My Treatment Approach: Chronic Lymphocytic Leukemia - Episode 5

Frontline Therapy for CLL: Chemotherapy-Free Regimens

Recommendations for using novel targeted therapies to treat chronic lymphocytic leukemia in the frontline setting.

Anthony Mato, MD, MSCE: We’ve decided this patient has an anemia related to CLL [chronic lymphocytic leukemia]. There’s no evidence of hemolysis. They have fatigue related to their anemia. There’s no other explanation for it. Thus, the patient needs therapy for their CLL and just remember that the patient was deletion 13q, IgHV [immunoglobulin heavy chain variable region] unmutated. We didn’t find a deletion 17p or P53 mutation, those tests, as Kristen suggested, were repeated and we’ve confirmed the same immunophenotype as was present at the time of diagnosis. Now, we need to take a little bit of a dive into what therapy would be most appropriate for this patient and I guess I could try to tackle this and then Kristen can add anything that you think I’m forgetting.

First and foremost, chemoimmunotherapy for me is not an option for this patient. She has IgHV unmutated disease. We already know from the many randomized trials of targeted therapy versus chemoimmunotherapy that the chemoimmunotherapy is always the worst option. I wouldn’t think about FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)], BR [bendamustine plus rituximab], obinutuzumab [Gazyva], or Anbesol [benzocaine] for this patient because of IgHV status alone. But then we’re stuck in a position where we have different options for a patient and to me there are 2 kinds of broad chemotherapy-free pathways one could think about. One would be a BTK [Bruton tyrosine kinase] inhibitor, and of course, we have 2 BTK inhibitors approved in the frontline setting, with or without an anti-CD20 monoclonal antibody or a PD-L2 inhibitor, which venetoclax [Venclexta] is the only one with obinutuzumab. Maybe I’ll tackle the BTK inhibitor part, and then Kristen, you can talk about kind of practical steps or what are the impractical steps of starting venetoclax. In terms of BTK inhibitors, we have 2 approved options that we talk about with patients.

One is ibrutinib [Imbruvica], one is acalabrutinib [Calquence]. Ibrutinib is approved based on the RESONATE-2 trial, which randomized it versus chlorambucil overwhelmingly positive but of course chlorambucil is not much of a control. It has subsequently been compared to other things that are more relevant in combination with obinutuzumab; it was compared to obinutuzumab/chlorambucil positive trial, that was the iLLUMINATE study. It was compared with Rituxan in combination with rituximab versus FCR in ECOG [Eastern Cooperative Oncology Group] 1912 trial, positive for PFS [progression-free survival] and OS [overall survival]. It was also compared with or without rituximab versus BR in the Alliance trial which was positive for PFS but not OS. Thus, trial after trial, randomized trial, frontline setting, ibrutinib has been proven to be better than the comparator, it does have some issues.

Adverse events can be tricky, and I’ll ask Kristen maybe also to comment on the A profile BTK inhibitors. But one of the things it does have going for it that’s important is long term follow up, then we do have 7-year long-term follow up datafrom the RESONATE-2 trial showing that more than 60%—I’m forgetting the exact number—are still progression-free on drug in approximately 50%, or progression-free, and then approximately 50% are still on drugs. Thus, a pretty impressive number for a once oral daily medication. The alternative option is acalabrutinib which is approved with or without obinutuzumab based on the ELEVATE TN trial, which compared… versus obinutuzumab/chlorambucil. Trial was positive for PFS, not OS, but interestingly, the obinutuzumab seemed to add something to the acalabrutinib, so acalabrutinib/obinutuzumab was better than acala [acalbrutinib] mono from a perspective of PFS at 24 and 48 months and the differential for PFS actually got better over time. Thus, BTK inhibitors are a great choice. Kristen, would you agree a relatively easy option for starting for patients regardless of whichever one you choose?

Kristen Battiato, AGNP-C: Absolutely. Usually when we start BTK inhibitors, we’ll start them in clinic and then they’ll just have to come in weekly for labs for monitoring, and then we’ll see them back in another month and then we can usually space out their visits. And like you said, they’re usually overall top—overall well tolerated and it doesn’t require as much follow up as the other regimen we’re going to talk about in a minute to obinutuzumab/venetoclax.

Anthony Mato, MD, MSCE:We’re pretty conservative in our clinic. We check labs weekly for the first 4, 8 weeks, but just if you look back over all the BTK inhibitors we ever started, I’m just trying to think it’s a very small to maybe close to 0% of patients where we ever get a CDC [complement-dependent cytotoxicity] and do anything with the results or chemistry. They’re usually fine during those first couple months

Kristen Battiato, AGNP-C: Yes. There’s very little risk of tumor lysis even in higher risk patients, so we just make sure that they’re doing OK. It’s more of a symptom check-in too, make sure they’re tolerating it well, and helping guide them through the first couple of weeks of therapy.

Anthony Mato, MD, MSCE: Then, venetoclax/obinutuzumab was approved based on the CLL14 trial versus chlorambucil/obinutuzumab. This is generally morbid patient population was positive for PFS updated data, I think at 4 or 5 years now looks great. What’s nice about it is the time limited therapy, but…is complicated in terms of the ramp up and also open obinutuzumab when we start with that. Kristen, could you just practically walk us through, you’re starting a new patient, let’s say outpatient medium risk for TLS [tumor lysis sundrome]. What are the pitfalls that can happen and how do you manage that?

Kristen Battiato, AGNP-C: We’ll often prepare patients just to initiate therapy with obinutuzumab and venetoclax by starting an antihyperuricemic agent, such as allopurinol. They’ll start that 7 days prior to infusion. On day 1, they’ll come in early. We’ll clear them for therapy and we’ll often premedicate with dexamethasone, Benadryl, and acetaminophen. The infusion is very—the infusion is run very slowly. Over the first day we split the infusion dose—it’s 100 milligrams on the first day and 900 milligrams on day 2. If there is an infusion reaction, the nurse will often stop the infusion immediately and monitor for signs and symptoms. The patient will often require additional supportive medications such as additional corticosteroid, histamine 2 blocker, and Benadryl depending on what their symptoms are. After the infusion, we’ll monitor for TLS as they’re at the highest risk for the first week as they’re rapidly debunking their disease. Patients will often require additional IV [intravenous] hydration and other and patients will often require additional IV hydration and other supportive medications if there’s evidence of tumor lysis.

Anthony Mato, MD, MSCE: That’s good.

Kristen Battiato, AGNP-C: I’m going to go into the ramp up now. The obinutuzumab –

Anthony Mato, MD, MSCE: I was going to say OK, that’s good about the obinutuzumab. I agree, there’s a lot of risk of, of infusion-related reaction particularly when they have poor risk disease or from a perspective of TLS, but what about the ramp up with just the practical aspects of it?

Kristen Battiato, AGNP-C: Yes. The ramp up would begin on week 4 of month 1 and it’ll be a 5-week ramp-up. This requires that patients come in twice weekly for the first 5 weeks of the ramp up where they’ll have to come in for tumor lysis labs, which are drawn pre-dose 6 to 8 hours post dosing and 24 hours post dosing. They’ll get IV hydration on days 1 and 2 for tumor lysis monitoring and they’ll continue allopurinol at this time.

Transcript edited for clarity.