Presentation by Dr Jason Chandler, West Cancer Center
Quick Summary
For patients presenting with Mantle Cell Lymphoma, there has been a paradigm shift away from intensive, curative intent therapy to less toxic therapy aimed at achieving remission with long term disease control.
Autologous stem cell transplant (ASCT) remains the current standard of care, but not all patients are candidates for ASCT, and some evidence suggests, with newer therapies, patients can achieve good long-term disease control without ASCT.
Patient’s comorbid conditions and MIPI score should be considered when deciding on a 2L therapy.
Additional options including pirtobrutinib and CAR-T cells are now available for 3L or higher treatment that can achieve durable remissions, even in heavily pre-treated patients.
At the 2023 Community Cases Conference held in Memphis, Tennessee, Dr Jason Chandler from West Cancer Center presented a patient case detailing treatment of a hematologic cancer patient. His focus was on clinical cases which incorporate some of the more practice-changing developments in the field.
The Case
The patient, a 66-year-old male, presented to an ENT physician with difficulty swallowing, and a laryngoscopy showed a mass that nearly completely obstructed his right nares, and a biopsy of the mass was obtained. His past medical history was notable for hypertension, anxiety, depression, substance abuse and heart problems (atrial flutter). He is divorced, lives alone, and quit smoking about 15 years ago. His family history was notable only for skin cancers. His biopsy results revealed a B-cell lymphoma with CD20 expression, and CD5 co-expression. The Ki67 expression, an indicator of proliferative rate, was 40-50%. On further testing it was determined that the patient had Mantle Cell Lymphoma (MCL).
General Considerations
Dr Chandler noted the relevant aspects of the case, specifically the patient’s age (66 y/o), with cardiac issues, substance abuse, lack of support system at home, and clinical stage III disease, which can be incorporated into the patient’s “MIPI” score, or Mantle Cell Prognostic Index, and revealed a high-risk score for this patient. Dr Chandler noted that most of the approved drugs for lymphoma seek approval for the MCL indication first, as this represents an area of current unmet clinical need, and thereafter the drugs are approved for other types of lymphoma such as diffuse large B-cell lymphoma. He noted a decision is typically made at this point, based on the results of molecular testing, as to whether the patient is expected to have an aggressive course or an indolent course, and because the patient is positive for a specific mutation called Sox11, this patient falls into the more aggressive category, typically seen in ~ 70-80% of patients.
Considerations for Treatment
Dr Chandler noted the availability of the very aggressive, “R-Hyper-CVAD” chemotherapy regimen which, due to its intensity, frequently entails multiple hospitalizations but is associated with a 3-year overall survival (OS) rate of 82%. He also noted the Nordic regimen of alternating R-CHOP and R-DHAP chemotherapy, which showed median OS of 12.7 years and a median progression-free survival (PFS) of 8.5 years. He noted the treatment paradigm in years past, which was to try and ‘cure’ patients by using very aggressive chemotherapy regimens, but that long-term follow up data at approximately 15 years ultimately showed that patients were not cured of their disease and would eventually relapse. The current treatment approaches, Dr Chandler noted, are therefore designed instead to keep the patient’s disease in check, while doing less overall harm to the patient by using less aggressive chemotherapy regimens. In this regard, he noted trials utilizing rituximab (Rituxan) and bendamustine alone, or reduced doses of cytarabine which achieved very good PFS and OS rates.
First-Line Therapy
Continuing the case, the patient received, as first line therapy, bendamustine + Rituxan, alternated with high dose cytarabine + Rituxan. Because the patient had problems with his initial treatment, severe anxiety and depression, and lacked a social support system at home, he was not considered a candidate for curative therapy with an autologous stem cell transplant (ASCT), which remains a standard of care for such patients. The patient nonetheless achieved a complete response (CR) to his initial therapy and was placed on Rituxan maintenance therapy every 2 months.
Second-Line Treatment
After 3 years in remission, the patient relapsed, and Dr Chandler reviewed the second line (2L) options. He noted that although there are a number of options, the preferred option is using a “covalent type” Bruton’s Tyrosine Kinase, or BTK inhibitor such as ibrutinib (a first-generation drug), as well as the newer options of acalabrutinib, or zanubrutinib. The adverse event profiles of these drugs differ, and Dr Chandler noted that zanubrutinib is associated with less cardiac issues such as atrial fibrillation and flutter. As such, due to the patient’s existing cardiac problems, zanubrutinib might be a better option for the patient. He also reviewed data from the phase III Triangle study presented at the American Society for Hematology (ASH) meeting in 2022, which was aimed at possibly eliminating the need for ASCT by moving ibrutinib upfront in treatment (i.e., prior to relapse). He noted the results which showed that patients treated with ibrutinib upfront did similarly well regardless of whether they received ASCT or not. While provocative, Dr Chandler noted the results from Triangle have not as yet changed standard of care. They nonetheless suggest that other options besides ASCT might be available in the future.
Third-Line Treatment
Returning to the case, 6 months after his 2L treatment with zanubrutinib, the patient experienced a relapse and Dr Chandler then considered third line (3L) options. He noted the recent approval of pirtobrutinib, a novel (“non-covalent”) BTK inhibitor with a distinct mechanism of action, which also differs in its side effect profile. Results for this drug in BTK-pretreated MCL patients showed an overall response rate (ORR) of 51%, while in MCL patients not previously treated with BTK inhibitor, the ORR was 82%. Lastly, Dr Chandler reviewed results from the ZUMA-2 trial which evaluated the use of another type of treatment, chimeric-antigen receptor (CAR) T-cells, in patients with relapsed MCL. He noted that patients who received the CAR-T therapy brexucabtagene autoleucel and achieved a CR did extremely well, with excellent PFS observed out to 5 to 6 years in a heavily pre-treated patients, although the PFS of those with a partial or no response were uniformly poor.
Summary
Summarizing this case of Mantle Cell Lymphoma, Dr Chandler noted that, while there are multiple first line options for MCL, Rituxan and high dose cytarabine along with initial chemotherapy are the most important components of treatment. ASCT remains standard of care for those patients who are able to tolerate the procedure, although with newer regimens including upfront ibrutinib, it may soon be possible to forgo ASCT with good outcomes. In the 2L setting, BTK inhibitors of the covalent type (ibrutinib, acalabrutinib, and zanubrutinib) are the preferred option. Dr Chandler noted that the non-covalent BTK inhibitor pirtobrutinib and CAR-T cells are both options for MCL patients in the 3L or higher treatment setting, both of which have excellent outcomes. He concluded this case by noting the paradigm shift for MCL patients, in the face of an expanding array of treatment options, moving away from very aggressive but curative treatments like ASCT, toward less aggressive regimens that can still achieve long-term disease control for patients.
See more from the 2023 Community Cases Memphis Conference here.
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