First-Line Therapy Options in CLL


John Allan, MD, highlights treatment options in the first-line setting for chronic lymphocytic leukemia.

John Allan, MD: There are a lot of current first-line therapy options, and it's very difficult now to navigate these waters in any efficient manner with your patients. It used to be a relatively straightforward conversation when initiating treatment for a patient when there was only one targeted agent available, like ibrutinib and/or you had chemotherapy options. Now, not only do you have multiple BTK inhibitors approved in a frontline setting, that have different potential side effect profiles, but you also have different classes of drugs of targeted agents that are approved in frontline setting that also offer a fixed-duration approach. This is very different than what we do with BTK inhibitors, which is a continuous therapy treat-to-progression type of paradigm.

Getting all of this data out to the patient and having them understand this nuance and these options in the absence of any real head-to-head data of these various opportunities is a little bit of an involved discussion to have. So, it's something that I think is wise to initiate months before you are talking about treatment, so when you are needing therapy, you're not having to explain these and the patient is having to really wrap their head around it and make these decisions in a quick manner. I initiate these talks about the treatment options relatively early when I see some disease activity, despite the fact that I may have three months to a year before I think they might need treatment.

The big options would be in the frontline setting, BTK inhibitors, plus or minus anti-CD20 [B-lymphocyte antigen CD20], and that includes rituximab or an obinutuzumab, and the two BTK inhibitors currently FDA approved in CLL and the frontline setting are ibrutinib and acalabrutinib. The other targeted agent approach is a BCL2 [B-cell lymphoma 2] venetoclax-based approach in combination with obinutuzumab, and that is a fixed-duration approach. And then, you have chemoimmunotherapy options, like bendamustine, rituximab, or even FCR [Folin's phenol reagent] for potentially young fit low-risk patients.

I've moved away from chemoimmunotherapy use, so it's really restricting patients to understanding options with targeted agents, and I've found that age is a big factor on which approach I want to use. Frequently, my older patients are not able to come in as often for the venetoclax-based ramp up, and the eight weeks when you're utilizing that the venetoclax or obinutuzumab approach that it requires of the patient.

There's a little bit of an investment of time, and a willingness and an ability, to do that. I find my younger patients are really wanting to not be on drug. If they're in their 50s or 60s they want to kind of have a treatment, get off of drugs, feel well, and are most interested in fixed-duration approaches.

I found that age is a big differentiating factor. What that age cut off is, is not necessarily clear in my head. A general guideline is around 75 years or older, I'm thinking BTK inhibitors. If they're younger than that and/or fit and/or able to come in and handle the ramp up and understand it, I'm willing to offer that to any patient. It's a difficult thing to think about; obviously, comorbidities, like atrial fibrillation, can make you steer away possibly from BTK inhibitors in general. I have many patients that have had a history of it or currently are in atrial fibrillation, and it doesn't necessarily make me shy away from using those classes of drugs if I think it's really the best for them.

The next big class, a big category that helps me differentiate which approach to use, BTK inhibitors versus venetoclax-based approaches, is risk. If you have high-risk features, like del17p or P53 mutations, I typically steer away from fixed-duration approaches without great evidence to state that there's any reason for that. Some of the data that has been demonstrated from full analyses have shown that some of the overall high-risk features have been overcome a little bit by BTA [benzotriazole] inhibitors.

Now, what we know with venetoclax-based therapy is that medium progression-free survival for del17p patients is inferior to those without it after one year of treatment, and stopping with a medium progression-free survival of about four years. What we don't really know is how if you continue on venetoclax in these patients, would they do better? And how do they stack up comparatively to a continuous BTK inhibitor approach versus that? We don't have that data, so I think it's appropriate to use any of these approaches in these high-risk patients. I just favor the longer-term data and understanding that certainty a little bit with BTK inhibitors, and therefore that has been my go-to, but it's not wrong to utilize a fixed-duration approach for these patients.

For IgHV on mutated status, I don't typically worry too much about that in terms of thinking about my approach for the patients. We have good data from the long-term update ofRESONATE-2 [RESONATE-2 Imbruvica for frontline CLL/SLL], where IgHV mutational status does not seem to play a role in predicting someone who is going to have an inferior outcome when you use continuous inhibitor BTKs. Whereas in the CLL14 [CLL14 Trial: Fixed-Duration Chemotherapy-Free Regimen for Frail Patients with Treatment-Naïve CLL] study, we have identified those patients with an IgHV unmutated status to have an inferior progression-free survival compared to those who do not with immediate PFS [progression-free survival] of about five years. Now, five years of treatment, four of those are off of therapy, half of the patients still haven't progressed, it's still pretty good. I don't think we've gotten to a point where we identify someone with an IgHV unmutated status and say you cannot have a fixed-duration approach. Really, what's going to inform that answer is the retreatment data. How well do those patients respond to a second round? If they went four or five years, and then progress and need therapy, do they get another four or five years? And over the decade, you end up in the same place, but in that approach, you only have two years of therapy.

That remains to be seen. It's going to be a big factor on whether which way that pendulum swings. With combination therapy, it's going to be a difficult question to answer. Those are the big things that I think about: age, comorbidities, and molecular risk factors. Those are big factors that weigh in when I have these discussions about which approach is going to be best.

Transcript Edited for Clarity

Initial Presentation

  • A 67-year-old man presented to PCP with complaints of fatigue and night sweats
  • PMH: patient takes OTC antiacid tablets a few times a week for a “sensitive” stomach
  • PE: Enlarged mobile lymph nodes bilaterally (~1.5 cm), no palpable spleen or liver
  • Laboratory findings:
  • WBC; 102 X 109/L
  • Lymphocytes; 79 X 109/L
  • Hb; 11.4 g/dL
  • Platelets; 180 X 109/L
  • ANC; 1,900/mm3
  • LDH 1470 U/L
  • Cytogenetics; del(11q), IgVH-unmutated
  • beta2M, 3.0 mg/L
  • Rai Stage I

Treatment Plan

  • Patient was started on ibrutinib
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