By Peter Martin, MD
Most clinicians and researcher agree since mantle cell lymphoma (MCL) was first described 25 years ago patient outcomes have improved considerably. What remains unknown, however, is why outcomes are improving.
In an international, phase III clinical trial from the European MCL Network that was recently published in The Lancet, investigators demonstrated that progression-free survival could be doubled by the addition of rituximab, dexamethasone, cytarabine, cisplatin (R-DHAP) to standard chemotherapy and autologous stem cell transplantation. Whereas in the early 1990s, data suggested that patients might expect to live for 2-4 years, new findings demonstrated that patients can achieve decade long remissions. The strange thing about this remarkably positive study is that the overall survival was similar in both arms despite significant differences in virtually all other outcome measures. In fact, in the vast majority of MCL related phase III trials, despite great improvements in depth and duration of response, the overall survival of the experimental and control arms is the same.
While we celebrate the successes that each of these studies represents, important questions remain. Why are the patients in the control arms doing so well? Why are patients treated with the older, less effective therapies living as long as patients randomized to receive new therapies, and why are they living longer than patients receiving those therapies a couple decades ago?
Some of these questions can be answered by perception biases and advances in supportive care. For example, if patients in 2016 are being diagnosed with MCL earlier than they might have been diagnosed in the 1990s, they would appear to live longer, a phenomenon known as lead-time bias. Improvements in pathology may also lead to what is known as selection bias. Previously, patients with less aggressive variants of MCL were misdiagnosed as having other kinds of lymphoma, while a more representative sample is included in today’s studies. Similarly, perhaps people enrolled in recent clinical trials are healthier than they were in the past, another form of selection bias. Perhaps supportive care has improved, allowing people to live longer with lymphoma, or tolerate therapies that might have been considered overly aggressive in the past. If any or all of these hypotheses are true, hematologists around the world cannot claim credit for the perceived improvements.
It is clear that people with MCL are living longer with a higher quality of life. They have more options for treatment and these gains are due to clinical trials. In the past decade, the use of rituximab has expanded while bortezomib, temsirolimus, ibrutinib, and lenalidomide, all better tolerated than many historical options, have been approved. If this is true, it suggests that the path to continued improvements relies on the development of new, well-tolerated approaches, and it suggest that front-line therapies without curative potential must evolve to become less toxic so that subsequent lines of therapy remain feasible.