Category: Patient Education

Treating Mantle Cell Lymphoma: Why Are Patients Benefitting From New Therapies?

Picture1By 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.

The FDA Accelerated Approval Designation: A Primer

Picture1By Peter Martin, M.D.

As a response to the HIV/AIDS crisis of the 1980s the United States FDA developed guidelines for the Accelerated Approval designation in 1992. The purpose was to speed up the approval process and provide new treatments to the patients most in need. The program was an instant improvement, resulting in the approval of 80 drugs, including 29 cancer drugs, in the first decade, and was subsequently updated as part of the Food and Drug Administration Safety and Innovation Act in 2012. Under these guidelines the FDA can designate the Accelerated Approval label for new treatments that address a serious medical condition, and which are thought to offer a meaningful advantage over existing therapies.

The FDA’s criteria for making this designation is based on the scientific support for the measurement of surrogate or intermediate clinical endpoint in the treatment, and the likelihood it will predict a clinical benefit compared to available therapies in an area of unmet need. For example, in the past it may have been necessary for a new drug to prove a survival advantage compared to standard therapy in the context of a randomized phase III trial. It could take up to a decade to reach this benchmark for approval. Under the Accelerated Approval designation, a drug might be approved for an unmet need if it could demonstrate tumor shrinkage based on radiological imaging, which would likely be associated with a durable clinical benefit. Because the FDA requires a high degree of scientific support for the use of a surrogate endpoint, drugs that are approved under the Accelerated Approval program usually go on to receive full approval 3-4 years later on average, following the completion of confirmatory studies demonstrating clinical benefit.

This is not always the case, however, and some drugs that receive Accelerated Approval designation are subsequently withdrawn from the market when a confirmatory study fails to provide sufficient evidence of clinical benefit (e.g., bevacizumab for breast cancer). There is also the risk that a drug that had received accelerated approval will later demonstrate significant side effects during larger studies (e.g., this was part of the reason that gemtuzumab ozogamicin was withdrawn from the market in 2010). Other times, an application for accelerated approval might be denied, but the drug eventually receives full approval following completion of larger studies (e.g., TDM-1 for breast cancer). The definition of “unmet need” is another stumbling block to efficient drug development. Some developers might perceive an unmet need in settings where all available therapies have been exhausted, while the true need lies much earlier in the course of a disease where available therapies provide only limited benefit.

The Accelerated Approval program has provided access to dozens of drugs years earlier than they would otherwise have become available, improving the lives of countless patients with cancer and other conditions. However, the designation is not a panacea.  Physicians and patients should be aware of the evidence behind the designation of a given drug and should continue to follow the drug development process as new information comes to light.

Previous Entries in the Primer Series

The FDA Approval Process
The FDA Breakthrough Therapy Designation

Clinical Trial Participation May Improve Outcomes for Patients with Lymphoma

Picture1By Peter Martin, M.D.

Recently researchers from the Mayo Clinic presented data at the 2016 ASCO annual meeting suggesting that clinical trial participation might be associated with a survival benefit. The researchers used the Mayo Clinic Lymphoma Database to identify patients with relapsed Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), or relapsed mantle cell lymphoma (MCL), and compared the characteristics and outcomes of those enrolled in clinical trials versus those who were eligible, but not enrolled in clinical trials. Between January 2001 and December 2014, 340 patients with DLBCL, 159 with MCL, and 115 patients with HL were identified. Over this same period 47 unique Phase 1-3 trials led to the FDA approval of 17 treatments.

94 of 340 (27%) DLBCL, 63 of 159 (41%) MCL and 66 of 115 (57%) HL patients were enrolled on a clinical trial at some point during therapy, with 38% of patients enrolled in more than 1 study. Researchers found that the median survival of patients treated in a clinical trial was roughly twice as long as patients not treated on a clinical trial in all 3 lymphoma subtypes. There are several possible sources of bias or confounding that might explain the difference, despite the researchers’ efforts to control for these variables. Clearly, more research in this areas is indicated. Nonetheless, the magnitude of benefit was striking and should be reassuring to patients considering clinical trial participation.