Andre H. Goy, MD, on Unresolved Questions in Mantle Cell Lymphoma

“It’s time to dissect MCL and account for its molecular heterogeneity when refining our treatment.”

Andre H. Goy, MD, is physician-in-chief of the Hackensack Meridian Health Oncology Care Transformation Service; and chairman, chief physician officer at the John Theurer Cancer Center of Hackensack University Medical Center in Hackensack, New Jersey; and program chair of the 27th Annual International Congress on Hematologic Malignancies^®, hosted by Physicians’ Education Resource^®, LLC (PER^®).

M antle cell lymphoma (MCL) continues to pose complex challenges when it comes to the treatment of patients with both frontline and relapsed/refractory disease. There’s a lack of consensus on the best treatment, and disease heterogeneity continues to stymie efforts for optimization.

In an interview with ONCOLOGY^®, Andre H. Goy, MD, discussed the most pressing unresolved questions in the current treatment of MCL. He explored the plethora of MCL subtypes and the need for further knowledge of its genetic diversity. Additionally, he provided an overview of the most critical unmet needs and the prospects for future developments in this treatment landscape.

Q: What are some unresolved questions in the current treatment of MCL?

GOY: MCL is a rare subtype of lymphoma. It has the reputation of being highly heterogeneous [and tends to] become chemoresistant over time. [This has given rise to] a very active field of clinical research. Six drugs are currently approved, including 3 BTK [Bruton tyrosine kinase] inhibitors, lenalidomide [Revlimid],bortezomib [Velcade], and some game-changing [chimeric antigen receptor] T-cell therapies. Most of the progress has occurred in the relapsed/refractory setting.

[However, there’s a lack of consensus] on the best frontline treatment for MCL, as well as a disconnect between outcomes in clinical trials [and real-world outcomes]. Studies have shown that high-dose rituximab [Rituxan] after stem cell transplant improves outcomes in the frontline setting. Novel therapies in the relapsed/refractory setting have also yielded much better outcomes. A median overall survival [OS] exceeding 10 to 12 years [can be observed] in some clinical trials, particularly in younger patients. In those who are older than 65 years, we often use high-dose therapy, or a dose-intensive regimen, such as hyper-CVAD [modified hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] with or without transplant.

However, in real-world frontline settings, more than half of all patients still receive just BR [bendamustine (Bendeka) plus rituximab] or R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone]. There is a disconnect between the regimens used in clinical trials and those used in the real world. In both younger and older patients, median time to next therapy is 2 years, [which indicates] a clear need for improvement.

[Analyses of] real-world data from 15 years ago vs more recent data have shown that improvements in outcomes have mostly occurred in younger patients. In older patients, real-world data suggest a median OS in the range of 3 to 5 years.

There has also been enormous progress in our understanding of the diversity of biological presentations of MCL. Several subtypes [have been identified], including indolent MCL, which is clearly a different disease. It has a different gene expression profile, it’s SOX11 negative, and patients present with splenomegaly, a high white blood cell count, and very little lymphadenopathy. [This subtype] is genetically stable and can be monitored for many years. Some cases can become more complex or develop TP53 mutations, which changes the optimal treatment but doesn’t make the disease progress any faster.

Meanwhile, classical MCL can [arise in the form of] 3 presentations. The very aggressive blastoid pleomorphic high proliferation index by Ki-67 [accounts for] 50% to 90% of cases. These patients have a complex karyotype, TP53 mutations/deletions, MYC rearrangement, and other abnormalities that make them high risk. This presentation has worse prognosis with a median OS, regardless of dose intensity, of 1.6 years to 1.8 years. Even patients who achieve complete response [CR] tend to relapse very quickly.

At the other end of this category, you have low-risk MCL, often called smoldering MCL. These patients experience routine discovery of lymphadenopathy on imaging or colonoscopy and have low-bulk disease and few risk factors. These patients can be monitored. For them, the median time until the end of therapy is usually 1 to 3 years. In the middle, you have the rest of patients who can, to varying degrees, have TP53 abnormalities and genetic high-risk features, making this a disease on a spectrum. It’s therefore important to remember the great variety of genetic high-risk features of MCL, [which] are now accessible in routine practice using NGS [next-generation sequencing].

Q: With these factors in mind, how do you manage MCL?

GOY: Patients with indolent MCL can be evaluated for years and should not be enrolled in the standard clinical trials. They have very different genetic profiles and [usually] very stable disease. Patients with indolent MCL who need treatment can receive doublet chemotherapies like R2 [rituximab plus lenalidomide], which is an easy treatment in patients who are often poor candidates for chemotherapy. More appealing is the combination of BTK inhibitors with rituximab, such as ibrutinib [Imbruvica] plus rituximab, which results in very high CR and overall response rates in this setting. We know that patients with some high-risk molecular features [can also receive these therapies] with no difference in CR rates. [If] they have a TP53 mutation, for example, they tend to relapse faster but still have a better response than with chemotherapy.

On the other end of the spectrum, patients with blastoid variant MCL tend to perform poorly regardless of which therapy is used. [For them], a doublet or triplet biological combination can be effective. The WINDOW-1 trial [NCT02427620] supported the use of ibrutinib, rituximab, and hyper-CVAD.¹ The ongoing WINDOW-2 trial [NCT03710772] is testing the same regimen plus venetoclax [Venclexta]. The early data on these treatments show very high rates of CR in the frontline setting, which isn’t surprising. [Moreover], ibrutinib/venetoclax also resulted in high CR rates in the relapsed/refractory setting, even in patients with TP53 abnormalities. [These responses were] sometimes so durable that patients stopped therapy and were in remission 2 years later, so that’s a promising direction.²

For patients who are not candidates for chemotherapy, [available triplets] are basically combinations of a BTK inhibitor, a BCL2 inhibitor, and an anti-CD20 antibody, and they all tend to result in very high CR rates and more than 70% of patients with MRD [minimal residual disease]–negative remission.

[However], it’s still unclear if chemotherapy is required after these treatments. We don’t have that answer yet. The WINDOW-2 trial stratifies patients based on low vs high molecular risk features, and [the study is designed so that] those with low molecular risk features who achieve a CR will not proceed to high-dose therapy.

[The question of the ideal treatment also remains] for in-between cases of MCL, those who don’t have high-risk features like blastoid variant but still may carry molecular abnormalities; this is why NGS is so important. Traditionally, these patients were managed based on a dichotomy of their ability to tolerate high-dose chemotherapy with or without transplant. For example, patients younger than 60 or 65 years would be administered cytarabine/rituximab induction followed by transplant. Older patients, meanwhile, would receive VR [bortezomib plus rituximab] followed by maintenance rituximab. VR-CAP [VR plus cyclophosphamide, doxorubicin, and prednisone], which is replacing vincristine with bortezomib, has very impressive long-term survival benefits and is followed by maintenance rituximab. Many expectations [arose] surrounding BR with or without bortezomib, [but] that trial [NCT01415752] did not show a benefit.³ What it did show was that BR plus maintenance rituximab resulted in a median progression-free survival [PFS] of more than 6 years in this patient population. This is superior to what you see in the real-world setting and reflects the selection process.

Then you have BR plus ibrutinib examined in the SHINE trial [NCT01776840], which introduced these novel agents as part of the chemotherapy backbone.⁴ Instead of using biological therapy followed by chemotherapy, efficacy for combining these biological agents with the chemotherapy [was examined]. While this combined therapy resulted in a 2.5-year improvement in PFS, it was disappointing because the CR rate was not much higher. There was no difference in survival, including in patients with TP53-positive, high-MIPI [Mantle Cell Lymphoma International Prognostic Index] disease, or with other high-risk features. The rationale was that ibrutinib seemed less affected by high-risk molecular features in the relapsed/refractory setting, and so therefore it could improve outcomes in the frontline setting. [Given these data, however], it might be more effective to give patients this biological therapy early on and then give chemotherapy later rather than trying to combine them. Ibrutinib had more toxicity, particularly myelotoxicity and infection. Additional ongoing studies are testing if chemotherapy can be replaced by other therapies.

Lastly, younger patients who can tolerate dose-intensive therapies can receive a transplant, with induction and maintenance including a cytarabine-and-rituximab–based conditioning regimen.

Real-world data show that we need to make progress [in this space] and that real-world outcomes are not as optimal as those seen in clinical trials. It’s time to dissect MCL and account for its molecular heterogeneity when refining our treatment indications. We don’t yet know the best sequence of treatments. Also, maintenance has become part of the standard of care, even after high-dose chemotherapy, since it has demonstrated improvement in duration of response, relapse-free survival, and OS quite dramatically. [Nonetheless], several questions linger: How long is maintenance necessary? What is the long-term toxicity? Could we administer maintenance therapy based on MRD? Could we improve outcomes with something other than rituximab? There are ongoing maintenance trials examining R2/ibrutinib after transplant, among others. The fact that maintenance therapy still benefits this patient population [indicates that] our treatments don’t achieve a deep enough response early on.

The last unresolved question in MCL is regarding MRD, which has been shown to be an impactful [prognosis indicator] across the board. This is critical because patients who have a deep and early response, both with PFS and OS, perform far better than patients who don’t have that response.

The question becomes whether we can identify an MRD threshold to customize treatments. In the Nordic MCL2 trial [ISRCTN87866680], patients were preemptively administered rituximab [if they were MRD positive] and relapse was delayed further by well over 5 years.⁵ This is where the field is going, and [patients have] many opportunities to participate in ongoing clinical trials to help answer some of these unresolved questions.

Overall, [the abundance of new data] show that we are taking a fresh look at MCL and starting to refine treatments [to improve outcomes for patients].

The transcript has been edited for clarity.

References

1. Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. Lancet Oncol. 2022;23(3):406-415. doi:10.1016/S1470-2045(21)00638-0
2. Wang M, Ramchandren R, Chen R, et al. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021;14(1):179. doi:10.1186/s13045-021-01188-x
3. Smith MR, Jegede O, Martin P, et al. ECOG-ACRIN E1411 randomized phase 2 trial of bendamustine-rituximab (BR)-based induction followed by rituximab (R) ± lenalidomide (L) consolidation for mantle cell lymphoma: effect of adding bortezomib to front-line BR induction on PFS. J Clin Oncol. 2021;39(15 suppl):7503.doi:10.1200/JCO.2021.39.15_suppl.7503
4. Wang M, Jurczak W, Jerkeman M, et al. Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma (MCL). J Clin Oncol. 2022;40(suppl 17):abstr LBA7502. doi:10.1200/JCO.2022.40.17_suppl.LBA7502
5. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175(3):410-418. doi:10.1111/bjh.14241