Q: What are the most useful and relevant biomarkers and prognostic factors that help inform treatment decisions in patients with MCL?

The presence of 17p deletions and/or TP53 mutations suggests that the patient is not going to respond as well to traditional cytotoxic chemotherapy as those without these factors. If such markers are found in the frontline setting, the question is: What do you do? None of the targeted agents have frontline indications at this point, and there are no data telling us how well they work as frontline therapy in high-risk patients. Most of us will offer cytotoxic chemotherapy but will be very candid with our patients by telling them that we are not expecting it to work extremely well. At the same time, you might start to consider your second-line treatment options, such as targeted therapies.

It is particularly important to look for the TP53 mutation in younger patients at diagnosis. If present, it tells you that you need to start rethinking your strategy, and it is a real dilemma. Young patients with MCL would typically receive intensive chemotherapy with high-dose cytarabine and stem cell transplant; however, the results of this strategy are unsatisfactory if they have TP53 mutations. It makes no sense to pursue an ineffective therapy. I would try to find a targeted agent, perhaps as part of a clinical trial in the frontline setting, such as lenalidomide or a Bruton tyrosine kinase inhibitor. Allogeneic stem cell transplantation is an option at first remission or at the time of relapse. I would start looking for suitable donors while in the process of getting that patient into remission so that this approach may be considered.

The Mantle Cell Lymphoma International Prognostic Index (MIPI) score is useful in certain scenarios, but it rarely influences my decision making; it might help me, for instance, when deciding whether intensive chemotherapy is advisable in an older patient. The Ki-67 proliferation index is an important prognostic marker that has been very reproducible in many studies. A proliferation rate of more than 30% predicts worse outcomes and a proliferation rate below 10% predicts better outcomes. The MCL35 gene expression proliferation assay can be thought of as a slightly better (ie, more accurate and reliable) version of the Ki-67 assay and offers a similar type of risk group stratification.

The MIPI has proven useful for assessing the relative risk of progression. This index is based on easily obtained clinical parameters, including the patient’s age, ECOG Performance Status, and lactate dehydrogenase. More recently, we have added the Ki-67 marker, which identifies proliferating cells and is associated with more aggressive disease.

The identification of SOX11 is important because patients with MCL lacking mutations in SOX11 appear to have a more indolent clinical course than patients who have MCL with SOX11 mutations. As such, knowledge of the mutation status of SOX11 could impact treatment decisions. IGHV sequencing is not typically done, but it may be useful for identifying clinically indolent disease, which generally expresses mutated IGHV. I agree that it is important test for TP53 mutations. I would not give chemotherapy to a patient who has MCL with inactivating mutations in TP53 because chemotherapy is not likely to benefit such individuals.

TRAIL receptor 2, myc, and RAN GTP-binding nuclear protein are investigational prognostic markers that may associate with genetic changes that act as subclonal drivers of MCL, and their expression can be measured in fixed specimens by quantitative reverse transcription polymerase chain reaction. It would advance the field if we could identify the genetic features of subclones of MCL in any one patient and examine their relative growth rates or relative responses to therapy. This is challenging, however, as the neoplastic cells of patients with MCL often are not widely distributed in contrast to the neoplastic cells of patients with chronic lymphocytic leukemia, in which there is recirculation of neoplastic cells between blood, bone marrow, and lymphoid compartments. Nonetheless, identifying the genetic changes and mechanisms responsible for the development of the disease and the features associated with disease progression or response/resistance to therapy will be critical for developing novel and effective treatments for patients with MCL.

I calculate the MIPI for every patient, although other factors are likely more helpful in selecting therapies. The MIPI score can be useful for a community physician who may be uncomfortable treating a patient with a high MIPI score. In this case, the MIPI score can serve as a type of relative comparator and may help to steer the patient toward or away from aggressive treatment. We have used the Ki-67 index to help with the prognosis of these patients for a long time, and, more recently, some of the molecular markers, including the TP53 and the SOX11 expression. When used in combination, these factors help us to determine the prognosis of the patient and to identify the best treatment options. If patients have a high Ki-67 index or a TP53 mutation, they will have more aggressive disease and may benefit from more aggressive treatment or participation in clinical trials. Many oncology centers offer a standard MCL panel that includes TP53 and SOX11 testing. I check these markers in every individual with MCL, as they are also helpful when discussing prognosis and treatment options with patients.