Musings on Progress Against Lymphoma:
2011 Highlights, Looking ahead – our Wish listGreetings,
I am writing to wish everyone a happy and enriching New Year and to reflect on what has been achieved in the fight against lymphomas and the work that remains to be done – from my perspective at least.
First it’s important to note that optimism and hope remain warranted, because there are so many ways to effectively target lymphoma cells, internally but also on the cell-surface – most famously by targeting cd20.
Further, it has proven feasible to reprogram the cells with epigenetic therapy, such as with Romidepsin.
It also appears feasible to treat lymphomas by targeting bystander cells in the so-called microenvironment, the non-malignant cells which appear to aid, promote, and protect the malignant lymphocytes. (For example, Lenalidomide is thought to be active in this way)
… So, unlike the tried and true agents used to treat lymphoma, there are no shortages of plausible and promising strategies in development in clinical trials!
For new patients it’s important to note that lymphomas, being blood cell cancers, are highly sensitive to standard therapies … chemotherapy and radiotherapy … and it has proven to be sensitive to biologic and targeted agents.
Perhaps we should not be in such a rush to replace the tried and true, it might be in our best interest to recognize their strengths, while finding ways to reduce their toxicities and enhance their activity to achieve more cures?
Our personal history with lymphoma began in 1996, in the pre-Rituxan era. There were but two choices at the time, chemotherapy or radiation for the treatment of the “incurable” indolent lymphomas. We owe a personal debt to the innovators of the new agents that were approved after Joanne was diagnosed, but equally to the brave individuals who participated in the trials! Joanne did not get much benefit from Rituxan, but using radioimmunotherapy (RIT) soon after high-dose Cytoxan chemotherapy dramatically changed the clinical course of her aggressively behaving indolent lymphoma, which prior to that sequential therapy relapsed quickly after each treatment – many, many times over seven years.
So the approval of new drugs is PART of what it takes to make progress. We need to also learn how to BEST USE these drugs by doing Comparative Effectiveness Research (CER) – where one approach is compared to another in a randomized controlled study.
For example, this year at ASH an NCI-funded study called RESORT demonstrated in a convincing way that giving Rituxan as-needed is just as good as giving it automatically on a regular schedule … as maintenance. Notably, in this tax-payer-funded study, the as-needed approach also decreased how much Rituxan was given, nearly 4-fold:
Copying:
“The mean number of Rituxan doses/pt (including the 4 induction doses) was
15.8 (range 5- 31) for Maintenance Rituxan and
4.5 (range 4-16) for Rituxan Retreatment (as needed)”The findings of this CER study (about 12 years after the approval of the drug!) should substantially reduce the cost of health care (an increasing concern in our times) while decreasing the amount of treatment we are exposed to in order to achieve the same result. Importantly, using less Rituxan may also reduce the incidence of infections, which can impair our quality of life of course … and is also expensive to treat.
Meanwhile, the place of radioimmunotherapy (RIT) remains uncertain. The low use of RIT persists, in my opinion, because there’s insufficient data from head-to-head studies against the standards of care for the indolent lymphomas (CER missing in action). The lower-than-anticipated study of RIT in turn influenced by the low usage. After all, why study a drug that hasn’t been a commercial success?
– a “Catch-22.”
However, there have been signals of renewed interest in RIT-based clinical research, which might increase further IF*, with longer follow-up, CHOP-Bexxar proves superior to CHOP-R as the first therapy for advanced follicular lymphoma. Although I wonder if this will prove to be the best possible use of RIT – if less induction chemo might often be better than more – prior to RIT, given the immune-mediated mechanism of RIT?
Meanwhile a gaggle of new agents are showing promise against lymphomas in early-phase clinical trials.
Good news …yes, but this is also a “poverty of riches,” because each new agent must compete for the same participants in a very small pool of patients who participate in trials – approximately 5%–the reason for PAL’s mission to help to advance the routine and informed consideration of clinical trials.
2011 Highlights
- The CALGB study comparing R-CHOP to dose-adjusted R-EPOCH is finally close to full accrual. It may change the standard of care for DLBCL, and help to guide therapy by molecular characteristics of the disease – by genetic profiling.
- The RESORT study shows that giving Rituxan as-needed is as good as giving it on a maintenance schedule – for folks with untreated FL with low tumor burden.
- Brentuximab vedotin (BV) is proven to be effective against relapsed Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL)
Will we see new versions of conjugated antibody targeting other receptors?Can we substitute BV for one or more of the chemo agents in the first-line treatment of Hodgkin’s, such as the toxic Bleomycin?- Rituxan maintenance improves the survival of older patients with MCL compared to interferon.
- Bendamustine-R is supplanting R-CHOP as initial primary therapy for the indolent lymphomas and perhaps also MCL. Is it better than FCR in CLL/SLL … that question is being evaluated in trials?
- The continued advances in understanding the biology and genetics of CLL/SLL
- The dramatic potency of engineered t-cell therapy demonstrated in a few patients with very advanced and refractory CLL/SLL – which is also being explored in other advanced lymphomasWill CAR adoptive immunotherapy be the “home run” technology we have been waiting for?
- The encouraging activity and safety profiles for the new targeted agentsWill these agents lead to cures when used with standard therapies? Will they help to manage the indolent lymphomas better as needed?
- The encouraging durable responses for fractionated cd22 radioimmunotherapy.A therapy that effectively targets CD22 target could be urgently needed due to the wide use of cd20 antibody – Rituxan, which cannot be used indefinitely
- The proven activity of HDAC inhibitors (epigenetic therapy) in t-cell lymphomasWill these agents lead to cures when used with standard therapies first line? Will they help to manage the indolent lymphomas better as needed?
Looking Ahead – My Wish List:
- That patients are routinely offered an opportunity to help evaluate new therapies that have shown a potential to improve on standard therapies or work when standard therapies do not, or to cure the indolent lymphoma, or to make the curative therapies safer in the long term without compromising efficacy
- To rapidly evaluate newly approved targeted agents, such as brentuximab vedotin, for the treatment of relapsed lymphoma and to evaluate their use in first line therapy.And that the participants also benefit by participating in the trials!
- To rapidly evaluate the activity and safety of other targeted agents – and there are many(CAL101, and the btk-inhibitor appearing to have the most encouraging efficacy and safety of the lot so far)And that the participants also benefit by participating in such trials!
- To identify biomarkers (factors in the blood or tumor sample) that can predict the clinical course of a lymphoma in order to guide how aggressive one needs to be with therapy and to guide when to treat.So we don’t over-treat or under-treat, or treat unnecessarily or too soon.And that the researchers collaborate and develop the standardized procedures that are needed to do this type of research – and that patients participate in the studies and contribute the tissue!
- To identify biomarkers that predict response to specific treatments in order to avoid therapies that don’t work – to limit unproductive toxicities, which can narrow the range of future optionsAnd that the researchers collaborate and develop the standardized procedures that are needed to do this type of research – and that patients contribute the tissue!
- To find therapies that are effective when standard therapies are not – or in patients who cannot tolerate standard therapiesFor example, to rapidly continue to evaluate the engineered t-cell therapy (CAR-19) and that strategies to “turn off” the t-cells when the remission is achieved also proves feasible and reliableOr to manage lymphomas with less toxic targeted therapies as needed.
- To evaluate again new adaptive immunotherapy protocols (vaccines and vaccine adjuvants) as consolidation therapies – to help prevent relapse or delay the need for more toxic therapies.Regrettably the idiotype vaccines have not been proven effective as tested (no matter the hype being distributed by the one surviving sponsor – Biovest). Patients continue to have a strong interest in this approach – one that supports instead of impairing immunity – and will likely participate in trials, which should not ask of them to use sub-standard induction therapies in order to test if they work! Perhaps low dose Lenalidomide vs. Lenalidomide (L) + vaccine in untreated indolent who do not need treatment? Just a thought, but L is not without its issues and risks.
- To rapidly find new ways to assess response to standard and investigational treatment (by imaging or blood makers) to avoid over- or under-treating patientsFor example, if biomarkers for minimal residual disease are discovered AND validated, the test could be used to rapidly compare the efficacy of new agents without having to wait for relapse events – the time to progression and related endpoints that require years to measure when evaluating treatments for the indolent lymphomas. (Noting that it was the validation of viral load as a surrogate for efficacy in HIV studies that contributed to the rapid advances made against that disease.)
- That patients and caregivers ask good questions – including which trials to participate in – the informed questions that are needed to make the very best doctors even better.
- That patient advocates continue to participate in the design of clinical trials to help make trials that prove to be “good science and good medicine” – that will quickly lead to full enrollment and provide reliable answers to the clinical questions, which makes progress possible.
Yours in the fight,
Karl Schwartz
President, Patients Against Lymphoma
Lymphomation.org
Evidence-based information on lymphoma, independent of health industry funding