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.
In an interview during the 2018 OncLive®
State of the Science SummitTM
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.
OncLive: How has the field of MCL evolved?
: 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.
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.
What are some clinical trials examining combinations in MCL?
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.
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.
How have prognostic markers impacted treatment?
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.