Mantle Cell Lymphoma Refractory

Mantle cell lymphoma can stop responding to treatment or return after remission, presenting one of the most difficult challenges in cancer care today.

Table of contents

• Understanding Relapsed and Refractory Disease
• Treatment Options Available
• FDA-Approved Therapies
• Stem Cell Transplantation
• CAR T-Cell Therapy
• Outcomes and Prognosis

Understanding Relapsed and Refractory Disease

Although mantle cell lymphoma usually responds well to initial treatment, patients tend to experience disease return or resistance over time. The term relapsed refers to disease that reappears or grows again after a period of remission, which is a time when cancer activity stops or disappears. The term refractory is used to describe when the lymphoma does not respond to treatment, meaning that cancer cells continue to grow, or when the response to treatment does not last very long.^[1]

For patients who relapse or become refractory, secondary therapies may be successful in providing another remission. Like other forms of non-Hodgkin lymphomas (a group of cancers that affect the lymphatic system), there is no consensus on the best treatment for relapsed or refractory mantle cell lymphoma. However, there are an increasing number of treatment options available for these patients.^[1]

The development of covalent Bruton’s tyrosine kinase inhibitors (cBTKi), which are targeted drugs that block specific proteins in cancer cells, has improved the management of relapsed and refractory disease over the last decade. However, approximately a third of mantle cell lymphoma patients treated with these inhibitors are refractory, and up to 69% of patients who do respond at first will experience disease progression by two years on treatment. Effective management of patients whose disease has either relapsed or become refractory to cBTKi therapy is arguably the greatest current unmet need in mantle cell lymphoma.^[3]

Treatment Options Available

The type of treatment recommended for any individual patient depends on several factors, including the timing of the relapse, the patient’s age, extent of disease, overall health, and prior therapies received.^[1]

Historically, disease that has progressed after cBTKi therapy was often aggressive, resistant to further therapy, and associated with poor patient outcomes, with a median life expectancy ranging between 2.9 and 8.4 months in various case series. A multitude of ongoing trials are evaluating novel therapies in this context, but management remains challenging due to the paucity of effective agents with regulatory approval.^[3]

FDA-Approved Therapies

The following agents have been approved by the FDA for treatment of relapsed or refractory mantle cell lymphoma:^[1]

• Acalabrutinib (Calquence)
• Bortezomib (Velcade) with or without rituximab
• Brexucabtagene Autoleucel (Tecartus)
• Lenalidomide (Revlimid) with or without rituximab
• Zanubrutinib (Brukinsa)

Although not approved in combination, bortezomib and lenalidomide may be used with rituximab (Rituxan). Additional agents and regimens that are commonly used for the treatment of relapsed or refractory mantle cell lymphoma include bendamustine (Treanda) with or without rituximab, and combination chemotherapy with or without rituximab.^[1]

The rates of complete response reported in phase II studies after a median of two prior lines of therapy were 21% with ibrutinib, 43% with acalabrutinib, and 77.9% with zanubrutinib. Pooled analyses from longer term follow-up has demonstrated a median progression-free survival (the length of time during and after treatment that a patient lives with the disease but it does not get worse) of approximately 13 months, extending up to 26 months when these agents are used specifically in the setting of first relapse.^[3]

Stem Cell Transplantation

Stem cell transplant can be effective in patients with relapsed or refractory mantle cell lymphoma. There are two types of stem cell transplants: allogeneic (in which patients receive stem cells from another person) and autologous (in which patients receive their own stem cells).^[1]

Autologous stem cell transplant is generally considered after initial therapy rather than in relapse, but may be an option for medically fit patients who have shown a good response to treatment of their relapsed disease. In the case of younger, medically fit patients, intensive chemotherapy followed by allogeneic stem cell transplantation is a higher risk, but potentially a curative option.^[1]

Allogeneic stem cell transplantation appears to have curative potential for relapsed mantle cell lymphoma. The problem is the risk. There is about a 20% to 30% chance of dying from a transplant-related complication in the first 2 years after that strategy. For young patients, though, this should be offered as an option. If you’re 58 years old with relapsed mantle cell lymphoma, the odds of making it to age 65 or 70 are not very good. And so, taking this high-risk approach of the allogeneic stem cell transplant may actually become your best option if you’re a young patient with relapsed disease.^[17]

Allogeneic stem cell transplant has an established role in appropriate candidates; however, contemporary consensus is to preferentially offer CAR T-cell therapy.^[3]

CAR T-Cell Therapy

CAR T-cell therapy is a treatment that uses genetically modified immune system T cells to attack tumor cells. This therapy was approved by the FDA in July 2020 for patients with relapsed or refractory mantle cell lymphoma. The therapy has been shown to be effective in patients with other forms of non-Hodgkin lymphoma.^[6]

Contemporary consensus is to preferentially offer chimeric antigen receptor (CAR) T-cell therapy for patients whose disease has relapsed or become refractory to cBTKi therapy.^[3]

Outcomes and Prognosis

Mantle cell lymphoma is associated with a challenging outlook, though recent advances have improved the prognosis of the disease. With about 4,000 new cases each year, mantle cell lymphoma accounts for about 5% of all non-Hodgkin lymphomas in the United States.^[4]

In the pre-BTK inhibitor era, the median progression-free survival in relapsed or refractory disease was 4 to 9 months. With the introduction of ibrutinib, the median progression-free survival improved to 13 to 14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTK inhibitors inevitably develops in a subset of patients. Outcomes after progression on BTK inhibitors are extremely poor, with a median overall survival of 6 to 10 months.^[9]

There is currently no cure for mantle cell lymphoma. But many people go into remission after initial treatment. Remission is a period when cancer activity stops or disappears. How long it lasts can vary from person to person. In most cases, mantle cell lymphoma relapses, or returns, within a few years. People with this disease may experience multiple periods of remission and relapse.^[14]