CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 15, 2025
Expiration: October 14, 2025
Case Study: Newly Diagnosed Patient With MCL
Here, I would like to discuss the treatment of a 65-year-old male patient who is newly diagnosed with classical MCL. The patient’s disease does not harbor any TP53 alteration (gene mutation or protein overexpression). The Ki-67 score is less than 10%. However, he has multiple comorbidities, including diabetes, neurologic disease and cardiac disease.
For this patient, my treatment choice would be a combination of a covalent BTK inhibitor and standard-dose chemoimmunotherapy. The most tolerable for this patient would be BR, and my choice of a covalent BTK inhibitor would be acalabrutinib. Post induction, I would use acalabrutinib plus rituximab maintenance. My treatment choice for this younger but unfit patient with multiple comorbidities is based on current EMA approvals and the results from clinical trials showing that the addition of a covalent BTK inhibitor to conventional chemoimmunotherapy will improve PFS for patients in this setting.
Next, I will explain in more detail the available evidence guiding my treatment choice for this patient.
TRIANGLE: Randomized Phase III Trial of ASCT After Rituximab/Ibrutinib/Ara-C Induction in MCL
TRIANGLE is a very important randomized, 3-arm phase III trial that investigated alternating R-CHOP/R-DHAP with or without ibrutinib.16 There were 2 ibrutinib-containing arms, and patients on only 1 of these arms received ASCT whereas patients on the other ibrutinib-containing arm did not receive ASCT. On both ibrutinib-containing arms, treatment with or without ASCT was followed by 2 years of ibrutinib maintenance therapy. Rituximab maintenance could be received according to national guidelines in all responding patients regardless of treatment arm. The TRIANGLE trial was conducted by the European MCL Network. It enrolled 870 patients aged 65 years or younger with previously untreated stage II-IV MCL who are ASCT-eligible and suitable to receive treatment with high-dose cytarabine. The primary endpoint was FFS, and the secondary endpoints included response rates, PFS, overall survival (OS), and safety.
TRIANGLE: 4-Yr FFS and 4-Yr OS
Updated results after longer follow-up (median follow-up of 55 months) demonstrated the superiority of immunochemotherapy plus ibrutinib with ASCT (Arm A + I) vs standard immunochemotherapy alone (without ibrutinib) followed by ASCT (Arm A) with respect to both the 4-year FFS rates (82% vs 70%; HR: 0.64; P = .0026) and the 4-year OS rates (88% vs 81%; HR: 0.587; P = .0036). The 4-year FFS rates demonstrated that Arm A + I was not superior to Arm I in which patients received immunochemotherapy plus ibrutinib without ASCT (82% vs 81%; HR: 0.83; P = .21). In addition, even after longer follow-up, the FFS superiority of Arm A to Arm I was not confirmed (70% vs 81%; HR: 1.29; P = .9890). In terms of OS, the results demonstrated the superiority of Arm I and Arm A + I vs Arm A (90% vs 88% vs 81%, respectively). In all, these results confirm the superiority of adding ibrutinib to immunochemotherapy without ASCT (Arm I) over ASCT-containing-treatment without ibrutinib (Arm A) with respect to both FFS and OS.
TRIANGLE: Safety and Potential Impact
The addition of ibrutinib to R-CHOP/R-DHAP did not significantly increase overall toxicity in the TRIANGLE trial. Ibrutinib did not increase the risk of serious infection after undergoing ASCT. However, Arm A + I was more toxic than Arm A or Arm I with more grade 3 or higher infections and infestations (34% vs 15% vs 26%, respectively) and more blood and lymphatic system disorders (54% vs 23% vs 28%, respectively).
To this end, the current standard of care based on the results of the TRIANGLE trial is Arm I which includes induction therapy with alternating R-CHOP/R-DHAP and ibrutinib without ASCT followed by 2 years of ibrutinib maintenance plus rituximab maintenance. So, ASCT can be omitted for the majority of younger patients with MCL.
SHINE: First-line Ibrutinib + Bendamustine/Rituximab Followed by Rituximab Maintenance in Older Patients With MCL
The randomized, phase III SHINE trial is another important study that was conducted in elderly patients. SHINE investigated induction BR with or without ibrutinib followed by rituximab maintenance in patients who achieved a CR or partial response (PR) to induction therapy.17 On the ibrutinib-containing arm, ibrutinib was given until disease progression or unacceptable toxicity. The trial enrolled a total of 523 patients aged 65 years or older with previously untreated stage II-IV MCL without any plan to undergo SCT. The primary endpoint was investigator-assessed PFS in the intent-to-treat (ITT) population and the secondary endpoints included ORR, OS, and safety.
SHINE: PFS (Primary Endpoint)
The primary endpoint of PFS in the ITT population was significantly improved with the addition of ibrutinib to BR as induction therapy. In the ibrutinib-containing arm, the median PFS was 80.6 months vs 52.6 months in the BR only arm after a median follow-up of 7.1 years (HR: 0.75; 95% CI: 0.59-0.96; P = .011). Of importance, the median PFS on the ibrutinib-containing arm was prolonged by more than 2 years compared to the BR only arm.
Among patients with nonclassical histology, the median PFS was 25.6 months with the addition of ibrutinib to BR vs 10.3 months with BR induction alone (HR: 0.66; 95% CI: 0.32-1.35). Similarly, in the population of patients with a TP53 mutation, the addition of ibrutinib to BR significantly improved the median PFS vs BR induction alone (28.8 vs 11.0 months; HR: 0.95; 95% CI: 0.50-1.80).
OS (Key Secondary Endpoint) and Safety
In terms of OS, there was no difference between the treatment arms (57% vs 55%; HR: 1.07; 95% CI: 0.81-1.40). There were more deaths due to disease progression on the BR only arm vs the BR plus ibrutinib arm (20.6% vs 11.5%). However, there were more treatment-emergent AEs on the ibrutinib-containing arm vs BR only arm (10.7% vs 6.1%).
ECHO (ACE-LY-308): Acalabrutinib + BR vs Placebo + BR in Older Patients With Untreated MCL
The ECHO trial has a very similar design to SHINE, and both trials enrolled the same patient population. The main difference between ECHO and SHINE is the choice of covalent BTK inhibitor studied. The ECHO trial is yet another important trial in previously untreated MCL. On the phase III ECHO trial, a total of 598 patients aged 65 years or older with previously untreated MCL who were ineligible for ASCT were randomly assigned to receive BR with either acalabrutinib or placebo.18 Acalabrutinib or placebo was given until disease progression or unacceptable toxicity. On both arms, maintenance rituximab was administered for 2 years in patients who achieved CR/PR to induction therapy. Of note, crossover from the placebo arm to the acalabrutinib arm was allowed after disease progression. The primary endpoint was PFS by independent review committee (IRC) and the secondary endpoints included ORR, OS, and safety.
ECHO (ACE-LY-308): PFS, ORR, and OS
This was also a positive trial, showing a clear advantage in terms of PFS with the addition of acalabrutinib to BR. The median PFS on the acalabrutinib plus BR arm was 66.4 months vs 49.6 months on the placebo plus BR arm (HR: 0.73; 95% CI: 0.57-0.94; P = .0160). The ORR in the acalabrutinib-containing arm was 91% (CR: 66.6%) vs 88% (CR: 53.5%) on the BR only arm. At the time of data analysis (after a median follow-up of 45 months), the OS data were immature but there was a trend towards an OS advantage on the acalabrutinib-containing arm despite the inclusion of patients who crossed over to the acalabrutinib arm after experiencing disease progression on the placebo arm (HR: 0.86; 95% CI: 0.65-1.13; P = .2743).
ECHO (ACE-LY-308): AEs of Interest
Grade 3 or higher AEs of interest with acalabrutinib plus BR were comparable to those observed on the placebo plus BR arm. Among the grade 3 or higher AEs of clinical interest reported on the acalabrutinib arm vs the placebo arm, atrial fibrillation was reported in 3.7% vs 1.7%, respectively; hypertension was reported in 5.4% vs 8.4%, respectively; and infections were reported in 41.1% vs 34.0%, respectively. Of note, more patients on the placebo arm experienced grade 3 or higher hypertension compared with those on the acalabrutinib arm. On both arms, the median duration of treatment exposure was similar.
Case Study Continued: Newly Diagnosed Patient With MCL
So, back to the case of the 65-year-old unfit, male patient with newly diagnosed classical MCL. My treatment choice was based on the results of the TRIANGLE, SHINE and ECHO trials.16-18 The patient is unfit with multiple comorbidities and unlikely to be able to tolerate anthracyclines, making regimens such as VR-CAP or R-CHOP alternating with R-DHAP too aggressive. The only chemotherapy-based regimen that I would consider for this patient is BR. However, the addition of a covalent BTK inhibitor to BR will significantly improve treatment outcomes. Because the patient has preexisting cardiac-related comorbidities, the covalent BTK inhibitor of preference for this patient is acalabrutinib. In my clinical experience, acalabrutinib is more tolerable and has a more favorable safety profile when used in combination with BR for an unfit patient with cardiac disease compared with ibrutinib plus BR. So, since the CHMP recently adopted a new indication for acalabrutinib to include the treatment of adult patients with R/R MCL, acalabrutinib is my preferred option for this patient.
MANGROVE: Zanubrutinib + Rituximab vs BR for Untreated MCL
MANGROVE is an ongoing randomized phase III trial comparing zanubrutinib in combination with rituximab vs BR for 500 patients aged 60 years or older but younger than age 70 with MCL and preexisting comorbidities precluding ASCT.19 On the zanubrutinib-containing induction arm, patients will receive zanubrutinib monotherapy until disease progression. The primary endpoint is PFS by IRC, and the secondary endpoints include investigator-assessed PFS, ORR, OS, and safety. We are awaiting the readout of this trial and hope the results will soon become available.
ENRICH: Ibrutinib-Rituximab vs Immunochemotherapy for Previously Untreated Older Patients With MCL
The phase III ENRICH trial was conducted for SCT-ineligible patients aged 60 years or older with previously untreated, measurable, stage II-IV MCL harboring either cyclin D1 overexpression or t(11;14)(q13;q32) without any central nervous system involvement.20 Patients were stratified by investigator’s choice of R-CHOP or BR. Thereafter, patients were randomly assigned to receive either ibrutinib plus rituximab or rituximab-based chemotherapy. Those who received ibrutinib plus rituximab as induction therapy also received maintenance ibrutinib plus rituximab for 2 years while those on the rituximab-based chemotherapy arm received maintenance rituximab for 2 years. A total of 397 patients were enrolled on the ENRICH trial. The primary endpoint was PFS and the secondary endpoints included OS and safety. Of note, ENRICH is the first trial to challenge the use of aggressive chemoimmunotherapy for elderly patients with MCL in the frontline setting. It was conducted by the British Lymphoma Group in collaboration with the Nordic group.
ENRICH: PFS (Overall Population)
In the overall patient population, the median PFS among patients who received ibrutinib plus rituximab was 65.3 months vs 42.2 months among those who received rituximab-based chemotherapy (HR: 0.69; 95% CI: 0.52-0.90; P = .003). This was a positive trial showing a clear advantage in terms of PFS for the covalent BTK inhibitor–based, chemotherapy-free regimen.
ENRICH: PFS of IR vs Choice of R-CHOP or BR Immunochemotherapy
The 5-year PFS among patients on the ibrutinib plus rituximab arm was 52.4% vs 19.2% for those who received R-CHOP (HR: 0.37; 95% CI: 0.22-0.62). Among those who received BR, the 5-year PFS was 47.4% vs 50.8% among those who received ibrutinib plus rituximab (HR: 0.91; 95% CI: 0.66-1.25). Of interest, the PFS advantage of adding ibrutinib to rituximab was more evident when compared with R-CHOP, demonstrating that patients aged 60 years or older with MCL fare poorly when treated with R-CHOP compared with ibrutinib plus rituximab, a chemotherapy-free regimen, in the frontline setting. In conclusion, R-CHOP is an inferior treatment option and one that should be avoided for older patients with MCL compared with ibrutinib plus rituximab or BR.
Efficacy of Combining a Covalent BTK Inhibitor With Venetoclax in MCL
Of significant importance, covalent BTK inhibitors are currently being investigated in combination with the BCL2 inhibitor, venetoclax, both in the frontline and R/R settings. For example, the phase II BOVen trial investigated zanubrutinib plus venetoclax and obinutuzumab in previously untreated patients with TP53-mutated MCL. Among 25 patients, the best ORR was 96%, including a CR rate of 88%. More than 80% of the patients achieved undetectable measurable residual disease, and the PFS and OS rates at 2 years were 72% and 76%, respectively.21
The single-arm OAsis trial examined ibrutinib in combination with venetoclax and obinutuzumab in patients with MCL, and the combination was well tolerated, yielding high response rates among patients with previously untreated and R/R MCL.22
SYMPATICO is a randomized, double-blind, placebo-controlled, phase III study that investigated ibrutinib plus venetoclax in R/R MCL.23 After a median follow-up of 51·2 months, results from SYMPATICO demonstrated that ibrutinib in combination with venetoclax significantly prolonged the median PFS vs ibrutinib plus placebo in patients with R/R MCL (31.9 vs 22.1 months; HR: 0·65; 95% CI: 0·47-0·88; P = ·0052).
Case Study: Patient With R/R MCL Requiring Second-Line Therapy
Now, I want to discuss the treatment of a 68-year-old man with R/R classical MCL in need of treatment. This patient is unfit and has uncontrolled hypertension and atrial fibrillation. His disease is negative for TP53 alterations (no genetic mutation or protein overexpression) and del(17p) negative with Ki-67 <15%. The patient received rituximab monotherapy as first-line therapy before experiencing disease progression 36 months after completing treatment.
It is important to note that this patient has never been exposed to chemotherapy. Besides being unfit with uncontrolled hypertension and atrial fibrillation, the patient’s disease has no high-risk biologic factors such as a TP53 alteration, nonclassical histology, or a high Ki-67 score. Therefore, the optimal choice for this patient is BR plus a covalent BTK inhibitor. The patient is unlikely to be able to tolerate an anthracycline-containing chemotherapy regimen because of his preexisting cardiac-related comorbidities. Due to the presence of uncontrolled hypertension and atrial fibrillation, he is unlikely to tolerate ibrutinib. On this basis, and based on the current approvals in the EU, I would recommend acalabrutinib plus BR followed by acalabrutinib and rituximab maintenance for this patient, based on the results of the ECHO trial.18
CCO has developed an Interactive Decision Support Tool which can be used to access first-line treatment recommendations from 5 EU experts for patients with newly diagnosed MCL based on multiple disease characteristics, including the presence or absence of high-risk features and/or comorbidities, age at diagnosis, and the level of fitness, which can be found here.
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