Treatment Approaches for High-Risk Chronic Lymphocytic Leukemia

EP: 1.Case Presentation: A 67-Year-Old Man with Chronic Lymphocytic Leukemia

EP: 2.Testing and Risk Stratification in CLL

EP: 3.First-Line Therapy Options in CLL

EP: 4.Chronic Lymphocytic Leukemia: RESONATE-2 Trial

EP: 5.Comparing BTK Inhibitors in CLL Treatment

Now Viewing

EP: 6.Treatment Approaches for High-Risk Chronic Lymphocytic Leukemia

EP: 7.The Future of Chronic Lymphocytic Leukemia Treatment

John Allan, MD: One question comes up is how real-world evidence informs our use of targeted agents versus chemoimmunotherapy and patients' risk. I think real-world evidence is valuable. I do think it does mimic frequently what we see in the prospective trials. Sometimes we can get the real-world evidence before we have a prospective trial readout, and it can help predict what it might look like and/or what to expect.

Additionally, it tells us what's happening in the real-world. These are real-world patients, patients with elevated graphene, or mild liver dysfunction, whatever it might be.

Someone who's going to be excluded are now on these drugs and are being captured by real-world databases. We can identify really what are real, or potentially real, discontinuation rates, or drug dose reduction rates, and how is that progression-free survival? There are a few limitations though in real-world evidence, and that is that it's database-driven. These databases are typically not queried and curated as well as prospective clinical trials are.

Often, patients aren't scanned at specific time points to truly assess responses, so we're assuming complete remissions despite the fact that many times bone marrows aren't had and/or possibly there's no response available because of scan has never been done, despite the fact that the patient meets criteria for a partial response or even a CR, based on hematologic parameters. There are some limitations based on this, just based on how well curated the databases are and how well queried they are to really make the data nice and clean.

Although, they are valuable, they identify hypotheses generating questions, and they can lead to some preliminary evidence which gives people comfort. One would be kind of sequencing. One question that I think a lot of people became comfortable with is using a BTK inhibitor after a venetoclax-based regimen, based on some real-world evidence. There is absolute value there. I just caution you to not overinterpret the data because for some of these limitations that are typically written in the manuscripts when they are published.

John Allan, MD: A question comes up if they had other high-risk features, would it change what I would do? I think in this current day and age, where we have monotherapy, approaches in combination treatment approaches, are not currently approved, or recommended off of a clinical trial...I don't know if I would have changed anything differently.

My practice is to have high-risk patients with del17p specifically, or PPD3 [purified protein derivative 3] disruption, utilize BTK inhibitors. The caveat being there's no real strong evidence to suggest that, that is my opinion. I think any approach for them is relatively good, but I just have comfort in the long-term data, and understanding what to expect and following that classic sequence. I guess you can ask, what would you do if this patient had lower risk features?

I typically use these targeted agents for all patients. I don't really consider chemoimmunotherapy for any patient with CLL today. I really try to steer away from that. We have several clinical trials that show the benefits of targeted agents over chemoimmunotherapy, like real chemoimmunotherapy regimens, such as bendamustine or FCR, and showing PFS and even potentially modest OS [overall survival] benefits. When you look at those subgroups, the low-risk patients seem to have the same outcomes progression-free survival response rates, etc, as the chemoimmunotherapy arm. People are arguing, well you're not doing a detriment to younger or to low-risk patients.

I counter that with the potential to select chemo-resistant, high-risk clones upon relapse. FCR has immune suppressive and 5% to 10% MDS AML risks 10 years later. I think all of these benefits, even though in these low-risk patients, they may do the same long-term, I think there's value in diminishing the toxicity and having comfort knowing that these low-risk patients may not need another class of drugs if you utilize a BTK inhibitor first. I wouldn't change much about this case on the treatment approach. I agree with everything that was done, and I think for this patient, ibrutinib specifically made sense given the fact of the PPI use.

John Allan, MD: The question comes up to speculate about how this patient is going to do in the future. I can tell you based on Resonate-2, looking at what the data says that they're going to have a great outcome. As long as they can stay on this drug, primary resistance is probably going to be pretty low. Seven years later, I would think that the patient numbers, it's still not even a coin flip; it still favors, 61% of patients are progression-free. Close to half of the patients are on drugs still at year seven. I think they're going to do fine. I have many 11q-deleted patients, very similar presentations to this that remain on the drug five to seven years out. So hopefully they won't progress, but obviously if they do, we've got great options.

The fact that they're just on monotherapy BTKi never have seen chemoimmunotherapy, they're going to respond beautifully to venetoclax, that's without a doubt. Venetoclax-based regimen, some combination, potential clinical trial would be a good option for this patient if they relapsed. A venetoclax-based option is typically the second-line standard. We just flipped the sequence. If it's a BTKi first, we utilize venetoclax second. If we utilize venetoclax first, and you'd spend that whether you treat it or just early relapse, you use the BTK inhibitor second. Our experience is growing with all these different sequences, but ultimately the data suggests, and personal anecdotal evidence suggests, that patients are salvaged with these regimens.

Once you start to truly progress and you're resistant to both BTKis and venetoclax-based treatments, you are a higher-risk patient. That's where we are thinking about clinical trials. In that setting, PI 3-Kinase [phosphoinositide 3-kinase] may have some potential role and so that's something you can consider. CAR T-cells [chimeric antigen receptor T-cells] are in clinical trials, as well as potential reversible inhibitors are options for these patients who remain resistant.

There are new classes of agents that are coming around BTK degraders, other CDK9 [cyclin-dependent kinase 9], and MCL-1 [induced myeloid leukemia cell differentiation protein Mcl-1] inhibitors to overcome potential venetoclax-based resistance. There is a lot of research being done and it's true, double refractory patients can have a very aggressive disease transform on you and/or be resistant and can be very problematic. Those patients can also be salvaged with high dose high-enough does of prednisone and some of these other types of regimens, acalabrutinib, things along those lines. Maybe we are considering allogeneic transplant, if eligible still, potentially for some of these patients.

I think the vast majority of patients are going to probably need one or two classes of drugs in their lifetime. If you're looking at the average 70-year-old patient with average risk CLL, we're probably not going to see these super-resistant patients in the near future. That's the positive thing to think about. We really need to worry about these 20% to 30% of patients with del11q or del17p p53 mutations as the ones who might be failing these drugs that we're still worrying about 10 years from now.

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