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Robust data needed to settle maintenance therapy debate in hematologic malignancies
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The value of post-induction maintenance therapy in hematologic malignancies has gained renewed attention over the last few years.
For the most part, this resurgence of interest has been driven by two primary factors: the unacceptably high relapse rates in patients with these diseases, and the emergence of new, often well-tolerated and — in many cases — orally available agents.
The development of new, less-toxic treatments has shifted the cost–benefit equation and forces us to re-examine whether prolonged maintenance therapy after remission induction is a meaningful approach.
Maintenance gains acceptance
John Sweetenham
There is plenty of research activity in this area at the moment. A search of abstracts from the 2014 ASH Annual Meeting and Exposition showed 10 abstracts with maintenance therapy in the title. Upon closer inspection of the program, there were many other clinical studies that addressed the role of prolonged post-remission therapy, which is really maintenance therapy by another name.
Maintenance therapy certainly has gained wide acceptance and is now included in National Comprehensive Cancer Network (NCCN) guidelines for some patients with lymphoma and multiple myeloma. As our treatment paradigms and goals shift toward disease control rather than cure, at least for some of the indolent diseases, the concept of prolonged therapy has gained further traction. That said, there is still uncertainty about the benefit of maintenance therapy, and this has become the subject of “pro and con” debates at many meetings in the last couple of years.
During one recent week, I saw three patients with indolent lymphomas — two follicular and one mantle cell — on maintenance rituximab (Rituxan; Genentech, Biogen Idec), which I recommended about 6 months ago. All three are in remission and doing well. I made the decision to recommend maintenance after detailed discussion with these patients, explaining that — for the most part — the data regarding maintenance in this situation are based on improvements in PFS rather than OS.
I have taken this approach ever since the original presentation of the PRIMA study results for follicular lymphoma and a large European randomized trial for mantle cell lymphoma, which did show an overall survival benefit on subset analysis.
Data-driven decisions
I have been comfortable with this decision until recently. Now, I’m not so sure. The seeds of doubt were planted after I read an account of a debate between two eminent lymphoma specialists who concluded that the decision to use maintenance rituximab is a “philosophical” one based on whether you believe PFS rather than OS is a meaningful endpoint. I totally disagree.
The decision to use, or not use, maintenance should be driven by data that show benefit for patients. We don’t have those data available to us because the studies so far have been inconclusive, have often had less-than-optimal designs, and have not focused on the critical issue of patient benefit and effectiveness vs. efficacy.
There are emerging — and, in some cases — relatively mature data now regarding the use of maintenance rituximab in follicular lymphoma. The most notable of these are a randomized trial from the Swiss SAKK trials group, the Eastern Cooperative Oncology Group (ECOG) RESORT trial, a randomized trial from the UK National Cancer Research Network and the PRIMA trial cited above.
All of these studies, which include patients of varying risk groups and varying primary therapies, show the same basic result. Maintenance therapy with rituximab improves PFS but has no effect on OS. The PFS advantage was enough to establish rituximab maintenance as a standard for those patients with poor-risk disease who had initially received R-CHOP chemotherapy.
As new front-line therapies — notably bendamustine (Treanda, Cephalon) and rituximab (B-R) — have been adopted, many oncologists have given maintenance therapy after this regimen, assuming that a similar benefit is likely. I have done this, too. I have explained to my patients at great length that the use or rituximab maintenance after B-R has not been evaluated in a completed clinical trial but such a benefit seems likely and the downside is minimal.
I have felt comforted by the fact that the NCCN guidelines have validated this approach. Furthermore, there are two major studies — one from the StiL Group in Germany, reported at ASH 2014, and the ECOG 2408 trial — which are testing this approach prospectively. Can we expect definitive answers from these and other studies? Probably not.
The problem in the studies cited above, and for many others that address maintenance questions, is the selection of meaningful endpoints.
Nobody would argue that PFS is a meaningful endpoint inasmuch as it is a measure of the efficacy of therapy. For diseases such as follicular lymphoma, it is very difficult to demonstrate OS benefit in a trial setting because these diseases typically respond to multiple lines of therapy over many years. The effect of an individual line of treatment on OS is likely to be obscured by subsequent treatments. The PFS benefit is typically lost in translation to OS. In a situation where the only efficacy signal is likely to be a PFS benefit, we need to look for other endpoints to determine patient benefit. It’s not a philosophical debate, but rather a question of asking the right questions in a trial context.
Similar uncertainties exist for other hematologic malignancies. Results for maintenance approaches in mantle cell lymphoma and multiple myeloma have shown similar trends to those in follicular lymphoma, as PFS benefits are almost always seen. Effects on OS are less consistent, although have been seen variably in some studies in these diseases.
Meaningful data needed
A new study presented at ASH has extended this debate into the management of Hodgkin’s lymphoma. The AETHERA study addressed the use of maintenance therapy with the antibody–drug conjugate brentuximab vedotin (Adcetris, Seattle Genetics) following high-dose therapy and autologous stem cell transplantation in poor-risk patients with relapsed or refractory Hodgkin’s lymphoma.
I should point out that I was an investigator on this trial and have received funding from the sponsor. This placebo-controlled study reached a similar conclusion to many other maintenance studies — an improvement in PFS with no benefit in OS. Will this approach now get widespread use? Quite likely. The rituximab experience certainly sets a precedent for this, but we will not have answers to many of the important questions regarding the effectiveness of this therapy in this setting.
There are concerns common to all of the new maintenance strategies being adopted in lymphoma and myeloma at the moment. First and foremost, the efficacy benefits — with notable exceptions — largely are restricted to PFS. In view of this, toxicity and quality of life should become major determinants of patient benefit.
Accumulating data suggest that many of the drugs commonly used in the maintenance setting at the moment — such as rituximab, brentuximab vedotin, lenalidomide (Revlimid, Celgene) and bortezomib (Velcade, Millennium) — have significant and occasionally life-threatening toxicity. Robust quality-of-life endpoints have been incorporated into few of the completed or on-going studies (ECOG 2408 is a notable exception).
This is a therapeutic area where comparative-effectiveness research studies are essential to guide us in selecting treatment with true patient benefit. Cost and cost-effectiveness also are major, largely uninvestigated areas in this context. Virtually all of the drugs used in the maintenance setting are expensive. Many of the new, orally available targeted agents may have a role in prolonging or deepening remission. Their long-term use is already being evaluated in prospective studies and, if these studies are positive, the increased financial burden on our health system will be huge. In the absence of robust effectiveness and cost data, justifying the prolonged use of these agents will be an uphill task.
The question of whether we can afford to use prolonged post-remission therapy will depend upon multiple factors, not least of which is the demonstrated cost-effectiveness of the approach. The question of whether we can afford not to use maintenance likewise will require meaningful effectiveness data. Hopefully the next generation of prospective trials will provide some answers and the philosophical debate can move on to other subjects.
References:
Ghielmini M. Blood. 2004;103:4416-4423.
Kahl BS. J Clin Oncol. 2014;32:3096-3102.
Moskowitz CH. Abstract #673. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.
Rummel MJ. Abstract #623. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.
Salles G. Lancet. 2011;377:42-51.
Taverna CJ. Abstract #508. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2013; New Orleans.
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John Sweetenham, MD, FRCP, FACP, is HemOnc Today’s Chief Medical Editor, Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at the University of Utah. He can be reached at john.sweetenham@hci.utah.edu.
Disclosure: Sweetenham reports honoraria from and a speakers’ bureau role with Seattle Genetics.