Wang Details Caveats to Standards of Care for Treating Patients With MCL

Michael L. Wang, MD

When treating patients with mantle cell lymphoma (MCL), early identification and appropriate frontline therapy remains critical, and therapies may vary for those 65 years and older compared with patients under the age of 65, with several additional factomd andersonrs also having a role in approaching treatment options for a new patient in the clinic, according to Michael L. Wang, MD.

Wang, a professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston, explained the factors he considers when determining the optimal therapeutic strategy for patients with MCL during the 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma.¹

Characteristics to Examine in New Patients

Although age under 65 years and 65 years and older are used to stratify patients, Wang noted that translating these criteria to the clinic, a range of plus or minus 5 years can be used to adjust for care. Factors to consider include performance score. For example, Wang cited a very healthy 70-year-old patient or a patient who is 60 years with comorbidities and a low performance score.
In addition to determining urgency of care, examining the patient’s cardiac history is crucial with renal and bone marrow function also being key factors. Treatment history with response from last therapy, duration of prior treatments, and history ofBruton tyrosine kinase (BTK) inhibitors should also be considered along with further parameters such as toxicities and transplant history.

“Clinically you absolutely want to know the patient’s cardiac history and you want to know their kidney history,” Wang said. “Cardiac history is very important; I will not feel comfortable starting the patient with a BTK inhibitor without getting [a] cardiology consultation, electrocardiogram, stress tests, [and] echocardiogram.”

Attention should be given to the organ system as a spleen over 20 cm may rupture and gastrointestinal (GI) bleeding can be severe. Central nervous system involvement when it is high-risk should be monitored as well.

“Gastric MCL is quite commonly seen and sometimes you do an endoscopy but find that [the patient] had a volcano sitting there—there’s a crater and near the crater there’s a big artery ready to burst.”

Examining pathology is key to determine if the MCL is pleomorphic or blastoid, and as MCL has 2 presentations, one of them being chronic lymphocytic leukemia, and this needs to be specified. Wang also noted he will run laboratory analyses such as creatine and lymphocytosis tests, and staging for MCL is more “up in the air” than staging is for other types of lymphoma, at MD Anderson Cancer Center, he will confirm complete response with PET/CT scans, bone marrow, and GI biopsies.

As knowledge on the role of genetic abnormalities continues to grow in MCL, there are limited data in many areas and it is unknown whether certain mutations, such as CARD11, will prove to be reliable targets. Other driver mutations, such as NOTCH1, NOTCH2, and c-myc have been shown to be associated with poorer outcomes. Wang highlighted that data may be gleande through programs such as the MCL Program of Excellence at MD Anderson in which patients with relapsed or refractory MCL undergo a front-door genetic panel and minimal residual disease and RNA-sequencing.

Frontline Therapy

“Frontline therapy for MCL is the most important therapy [as] many patients have only one opportunity [for treatment],” Wang said. “Each time you give a therapy the efficacy goes down [and] the interval of remission shortens until about 5 to 10 cycles, [then] the resistance becomes 100 [and] the efficacy becomes 0.”

The natural history of MCL has shown that patients tend to be in remission and then relapse, with this occurring multiple times. Giving the best treatment in frontline when the patient’s immune resources, bone marrow, and organs are still in good condition is important. Wang noted he uses doublet therapies for those with high-risk disease because single-agent rituximab (Rituxan) is not adequate. Maintenance therapy is critical as well and other factors to keep in mind during treatment are toxicities, COVID-19 infection, and the personal history of patients including insurance, family support, and home location.

“There is art in maintenance after frontline therapy. Rituximab is useful [to] prolong overall survival after almost any therapies,” he said.

Frontline Therapy for Patients 65 Years and Above

Although rituximab plus ibrutinib (Imbruvica) has demonstrated high response rates and can be used effectively, atrial fibrillation remains a prominent cardiac toxicity occurring in approximately 24% of patients.² The R² regimen of lenalidomide (Revlimid) and rituximab is an effective therapy that can be dose adjusted for renal failure. Wang noted he would also use the combination in patients with certain disease characteristics, such as tonsillar MCL or lymphoma that moves in the renal gland.

For patients with high-risk disease—a Ki67 index greater than 50%, a TP53 mutation, and/or pleomorphic/blastoid disease—treatments include the SHINE regimen (ibrutinib, bendamustine[Bendeka]/rituximab and rituximab maintenance)³, rituximab plus ibrutinib maintenance for 2 years, acalabrutinib (Calquence)/venetoclax (Venclexta)/rituximab, or acalabrutinib plus R². Wang said that rarely are bendamustine/rituximab and rituximab maintenance used or RCHOP plus rituximab.

MD Anderson is also evaluating rituximab plus acalabrutinib, rituximab plus pirtobrutinib, rituximab/pirtobrutinib/venetoclax, and ibrutinib monotherapy for smoldering MCL.

Frontline Therapy for Patients Under 65 Years

Younger patients with high-risk disease can receive the Window 2 study (NCT03710772) therapy of ibrutinib, venetoclax, and rituximab followed by a risk-stratified observation or short-course R-hyper-CVAD, according to Wang. Additional therapies include rituximab plus ibutinib with or without venetoclax maintenance for 2 years, acalabrutinib/venetoclax/rituximab, or acalabrutinib plus R².

The Window-3 trial (NCT05495464) is ongoing at MD Anderson evaluating more treatment combinations for patients in this subgroup.

Further Options

Approved agents for the treatment of MCL are bortezomib, lenalidomide, ibrutinib, acalabrutinib, zanubrutinib, the CAR T-cell therapy brexucabtagene autoleucel (Tecartus), and, most recently, pirtobrutinib (Jaypirca). Targeted agents and combinations such as BTK inhibitors, brexucabtagene autoleucel, chemotherapies, and stem cell transplants are under additional investigation as well.

Additionally, low-dose radiation for patients with an ATM mutation has shown efficacy and Wang noted that only 1 to 2 cycles of radiation are needed. “Forty percent of patients have a frontline ATM mutation,” he said. “When you have ATM mutation the tumor is exquisitely sensitive to radiation…so radiation therapy is a great therapy for MCL, sometimes you don’t have to use high doses.”

References

1. Wang, ML. How I treat MCL in 2023. Presented at: 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma, February 23-26, 2023; Miami Beach, FL.
2. Jain P, Zhao S, Lee HJ, et al. Ibrutinib with rituximab in first-line treatment of older patients with mantle cell lymphoma. J Clin Oncol. 2022;40(2):202-212. doi:10.1200/JCO.21.01797
3. A study of the Bruton’s tyrosine kinase inhibitor ibrutinib given in combination with bendamustine and rituximab in patients with newly diagnosed mantle cell lymphoma. ClinicalTrials.gov. Updated February 24, 2023. Accessed February 27, 2023. https://clinicaltrials.gov/ct2/show/NCT01776840