CME
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: December 05, 2023
Expiration: December 04, 2024
Introduction
In this module, Ana Marin-Niebla, MD, PhD, and Stephan Stilgenbauer, MD, review key data presented at hematology conferences during 2023 on the use of BTK inhibitors in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).
Clinical Care Options plans to measure the educational impact of this activity. A question will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
Introduction to Mantle Cell Lymphoma
Stephan Stilgenbauer, MD:
MCL is a difficult disease to treat. It combines the unfortunate features of aggressive lymphoma and indolent lymphoma, and until some time ago, we did not have great treatment options available. However, with novel developments, in particular targeted treatments, we have seen quite remarkable progress for our patients. And BTK inhibitors were the first truly transformative treatment to become available. Would you agree?
Ana Marin-Niebla, MD, PhD:
In an incurable disease such as MCL, BTK inhibitors—and ibrutinib was the first one we had approved in the EU—have changed the treatment paradigm, particularly in the relapsed setting. Hopefully, we will have BTK inhibitors available soon in the frontline setting.
SHINE Trial: First-line Ibrutinib Plus BR Followed by Rituximab Maintenance in Older Patients With MCL
Stephan Stilgenbauer, MD:
There have been interesting trials of BTK inhibitors conducted in the frontline setting in MCL such as SHINE1 and, more recently, TRIANGLE.2 Would you be able to elaborate on what these trials have shown?
Ana Marin-Niebla, MD, PhD:
Before the TRIANGLE trial, which is arguably the most relevant of the practice-changing trials we have now, we had the SHINE trial,1 which was the first time we saw the efficacy of ibrutinib in combination with a standard frontline regimen in MCL.
In patients not eligible for intensive treatment, the SHINE trial combined ibrutinib with bendamustine/rituximab (BR) followed by rituximab maintenance.1 The study arm was ibrutinib administered continuously with BR for 6 cycles and then rituximab maintenance compared with a control arm of BR followed by rituximab maintenance. The goal of this study was to demonstrate an advantage in progression-free survival (PFS) with the addition of ibrutinib to BR, and the study was positive with a median PFS of 80 months with ibrutinib plus BR vs 53 months with BR alone.
Also, the time to the next treatment was improved with the addition of ibrutinib to BR: not reached with ibrutinib plus BR vs 92.0 months with placebo plus BR (HR: 0.48; 95% CI: 0.34-0.66).1 Unfortunately, however, this trial did not lead to the approval of ibrutinib in the first-line setting because of the toxicity of this combination and also because the overall survival (OS) was not significantly different.
Triangle: Ibrutinib Plus Chemotherapy With or Without ASCT for Untreated MCL
Ana Marin-Niebla, MD, PhD:
The results of the TRIANGLE study were first presented at the 2022 ASH Annual Meeting.2 This is a very relevant study designed in the European MCL Network for younger patients eligible for intensive treatment.
This study recruited more than 800 patients with untreated MCL from 13 European countries and Israel. Here, ibrutinib was combined with the current standard treatment in younger patients, which is rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP)/rituximab plus dexamethasone/cytarabine/cisplatin (R-DHAP), alternating for 6 total cycles, followed by autologous stem cell transplant (ASCT) and then observation, initially.2 However, following the publication of the LYMA trial,3 which demonstrated that rituximab maintenance added to the survival of patients after ASCT, the TRIANGLE study was amended to include rituximab maintenance in all arms, as well.
So, we had the control arm, R-CHOP/R-DHAP, followed by ASCT, and then rituximab maintenance.2 In the first experimental arm, ibrutinib was combined with R-CHOP, alternating with R-DHAP, and followed by ASCT and then ibrutinib and rituximab maintenance. A third arm was added to the study with ibrutinib in combination with R-CHOP, alternating with R-DHAP, and ibrutinib and rituximab maintenance, but forgoing ASCT with the hypothesis that perhaps adding ibrutinib could allow us to eliminate the need for transplant if it were more effective.
TRIANGLE Trial Outcomes
Ana Marin-Niebla, MD, PhD:
In the TRIANGLE study, failure-free survival was higher in both arms with ibrutinib vs the control arm without ibrutinib.
What was most interesting was whether ASCT was adding a survival benefit between the two arms with ibrutinib. Although the analysis is still early, failure-free survival was similar in both arms with ibrutinib, regardless of whether patients had an ASCT.2 One of the conclusions of this study is that when ibrutinib is added as induction and maintenance therapy for younger patients with MCL, we could probably skip ASCT and all the associated toxicity. However, longer follow-up is needed to confirm these findings.
Finally, another very interesting observation from this study that results in somewhat of an ethical conflict—now that we have these data but do not yet have ibrutinib available for use in the first-line setting—is that for the first time in MCL, we have seen an advantage in patients with TP53 alterations. In this study, there was a failure-free survival benefit in patients with TP53 alterations treated in the study arm with ibrutinib and ASCT vs the standard arm without ibrutinib. And this is something in MCL that had not been seen yet.
Changing Paradigm of Frontline Treatment for MCL
Ana Marin-Niebla, MD, PhD:
I anticipate that the TRIANGLE study will change clinical practice. Returning to discussion of the SHINE trial in older patients and the inability to obtain ibrutinib in the first-line setting for MCL, we eagerly await results from the ECHO trial (NCT02972840). This is combining acalabrutinib, which has a more favorable toxicity profile compared with ibrutinib,4 with the same combination of BR and rituximab maintenance. We are awaiting the results of the ECHO trial because perhaps if this study is positive, we may see acalabrutinib approved for older patients in the first-line setting.
CAR T-Cell Therapy for MCL
Stephan Stilgenbauer, MD:
Now with ibrutinib potentially moving to the frontline treatment paradigm, we also need to think about how to salvage patients if they relapse. CAR T-cell therapy has caused quite some enthusiasm in MCL. Could you provide some background on CAR T-cell therapy and potential combinations with BTK inhibitors?
Ana Marin-Niebla, MD, PhD:
Immunotherapy appears to be very effective in MCL, and we currently have 1 CAR T-cell therapy approved: brexucabtagene autoleucel (brexu-cel).5,6 Brexu-cel was approved following results of the ZUMA-2 trial, which was the first time we saw a treatment show a significant benefit for patients after failure of BTK inhibitor therapy. Prior to the ZUMA-2 trial,7 any relapse or salvage therapy option we had for patients who had failed ibrutinib in previous lines would only result in OS between 4 months and 12 months, at the most.
ZUMA-2 Outcomes
Ana Marin-Niebla, MD, PhD:
After 3 years of follow-up, the median OS of brexu-cel in ZUMA-2 was 46.6 months, and the median OS was not reached in patients who had achieved a complete response with brexu-cel.8 Most patients (68%) with MCL treated with brexu-cel achieved a complete response, with an overall response rate of more than 90%.
There was also a very interesting observation from the ZUMA-2 study. All patients included in the trial had previously received and failed a BTK inhibitor—either acalabrutinib or ibrutinib.8 An observation with longer follow-up was that those patients who had previously received ibrutinib had higher levels of CAR T-cells in the peripheral blood. This appears to be a favorable effect, correlated with prolonged response and longer PFS, although this is a hypothesis that should be confirmed.
Future Directions
Ana Marin-Niebla, MD, PhD:
These data have led to the development of studies evaluating the combination of ibrutinib with CAR T-cells. The TARMAC study is a phase II trial of 20 patients evaluating the combination of ibrutinib and tisagenlecleucel (tisa-cel).9 Ibrutinib was initiated at least 7 days before leukapheresis and continued throughout bridging (optional), lymphodepletion, and 6 months after tisa-cel infusion. With this time-limited administration of ibrutinib in addition to CAR T-cell therapy, the responses were maintained without adding significant toxicity in comparison to what we would expect with CAR T-cell therapy alone.
Pirtobrutinib for MCL
Stephan Stilgenbauer, MD:
Thank you for elaborating on this very innovative but also demanding treatment option, and fortunately, we have other developments not only on the horizon, but already partly approved in MCL such as noncovalent BTK inhibitors like pirtobrutinib. Can you discuss the difference compared with covalent BTK inhibitors and provide your thoughts on this treatment option?
Ana Marin-Niebla, MD, PhD:
Pirtobrutinib was authorized in the EU in October 2023 for patients with R/R MCL following previous treatment with a BTK inhibitor.10 The FDA had approved pirtobrutinib in January 2023 for R/R MCL after at least 2 previous lines of systemic therapy, including a BTK inhibitor.11 Pirtobrutinib is the first noncovalent, reversible BTK inhibitor for which we have data in MCL.12 The main difference between pirtobrutinib and the covalent BTK inhibitors is the binding to the BTK: There is no direct interaction with the cysteine 481, unlike any of the covalent BTK inhibitors.13
Therefore, pirtobrutinib is highly active in tumors both with and without BTK C481S mutations. Pirtobrutinib also has a high selectivity for the BTK protein, more than 300-fold over all the kinases.13 This is the main difference between pirtobrutinib and the covalent BTK inhibitors, and this translates into a favorable toxicity profile. The BRUIN study is a phase Ib/II study that is including several histologies to assess the efficacy and safety of pirtobrutinib. And we already have results from the primary analysis in MCL.12
BRUIN CLL
Ana Marin-Niebla, MD, PhD:
We currently have efficacy and safety data on 90 patients with MCL treated with the recommended phase II dose of pirtobrutinib 200 mg from the BRUIN trial, which has been previously published12 and presented at the 2023 International Conference on Malignant Lymphoma.14 Pirtobrutinib is effective in patients who have failed previous covalent BTK inhibitors, with an overall response rate of 56.7% and complete responses of 18.9%. Pirtobrutinib also has a very favorable toxicity profile with reduced rates of typical BTK inhibitor–associated toxicities, such as atrial fibrillation and hypertension.
Future Directions With BTK Inhibitors in MCL
Ana Marin-Niebla, MD, PhD:
Pirtobrutinib is a new option that we have in MCL, and it is interesting because the approval of pirtobrutinib in the EU is in patients who had previously received a covalent BTK inhibitor,10 but it does not mention how many previous lines of therapy that patient had to have received, unlike in the FDA approval.11
In the future, if we have ibrutinib or all covalent BTK inhibitors approved in the first-line setting for MCL, pirtobrutinib could be used immediately after that—so, not necessarily from the third-line setting and on. Brexu-cel is approved in the United States for R/R MCL,5 but in the EU, brexu-cel is only approved after 2 previous lines of therapy, 1 of which should be a BTK inhibitor.6 We cannot use CAR T-cell therapy in the EU until the third-line in MCL. The approval of pirtobrutinib and evolving treatment paradigm in MCL brings some interesting considerations in terms of sequencing of therapy.
Ibrutinib has already changed the treatment paradigm in the relapsed setting in the EU. At present, this is the standard option at first relapse in the EU. In the United States, the indication of ibrutinib for MCL was voluntarily withdrawn in April 2023.15 However, covalent BTK inhibitors have already arrived in the first-line setting. I believe we will have them in combination with chemotherapy as in the TRIANGLE and hopefully ECHO studies in the EU.
We already have data on ibrutinib as a way to enhance the activity of CAR T-cell therapy. CAR T-cell therapy is already approved, but we also have very exciting data with glofitamab and other bispecific antibodies. In general, when we have BTK inhibitors moving to the first-line setting, we will already have a number of effective and promising options with which we could rescue patients who are relapsing from frontline BTK inhibitors. There are other current unmet needs in MCL including treatment of high-risk patients with TP53 mutations, blastoid disease, and high Ki-67. I hope immunotherapy is an option for them, and for those patients relapsing early from first-line treatment, I anticipate upfront immunotherapy will be an optimal approach.
Introduction to CLL
Ana Marin-Niebla, MD, PhD:
CLL is always ahead of MCL, and ibrutinib and the BTK inhibitors started first in CLL. Can you describe how BTK inhibitors have changed the treatment paradigm in CLL?
Stephan Stilgenbauer, MD:
Ibrutinib was the first BTK inhibitor approved in CLL, initially in the R/R setting, and then later expanded to include the frontline setting. This subsequent approval was based on several frontline trials including the Alliance,16 ECOG 1912,17 and iLLUMINATE18 studies, which demonstrated superiority of continuous monotherapy with ibrutinib over our previous standard chemoimmunotherapy. This improved efficacy is particularly pronounced in high-risk subgroups such as patients with unmutated IGHV, del(17p), or TP53 mutation. Although continuous ibrutinib therapy is usually well tolerated, it is associated with adverse events (AEs) such as arrhythmias, atrial fibrillation, hypertension, bleeding events, that may accumulate over time. Therefore, this has led to newer developments and approaches in this setting.
Time-Limited Therapies
Ana Marin-Niebla, MD, PhD:
What developments have there been regarding BTK inhibitor combinations and the move to time-limited therapy?
Stephan Stilgenbauer, MD:
BTK inhibitor monotherapy is usually administered continuously until disease progression or unacceptable AEs. Now most recently in the EU, the combination of ibrutinib plus venetoclax was licensed based on the data from the GLOW trial.19 The GLOW trial evaluated obinutuzumab plus chlorambucil against fixed-duration ibrutinib plus venetoclax, with ibrutinib given as a short lead-in and then 12 months of combined treatment with ibrutinib plus venetoclax in older or unfit patients in the frontline setting.20 This trial has shown significantly superior PFS for ibrutinib plus venetoclax and a relatively good tolerability profile.
At the 2023 ASH Annual Meeting, we will see very interesting data from the FLAIR trial.21 The FLAIR trial among younger and fitter patients with CLL evaluated ibrutinib plus venetoclax in a minimal residual disease–guided fashion, but also limited-duration treatment against our former standard of fludarabine/cyclophosphamide/rituximab (FCR).22 And the FLAIR trial, remarkably so, shows not only a highly significant superiority regarding PFS, but also OS of ibrutinib plus venetoclax vs FCR.21
Ana Marin-Niebla, MD, PhD:
This is very interesting because it was thought that FCR could be curable in CLL.
Stephan Stilgenbauer, MD:
Absolutely. These are truly very interesting results, and we are looking forward to seeing more details at the 2023 ASH meeting. To me, ibrutinib plus venetoclax is yet another very valuable frontline treatment standard in CLL.
Second-Generation BTK Inhibitors
Ana Marin-Niebla, MD, PhD:
What about the second-generation BTK inhibitors?
Stephan Stilgenbauer, MD:
As stated, ibrutinib has been transformative in treating CLL. However, because of some off-target effects as well as some on-target toxicity, more specific and better tolerated BTK inhibitors have been developed, such as acalabrutinib and zanubrutinib. Of importance, both have been compared against ibrutinib in head-to-head trials in the R/R setting. In the ELEVATE-RR trial, acalabrutinib was noninferior to ibrutinib regarding PFS and demonstrated similar overall response rate and OS.23 In addition, acalabrutinib had a better tolerability profile with a reduction of virtually all class-associated AEs, most notably cardiac events such as atrial fibrillation, but also hypertension, arthralgia, and other BTK inhibitor–related AEs.4
Now, in an interim analysis of the ALPINE study, zanubrutinib has shown better PFS compared with ibrutinib, which is remarkable, and a somewhat better tolerability profile, mostly because of the reduction of cardiac toxicity such as atrial fibrillation and other cardiac events while other class-associated AEs were virtually unchanged.24,25 We will see another update from the ALPINE study at the 2023 ASH Annual Meeting,26 which we are looking forward to very much.
Pirtobrutinib for CLL
Ana Marin-Niebla, MD, PhD:
Finally, what is the role of pirtobrutinib in CLL?
Stephan Stilgenbauer, MD:
As mentioned, pirtobrutinib is a new noncovalent BTK inhibitor. The key principle is that pirtobrutinib does not rely on the presence of cysteine in the position 481 in the protein, which is the most common resistance mutation acquired during treatment with a covalent BTK inhibitor. Therefore, pirtobrutinib is being developed in the setting of patients who were R/R or intolerant to previous covalent BTK inhibitor therapy.
In the CLL segment of the BRUIN trial, pirtobrutinib showed remarkable efficacy in patients with CLL. These were heavily pretreated patients with a median of 3 previous lines of therapy. In addition to a covalent BTK inhibitor, many patients had previously received chemoimmunotherapy or BCL2 inhibitors. The median PFS was 19.6 months.27
Not only did we see very good responses, but the tolerability profile of pirtobrutinib was very favorable in the BRUIN trial particularly in terms of the class-related AEs such as bleeding or atrial fibrillation. Overall, given the heavily pretreated population, tolerability looks very good. At present, pirtobrutinib is not approved for CLL in the EU but was approved by the United States FDA on December 1, 2023 for patients with CLL/small lymphocytic lymphoma who have received at least 2 previous treatments, including a BTK inhibitor and a BCL-2 inhibitor.11 It is also included in guideline recommendations.28 Based on the results of the BRUIN trial, pirtobrutinib is currently in clinical development in earlier lines of treatment (NCT04965493; NCT04666038) and also in the frontline setting (NCT05023980).
Therefore, an interesting question arises: Where do we place pirtobrutinib in the near future in the entire treatment context of our frontline treatment options in CLL?
Future Directions in CLL
Ana Marin-Niebla, MD, PhD:
In summary, what do you anticipate coming next in the management of CLL, including other options such as CAR T-cell therapy?
Stephan Stilgenbauer, MD:
We have good options with our current frontline treatment selections: continuous therapy with ibrutinib, acalabrutinib, or zanubrutinib; or fixed-duration ibrutinib plus venetoclax or obinutuzumab plus venetoclax. There are ongoing trials combining acalabrutinib or zanubrutinib with BCL2 inhibitors (NCT05057494; NCT05650723). These combinations are analogous to ibrutinib plus venetoclax, and aim to provide all oral chemotherapy-free treatment options in the frontline setting. Beyond that, other combinations including pirtobrutinib are also in development, as well as clinical trials of bispecific antibodies and CAR T-cell therapy for patients who still relapse after all these treatment approaches. However, these are certainly still experimental approaches that are not yet available in standard practice.
Back