Ibrutinib With Immunochemotherapy/ASCT Improves MCL Survival

Why It Matters

Mantle cell lymphoma (MCL) is a rare, aggressive B cell non Hodgkin lymphoma (NHL) which usually presents late. It accounts for approximately 5% of all NHLs with approximately 4,000 new cases diagnosed annually in the United States. The disease is more common in older men, but the patients entered onto the current trial are generally younger and fitter. The disease is usually not curable with established therapy, and therefore length of first remission has become a major endpoint in the development of effective treatment regimens.

For the younger patient who is a good candidate for treatment, the traditional approach for several years has included cytarabine-containing immunochemotherapy (induction) followed by ASCT (transplant) and then maintenance rituximab. This approach provided superior long term disease control over chemotherapy for the older patient with DLBCL, but was not without risk of both acute and delayed toxicities from the high dose therapy and transplant themselves. In recent years as more targeted therapies have entered clinical practice and been shown to induce more complete and longer duration remissions early in the treatment of de novo or relapse DLBCL, clinicians are beginning to consider whether or not transplant is necessary for all patients who are eligible for this approach.

Ibrutinib is a BTK inhibitor with initial evidence of activity in relapsed mantle cell lymphoma. Promising results have been observed, with complete remissions and durable responses observed in some patients who had received no prior therapy for their indolent non-Hodgkin lymphoma (NHCL). These data support the use of BTK inhibitors in the first line setting. The TRIANGLE study investigated the combination of ibrutinib with immunochemotherapy (R-CHOP), with or without ASCT, as front-line therapy for patients with mantle cell lymphoma.

The clinically important finding from TRIANGLE is that the addition of ibrutinib to immunochemotherapy and ASCT improved failure free survival compared to the pretrial standard of immunochemotherapy plus ASCT. In the main analysis (with a median followup of 31 months for patients on ibrutinib), failure free survival at 3 years was 88% for the ibrutinib plus immunochemotherapy plus ASCT arm compared to 72% for the immunochemotherapy plus ASCT arm. Importantly, TRIANGLE did not show that the older ASCT based standard was superior to an ibrutinib containing approach in which the transplant was omitted from the treatment protocol. This challenges the assumption that ASCT should remain a routine part of the treatment protocol for all younger eligible patients with these characteristics of Hodgkin lymphoma.

Additional follow up in this study also continues to support the survival signal. Update abstract summaries and correspondence have also been received showing strong failure free survival and overall survival for patients treated with frontline chemotherapy + ibrutinib. However, this study does not show that adding ASCT to ibrutinib improves outcomes for all patients in this study. This does not mean that all patients who relapse or who are refractory to initial therapy will not achieve a benefit from subsequent ASCT. However, these data do limit the rationale for initially incorporating ASCT into the treatment of patients with newly diagnosed symptomatic hairy cell leukemia.

While the treatment outcome duration may seem a simple parameter, it is by no means synonymous with quality of life. Longer duration of the first remission translates into a longer interval to potential relapse, a longer time to require salvage treatment, and a longer time to make appropriate second line treatment decisions, such as BTK inhibitor retreatment or referral for CAR T cell, and other high intensity rescue strategies. Patients and their loved ones don’t want to count minutes, hours or days. They want to have more time to enjoy life, spend time with family and friends, work and pursue other activities they enjoy. They want to be able to plan for the future, to anticipate what is to come rather than being blindsided by a sudden change for the worse due to relapse and its emergencies.

This is not a benefit without trade-offs. Grade 3 to 5 hematologic adverse events and infections were more common in patients on maintenance or follow up on the ASCT plus ibrutinib arm compared with the non-transplant ibrutinib arm or the transplant arm. Although ibrutinib significantly improves efficacy, it comes with additional complications and supports when given in conjunction with prolonged immune suppression from transplant.

In addition to the possible adverse reactions related to the mechanism of action of Ibrutinib, there are some other aspects, often deriving from the clinical practice experience, which must be taken into consideration in relation to this class of agents. These issues must be discussed in the real world setting in which patients are treated with Ibrutinib. In the SPC these issues are listed as increased risk of hemorrhage, infections, cardiac arrhythmias, heart failure, hypertension; neutropenia; second primary malignancies; other clinically important events and possible interactions and adaptations with CYP3A inhibitors and inducers. Thus, patient management on Ibrutinib involves more than just writing a prescription for this medication. The healthcare provider should inquire about all of the current medications their patient is taking before initiating ibrutinib treatment and screen their patient for cytopenias. Additionally, patients should be educated on the cardiovascular and bleeding related symptoms that require urgent medical evaluation.

The immunohistochemical detection of TP53 abnormalities in mantle cell lymphoma is timely. The standard of treatment is evolving, and the rapidly increasing knowledge of this disease is just beginning to translate into improved frontline therapy regimens. As our understanding of the disease’ s biology and clinical behavior continue to evolve, high risk disease features such as TP53 abnormalities, blastoid or pleomorphic features and a high proliferation index will continue to predict a poor prognosis. These factors may determine whether the patient with MCL would benefit from the addition of transplantation into his or her treatment regimen or if alternative salvage strategies may be indicated. The subject has been recently reviewed in several articles emphasizing a shift in approach to the frontline therapy for mantle cell lymphoma with a trend toward risk adapted therapy for individual patients formerly deemed transplant eligible. See recent review article after TRIANGLE trial.

Who It Affects

The greatest benefit is realized in application to young and fit patients with mantle cell lymphoma who are being evaluated for the need for intensive therapy and ASCT. In these patients, addition of ibrutinib to immunochemo-therapy and/or transplantation can potentially enhance the depth and duration of response. For the older patient with significant comorbidities, however, the clinician must balance efficacy with tolerability and may often choose less intensive chemotherapy regimens or even single-agent, targeted therapies.

The translation of existing evidence regarding the use of targeted therapy in hematology into clinical practice will require the active participation of hematologists and transplant teams in the implementation of targeted therapies in the context of standard-of-care induction and/or post-transplant consolidation/maintenance strategies. This could potentially involve the translation of targeted therapy into the patient’s treatment plan before the collection of their stem cells or around the time of their transplant. In addition to these roles for hematologists and transplant teams, oncology pharmacists and staff from outpatient clinics will be essential in enhancing patient compliance with oral therapy; in managing potential drug–drug interactions; and in the monitoring of patients for long-term toxicities.

The evolution from an inpatient transplant based treatment protocol to an outpatient maintenance therapy protocol will have pronounced impacts on both the financial bottom line and operations of payers and health systems. Providers will need to develop strategies to manage the costs of authorizing combination regimens and extended duration maintenance therapy as well as reassess the use of inpatient transplant in the setting of increased use of other resources. These shifts will affect not only organized providers but also individuals and support systems including patients, their families, and patient advocacy groups and caregivers.

Another consideration is equity and access concerns. Patients and families in rural locations and from less affluent oncology programs may find it particularly challenging to access the specialized transplant services and consistent access to oral targeted therapies required for management of hematological malignancies. Disparities may worsen unless strategies are developed to address issues of insurance coverage, telemedicine follow-up, and the integration of community-based oncology programs and specialist transplant centers.

What Changes

• Eligible patients should be offered a conversation about adding ibrutinib to first-line therapy: clinicians must present the potential for longer remissions alongside the increased risk of hematologic toxicity and infections so that patients can make informed, preference-sensitive decisions.
• Transplant planning will be individualized: teams should reassess routine use of autologous stem cell transplantation when ibrutinib is part of induction and maintenance, reserving ASCT for patients where the additional benefit is clear or where transplant remains preferred for long-term disease control.
• Care pathways must strengthen supportive measures: expect greater emphasis on infection prevention, closer blood count monitoring, proactive management of drug–drug interactions, and clear survivorship plans to detect and manage late complications, including secondary cancers.
• Systems and payers should prepare for cost and access shifts: coverage policies, drug prior-authorization processes, and transplant resource planning must be aligned to ensure equitable access and to manage the financial impact of extended targeted therapy use.

References:

https://pubmed.ncbi.nlm.nih.gov/38705160/

References:

https://pubmed.ncbi.nlm.nih.gov/38705160/ https://clinicaltrials.gov/study/NCT02858258