How to Choose Between Fixed-Duration vs Continuous BTKi Therapy for CLL

At a regional Institute for Value Based Medicine® (IVBM) event in San Francisco, Sophia Humphreys, PharmD, MHA, BCBBS, a practicing pharmacist and health system director at Sutter Health, discussed the advantages and disadvantages of various treatment options for patients with chronic lymphocytic leukemia (CLL).

Sophia Humphreys, PharmD, MHA, BCBBS

The American Journal of Managed Care® (AJMC®): When considering fixed-duration options compared with continuous Bruton tyrosine kinase inhibitor (BTKi) therapy, what patient-specific factors, such as comorbidities and treatment goals, should drive the decision for first-line treatment, and how do you balance these clinical factors with the cost-effectiveness and value-based care implications?

Humphreys: That's a great question, because when we select therapy, we really wanted to look at what benefits our patient the most, before we even think about pharmacoeconomic factors. For example, the fixed-duration options, such as Venclexta + Gazyva [venetoclax + obinutuzumab], and other agents that include Venclexta.

What we wanted to consider is that it might be preferred over any single BTK inhibitors for patients with cardiovascular disorders or uncontrolled hypertension and at high risk for bleeding—for example, if they have low platelets or have other conditions that require anticoagulation. However, a BTK inhibitor might be preferred over Venclexta plus another agent, the combo treatment that we just mentioned in patients with kidney impairment. Kidney impairment increases the risk of tumor lysis syndrome with Venclexta. So, for these patients, we would prefer to keep them on the BTK inhibitors. Also, we wanted to avoid any combination that included Venclexta for patients who are either on nephrotic medications that has nephrotoxicity or who are taking a strong IIIa inhibitor, because these will both increase the risk for the patients to have tumor lysis syndrome.

For patients with CLL, there's a specific population who have the 17p deletion or the tp53 mutation. They are at higher risk for not responding to therapy or experiencing early relapse. So, for those patients, first time, we're still considering BTK inhibitors.

You mentioned the pharmacoecomonic considerations, which is very important, because if we think about a combination therapy vs an ongoing BTKi treatment, you are looking at 12 months vs an ongoing treatment. There's a well-done study led by Yale University and the University of Pennsylvania, in collaboration with a large group, including many experts and a couple manufacturers. They calculated the real-world comparison of health care cost between the BTK inhibitor vs the combination that included Venclexta. They have seen that 6 months after completion of the fixed-duration treatment, they see more than $8000 per-patient per-month savings for the combo with fixed-duration vs ongoing treatment with BTKi.

AJMC: In your opinion, how might measurable residual disease (MRD) testing be integrated into clinical practice to guide the duration of therapy, and what are the potential benefits and challenges of using MRD as a treatment end point?

Humphreys: For this question, we do not have a clear answer yet. As you know, the assessment using measurable residual disease has emerged as a highly-sensitive indicator for disease burden during and at the end of each treatment. Of course, ideally, we wanted to see undetectable, measurable residual disease status, right? However, [with] the test itself, I do not see it widely used to all patients, and really it depends on the practice. So, to have the adoptable measurement and to have a standardized practice guideline would help our practitioners and help our frontline physicians to really standardize practice; but for now, I do see variations of use.

AJMC: With the introduction of newer agents, how should physicians approach sequencing therapies in patients with relapsed or refractory CLL? Additionally, in what scenarios do you see a role for rechallenging patients with therapies they have previously received?

Humphreys: What I see normally, BTKi is still the first line. However, I have seen even Breyanzi [lisocabtagene maraleucel], the new CAR [chimeric antigen receptor] T-cell therapy for CLL, being used. However, the majority of use is still for large B-cell lymphoma. Of course, this is for relapsed or refractory patients.

AJMC: The Inflation Reduction Act (IRA) is expected to influence the choice of BTKis. How do you anticipate this legislation will affect the use of established agents like ibrutinib vs newer options such as zanubrutinib, particularly with regard to access and prescribing patterns?

Humphreys: Yeah, this one is a very exciting topic. As you know, BTKis are high-cost, and I am very excited to see the new price for ibrutinib coming out. However, if we think about the newer agents, a lot of them did claim to have equal or even superior efficacy data and have less toxicity, especially for CV [cardiovascular] toxicity. We've reviewed the ALPINE [NCT03734016] study in detail recently, as you have mentioned. Zanubrutinib in the ALPINE study was reported to have significantly prolonged both progression-free survival as well as overall response rate compared with ibrutinib.

What we are seeing now is that there's newer agents coming, [claiming] to have less side effects, especially CV side effects, and to have comparable or higher efficacy data. So, like we have mentioned in the beginning of the interview, [we need to] consider patient-specific choices and how patients would tolerate ibrutinib, and if we need to use a newer agent, or for some patients, we can switch them to the fixed-duration combo. So, of course, if you think about the adverse event as reported in the ALPINE study, we did see much lower atrial fibrillation, for example, for zanubrutinib compared with ibrutinib.

AJMC: As the CLL treatment landscape continues to evolve with new therapies and diagnostic tools, what do you see as the most significant emerging trends or research priorities that could reshape clinical practice in the coming years? How should clinicians prepare for these changes to optimize patient care?

Humphreys: That's a large question, and I would say that now, what we are seeing is the progression of the targeted treatment that's becoming more and more precise. We started from BTKis and then moved into fixed combo, and then now we are having CAR T choices. These are the first CAR T choices for our CLL patients, which is quite exciting, especially for patients with treatment resistance, refractory or relapsed patients, and especially for patients with 17p deletion or tp53 mutations. So, all those new treatment options are in the pipeline, and the pipeline for CLL treatment is quite lively. We are hoping to see more choices.