MCL Leader Discusses Optimal Disease Management

Andre Goy, MD

Although it is a treatment goal for patients with mantle cell lymphoma (MCL) to achieve a minimal residual disease (MRD)-negative state and experience extended durations of response to therapy, most of them will relapse, according to Andre Goy, MD.

Ibrutinib (Imbruvica), lenalidomide (Revlimid), acalabrutinib (Calquence), and bortezomib (Velcade) are the treatment breakthroughs that have been integrated into the paradigm for patients with MCL. Moreover, prognostic markers and next-generation sequencing help physicians determine which therapies to administer on an individualized basis.

OncLive: How has the field of MCL evolved?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Goy, chief, Division of Lymphoma, chairman and director, John Theurer Cancer Center, discussed the evolution of MCL treatment, specifically the integration of new agents in both the frontline and relapsed/refractory settings, and the importance of MRD status and maintenance therapies.Goy: The field of MCL is rapidly evolving. We now have 5 newly approved novel therapies between the United States and Europe that have begun to be integrated into standard frontline regimens. We know that rituximab (Rituxan), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) alone or bendamustine and rituximab (BR) alone is not sufficient in MCL. The median progression-free survival (PFS) with R-CHOP is 14 to 18 months as patients become chemoresistant over time.

It is well established that dose-intensive therapy and cytarabine-containing regimens show a much better outcome in terms of PFS and overall survival (OS). These regimens showed a PFS in excess of 7 years and a higher OS. These results were confirmed in multiple real-world observation settings in the United States and Europe. Cytarabine-containing regimens are better and show an earlier and higher incidence of molecular complete remission (CR) and deeper responses.

What are some clinical trials examining combinations in MCL?

However, dose-intensive strategies without high-dose therapy and transplant are not necessarily feasible across the board, given the median age at diagnosis is around the mid-to-late 60s. Therefore, we need other regimens. The standard therapy has been kind of a default backbone. BR has been shown to be slightly superior to R-CHOP by itself and is less toxic in a short-term setting.The superiority of BR has served as a platform to integrate these newly approved novel therapies in combination with BR in the frontline setting. BR plus bortezomib showed a much higher CR rate in the relapsed setting. It has been tested in the frontline setting, as well. Some of the results in MCL are still pending but appear promising. BR with and without ibrutinib was tested in the SHINE trial with maintenance therapy. That has been completed, and we’re expecting the results soon. Similarly, there is an ongoing trial looking at exactly the same question, but with the second-generation BTK inhibitor acalabrutinib.

How have prognostic markers impacted treatment?

Finally, lenalidomide has also been integrated into the BR backbone in Europe with impressive results. The small study did yield concerns with toxicities and secondary primary malignancies, so that’s a potential issue. The treatment may be better served as more of a maintenance therapy. Lenalidomide is being looked at in a number of different ways in Europe as a maintenance therapy following high-dose therapy and standard therapy.We have been able to identify prognostic markers. Poor-risk patients do poorly regardless of what you do. One of the problems in MCL is chemoresistance. Poor-risk factors include the patients with a high Mantle Cell Lymphoma Prognosis (MIPI) score; these patients do worse even after high-dose therapy. The patients who have high Ki-67 of more than 30% and above, a blastoid presentation, or p53 are also deemed poor risk. One of the most important factors that is likely underestimated is the presence of p53 abnormalities or 17p deletion.

Now, we routinely test patients. We have done a pilot study and next-generation sequencing and concluded that among the common ATM abnormalities we found, up to 23% to 30% of patients have p53 abnormalities. These patients need new options regardless of their age, because they do poorly after high-dose therapy and transplant. That's where the stratification is headed, so that we can identify the subset of patients who need a chemo-free option that is not dependent on the p53 pathway.

Does MRD status impact a patient’s prognosis?

A study at The University of Texas MD Anderson Cancer Center consisting of an initial chemotherapy-free phase of ibrutinib and rituximab is impressive because the CR rate is close to 80% following the chemo-free option. There was also a very high incidence of molecular CR in patients who had been tested for MRD negativity and patients who received less cycles of hyper-CVAD as a consolidation treatment. The question is, “Can we push the envelope further and identify the subset of patients who are low risk and only need a non-chemotherapy option?” This is being tested in a number of different ways. We are looking at combining biological agents such as rituximab and lenalidomide, ibrutinib and venetoclax (Venclexta), rituximab plus ibrutinib, and a number of others.MRD negativity matters in MCL, as well as early response. However, a deep molecular CR translates into a much better outcome, both in terms of PFS and OS. This is regardless of the presentation, CR or partial response status, MIPI, age, and regimen. The question is, “Can we change a patient’s MRD-positive status to a negative status at the end of treatment?” The question remains whether or not high-dose therapy and transplant improves outcomes in patients. It may, but the data from the NORDIC regimen show that the outcomes prior to transplant are worse for patients who are MRD positive.

Can you speak to the data that supports the use of maintenance therapy?

The regimen looked at rituximab preemptively in patients who converted from MRD-negative to MRD-positive status; these patients received a standard dose of rituximab at 375 mg weekly for 4 weeks. Though the vast majority—94 patients—achieved MRD negativity, most of them relapsed. The biology of the disease shows resistance even in patients who experience extended duration of response. Although checkpoint inhibitors have not been obvious in MCL, combining other therapies like venetoclax and immunotherapy may be a way to address MRD status.The second thing that has been important in the last decade is the importance of maintenance therapy, specifically in elderly patients. In a large randomized trial in Europe, transplant-eligible patients older than 60 years received either R-CHOP or fludarabine, cyclophosphamide, and rituximab. A second randomization of interferon versus rituximab showed that the patients who had rituximab after R-CHOP did much better, both in terms of PFS and OS. The data also showed a 45% reduction in progression by using rituximab maintenance, even after high-dose therapy and transplant.

How has treatment changed for patients with relapsed/refractory disease?

Another question that is still unclear is the optimal duration of maintenance. Typically, maintenance treatment is given for 2 to 3 years. What is going to be an important question in the future, particularly in the context of pharmacoeconomics, is, “Can we customize and monitor maintenance, so that we don't have to treat patients indefinitely?”We have 5 approved agents overall—4 in the United States and 4 in Europe; these include ibrutinib, lenalidomide, acalabrutinib in the United States, and bortezomib. Temsirolimus (Torisel) is only approved in Europe. These drugs are allowing us to combine biological agents in the relapsed/refractory setting. Achieving a molecular CR in the relapsed/refractory setting will translate into a clinical benefit.

Although there are some differences in single-agent CR rates among these agents, we don't have a great idea of what the best sequence is. We know that the median OS in all of the phase II data is roughly around 20 to 22 months. Acalabrutinib seems promising, though the follow-up is not long enough. Lenalidomide and rituximab show impressive data as well as the combination of venetoclax and ibrutinib. The molecular CR in these combinations are starting to be so impressive that they may offer us a backbone in the relapsed/refractory setting that could potentially lead to continuing responses after stopping therapy. That's what we should be aiming for.