CLL Progress Propelled By Doublets, Triplets, and Response-Adapted Treatment

The ongoing goal in the research paradigm for frontline chronic lymphocytic leukemia (CLL) is to improve on the efficacy standard set with single-agent Bruton tyrosine kinase (BTK) inhibition. At the 43rd Annual Chemotherapy Foundation Symposium (CFS), John Allan, MD, associate professor of clinical medicine, Weill Cornell Medicine, highlighted ongoing efforts to build on this standard with doublet treatments, triplet regimens, and response-adapted approaches.

Ibrutinib Monotherapy: Frontline CLL Landmark Data

The established standard and target to improve upon in frontline CLL is single-agent BTK inhibition. Ten-year follow-up from the landmark phase 3 RESONATE-2 trial (NCT01722487) showed that at a median follow-up of 9.6 years, monotherapy with the BTK inhibitor ibrutinib (Imbruvica) reduced the risk of disease progression or death by 84% compared with chlorambucil chemotherapy in patients with CLL/small lymphocytic lymphoma.¹ The median progression-free survival (PFS) was 8.9 years with ibrutinib vs 1.3 years with chlorambucil (HR, 0.16; 95% CI, 0.11-0.22; P <.0001). The 5-year overall survival (OS) rates were 82.8% vs 68.4%, respectively.

CLL research has, for years now, been geared toward improving on the benchmark set by single-agent BTK inhibition, both in terms of efficacy and the potential to stop treatment and not be on endless therapy, Allan explained.

Doublets and Triplets

The primary strategy for building on the single-agent BTK inhibitor gold standard has been exploring doublet and triplet regimens in the frontline CLL setting.

AMPLIFY Trial

The open-label phase 3 AMPLIFY trial (NCT03836261) explored fixed-duration frontline combinations with the second-generation BTK inhibitor acalabrutinib (Calquence) and the BCL-2 inhibitor venetoclax (Venclexta).² Patients were randomly assigned to 1 of 3 treatment arms in the trial: acalabrutinib plus venetoclax (AV), acalabrutinib/venetoclax plus the anti-CD20 monoclonal antibody obinutuzumab (Gazyva; AVO), and chemoimmunotherapy with investigator’s choice of the FCR regimen of fludarabine-cyclophosphamide-rituximab or the BR regimen of bendamustine-rituximab.

Results showed that “The triplet [of acalabrutinib plus venetoclax and obinutuzumab] seems to eke out a win here,” said Allan.

The 3-year median PFS rates were 83.1%, 76.5%, and 66.5% with AVO, AV, and FCR/BR, respectively. The median PFS was not reached (NR) for AV and AVO compared with 47.6 months for FCR/BR.

Allan noted that the study was powered to measure AV vs chemotherapy, so that comparison was the primary end point evaluation for statistical significance. These data showed that the AV doublet did reduce the risk of disease progression for death by 35% vs FCR/BR chemotherapy (HR, 0.65; 95% CI, 0.49-0.87; P = .004).

Allan noted, however, that even though the study was not statistically powered to assess the triplet, AVO “clearly has benefit over AV and chemotherapy.”

He continued, “And so you might say, ‘Let's give AVO to everybody and maximize the treatments.’” Allan quickly dismissed that idea, noting that the obvious added toxicity with the triplet means it’s not appropriate for all patients, and so it becomes a matter of finding the right patients.

In this regard, Allan explained that mutation and risk status have emerged as factors to help identify which patients are optimal for the triplet vs the doublet.

The greatest benefit with AVO in the AMPLIFY trial occurred in high-risk patients—those whose tumors did not harbor an IGHV mutation (unmutated IGHV). In this high-risk group, the 36-month PFS rate was 82.8% with AVO vs 68.9% with the AV doublet and 56.8% with FCR/BR. The median PFS was NR for AVO vs 51.5 months and 43.3 months for AV and chemotherapy, respectively. The HR for PFS for AVO vs FCR/BR (HR 0.35; 95% CI, 0.23-53) was much better than the HR for PFS for AV vs FCR/BR (HR 0.69; 95% CI, 0.48-97).

Translating this research into the real world, Allan said, “The high-risk patients are a subgroup that, in my practice, I have started to focus on offering triplet therapies to and talking to them about this approach.”

In contrast, when looking at the subgroup of patients in the AMPLIFY trial who had lower risk, mutated IGHV disease, there was not a major difference in outcomes between the triplet and doublet regimens. The 3-year PFS rates were 86.0%, 83.6%, and 79.9% with AVO, AV, and chemotherapy, respectively, and the median PFS was NR across all 3 arms. The HRs for PFS were similar to those for AV (HR, 0.67; 95% CI, 0.39-1.14) and AVO (HR, 0.58; 95% CI, 0.32-1.02).

“In the subgroup with low-risk disease, AV patients do just as well,” said Allan, adding, “The nice thing about AV is that it is an easy oral regimen, there’s no antibody, so that decreases toxicity…and what we're trying to do in these types of patients is not add toxicity and then potentially overtreat them. And I think giving triplets to these lower-risk patients might be doing just that.”

GAIA/CLL13 Trial

Doublets and triplets were also explored in the open-label, phase 3 GAIA/CLL13 trial, which examined first-line venetoclax combinations vs chemoimmunotherapy regimens in patients with CLL.³ Results across the treatment arms showed that the 4-year PFS rate was 85.5% with the triplet of venetoclax-obinutuzumab-ibrutinib, 81.8% with the doublet of venetoclax-obinutuzumab, 70.1% with the doublet of venetoclax-rituximab, and 62.0% with chemoimmunotherapy (FCR/BR).

“Similarly as with AMPLIFY, the triplet had a benefit over the doublet,” said Allan. He noted, however, that when looking at subgroups defined by IGHV mutational status, “I didn't show it here [on my slides], but again, it's the same story [as with AMPLIFY]. The unmutated patients with higher risk disease are the ones who are benefiting from the triplet regimen and patients with lower risk, [IGHV-mutated] disease do phenomenally with basically any of the regimens, but obviously, we don't want to give them chemotherapy, because you can get the same benefits without the toxicity with the venetoclax-based treatments. But again, it’s really just focusing on these high-risk patients where you may want to maximize the treatment and give the triplet.”

He also expanded on the safety and tolerability of the venetoclax-obinutuzumab-ibrutinib triplet. “I think it's a relatively safe and easy regimen to use for patients. It's a little rough in the front with the obinutuzumab, but once you kind of get them through that first couple of weeks, it's pretty much smooth sailing for the most part, and patients can actually do very well, and immunosuppression is not so untenable and impossible to handle. And again, obviously, as a general practice, you need to be very careful and think about it before choosing the triplet.”

Response-Adapted Approaches

Researchers are also exploring whether the use of response-adapted approaches with these regimens can further enhance outcomes in CLL.

The open-label, multicenter, randomized phase 3 FLAIR trial (NCT04680052) in frontline CLL compared the ibrutinib-venetoclax combination and ibrutinib monotherapy with FCR.⁴

In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. Based on the response-adapted design of the trial, the duration of ibrutinib-venetoclax was defined by measurable residual disease (MRD) assessed in peripheral blood and bone marrow. Patients received the doublet for double the amount of time it took them to achieve undetectable MRD. For example, if you were MRD-negative at 1 year, you received 1 extra year of ibrutinib-venetoclax, and if it took 2 years for you to be MRD-negative, you received 2 extra years of ibrutinib-venetoclax.

Regarding time to MRD negativity, Allan said, “About 60% of patients get there at 2 years and are able to stop, and 70% of patients get there by year 3, and then essentially, you get diminishing returns beyond that. I've heard that how my colleagues practice is that they measure MRD at 1 year and at a year and a half so they know you're going to get treatment [based on the response-adapted study protocol] for 2 or 3 years, basically. That’s what they do; they stop dealing with it beyond that time point, because you kind of get this diminishing return. So you either get there [to MRD negativity] by year 2 or 3, or you don’t.”

Allan said the efficacy results of the study showed that the “doublet here clearly beat single-agent ibrutinib and FCR.” At 5 years, the median PFS was NR for ibrutinib–venetoclax and ibrutinib monotherapy and 69.2 months for FCR. The 5-year PFS rates were 93.9%, 79.0%, and 58.1%, respectively. The ibrutinib-venetoclax doublet reduced the risk of disease progression or death by 87% vs FCR (HR, 0.13; 95% CI, 0.08-0.21; P < .001) and by 71% vs ibrutinib alone (HR, 0.29; 95% CI, 0.17-0.49; P < .001). As expected, single-agent ibrutinib improved outcomes vs chemotherapy (HR, 0.44; 95% CI, 0.32-0.60; P <.001).

Survival was also observed to be better with the doublet. The 5-year OS rates were 95.9%, 90.5%, and 86.5% with the doublet, single-agent ibrutinib, and chemotherapy, respectively. As with PFS, ibrutinib-venetoclax improved OS vs ibrutinib alone (HR, 0.41; 95% CI, 0.20-0.83; P < .001) and FCR (HR, 0.26; 95% CI, 0.13-0.50; P < .001), and ibrutinib monotherapy improved OS vs FCR (HR, 0.64; 95% CI, 0.39-1.05; P = .075).

Allan shared his theory for why he thinks there’s a survival benefit with the ibrutinib-venetoclax regimen. He said patients achieving MRD negativity at relatively early time points are then stopping treatment early through this risk-adapted approach, and they are avoiding toxicities such as cardiac toxicities and infections. He believes that this reduction in toxicities, along with the efficacy benefit from the doublet, is extending patients’ lives.

Conclusion and Next Steps in Frontline CLL

In his concluding remarks, Allan said, “Doublets and triplets are now incorporated into our NCCN guidelines for CLL, opening up use in the US prior to full FDA approvals,” adding that, “Venetoclax-obinutuzumab, ibrutinib–venetoclax (fixed-duration [FD] or MRD-guided [MRDg]), AV/AVO (FD), and zanubrutinib-venetoclax (MRDg) are all options in the NCCN guidelines. Where to place them is still a little unclear, but it’s becoming clearer, and head-to-head data are still maturing and/or emerging.”

He also stressed the significance of reaching MRD-negative status. “I believe achieving deep undetectable MRD remissions remains important, and I strive to achieve this end point for most patients who want to stop therapy, particularly in the highest risk patients.”

Regarding next steps, Allan said, “We do still need oral doublets overall to maximize our depth of remissions, and on this front, the oral combinations of pirtobrutinib and venetoclax and zanubrutinib plus sonrotoclax are being explored to improve on undetectable MRD rates. They have looked promising so far and may become future standard bearers.”

REFERENCES

1. Burger JA, Barr PM, Robak T, et al. Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL. Blood. 2025;146(18):2168-2176. doi:10.1182/blood.2024028205

2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804

3. Fürstenau M, Kater AP, Robrecht S, et al. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024;25(6):744-759. doi:10.1016/S1470-2045(24)00196-7

4. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncology. 2023;24(5):535-552. doi:10.1016/S1470-2045(23)00144-4