EARLY ROUGH DRAFT (for advisors and the patient community)
The standard therapies for previously untreated indolent lymphoma are effective and induce long remissions - with our without maintenance, but there is a need to do better. The arrival of highly active targeted agents provide fresh new opportunities to improve on the standard approach. However, an expert consensus is needed regarding how to select patients for study (by eligibility), the choice of endpoints, and the length of follow up -- in part because of the controversy regarding the interpretation of the PRIMA study.*
* Cheson: Rituximab for Follicular Lymphoma: Maintaining an Open Mind
Because the median survival of patients with untreated indolent lymphoma is very long (8 to 14 years), Progression Free Survival (PFS) is the endpoint used to compare the efficacy of treatment protocols. It is, clearly, the only feasible way to evaluate new protocols for this indication.
PFS is a composite endpoint combining progression, relapse, or mortality as one event - measured from the beginning of therapy. An improvement in PFS can be a surrogate that predicts improved survival - depending on the indication (its natural history), the magnitude of the difference in PFS, and the offsetting symptoms, toxicities and risks. So, for example, an improvement in PFS of 4 months for the study protocol that is much more toxic than the comparator would not be persuasive.
It gets more complicated. Sometimes, as with PRIMA, the difference in PFS does not include a difference in survival of the elements in PFS. So for the PRIMA study, PFS is a misnomer. More accurately, the study showed a difference in time to relapse or progression favoring maintenance with no difference in mortality at 3, 4, and now 6 years.
... Absent a difference in overall survival in the two arms of a studyl, the tradeoffs require attention:
1) the impact of the extra treatment on quality of life (minor or substantial?), the cost of therapy (if copay will be required when the study results are applied),
2) the risk of having more therapy than is needed (important I feel), the added risks (small but not trivial), and possible impact of extra therapy on response to subsequent therapy (unknown).
That an update to PRIMA still has not shown a survival advantage for maintenance raises additional concern about the validity of PFS as a surrogate for improved survival in this setting.
* 6 Year Follow-Up Of The PRIMA Study of Rituximab Maintenance In previously untreated Follicular Lymphoma Pts following Frontline r-chemo http://bit.ly/1j082j2
We can look forward to a lively debate among experts on the interpretation of PRIMA at ASH this year!
That described (hopefully fairly) based on experience as a caregiver and support advocate, my sense is that a protocol that substantially improves PFS will be desirable to many patients independent of a survival benefit -- but only if the treatment adds minimal risk. So my personal take on PRIMA is that it's a toss up, a close call - and that patient preference will decide the issue - with the caveat that informing patients about the tradeoffs of maintenance Rituxan is challenging. (See Pros and Cons of Maintenance Rituxan)
As a research advocate, I feel that we need to select patients for study going forward based on individual risk factors - or to continue to use the PFS endpoint in similar ways but for select types of first line therapy.
For example, it seems that researchers can make better use of the PFS endpoint by:
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Testing novel agents with R-chemo followed by observation for all patients who have a current need to treat.
With this design an improved PFS at 3 years would show which induction therapy was superior without the offsetting/ confounding concerns that come with maintenance.
This design might be most appropriate for patients with lower-risk indolent lymphoma - such as by selecting only patients with PET negative results following induction therapy. The following report seems to support patient selection based on PET.
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ASH Paper: PET Compared With CT After Rituxan Induction Therapy In Follicular Lymphoma: National Lymphocare Study http://bit.ly/1f9TRuv
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Testing low toxic immune therapies in patients where there is no current need to trreat.
The rationale is based on idea that immune therapy will be more effective when the patients are treatment-naive and have minimum tumor burden, both of which can suppress immunity. The RESORT study can serve as a historical control in single arm screening studies to compare time to next treatment or time to next cytotoxic treatment. Initial therapy might not include Rituxan or could add agents that may enhance this active immunotherapy.
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Testing non-chemo agents (doublets/triplets) in patients with a current need to treat.
The rationale is based in part on a non-proven hope that these patients will then respond well to initial chemo-based protocols at relapse – roughly equivalent to treatment-naïve patients - having not been exposed yet to chemotherapy.
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Testing non-chemo agents (doublets/triplets) in patients with low tumor burden.
The rationale is based on encouraging report testing Rituxan monotherapy showing a delay to initial chemotherapy (RESORT). It is also based in part on a non-proven hope that these patients will then respond well to initial chemo-based protocols at relapse – roughly equivalent to treatment-naïve patients.
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Testing R-chemo protocols with novel maintenance protocols in patients with high-risk lymphoma.
Selecting patients with high-risk disease might be based on poor response to induction therapy (PET positive) or based on validated biomarkers, or on Minimum Residual Disease (MRD) status with PCR testing. The following reports seem to support the potential of MRD as a way to predict long term outcomes.
* ASH Paper, 2013: Minimal Residual Disease (MRD) Predicts PFS In Mantle Cell #Lymphoma: CALGB 50403 (Alliance) http://bit.ly/18Bzj6q See also: PAL - MRD in the News
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In summary, there's a need and new opportunities to evaluate novel upfront therapies for indolent lymphoma. Despite the controversy to date, PFS can be an informative endpoint for comparing novel upfront non-chemo induction therapies (AKA: doublets/triplets) with or without maintenance, and also novel upfront induction therapies -- without maintenance in patients with lower-risk disease.
PFS seems to have a better potential to be informative about long term outcomes when testing novel maintenance therapies in patients who have an inferior response to induction therapy - who are more likely to relapse quickly. Noting that a response-adapted approach would reduce the risk of over-treating patients who are likely to do well without maintenance treatment.
As the duration of treatment increases so does the importance of understanding the impact of the protocols on quality of life.
Cost is an increasing concern (particularly for out of pocket costs for oral drugs*) unless the study can demonstrate that the prolonged maintenance also improves survival - or that the more expensive protocol is focused on patients who are most likely to need and benefit from it. (Arguably, maintenance therapies may be as effective if used as needed as found for Rituxan in RESORT)
* NEJM 2013: Full Disclosure — Out-of-Pocket Costs as Side Effects
* The ASCO Post: IOM report on looming crisis in cancer care and research
Validating Minimal Residual Disease (MRD) status in a prospective study as a surrogate for survival would be a great advance over comparing time to relapse event for indolent lymphoma. Once validated, we might be able to compare protocols in months instead of years - and select patients appropriately for more sustained or novel therapeutic interventions.
See PAL - MRD in the News
What many patients want and desire is to be free of the disease and also from the burden and risks of treatments. Tailoring therapy to the needs of the patients will also help to reduce health care costs overall - projected to be an increasing problem.
I look forward to your feedback.
Karl Schwartz
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