Value-Based Care in CLL: The Promise of Fixed Duration Therapy

Seema A. Bhat, MD: I'm Dr Bhat. I am one of the physicians at The Ohio State University. I'm part of the chronic lymphocytic leukemia (CLL) group here. My expertise is in treating patients with CLL throughout the entire spectrum: asymptomatic, not needing treatment, all the way to relapse/refractory, as well as patients who have undergone Richter transformation or complications of CLL, for example, autoimmune complications. I am also part of the hairy cell leukemia group and treat hairy cell leukemia as well.

How has your experience informed your view on the optimal sequencing of therapies in CLL—particularly fixed-duration versus continuous options?

Dr Bhat: That's a very good question. We are blessed, at this time, that we have fixed-duration options in the form of venetoclax-based regimens. We now have 2 different options. We can combine venetoclax with an intravenous (IV) infusion in the frontline setting, with obinutuzumab in the relapsed setting. The study was done with rituximab, but we can combine it with obinutuzumab as well. Now, we can also combine venetoclax with BTK inhibitors, with or without obinutuzumab. For example, we just had results of the AMPLIFY study presented, where venetoclax was combined with acalabrutinib, which is a BTK inhibitor, and then there was another arm where obinutuzumab was added. These are 2 excellent fixed-duration regimens that we have available for our patients with CLL.

One thing I do want to mention here is that obinutuzumab is US Food and Drug Administration (FDA) approved; however, acalabrutinib/venetoclax, with and without Obinutuzumab, is not yet FDA approved, although it has been included in the National Comprehensive Cancer Network (NCCN) guidelines recently.

The other kind of regimen that we have, that we are all familiar with, is continuous covalent BTK inhibitors. We have ibrutinib, acalabrutinib, and zanubrutinib. Nowadays, we favor acalabrutinib and zanubrutinib because they have lesser cardiac risk compared to ibrutinib. How do we choose? It's always a discussion in our clinics. How do we choose who is best suited for the different modalities of treatment?

The fixed-duration regimens—definitely venetoclax-based fixed-duration regimens—offer the advantage of being time-limited. They offer the patients time off therapy. They don't have to continuously take their medications for the rest of their life. This is because they offer durable remissions, and also some of the patients get into what we call the undetectable minimal residual disease (MRD) status.

It's very well tolerated overall. The initial part of it is time- and resource-intensive because, to ramp up venetoclax, it does require monitoring of tumor lysis syndrome, so there are frequent labs. If there are labs that need to be addressed, patients have to come in for hydration. The early part is intense and, of course, when you combine it with an anti-CD20, you do have to come for those infusions.

However, despite that initial intensity for the patient as well as for the practices—where you have to have those resources in place so you can keep up with those kinds of monitoring—the advantage is that it doesn't last for a very long time, and there is an end in sight. This type of regimen is very well-suited for young, fit, and motivated patients who prioritize time off treatment and who do not mind coming in for that intense ramp-up and monitoring for tumor lysis syndrome. Again, patients who have standard-risk disease, especially those who have IGHV-mutated disease, are ideally suited for venetoclax plus obinutuzumab.

Some of the higher-risk patients, like patients with TP53 mutation or unmutated IGHV, there are data showing that venetoclax–obinutuzumab may not be the best regimen for those patients; however, we still use it. These are some of the things that we look into when we choose a specific regimen.

Additionally, we look at some of the comorbidities that the patients have. For example, a BTK inhibitor may not be the best regimen for someone who has underlying cardiac disease, uncontrolled hypertension, or uncontrolled atrial fibrillation. Those might not be the right patients for BTK inhibitors. There, you may want to lean more towards venetoclax with obinutuzumab. For a patient who's on a blood thinner, BTK inhibitors do increase the risk of bleeding. There you may want to lean more towards a venetoclax-based therapy.

On the other hand, given the risk of tumor lysis syndrome, if a patient has underlying renal disease and you don't want to jeopardize their kidneys any further, then venetoclax-based therapy should be avoided, and we can go with a BTK inhibitor in those situations.

Patient preferences definitely play into those discussions. We have to offer these options, and if a patient has a strong preference for one versus another, we have to look into those things as well.

Can you comment on how real-world patient populations—those with comorbidities, elderly, or rural patients—impact your therapy selection in CLL?

Dr Bhat: Yes, definitely. In the real-world population, when we see patients in the clinic, we don't cherry-pick our patients—we get everything. We do have to make those considerations. As I already mentioned, different things go into making those decisions. We look at disease characteristics; then we look at logistics, patient preferences, patient characteristics, their comorbidities, their medications, interactions with medications—these are all the things that we take into consideration.

Looking at disease characteristics, one of the major things is the patients who have a del(17p) or TP53 mutation. That's a specific population. Unless there's a contraindication to the use of a BTK inhibitor, I still prefer a BTK inhibitor in those situations.

In anybody else, especially in patients with standard-risk CLL, venetoclax-based time-limited therapy is okay. There, we look at any comorbidities that may interfere. For example, if a patient has underlying renal disease, they may not be best for venetoclax ramp-up due to the risk of tumor lysis which can affect the kidneys; or, if the patient preference is not to come in for regular monitoring—distance is an issue, travel is an issue, weather is an issue—they don't want to come for venetoclax or they don't want to come for the 6 months of obinutuzumab, then we can lean toward BTK inhibitors.

These are the different things we take into consideration when we have these discussions with our patients. I would also like to say that we are in a very good place that we have all these different choices. Having these different choices does increase the discussions that we have in our clinic, but this is a good problem to have. At least we can tailor a particular treatment to a particular patient based on their preferences, their risk profile, and their comorbidities.

From your perspective, how does venetoclax-based therapy compare with BTK inhibitors when evaluating both clinical and economic impact—particularly for fixed-duration use?

Dr Bhat: That’s a very important question. How do these 2 types of treatments, fixed-duration versus continuous treatment, match up clinically? We have spoken about it. Besides del(17p ), where we prefer BTK inhibitors, for the rest of the patients, we can choose either of the 2 based on various different things that I just talked about.

One of the specific things about these regimens is: what does it cost to the patient and to the health care system? A BTK inhibitor is indefinite treatment—as long as the disease is responding, which can be years, or the patient is not having any major side effects. Patients stay on these expensive medications for many years—we have patients in our clinic who have been on these medications for 5, 6, 7, 8, 9 years. The cost adds up. Being on these medications for so long, the cost adds up. These are expensive regimens, increasing the financial burden to the health care system and also to the patients. Patients have to pay their copays, so it increases the financial burden to the patient.

That links to adherence. If the treatment is burdensome to the patients, they don't want to take it. The duration of the treatment itself—taking a pill every day, twice a day—adds to their pill burden, and then, added to that, the financial burden.

On the other hand, venetoclax-based regimens do have higher costs up front because of increased monitoring for tumor lysis syndrome, which is resource intensive. You have to do more labs, and you have to get the patients into the infusion centers. If the labs are off, you have to take care of those patients—you have to give extra medications, extra hydration. There's a lot of monitoring for those 5 weeks. Sometimes, the patients may need admission for a treatment of tumor lysis syndrome.

Similarly, patients have to come in to get obinutuzumab—again, up-front resource intensive—but it eases off. The treatment is only for 1 year in the frontline setting and 2 years in the relapsed/refractory setting. Even though up-front treatment is more, overall it's limited to 1 or 2 years; it's still less costly compared to ongoing, continuous treatment with BTK inhibitors.

From a cost and finance standpoint, venetoclax-based fixed-duration treatment may be better with cost savings and overall lessening the burden on the health care system.

What barriers do you see in implementing fixed-duration therapies more broadly?

Dr Bhat: There are several barriers that limit the broader implementation of fixed-duration therapy in CLL. We have seen that with venetoclax/obinutuzumab. We talked about the logistical complexity with monitoring during the complex ramp-up scheduling. The monitoring is for tumor lysis syndrome, which can be very challenging in the community setting, where there may not be many resources in the community or for patients with limited access to specialized centers. That tends to be a challenge.

Up-front costs—we talked about that. We talked about the cost, which is increased due to initial tumor lysis monitoring, frequent visits to the hospital, and additional treatments to treat the tumor lysis syndrome, if it happens. It increases the up-front cost. There may be issues for the patient because some of the cost does go back to the patient in the form of copays, and some of the cost may be shared by the payers and the institution as well. That tends to be the issue.

The other very important factor that we have seen is that practices in the community setting may not be very familiar with the regimen, especially with venetoclax ramp-up. That tends to be a challenge. Sometimes we help out our community partners with that ramp-up at a major hospital or a university hospital, and then, once the patients get through that ramp-up—because we have more resources compared to the community—the patient goes back to their community oncologist. These are some of the challenges that we see in the community.

But there are other challenges. For example, there's anxiety at the end of that 1-year mark for the frontline treatment or 2-year mark for the relapsed/refractory treatment—especially in patients who are not MRD-negative or who do not have a complete response (CR) at that time point—there’s anxiety. There is also that indecision. Should we continue treatment? Because the trials were not done like that. Or should we just stop treatment the way the trials had done? There's a decision where you're not certain what to do at that point. We still follow the trial—we stop treatments—but there is definitely anxiety on the part of the patient as well as the oncologist. We see a lot of referrals related to this, where patients come to us at the end of the treatment to decide what they should do.

There's also anxiety about what happens next once we stop treatment. What about re-treatment? Thankfully, there are studies ongoing. There's the ReVenG study ongoing, which is looking at re-treatment with venetoclax after frontline treatment with a venetoclax-based regimen. Hopefully, with that data we will be more comfortable, but that is also an ongoing question on everyone's mind, including the patient's mind, what happens next? If I progress, will I respond to this treatment or will I need a different treatment? These are some of the things that are out there that lead to some uncertainties about this regimen.

Have you observed payer hesitation around fixed-duration therapy adoption, and if so, what clinical or economic evidence would help address those concerns?

Dr Bhat: Honestly, I have not personally had any experience where insurances have denied fixed-duration treatment, venetoclax plus obinutuzumab or venetoclax plus rituximab, in the relapse setting. These are FDA-approved treatments and are part of the NCCN guidelines. There is no reason that these should be denied. The newer venetoclax-based treatment—venetoclax plus acalabrutinib without obinutuzumab in the frontline setting—is not yet FDA approved but was recently added to the NCCN guidelines.

Honestly, I've not had an opportunity to prescribe it. I do have a patient on this combination, but it was done in a very funny way where I started with acalabrutinib and then added on venetoclax plus obinutuzumab because of the challenges I was having with acalabrutinib. The patient did end up being on an acalabrutinib/obinutuzumab regimen, but it wasn't like I submitted for approval for it. My intention wasn't to submit the approval, so I had no problems. I had no denials. I have not had any submission for acalabrutinib/venetoclax or acalabrutinib/venetoclax/obinutuzumab yet, but I don't foresee any problems. I don't foresee any denials.

We have a choice of BTK inhibitor, and payers may tell us to pick a particular BTK inhibitor. They may ask us to do acalabrutinib or they may ask us to preferentially do zanubrutinib. Those are the things that we have seen. Besides that I don't think I have encountered [issues with payer approvals]. But if there is payer hesitation around fixed-duration therapy adoption, particularly with venetoclax-based combinations, especially in the frontline setting, common concerns could be high up-front costs that we talked about because of adding obinutuzumab, which is expensive and an infusion in the clinic, or the monitoring for the tumor lysis syndrome. It's a high up-front cost, but they have to understand that the overall therapy tends to be less expensive compared to some of the indefinite options.

For higher-risk patients—for TP53 aberrations, or even for unmutated IGHV—I still prefer BTK inhibitors, but there may be payers who may deny that. I don't know. We have robust data. It's annoying, but it's a phone call.

We have to stand up and say, "No this is the right way to do it." The payers don't get to decide. There's a reason why I choose a particular treatment for a particular patient and, being an expert, we know what we are doing. That’s the way it should be. The payers should not be the ones making those decisions. I don't think they have the expertise, putting it in a very polite way. I could say more about it, but I want to be polite about it. They don't have that expertise.

What differentiating value does a time-limited treatment strategy offer to patients, providers, and the health care system as a whole?

Dr Bhat: Time-limited therapy is important. Looking at it from different standpoints for patients, the treating physician, and the health care system, it provides benefits all over.

For patients, time-limited therapy provides them treatment-free intervals. There's that end to the treatment, which they very eagerly await. After completing that, they go back to their regular life. That psychological burden of daily treatment goes away, and their quality of life is improved. They lead a normal, regular life, just like any one of us. I think that's very important and meaningful, giving them that normalcy in their life after they finish their treatment. This is very meaningful for them.

When you're limiting treatment to 1 or 2 years, you are reducing cumulative toxicity. We all know that BTK inhibitors, over time, can have cardiovascular toxicities, and they can have additional toxicities—high blood pressure has come up as a long-term toxicity. When you limit treatment to 1 or 2 years with a venetoclax-based therapy, you eliminate the risk of long-term toxicity.

Again, when you have time-limited treatment, adherence is not an issue compared to something which is ongoing for years and years. Patients fall into that routine, it may go on the back burner, and somewhere down the line, when they start feeling good, they may forget about taking the drug. But once they have a fixed time that they have to take it for, studies have shown that adherence improves.

Additionally, financial burden for the patients [improves], not just for the health care system. The patients don't have to pay out-of-pocket copays for years and years. It's definitely easier on their pockets.

For the physicians, they definitely don't have to manage long-term toxicity with ongoing treatment. Physicians have also seen that time-limited treatment increases patient engagement. There's something to look forward to, both for the patient and the physician. It definitely increases that engagement for the physician and the patient.

For the health care system as a whole, the big benefit is financial. Time-limited therapy does limit cost. It contains cost, although venetoclax regimens can be cost intensive up front, but given the fact that it's time-limited, the overall cost that BTK inhibitors add up to over years and years is not something that we see with venetoclax-based, time-limited therapy.

Also, resource utilization is less with venetoclax-based therapy, even though up front we may see more. Given that toxicities are limited, adverse events are limited—because it's 1- or 2-year treatment—there’s less resource utilization for adverse events. To compare to BTK inhibitors, patients can have atrial fibrillation, and then they have to be referred to cardio-oncology or a cardiologist, and then they have to have procedures for that. They may also have a bleeding event, and they may be hospitalized for that. Resource utilization is less with time-limited therapy compared to a continuous treatment with BTK inhibitors.

Overall, time-limited therapy aligns with the goals of value-based care. It delivers effective outcomes with lower long-term cost and treatment burden.