Clinical Lymphoma, Myeloma & Leukemia, Vol.21, Suppl.1 - September 2021

S186 E XABS- 2 38-MC L Tailori n g Upfro n t Therapy i n Ma n tle Cell L y m pho m a Brad Kahl 1, * 1 Washington University Medical School, St. Louis, Missouri, USA *Correspo n di n g author: bkahl@wustl.edu Keywords MCL, mantle cell lymphoma, tailoring, Bendamustine Abstract Mantle cell lymphoma (MCL) is a unique lymphoma subtype. The disease is considered moderately aggressive and largely incurable. However, outcomes have improved markedly over the past 20 years, largely due to the introduction of new therapeutic options. The prognosis for an individual patient can be estimated by applying the mantle cell lymphoma international prognostic index (MIPI-C), which integrates four clinical factors (age, LDH, WBC, and performance status) with the Ki-6 7 index. The approach to a newly diagnosed patients requires thoughtful individualization. For example, approximately 15% of patients will present with the leukemic, non-nodal version of MCL, which has a more indolent clinical course and better prognosis than classic MCL. If such patients are asymptomatic and without significant anemia or thrombocytopenia, they may start out on a strategy of observation, similar to a patient with chronic lymphocytic leukemia. More common are patients with classic MCL, and most of these patients will require therapy at diagnosis. Younger and more fit patients are typically managed with intensive treatment strategies than uses high-dose cytarabine during induction and autologous stem cell transplant consolidation. These patients will then typically receive maintenance rituximab for 3 years. This approach should generate a median progression-free survival of over 8 years. However, some patients do not experience such long remissions, and patients with deleted or mutated p53 genes are at particularly high risk for inferior outcomes. How to best manage these high-risk populations has not been established, and ongoing trials testing novel agents are underway. Patients who are not suitable for such intensive approaches due to age or co-morbidities are typically managed with bendamustine-based regimens such as BR or R-BAC. Recently presented data from the US intergroup trial E1411 show a median PFS of over 5 years in older MCL patients who received BR induction followed by 2 years of maintenance rituximab. Highly proliferative cases (Ki-6 7 over 50%) might be better managed with the R-BAC regimen, which incorporates low-dose cytarabine. Other options for older MCL patients include the VR-CAP regimen or the lenalidomide- rituximab (R2) regimen, although the latter is not FDA-approved. Several potentially practice-changing clinical trials incorporating novel agents such as BTK inhibitors into frontline therapy have completed enrollment and results are awaited. The TRIANGLE Trial, targeting younger fit MCL patients, evaluates the addition of ibrutinib to standard intensive therapy as well as the substitution of ibrutinib for intensive therapy. The SHINE trial and the Acerta 308 trial each test the addition of a BTK inhibitor (ibrutinib in SHINE and acalabrutinib in Acerta 308) to standard BR therapy in older MCL patients. There are ongoing trials in MCL that could also influence practice. In younger MCL patients, the US intergroup trial EA4151 evaluates individual patients for MRD negativity using a next-generation sequencing platform and randomly assigns patients to a de-escalation treatment strategy if MRD-negative after induction. In older MCL, an industry- sponsored trial is comparing standard BR therapy against novel agent therapy using the combination of zanubrutinib plus rituximab. In summary, major progress has been made in the frontline management of MCL over the past 2 decades, and several studies evaluating novel agents in the frontline setting are poised to improve outcomes even further. Ongoing unmet needs include better strategies for highly proliferative MCL and p53-mutated MCL.