What Is High-Risk Mantle Cell Lymphoma, and How Should We Treat It?

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Soon after mantle cell lymphoma (MCL) was recognized as a distinct subtype of B-cell non-Hodgkin lymphoma in 1992, researchers began to investigate the clinical outcomes of patients, noting the wide spectrum of outcomes that we still observe today. Refining our ability to prognosticate patients with MCL has been a major effort all the while using such information to inform treatment decisions and understanding the underlying disease biology of MCL.

Defining High-Risk MCL

We consider risk stratification within MCL based on clinical, pathologic, and molecular grounds. Patients with high-risk MCL typically present with a more rapid onset of symptoms and are frequently ill at diagnosis. The Mantle Cell International Prognostic Index (MIPI; age, lactate dehydrogenase, performance status, and leukocyte count) is a clinical scoring system and was shown to be prognostic in the up-front setting regardless of therapeutic approach.¹ According to MIPI, the median overall survival (OS) was 29 months in high-risk patients, 51 months for those who were intermediate risk, and was not reached for low-risk patients.

Many pathologic features are characteristic of high-risk MCL. In particular, the percentage of tumor cells staining for Ki67 correlates with aggressive behavior and shortened survival in numerous studies.² The combined MIPI incorporates Ki67 (< 30% vs ≥ 30%) and separated patients into 4 risk groups with 5-year OS rates of 85%, 72%, 43%, and 17%.³ Blastoid or pleomorphic histology⁴ is also associated with poor outcomes, as is tumor p53 overexpression.⁵

The most established high-risk genomic features include complex karyotype⁶ and TP53 aberrancy.⁷ Other genomic aberrations have also been associated with shortened survival, such as ATM alterations or CDKN2A/B deletions.⁸ The Nordic MCL2 study (ISRCTN87866680)⁷ established the inferior outcomes with TP53-aberrant patients undergoing high-dose therapy plus autologous stem cell rescue (HDT/ASCR). Herein, among 170 patients, those with mutated TP53 had a median progression-free survival (PFS) of 0.9 years vs 10.2 years for TP53-unmutated patients. Therefore, many eschew HDT/ASCR in patients with TP53-mutated MCL, and we follow this practice.

Treating High-Risk MCL

The optimal up-front treatment for patients with high-risk MCL is not fully defined, is evolving over time, and is individualized based on each patient’s clinical status, age, comorbidities, and goals of care.

Up-front Chemotherapy-Based Approaches

The TRIANGLE study (NCT02858258), which was presented in 2022,9 established a new up-front standard of care for patients with MCL who are eligible for HDT/ASCR. This study compared induction immunochemotherapy plus HDT/ASCR vs this approach plus ibrutinib (Imbruvica; during induction and maintenance) vs immunochemotherapy plus ibrutinib, followed by ibrutinib maintenance without HDT/ ASCR. Among 870 patients, only 15% were MIPI high risk. The ibrutinib- containing arms showed a benefit, and this effect was maintained even in high-risk patients (p53 overexpression > 50% or Ki67 ≥ 30%). Thus, TRIANGLE is a viable frontline treatment option for fit patients with high-risk MCL.

Chemotherapy-Free Approaches

Numerous studies have investigated up-front chemotherapy-free treatment regimens (TABLE),^10-13 including the multicenter BOVen study (NCT03824483; zanubrutinib [Brukinsa], obinutuzumab [Gazyva], and venetoclax [Venclexta]),^10,14 the OASIS study (NCT02419560; obinutuzumab, venetoclax, and ibrutinib), the VLR study (NCT03523975; venetoclax, lenalidomide [Revlimid], and rituximab [Rituxan]),11 and the ALR study (NCT03863184; acalabrutinib [Calquence], lenalidomide, and rituximab).¹²

The BOVen study solely enrolled patients with TP53 aberrancy, whereas patients in the ALR trial (n = 24) were 21% MIPI high risk, 29% had TP53-mutated tumors, and 37% had Ki67 greater than or equal to 30%.

Patients in VLR (n = 29) were a more high-risk population: 88% were MIPI high risk, 7% had blastic or pleomorphic histology, 2 had TP53-mutated tumors, and 5 had TP53 deletions.

Finally, in OASIS (n = 15), 55% of patients were MIPI high risk, 1 (7%) patient had pleomorphic histology, 2 (13%) patients had TP53-mutated tumors, and 6 (40%) patients had 17p deletions.

Although early promising results are seen, longer follow-up is needed.

Relapsed/Refractory High-Risk MCL

CD19-directed chimeric antigen receptor (CAR) T-cell therapy (brexucabtagene autoleucel [brexu-cel] and lisocabtagene maraleucel [liso-cel]) is an efficacious treatment approach for relapsed/refractory (R/R) high-risk MCL.

Recently updated data (median follow-up, 35.6 months) from the ZUMA-2 study (NCT02601313; n = 68)¹⁵ of brexu-cel showed noteworthy overall response rates (ORRs): complete response rate (CRR) of 100% for 6 patients with TP53-mutated MCL, an 82% ORR and 53% CRR for 17 patients with blastoid MCL, and an 89% ORR and 76% CRR for 37 patients whose MCL who had a Ki67 of greater than or equal to 50%.

Only 2 patients with TP53- mutated MCL and 4 patients with blastoid MCL were still in remission at time of publication. A large consortium study of real-world data for brexu-cel use showed a lower CRR (72% vs 88%) for patients with TP53-mutated MCL.¹⁶

Liso-cel was studied in 32 patients,¹⁷ many of whom had high-risk features: 37.5% with blastoid morphology, 72% with Ki67 of greater than or equal to 30%, and 22% with TP53- mutated MCL.

Consolidative Allogeneic HCT

For patients with high-risk MCL and/or patients with R/R MCL, we often consider consolidative allogeneic hematopoietic cell transplantation if another remission is attained and there is a suitable donor identified. Long-term follow-up data¹⁷ suggest this approach has curative potential. Despite encouraging advancements, there remains a number of unanswered questions in high-risk MCL:

1. Are there molecular subgroupings within high-risk MCL that can further refine prognostication to tailor treatments?

2. How can we build on the success of the TRIANGLE study in future efforts?

3. Are chemotherapy-free regimens safe and effective in the frontline treatment of high-risk MCL? Are specific subgroups particularly suitable?

4. What is the role, if any, for up-front CAR T-cell therapy for treating high-risk MCL? This is the design for the CARMEN study (NCT01880567) of rituximab-ibrutinib (R-ibrutinib) followed by CAR T-cell therapy vs R-ibrutinib plus chemotherapy from the European MCL Network. Additionally, what is the durability of responses to CAR T in R/R MCL, and how will these data compare with outcomes with bispecific antibodies?

Concerted, multicenter, collaborative efforts are needed to urgently address these questions and to ultimately help patients.

Zachary Epstein-Peterson, MD, is a lymphoma specialist at Memorial Sloan Kettering Cancer Center. Anita Kumar, MD, is a lymphoma specialist at Memorial Sloan Kettering Cancer Center

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