Expert Looks to Genetic Testing for Next Leap in MCL

Grzegorz S. Nowakowski, MD, discusses ongoing efforts to determine prognostic factors of mantle cell lymphoma and what other challenges lie ahead.

Researchers are conducting gene expression profiling studies to explore potential prognostic factors of developing mantle cell lymphoma (MCL), a challenging issue oncologists are currently facing, according to Grzegorz S. Nowakowski, MD.Results of a study presented at the 2016 ASCO Annual Meeting demonstrated early promise with the NanoString platform, using the Affymetrix U133 microarray gene expression with the MCL55 assay, to measure the proliferation signature in RNA that is derived from formalin-fixed paraffin-embedded tissue.

Results showed that the novel MCL55 assay, which contains a 16-gene proliferation signature, yielded gene expression of sufficient quality to assign a score and risk group in 98% of the archival paraffin-embedded tissue from the overall 110 patients, assigning patients to high-, intermediate-, and low-risk groups. The median overall survival (OS) differed among the high-, intermediate-, and low-risk groups at 1.1, 2.6, and 8.6 years, respectively (P <.001).

In an intention-to-treat population of 59 of these patients with an autologous stem cell transplant to consolidate response, the median OS differed again across the high-, intermediate-, and low-risk groups at 1.4 years, 5.9 years, and not reached, respectively (P <.001). The findings suggest that the MCL55 assay for paraffin-embedded tissue can use the proliferation signature to define groups of patients with MCL with different OS.

In an interview during the 2017 OncLive® State of the Science Summit on Hematologic Malignancies, Nowakowski, an assistant professor of Medicine at Mayo Clinic, discussed the current work being conducted to determine prognostic factors of MCL and what other challenges still lie ahead.

OncLive: At this point in time, what are some of the key factors involved in choosing a first-line, second-line, and beyond treatment for patients with MCL?

Nowakowski: One factor which I am not taking into consideration, but I would like to, is biological heterogeneity of the disease. We know that some of the patients have relatively indolent disease progressing over the years, while other patients have rapidly progressive disease. The vast majority of patients come right in the middle. It would be nice to have a biologic prognostic factor to predict the clinical course of those patients, because this would help us in selecting the most appropriate therapy for them.

There is such an attempt being made: the NanoString platform [with the MCL55 assay] which uses gene expression profiling from paraffin-embedded tissue. There was something presented at the 2016 ASCO Annual Meeting, which showed the specific signatures that might be predicting the outcome of these patients. Hopefully, at some point, we will have it in the clinic and that is what I would really like to use.

What I use right now is patient performance status and age. Age is an important factor; traditionally younger patients who are fit are treated with more aggressive chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation. In elderly patients, it comes down to less intensive options. Bendamustine-rituximab is frequently employed. It has shown better progression-free survival than therapy with R-CHOP in a randomized study; it is well tolerated and is very commonly used in this setting.

A nonchemotherapy-based backbone with lenalidomide and rituximab is sometimes used, as well. Sometimes patients have a strong preference whether they want chemotherapy or a “pill-like” option; that is also taken into account with dose decisions.

What we really need though, over time, [are treatment decisions] based on biological prognostic factors, rather than just age and performance status. It would be interesting to compare those nonchemotherapy approaches against more of an aggressive approach used in younger patients. It may be that, in the future, combinations of targeted agents are much less toxic than intensive chemotherapy regimens with transplant, and could be as effective—if not more—than traditional cytotoxic intensive chemotherapy.

Where is the field at currently with biomarker development?

For a long time, we have been using perforation in the index of Ki-67, which is prognostic in this setting. However…right now, there is no evidence that high Ki-67 should necessarily guide the next selection of therapy. There are various studies addressing these issues.

The promising approach is the gene expression profiling of the NanoString platform, which again is looking at the expression of multiple genes that can be in the paraffin-embedded tissue. This is clinically important because fresh issue is sometimes difficult to obtain, and it provides a stratification platform for those patients. The initial results are very interesting and now we hope to see more studies in this area. The type of lymphoma on this platform that was found to be applied successfully in the clinical trial is in diffuse large B-cell lymphoma. Hopefully, we will see the same progress in MCL.

What are the common risk factors of developing MCL?

Just like with other lymphomas, the factors are poorly understood, so we don’t know the risk factors for development of MCL. This is a disease of the elderly, so we see it more commonly in elder patients and it is also more common in males.

Unfortunately, we know very little about the risk factors. This is in contrast to the biology of MCL, where we know exactly what is causing the cells to expand and proliferate. There is a translocation that involves the immunoglobulin gene, and cyclin D1. From a biological level, we know exactly what happens to the genes in MCL that drives this lymphoma. However, we do not understand the precipitating factor as to why people develop this event.

The perception, though, is that it is quite a random event. Normal lymphocytes and B cells are being developed to fight infections, and occasional errors in the genetic machinery of the cells can happen. It is a completely random event and it happens all the time in random cells—even as we are sitting here. If you’re unlucky enough in this random process, 2 very critical genes can fuse into MCL and then it drives the development of this lymphoma.

Of all the different challenges in MCL, what should researchers tackle first?

The priority would be biologic stratification of the risk in MCL and better understanding of the heterogeneity that we see in the clinic. That is a priority for this biology. We need to know the drivers and we know some of the signaling pathways, but further expansion of this knowledge of signaling pathways can introduce us to new targeted agents to the treatment landscape of MCL. That is another important area of research.

In terms of clinical development, I would like to see some merger of approach in treatment of the patients. We give younger patients a more aggressive treatment followed by transplant, while older patients have a more milder treatment followed by rituximab maintenance or observation. What we need are studies comparing those approaches, because it is possible that the results in younger patients with some of those less-intensive combinations could be very good as well. That is something very much needed in the field.

Overall, what are your thoughts on how the field is changing?

This is a very exciting time in lymphoma and cancer in general, with many new agents being very rapidly developed. In fact, what we are focusing on now are combinations of these agents, how to best introduce them to patients, and in what sequence. Participation in clinical trials of those agents is critical, and we encourage providers and patients to participate in them. You can see that people live longer if they do participate in clinical trials. In fact, also at the 2016 ASCO Annual Meeting, we presented the abstract which showed that patients who elected to participate in a clinical trial versus standard therapy did survive longer. This is partially driven by the fact that we have access to these new agents which we didn’t have in the past. This is a time of great excitement in oncology.

Scott DW, Abrisqueta P, Wright G, et al. Prognostic significance of the proliferation signature in mantle cell lymphoma measured using digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2016;34 (suppl; abstr 7510).