Martin and colleagues were among the first to investigate clinically indolent presentations of MCL, reporting that many of these patients could be initially monitored without immediate treatment. Indolent MCL has largely been defined retrospectively and is characterized by non-nodal presentations, mutated IGHV genes, very low MCL burdens, gastrointestinal-only presentations, a lack of high growth rates as measured by the Ki-67 proliferative index, and a lack of substantial inflammation. Symptomatic MCL is not considered indolent, and we advance treatment regardless of these features.

For some patients, expectant management may last for up to 10 years or longer, but this period is typically much shorter. Kumar et al observed a median duration of 23 months in their analysis. Retrospective data further suggest that patients who are treated after a period of initial observation do no worse than those who are treated immediately. 

Several lines of evidence suggest that when we diagnose indolent MCL, we are actually just catching it before it has become proliferative and aggressive. Researchers are thus investigating whether we can intervene to prolong the indolent phase and whether treatment, once required, needs to be as intense as is required in aggressive presentations. A recent observational study among those who deferred therapy for at least 90 days reported that patients who received intensive therapy did not experience longer overall survival than those who received less-intensive initial therapy; this was a retrospective analysis, with all of the caveats that go along with that.

The phase 2 IMCL-2015 study prospectively enrolled asymptomatic patients without high-risk histological features and treated them with frontline ibrutinib plus rituximab. Indolent MCL was defined using criteria that are all quite reasonable, and the treatment achieved undetectable minimal residual disease (MRD) in the peripheral blood in 87% of patients. At 2 years, researchers noted that 24 of 35 evaluable patients could discontinue ibrutinib because of undetectable MRD. At the last reported cutoff, 19 patients continued having undetectable MRD, with the maximum follow-up after planned discontinuation being 34 months. Only 1 clinical relapse has been detected after MRD conversion within those 24 patients. The only unexpected toxicity was 1 case of severe aplastic anemia.

Findings from the IMCL-2015 trial suggest, firstly, that we can safely intervene in indolent MCL. They also suggest that we might be able to extend the indolent phase of MCL using punctuated finite therapy, although we currently lack randomized comparative data. Disease progression was reported in 4 patients, 3 of whom had TP53 mutations at enrollment. I think that this is a different subset that will require a different approach, even if the presentation is indolent.