgVH mutational analysis, to recognize whether a patient is mutated or unmutated.

Henry: I know from my entire life in oncology that when anybody says TP53, that's bad. But with the IgVH, do you prefer it to be mutated or unmutated?

Roeker: Mutated IgVH disease tends to respond a bit better to therapy.

Henry: When it comes to treating a patient fitting this description, I usually recommend an approach of "if it bothers you, it bothers me." By that, I mean that the patient is experiencing fevers, chills, night sweats, lumps or bumps in their neck, an enlarged liver and spleen, the rest of their CBC is a mess, or their creatinine is high from lymph node swellings blocking their ureter. Would you recommend roughly the same approach in this patient?

Roeker: Absolutely.

Choosing Your First Treatment

Henry: Perhaps the patient gets a second opinion at Sloan Kettering before returning to me in Philadelphia, at which point he progresses with those symptoms I just noted. If the patient is IgVH unmutated, what's your first therapy?

Mato: In our algorithm, if he's IgHV unmutated, that basically takes chemoimmunotherapy combinations off the table regardless of whether he's young or fit. That means no fludarabine-cyclophosphamide-rituximab, bendamustine-rituximab, or even, I would argue, obinutuzumab-chlorambucil. Unless there's some extreme reason why an unmutated patient like this would be on a pathway to receiving a novel agent as first therapy.

The choices for those first-line therapies keep expanding, and did so further at this past year's ASH meeting. The standard options are ibrutinib, plus or minus obinutuzumab. Ibrutinib was the first novel agent approved in the frontline setting and now has two indications there.

You also have an option of venetoclax plus obinutuzumab, the regimen approved by the US Food and Drug Administration (FDA) following the CLL14 trial. That is a time-limited, 12-month therapy.

Then the third option, which more recently received FDA approval and received National Comprehensive Cancer Network guidance as a preferred category, would be the Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib with or without obinutuzumab.

These are the three different novel agent–based therapies available to patients. Each has a different adverse-event profile, schedule, and benefit to its approach.

Henry: So it requires a discussion. At the moment, you wouldn't say, "Well, this is option #1, #2, and #3, and we may not choose two of those"?

Mato: Dr Roeker and I have a pretty similar practice style. I think I speak for both of us when I say that we don't have data to tell us which to choose. The way I like to explain it to patients is that they're all winners. It just depends on whether you have the time for a dose escalation or for infusional therapy combined with a pill. Then you take into account comorbidities, as well as the adverse-event profile of the agents themselves, and help patients make a decision.

Advice for Using Venetoclax

Henry: Let's say the patient's white count is 100,000 µL and you're going to use the oral agent venetoclax. I know that in our practice, we kind of shake a little bit at that point, because things might go wrong. How do you handle that patient?

Roeker: When they're high-risk for tumor lysis syndrome (TLS), admitting the patient and closely monitoring fluids is definitely the safest thing to do.

Mato: And that's what the label suggests we should do.

Henry: What would be your starting dose and when would you step it up?

Roeker: It's 20 mg to start and then you have an escalation every 7 days. Sometimes those really high-risk patients need to be in-house for 48 hours once a week for the first couple of weeks, until their white count really comes down.

Mato: Also with that regimen, the antibody really improves the risk status before you have to give the venetoclax.

Roeker: Debulking with the anti-CD20 monoclonal antibody obinutuzumab really clears out a lot of the white count and hopefully melts away some of the nodes. It's relatively rare to have a patient at high risk for TLS in the frontline setting after obinutuzumab.

Henry: And that could be done at an outpatient infusion center before the venetoclax admission?

Roeker: Exactly.

Mato: Once that white count comes down, if you follow the guidance in the label, you don't have to admit the low- or medium-risk patients. That could be done in the clinic safely.

Henry: With the venetoclax therapy, can you say to the patient how long they need to be treated and what you are watching for regarding relapse?

Mato: Everybody gets a year's worth of therapy. But data were presented at the ASH meeting showing that 36-month progression-free survival is approximately 82% with venetoclax. So you have an 82% chance of being in remission 3 years after you start therapy and not requiring another therapy, which are excellent results given the fact that you've only had 1 year of therapy in total.

Henry: That's terrific, especially in an aging population where you've got these remissions out to 3 years. How would your treatment and remission expectations differ—of course, without the debulking need and the TLS—for acalabrutinib or ibrutinib?

Roeker: Ibrutinib and acalabrutinib are both treat-to-progression approaches. That's more appealing for the patient who either really doesn't want to come in to the hospital or doesn't want to think about an infusional-based therapy. For some people, that pill-a-day option is just a lot easier. Those are the kind of patients that we consider for these treatments. Of course, it's important to think about the side-effect profile and make sure that it's the right treatment for the patient.

Henry: Do these patients need to be on an antiviral or an antifungal as an ongoing background medication to watch for side effects?

Mato: There's no mandated antimicrobial prophylaxis for this patient population.

Treating Relapse

Henry: Let's consider a situation where this patient gets his 3 years of treatment and then experiences progression. Would the IgVH change as this patient comes in having relapsed?

Roeker: No, but your FISH can change; your TP53 mutational status can change.

Henry: If the patient is TP53 mutated, has had that year of venetoclax therapy, and now at 3 years out has suddenly relapsed, what's your therapy then?

Mato: You just asked the million-dollar question. You'd be preparing for a plenary session if you had that answer, because we just don't know.

The two big choices for patients in this situation would be to re-treat with the same regimen or to switch to a BTK inhibitor. We have limited information about re-treatment, in particular with venetoclax, and even less so in the frontline setting.

We have some emerging data about BTK inhibitors post-venetoclax. The good news is that it suggests that if you've never seen a BTK inhibitor before venetoclax, they work well after venetoclax. So that's a safe bet, with response rates exceeding 80%.

It is also very reasonable to think about re-treating with the same regimen. Over the next year we'll get a lot of information from that same CLL14 trial about re-treatment data.

Henry: For someone who goes back to the days of chlorambucil, this is spectacularly exciting that we have new agents, different classes, and you can switch to a different class at relapse.

In closing, I want to discuss the king of old therapies, rituximab. It's been out since the mid-1990s. Of course, now its patent has ended and there are two biosimilars. Have you had experience with these, and do you have a problem using a rituximab biosimilar?

Mato: I have not yet used a rituximab biosimilar. I suspect that many of us will use these agents as they are reviewed by our pharmacy and therapeutics committees. It's somewhat insurance driven, similar to the colony-stimulating growth factors, where the decisions are made for us.

I personally don't have a major problem with them. From what I know about biosimilars, which is sort of a medium amount, the FDA has gone through a lot of thoughtful considerations in determining what a biosimilar is and what the approval pathway is going forward. I feel pretty comfortable that if the FDA signs off on the rigorous testing to prove that an agent is biosimilar, than it could be acceptable for clinical practice.

Henry: That is my strong feeling. I think we're hoping to see some improvement in cost based on biosimilars, and they really have an incredibly strong vetting process at the FDA.

With that, I want to thank the CLL specialists Anthony Mato, a young rising attending, and Lindsey Roeker, a young rising fellow, for stopping by to talk about CLL at the ASH meeting 2019 in Orlando, Florida.

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