New Data on BTK Inhibitors for CLL and MCL: Experts Discuss EHA 2022

Best practices in treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) continue to be refined by ongoing clinical research. In this commentary, Othman Al-Sawaf, MD, and Lydia Scarfò, MD, discuss select BTK inhibitor studies from the 2022 European Hematology Association (EHA) Congress and their potential impact on the current standard of care in these hematologic malignancies.

Othman Al-Sawaf, MD:
The randomized phase III CLL13 study compared standard chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab (BR) vs 3 venetoclax-based regimens in fit patients with CLL: venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy with venetoclax plus obinutuzumab and ibrutinib. This trial explored whether fixed-duration combination approaches with targeted therapy can supplant CIT in fitter patients with CLL and compared efficacy and safety with doublet or triplet venetoclax-based combinations.

Results presented at EHA 2022 showed longer progression-free survival (PFS) with venetoclax plus obinutuzumab and venetoclax plus obinutuzumab and ibrutinib vs CIT (HRs of 0.43 and 0.32, respectively). Deep clearance of measurable residual disease (MRD) with the backbone of venetoclax and obinutuzumab also was observed.

Lydia Scarfò, MD:
These results imply that CIT may no longer have a role in the frontline setting, as we now have targeted therapy regimens that can provide long-term disease control. I prefer to avoid exposing patients to some of the long-term adverse events that can be associated with CIT, including the development of myelodysplasia or acute leukemia.

An ongoing area of interest is the question of whether triplet therapy with venetoclax, obinutuzumab, and ibrutinib is actually superior to doublet therapy with venetoclax plus obinutuzumab. Dr Al-Sawaf, what do you think?

Othman Al-Sawaf, MD:
We can’t say for sure at the moment. Adding ibrutinib to venetoclax plus obinutuzumab did not significantly improve MRD responses or rates of undetectable MRD at the end of treatment, and PFS rates at 3 years were not significantly better with ibrutinib, even in patients with unmutated IGHV. So far, the mild improvements seen with ibrutinib in this study are not robust enough to support the triple-drug combination. It is possible it could benefit patients with CLL and TP53 aberrations, but those patients were not included in CLL13.

CLL: FLAIR

Lydia Scarfò, MD:
Data from the phase III FLAIR trial also were presented at EHA 2022. This study is an adaptive-design trial in patients with previously untreated CLL and has several arms; at EHA 2022, interim data were presented from patients who had been randomized to receive ibrutinib or ibrutinib plus venetoclax. Results showed excellent rates of undetectable MRD in both bone marrow (65.4%) and blood (71.3%) with ibrutinib plus venetoclax vs 0% with ibrutinib alone. However, ibrutinib monotherapy is known only anecdotally to improve MRD, making it an odd choice of endpoint. At 9 months post randomization, similar overall response rates (ORRs) were observed with ibrutinib plus venetoclax vs ibrutinib alone (88% vs 86%); however, the CR rate was much higher with the combination (60% vs 8%).

Othman Al-Sawaf, MD:
FLAIR is a very interesting study because it attempts to address many questions in a randomized setting, including the use of an MRD‑guided approach to treatment, whereby MRD is not just observed but actually used to decide on treatment duration. MRD-guided treatment also was not based on a single assessment but rather on multiple assessments. The clinical conclusions we can make here are limited due to the lack of survival data. However, it is clear that the undetectable MRD rate will remain at 50% to 60%, as seen in other studies of ibrutinib plus venetoclax (eg, GLOW, CLL13). It is unclear how much this might affect PFS in the long run.

In this study, the median time to undetectable MRD was 12 months, which is a rationale for longer treatment with the all-oral combination of ibrutinib and venetoclax. Fixed-duration ibrutinib plus venetoclax is expected to be approved by the FDA for CLL in the future, but these data suggest that longer treatment may be warranted. In 2-3 years, it will be interesting to see just how helpful MRD-guided therapy actually is in a randomized setting. It may be that a fixed-duration approach for an all-comer population is more sensible, per CLL13.

CLL: Acalabrutinib for High-Risk CLL

Lydia Scarfò, MD:
At EHA 2022, Davids and colleagues presented a pooled analysis that examined long-term efficacy of acalabrutinib in patients with CLL and higher-risk features, such as del(17p), mutated TP53, unmutated IGHV, or a complex karyotype (≥3 aberrations). This analysis incorporated results from more than 800 patients in 3 studies in treatment-naive CLL (ELEVATE-TN, CL-001 [treatment-naive cohort], CL-003) and 3 studies in relapsed/refractory CLL (ASCEND, ELEVATE-RR, CL-001 [relapsed/refractory cohort]). In treatment-naive CLL, data were derived from patients treated with acalabrutinib with or without obinutuzumab.

In this analysis, a 91% ORR was observed with acalabrutinib in treatment-naive patients with CLL with a del(17p)/TP53 mutation; a 96% ORR was observed in those with CLL with unmutated IGHV. Both median overall survival (OS) and median PFS were not reached in the treatment-naive group with CLL with a del(17p)/TP53 mutation. In the relapsed/refractory cohort, the ORR was 86% in those with a del(17p)/TP53 mutation and 87% in those with unmutated IGHV. Median PFS in this cohort was 38.6 months and 46.9 months, respectively. Median OS was 60.6 months and not reached, respectively.

Othman Al-Sawaf, MD:
In our clinic, we are increasingly using acalabrutinib as initial BTK inhibitor therapy. This is in part because of a slightly preferable toxicity profile for many patients compared with ibrutinib (as observed in the ELEVATE-RR trial, for example). Across all acalabrutinib studies to date, efficacy seems comparable to ibrutinib. With the caveat that cross-study comparisons can be problematic, this pooled analysis confirms the evidence from individual studies: In patients with high-risk features such as TP53 aberrations or a complex karyotype, continuous BTK inhibition provides very good disease control. In this dataset, the efficacy was similar to patients without high-risk features.

CLL: BRUIN

Lydia Scarfò, MD:
There remains an unmet clinical need for patients who have already received BTK inhibitors and BCL-2 inhibitors, with available treatment options either untested in this population or suboptimal for many patients. Pirtobrutinib (formerly LOXO-305) is an investigational next-generation noncovalent BTK inhibitor that acts independently of BTK residue C481, the site of covalent inhibitor binding and most frequently mutated residue among patients with BTK inhibitor resistance. At EHA 2022, Mato and colleagues presented results from the phase I/II BRUIN trial, which enrolled more than 250 patients with CLL who had previously been treated with a covalent BTK inhibitor. In this study, responses were seen in nearly 70% of patients; moreover, median PFS has not yet been reached, and only 1% of patients discontinued due to adverse events. Of note, there was a similar high ORR among patients with CLL with and without BTK inhibitor resistance and/or a BTK C481 mutation. Phase III clinical trials are currently enrolling with this agent in both the first-line and relapsed/refractory settings.

Othman Al-Sawaf, MD:
The emergence of noncovalent BTK inhibitors is intriguing, as they appear to be effective despite the presence of specific BTK mutations or pathway aberrations. Patients with specific aberrations are at higher risk of an adverse long-term prognosis, so I’m happy to see these promising data despite the short median follow-up (9.4 months). As reported in this presentation, 68% of patients responded to pirtobrutinib monotherapy, including those with BTK mutations or who are refractory to BCL-2 inhibition. With regard to tolerability, the use of a noncovalent mechanism of action appears to reduce BTK inhibitor toxicity, particular cardiovascular toxicity. I am encouraged that even with more than 600 patients, there is no signal for significantly increased rates of hemorrhage or other bleeding.

In the next few years, we will have more mature efficacy and safety data with pirtobrutinib, including data from trials in which this agent is combined with other targeted therapies, and this will allow us to correctly place pirtobrutinib within the CLL treatment paradigm.

MCL: SHINE

Lydia Scarfò, MD:
Compared with CLL, MCL is far more aggressive. The phase III SHINE study was designed to evaluate the addition of the BTK inhibitor ibrutinib to frontline therapy with BR for older patients with MCL (N = 523). In the primary analysis presented at the 2022 American Society of Clinical Oncology Annual Meeting and EHA 2022, results showed that the addition of ibrutinib to BR with rituximab maintenance significantly improved median PFS from 52.9 months to 80.6 months (HR: 0.75; P = .011), with a very long median follow-up of 84.7 months. Dr Al-Sawaf, do you think these findings will change clinical practice in MCL?

Othman Al-Sawaf, MD:
These are impressive data from a lengthy observation period. Nevertheless, it is difficult to say whether this study changes frontline treatment for patients with MCL who are older or unfit and not eligible for autologous transplantation. One concern with the findings from this study is that it is unclear how much benefit is derived from adding ibrutinib to BR, as there was no ibrutinib monotherapy arm in this study. This is similar to the HELIOS study in relapsed/refractory CLL comparing ibrutinib plus BR with BR alone.

In MCL, ibrutinib is often used as a salvage therapy and produces a PFS in the relapsed setting that is comparable to the PFS seen in SHINE. So, the question is, does giving ibrutinib following progression on BR provide a similar benefit to what was observed in this study? Of note, the addition of ibrutinib did add some toxicity, including more bleeding, atrial fibrillation, hypertension, arthralgias, and infections.

Overall, no, I do not think these data will change the standard of care for patients with MCL, and I do not expect treatment guidelines to change. There may be high-risk subgroups that could have a substantial OS benefit. If ibrutinib plus BR is used in the clinic, it will be an individualized decision.

Lydia Scarfò, MD:
I also would point out that studies in MCL are evaluating ibrutinib plus venetoclax as first-line therapy, and initial results with this chemotherapy-free combination are impressive. Hopefully, longer follow-up will confirm these promising signals and this regimen will become available in the clinic.

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