Adam Kittai, MD, on Sequencing, Cost, and the Road to CLL Cure

Adam Kittai, MD, of NYU Langone Health, offered a wide-ranging look at the most pressing unresolved questions in chronic lymphocytic leukemia (CLL) treatment today in a recent interview with The American Journal of Managed Care^®. When asked about what comes after a Bruton tyrosine kinase (BTK) inhibitor stops working, Kittai was candid that there isn’t enough data published right now to definitively guide sequential therapy decisions. He expects both BTK inhibitors and venetoclax-based regimens to remain active in the second line, while acknowledging that diminishing returns are a real concern. Kittai is also director, CLL Program, Perlmutter Cancer Center, and director, Lymphoma Program, Perlmutter Cancer Center - Long Island.

He also explored when a triplet regimen—acalabrutinib, venetoclax, and obinutuzumab (AVO)—is warranted and how minimal residual disease (MRD)–guided approaches, informed by the work of Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute, are beginning to shape practice.

On cost, Kittai noted that time-limited therapy is generally less expensive than continuous treatment, although most supporting studies used venetoclax-obinutuzumab (VO), an infused regimen, and the calculus may shift as all-oral combinations expand. Venetoclax’s dose ramp-up requires frequent lab draws and clinic visits; obinutuzumab adds infusion chair time. He acknowledged adjusting treatment recommendations based on financial circumstances, while noting high out-of-pocket burdens, are less common than expected.

He framed patients into 3 risk tiers—good, normal, and high—each carrying distinct unanswered questions. The 25% with good-risk disease may already be overtreated, and the approximately 20% with high-risk disease still lack strategies delivering durable control beyond a decade.

Looking ahead, Kittai sees promise in T-cell–directing and immune-based therapies but stresses that safety, not just efficacy, remains the central hurdle—until there is either a cure or a therapy safe enough to make a cure unnecessary.

This interview was lightly edited for clarity.

AJMC: As more patients receive combination therapy up front, what are the sequencing implications if there is a relapse?

Kittai: This is a great question. The answer is, we truly don’t know. I had said earlier that we don’t have any long-term data for AV, and that might be a reason to pick one of our more tried-and-true regimens, knowing how well they work, and I think that’s justifiable. Additionally, we don't have any studies in the relapse setting that have tested the modern-day sequence of a BTK inhibitor or a venetoclax-based regimen and then a BTK inhibitor and a venetoclax-based regimen. We don’t have those first studies published. The closest thing we have to that is the most recent pirtobrutinib study. But even in those studies, the median prior line of therapy was 3, and so a bunch of patients got chemotherapy in those studies as well.

We now have multiple studies that have read out, including AMPLIFY (NCT03836261) and also the CLL13 study (NCT02950051)—which were venetoclax regimens vs chemoimmunotherapy—and also now CLL17 (NCT04608318), where we’re going to see data spilling out, looking at the effectiveness of retreatment with the same regimens in the second line and also starting different mechanisms in the second line. Given that AV is given for 14 cycles of a time-limited nature, I do expect that if patients have a long treatment-free interval after that, they would do fine with receiving AV again or a venetoclax-based regimen.

We do know that generally the consensus in cancer care is that even if patients do well on a time-limited therapy and have a treatment-free interval that’s long, there is a sense of diminishing returns, where we don’t expect the same combination to work as well as it did in the front line. But we’ll see how more data come into play. I do expect that both options will continue to work in the second line, but we don’t have much data to support it, and we don’t know how well they will work or whether or not using them together is going to cause a significant diminishing return. But I do think that for the most part, they should do fine in the second line with the same regimen or switching to a VO or switching to a continuous third regimen as well.

AJMC: Do you see a meaningful role for triplet regimens, or should doublet therapy remain the standard for most patients?

Kittai: We now have 2 studies, this one and a study done through the alliance, that have shown a higher risk of death with the triplet arm. Granted, in both studies, they were done during COVID-19, and those high risks of death were due to COVID-19. We knew that patients who got anti-CD20 monoclonal antibodies, obinutuzumab in both cases, had a higher risk of death with COVID-19. Now that we know that COVID-19 is not as big of an issue, the question becomes, are we more comfortable with these triplets? The answer is it depends, just like everything else.

Other data were presented by Matt Davis from Dana-Farber that were [on the] MRD-guided triplet AVO for patients with TP53 aberrations. This regimen actually was added to the NCCN [National Comprehensive Cancer Network] guidelines based on this trial that showed really good outcomes using an MRD-guided therapy with AVO in patients who had these high-risk features. And so I think if I have a younger patient who really wants time-limited therapy but also wants to get the best chance to get their disease into a good remission, I would definitely think about using AVO, and I would probably do it using an MRD-guided manner like the study done by Dr. Davis at Dana-Farber. I think it really depends. I think I would reserve it for younger patients who I’m not as worried about the infection risk.

AJMC: From a value-based care perspective, how might fixed-duration regimens impact cost adherence and overall resource utilization vs continuous therapy?

Kittai: In terms of cost, there have been a few studies now that have shown that time-limited therapy is just cheaper than continuous therapy across the board, which makes sense. That being said, a lot of those studies were using VO, and the obinutuzumab is kind of underneath a different bucket because it’s infusion. We’ll see how those studies replicate when using all-oral AV. That being said, when I have a patient and they’re paying their out-of-pocket cost of $500 a month for these drugs—just pulling up a number—if they only have to pay $500 for 14 cycles, that’s much better than paying $500 indefinitely. It kind of depends on what’s happening with the patient.

Additionally, it’s actually very rare in my encounters that patients really do have high out-of-pocket costs, but it depends on the patient. I’ve actually had 1 patient that I chose to do time-limited therapy with because of the out-of-pocket costs. Now, in terms of utilization, the venetoclax does require a lot of utilization because we have to have the patient come in weekly for the dose ramp-up, and also get the labs 6 to 8 hours after and 24 hours after giving each dose in the ramp-up.

Obinutuzumab also requires a lot of utilization in the clinic because, A, [the patient is] taking up an infusion chair where they’re sitting for hours. B, there are infusion reactions and tumor lysis syndrome that can occur with the obinutuzumab, and they’re also getting it 8 times basically throughout the disease course. So in terms of utilization, continuous BTK inhibitors are probably a little bit better because they require less monitoring and fewer visits to the clinic. It’s sort of a wait. Generally, my preference is to pick the regimen that is cheapest and most effective and most safe for the patient. Certainly, if efficacy and safety are equal, it’s okay to pick a regimen based off of cost to the patient, for sure.

AJMC: Looking ahead, what key unanswered questions will be most important to refining frontline CLL treatment?

Kittai: I think that there are 3 buckets of patients. There are patients with good-risk disease, normal-risk disease, and high-risk disease. I think we’ve done a really good job at identifying normal-risk disease and how we should treat patients who fall into that big bucket in the center. However, the good-risk disease patients are about 25% of patients, and the high-risk patients are about 20% of patients, so there are a lot of patients on both ends whose treatment we haven’t really identified how to treat well. For instance, the good-risk disease patients are probably going to do well no matter how many...whatever we give them. I think we’re actually probably overtreating those patients, in general.

Can we create clinical trials for good-risk patients where we’re just not giving as much therapy otherwise? I think that’s a question that’s unanswered. Similarly for high-risk patients, even though now we have this MRD-guided therapy and continuous therapy that really has mitigated a lot of the risk of aberrations, these patients still eventually relapse. For these high-risk patients, we still haven’t figured a way to get their disease under control for over 10 years like we have with normal-risk and good-risk patients. I think that on both ends, there’s more work to be done.

Last but not least, across the continuum, we still haven’t created a cure, and in the flip to that, we still haven’t created a drug that is so safe that a cure doesn’t matter. Until we get to those points, there’s still a lot of work to do. I think that the revolution of T-cell–directing therapy and utilizing our immune system to attack the cancer will eventually come up with a cure for most cancers. The question becomes, how do you implement that in the clinic? We haven’t gotten to a point where those treatments are perfect and also not toxic. I think we’re some time away, but I am hopeful that we’ll have a cure in the future. But the question is, will the cure be safe enough? That’s where the next avenue comes.