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Patients Against Lymphoma

 

Advocacy >  Perspectives on

Pathways to Progress Against Lymphoma

Looking back on 2013 - a very good year

Last update: 01/19/2014

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Within is PAL’s compilation of the promising developments in the fight against lymphoma in the year 2013 – and there were many.  In short, we have an abundance of new classes of agents that have the potential to improve outcomes dramatically.

PAL will continue to develop resources that advance the routine and informed consideration of clinical trials which now, more than ever, can compare favorably to the standard way of treating many types of lymphoma.  

The ongoing challenge is to identify trials that match up well with the patient’s unique clinical circumstance and needs and to inform patients and community physicians about them.  To assist, we’ve created many new topic pages describing the innovations with links to related clinical trials, outcome reports, and our picks of trials of interest.

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The immediate outlook for patients with relapsed CLL and MCL has improved substantially because of the development, testing, and recent approval of targeted therapies -- progress made possible by outstanding basic science and rational drug design.

PAL topic: Agents that target disease pathways: http://www.lymphomation.org/agents.htm    

For CLL, impressive outcomes in trials have led or will lead to FDA approvals for ibrutinib (Imbruvica), idelalisib, obinituzumab (Gazvya), and CD19 directed t-cell therapy.  For MCL, a very effective and well- tolerate oral drug, Imbruvica, was rapidly approved for anyone with relapsed disease.

For the indolent b-cell lymphomas such as follicular and MALT (close cousins to CLL), the opportunities for progress are numerous.  However, choosing an informative study design for testing initial therapies is challenging due to the many years of follow up needed to compare them.

... Long follow up is needed because so many patients do well with the standard approach and because either approach may be as effective in respect to survival.  For example, in the PRIMA study, 49% of the observed patients did not relapse at 6 years, and maintenance and observation were equally good in terms of overall survival. 

... The PRIMA results at six years call into the question the value of the PFS endpoint in trial designs that test treatments against previously untreated, advanced, indolent lymphoma, as if it is one disease.

Moving forward, a response-adapted study design (based on PET or minimal residual disease tests following induction therapy) could spare many participants in trials from the risks and costs of additional treatment.  Selecting patients with the highest risk for relapse could also lead to faster comparisons of promising new protocols in cohorts of patients with the highest risk of relapse.

The potential to benefit from novel agents in the relapse setting are too numerous to discuss in detail here – even if you limit the discussion to combinations with Rituxan, such as Rituxan with ABT199, or with a PD1/L antibody, or with Idelalisib ,,, and so on.  

The future of radioimmunotherapy remains a concern – this time due to a poor showing when compared to Rituxan maintenance following Rituxan-based chemo.  Here the issue could be the study design: is it a fair test to compare Zevalin to Rituxan immediately after Rituxan-based chemo – two agents that compete for the same cd20 molecule?

For the most common aggressive lymphoma, DLBCL, surveillance by the patient (reporting symptoms) proved to be better than regularly scheduled imaging with CT scans, which should help to cut costs, reduce exposure to ionizing radiation, and scan anxiety in patients who have completed successful therapy.   Further, it was reported at ASH that testing for minimal residual disease with a simple blood test can detect relapse sooner than imaging.

Also for DLBCL we can expect that the approach to investigational therapy will be based on more reliable and affordable tests for the cell of origin, needed because at a molecular level these are distinct diseases that do not respond as well to regular CHOP-R therapy:   1) Germinal Center B-Cell-like (GCB) having a more favorable outcome to standard treatment, and 2) Activated B-cell like (ABC) having a higher risk of relapse. 

Determining the cell type of DLBCL will also guide the selection of investigational targeted agents to combine with regular therapy – such as lenalidomide and ibrutinib for the ABC type – to potentially increase the cure rate. 

There are also increasing opportunities to investigate the molecular and epigenetic biology of aggressive lymphoma to identify pathways of treatment resistance that can be targeted by therapy.  For example, epigenetic priming therapy (5-Azacytidine) has shown very promising results so far – an approach that might be effective across all subtypes of DLBCL in the first-line setting.    

Yet another encouraging report shows that an antibody-drug conjugate, developed and approved for Hodgkin Lymphoma, is very active in relapsed DLBCL – even when the lymphoma cells do not express high amounts of CD30, the molecule this drug binds to.

Further, testing for minimal residual disease following regular therapy is a potential new way to identify patients who need consolidation therapy in order to achieve a cure.

For Hodgkin lymphoma, the big news was the rapid approval of Adcetris – a potent antibody-drug conjugate targeting cd30 in the relapse setting.  The focus of continuing research for the first-line treatment of HL has been on how to maintain and improve the very high cure rate while reducing the toxicity that can lead to late adverse events, such as second malignancies, in this younger population.  In studies, treatments are escalated or minimized based on the response to induction therapy using PET imaging and so-called response-adapted protocols.

For the T-cell lymphomas, we have also seen progress in basic science and the development of related targeted agents; however, the path to progress is hampered by the very low incidence of the disease, which makes it challenging to do sufficiently powered studies.  The low incidence also decreases the financial incentive to advance new drugs for t-cell lymphoma among commercial sponsors.  Here, the key to progress will be to increase community center participation in cooperative group research in order to increase the opportunities for patients with t-cell lymphoma to participate in the studies.

For 2013, the headline events have been the clinical validation of targets in the b-cell pathway (ibrutinib and Idelalisib), and the emergence of a potent new immunotherapy: engineered t-cell therapy (CAR 19) that has curative potential, even in the chemotherapy-resistant setting for all b-cell lymphomas – indolent or aggressive.  

And there are truly additional reasons for enthusiasm and hope on other fronts as summarized below.

 Summary of highlights based on the agent or test,
       
with briefly described hopes and expectations:

Minimal Residual Disease status with PCR … with a simple blood test

Our hope for this test is based on new technologies and recent clinical reports: that PCR testing for tumor-specific DNA fragments in blood or marrow can accelerate the evaluation of new therapies for indolent and aggressive lymphoma (in months instead of years); and ultimately guide when to start, end, or change treatment in clinical practice.  Prospective validation is the key.  This would rapidly accelerate progress against lymphoma as a similar validated test (viral load) did for HIV treatments.

PAL topic: http://www.lymphomation.org/MRD.htm

Engineered T-cells: potent killer t-cells engineered to target tumors via the Chimeric Antigen Receptors (CARs)

Based on clinical reports in advanced / relapsed CLL and DLBCL, we can expect that the study of T-cell CARs targeting CD19 will expand to more types of lymphoma -- and ways to make this approach (based on modifications to our own immune cells) safer and more effective.  Importantly, there are two commercial sponsors for this technology, which are needed to expedite testing, manufacturing, and marketing should it be approved. 

CARs appear to have the potential to cure indolent and aggressive b-cell lymphomas even when advanced and refractory to multiple treatments.

PAL topic: http://www.lymphomation.org/programing-t-cells.htm

Targeting immune checkpoint blockade - with PD1/L antibodies, to activate immune rejection of tumor cells formerly blocked by tumor interactions with t-cells

Based on clinical outcomes in other cancers (but only one encouraging report in lymphoma so far), my hope is that this approach will enhance standard therapy, making it much more effective and with lower risk, and that it helps to sustain the remissions achieved with regular treatment, as we had hoped for in the case of vaccines.

PAL topic: http://www.lymphomation.org/-news-immune-therapy.htm

Inhibiting the inhibitors of cell death (apoptosis) – by targeting the BCL-2 pathway:

Based on a clinical report in double-treatment-refractory CLL, we can anticipate that ABT-199 will prove to be an effective new way to treat CLL and related b-cell lymphomas,  enhancing the efficacy of standard therapy.

PAL topic: http://www.lymphomation.org/apoptosis.htm

Oral drugs, with low toxicity, that effectively target the b-cell receptor pathway – already showing clinical benefit in the relapse setting, and winning FDA approval.

One big advantage lymphoma research has over research in other types of cancer is that the majority of lymphomas arise from mature b-cells that can be drugged with limited off-target effects – limiting or avoiding harm to precursor b-cells and allowing for restoration of immune function.

PAL topic: http://www.lymphomation.org/btk-inhibitors.htm

PAL topic: http://www.lymphomation.org/PI-3-kinases.htm

Exploiting epigenetic pathways – how malignant cells turn genes on or off to promote tumor cell survival and growth, and how drugs can target these pathways

Insights in this area have led to the approval of new drugs for t-cell lymphoma, such as Vorinostat (HDAC inhibitors) and a promising new approach to treating DLBCL by priming with a DNA methylation agent, 5-Azacytidine, thought to increase the sensitivity of the cells to standard treatments. 

PAL topic: http://www.lymphomation.org/HDACs.htm

Challenges tend to follow opportunities, such as the need:

To increase the rate of participation in trials due to the number of agents that require further testing to identify best use;

To increase, not slash, the budget for the National Cancer Institute and the cooperative group system;

To reign in the costs of new drugs and do away with copayment for oral cancer drugs without doing harm to the financial incentive to innovate. 

Requiring a co-payment for oral cancer drugs is unethical in our view, because it creates a disparity: excluding patients with lower income (many seniors) from access to very effective new drugs. Already, we have heard from investigators that patients have declined ibrutinib because of the “financial toxicity.”  

In closing, we give thanks to those who have supported our mission and look forward with optimism in 2014. As active participants in the Alliance and NCI Steering committee, patients have increasing opportunities to inform researchers about our priorities for publicly funded, cooperative group research.  Please feel free to provide comments and suggestions at any time.

All the best,

 

Karl Schwartz
President, Patients Against Lymphoma

 
Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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