Progress Against Lymphoma – 2012 PAL report

December 31st, 2012

Part 1 of 2:
Patients Against Lymphoma: 2012 overview of new classes of drugs on the Critical Path to approval
and our role in research advocacy



An important part of our mission is to partner with researchers in the fight against lymphoma  … such as, to provide patient perspectives on clinical trial design, raise awareness about trials, and to advance the routine and informed consideration of trials by patients and treating oncologists.

Fostering well-informed consent and awareness of trials also helps patients to understand the benefits and the limitations of standard therapies – helping patients to become more informed partners in their care.

We recognize that participation in a trial is not always appropriate and that enrolling in a study is a difficult decision that must be guided by trained physicians with first-hand information about the patient’s clinical circumstances.

… However, we believe that there are at least 7 clinical circumstances where participation in a trial can compare favorably to standard approaches.

What progress has been made in research
and what has been PAL’s role?

In short, many very promising new approaches to the treatment of lymphoma are emerging that will help us to manage lymphoma better and cure more patients – the classes of these drugs we list below.

PAL’s role in supporting clinical research is challenging to measure directly, due in part to privacy constraints.  So we rely on feedback from the community and measuring how often our educational materials and tools are used (clicked).

2012 Website usage statistics for


Unique visitors

Number of visits













See also About Our Trial Tools:

We also estimate our positive contribution to clinical research by the number of invitations to participate in the review of  trial concepts and study by professional organizations (ASCO, AACR, SU2C, and the Alliance) and the National Cancer Institute.

Before stepping through the exciting new developments in clinical research, a little background is needed to appreciate what it takes to bring a new drug forward – and therefore what it will take to make good on new insights into the biology of the disease and also the host environment, notably the immune system.

The “Critical Path” – from bench-side to bedside and the role of patients

Clinical science is an ongoing building process.  To use an analogy, each beam must be tested for safety and efficacy before being accepted as part of the structure – something secure for clinicians to prescribe for their patients and for science to build on.

Basic science has increased our understanding of the mechanisms or pathways that drive tumor growth and survival.  The goal  of clinical research is to design drugs that target disease pathways in order improve efficacy and reduce toxicity.

… Two example of “targeted drugs”: Rituxan, binding to cd20, AND the btk-inhibitor, which  bind to part of the malignant cell that is overactive and causing sustained growth.

Clinical-phase testing begins with important basic questions:  How much of the drug can you give the patient without causing bad effects?  How long does the drug stay in the body?  What signs of toxicity are seen in liver and kidney tests?  Are other important organs affected … the heart, lungs, brain … and so on?

Fast-forwarding to phase-III tests, the ultimate questions: Do we live better or longer when using the new protocol compared to the standard of care?  Almost any drug that has activity against a disease process will also have side effects.  Do these bad effects offset the positives?

The FDA, the independent reviewers of clinical studies, has provided a whitepaper on the drug discovery and testing process – the path of a new drug from the lab to the clinic.  This is called the  “Critical Path.”

The timeline from basic discovery to approval of a new drug can be 5, 10, or 15 years.  It is the clinical-phase of testing that takes the longest – about 7 years.


Unfortunately, some clinical trials never enroll enough patients and are terminated with the study question unanswered.  So progress against lymphoma takes great science, but it also requires our participation. The scientists simply can’t make progress against lymphoma without our help!

Independent and rigorous review of clinical trial outcomes is an essential process that weeds out unsafe or ineffective new drugs, a process that takes about 6 months.  Low referral in trials has many causes, but is largely a consequence of our fragmented and uncoordinated medical system.

Contrary to public perception it is the low referral rate by clinicians that delays and limits progress, not Regulatory Review.

Finally to an overview of the classes of new and approved drugs for lymphoma on the Critical Path:

Note: Here we provide a tool to help patients locate trials based on the type of agent

Thank you for your attention to the first installment of our 2012 report – and for your financial support that makes it possible.

See How to help

In the next installment we will give an overview of the progress that has been made in recent years based on new drug approvals and encouraging clinical outcome reports,  along with very exciting recent discoveries.

Karl Schwartz

President, Patients Against Lymphoma

Progress Against Lymphoma

January 4th, 2012

Musings on Progress Against Lymphoma:
2011 Highlights, Looking ahead – our Wish list


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:


“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
Evidence-based information on lymphoma, independent of health industry funding

Untreated Follicular lymphoma: Rituxan versus “Watch and Worry”

December 8th, 2010

… In Non-symptomatic, Non-Bulky, Previously Untreated Follicular Lymphoma  …  Commenting on A Preliminary Analysis  *


The recent ASH conference led to many press releases with titles like “Rituxan delays chemo for slow-growing lymphoma” and “Roche’s MabThera Delays Need for Additional Lymphoma Treatment, Study Says.  It’s our impression that the importance of the study has been vastly overblown in the flurry of media hype surrounding the conference.

Within we discuss the limitations of Progression Free Suvival and Time to New Treatment as ways to estimate clinical benefit in this study, and explain why longer follow up is needed to tell if either approach provides meaningful clinical benefit.  


The abstract published at ASH  (see link below) shows that Rituxan, when administered as first therapy – in this low risk and previously untreated population — delays the initiation of new treatment.  

The authors propose that “Time to New Treatment” is a way to compare Rituxan to Observation in previously untreated follicular lymphoma 

… the use of the word “NEW” being a creative way to compare very different events.  That is, “New treatment” means:  Time to FIRST Treatment for the observation group, versus Time to SECOND Treatmentin each of the Rituxan-treated arms of the study, because, stating the obvious, observation is not a treatment.  

The abstract doesn’t provide information on what clinical changes triggered the decisions to initiate the NEW therapy in the respective groups, nor does it explain why chemotherapy is the overwhelming new therapy choice, even in the observation group.  

… The selection of new therapy (chemo – 84%) suggests an expectation among these investigators that this use of Rituxan is appropriate only in patients with low levels of disease – judged to be not in need of treatment.  Is there clinical trial data that validates this expectation?

 “The primary endpoints were a) time to initiation of new therapy (chemotherapy or radiotherapy) and b) effect on quality of life.”  

 “New treatment was chemotherapy in 78 (84%),
    radiotherapy in 10 (11%),
    rituximab monotherapy in 2 (2%),
    surgery in 1(1%),
    currently not known in 2 (2%).”

Be aware that when to treat can be a very subjective decision for the indolent lymphomas, for which there is a wide range of indications for treatment, including “patient preference.”  ( See NCCN guidelines

That is, even for the same patient, the decision to treat can made long before, or a long after, treatment is indicated by NCCN or GELF criteria —  a decision that is dependent on patient reporting of symptoms, as well as physician and patient preferences.  

That Time to Next /New Treatment is a fuzzy endpoint is a familar concept to patients with indolent lymphoma who have consulted multiple oncologists about when to treat.

Since the investigators were aware which patients were receiving therapy or observation (it was an open label design), these were not blinded decisions – and therefore could be influenced (even if unconsciously) by investigator bias – and perhaps the patients discomfort with observation, which is often described by them as “watch and worry.”

So let’s take a look at some of the data pulled from the abstract, with a focus on the observation (“watch and wait”) group:  

The estimated median time to initiation of new therapy in the observation arm (arm A) was 33 months.

So the participants randomized to observation received what might be called a benefit of 3 years of therapy without treatment risks – again, assuming Time to NEW Treatment is a reliable measure of clinical benefit. 

Arm A – observation:
  Spontaneous remission was seen in 3%
  Partial Response =6%
  NC (no change) =74%
  Progressive disease PD=17% *

* An obvious follow-up question on the incidence of PD being:  What percent of the participants in the observation group were treated despite having had no progressive disease (PD), and how did that compare with arms B and C?    

… Progressive Disease (PD) seems the least controversial trigger leading to treatment (compared to patient-reported symptoms), assuming its validated by imaging or some other objective measure.  

… Since 17% in the observation arm of the study had PD it would be informative to know what were the other clinical events that led to treatment in the respective arms of the study - noting that the graphic shows more than 50% needing treatment at 48 months in the observation arm, and that 74% in the observation arm were reported to experence No Change (NC) in the status of the lymphoma. 

Versus the Rituxan treatment groups:

Arm B: CR+CRu=45%, PR=33%, NC=19%, PD=3%.
Arm C (with maintenance): CR+CRu=49%, PR=36%, NC=11%, PD=3%.


There is no compelling information provided on this measure, despite it being listed as a primary endpoint in this study.  QOL is very difficult to measure and compare  objectively.   However, adverse drug events can be measured, and, obviously, favor those who were not treated. While drug-related events might be offset by decreased symptoms in the Rituan-treated groups, such QOL measures were not provided:

 Drug-related Serious Adverse Events (SAE): 
(SAE were considered possibly, probably or definitely related to the study drug)
  Observation arm = 0/186
  Rituxan arm =4/84,
  Rituxan maintenance arm = 10/192).

  5 allergic reactions (two grade 3), 6 infections, 3 episodes of grade 4 neutropenia.


Survival is the most reliable endpoint for determining if either approach provides clinical benefit.  The other measures (such as PFS) are called surrogates which depending on the study design, the population, and the magnitude of the difference, may reasonably predict a surival benefit … or not.   

… Here we see no difference in mortality comparing the three treatment arms at this time.   That the sponsor has chosen Time to Next Treatment as the primary endpoint doesn’t mean that it it’s a good choice of endpoints to predicts a survival benefit.  That Survival was not listed as a primary endpoint raises the concern that follow-up of the participants might not be extended to compare survival outcomes in these patients. 

Survival, all groups:  “98% of patients remain alive and there was no different in overall survival between the 3 arms (p value >0.5).” 


Progression Free Survival  (PFS) is a combination endpoint measuring both mortality AND progression events and counting each as one event.   

… To a lay audience PFS probably suggests a survival benefit, but in this case it has nothing to do with survival because there was no difference in survival between the observation and treatment groups in this study.   

Again: “98% of patients remain alive and there was no different in overall survival between the 3 arms (p value >0.5).” 

Here we propose – to avoid media intrepretation errors - that PFS not be used in such reporting when there is no difference in the Survival part of this composite endpoint.

When reviewing commentary on this study, be aware that the sponsor of the drug will be inclined to present the results in ways that favor more usage of their product, that being the charter of any for-profit organization …  thus, it may provide the media with selective comments that support that goal and will tend to understate or fail to adequately discuss the limitations of the study design.

My hope is that the investigators will continue to monitor the participants of this study and report on the survival data and that patients and treating physicians will recognize the limitations of the information provided at this time, and the need for independent discussion of what this data does and doesn’t mean.   

Regarding the question whether these results should change clinical practice, we might restate the question this way:  Should John and Mary – each recently diagnosed with follicular lymphoma and without symptoms, or bulky disease, or evidence of progression –initiate Rituxan therapy without making use of these clinical indicators?  

 … The data shows that there are some potential benefits (assuming the benefit can be reliably measured by Time to New Treatment), but also that there was a increased incidence of adverse drug evens (AES) and no survival advantage at this time.  Not directly addressed in the abstract is the possibility of poorer responses to subsequent therapy (which is likely to include Rituxan) in this unique population.

So, and as already noted by some experts, only a survival benefit would be persuasive and ought to be practice changing — noting for the benefit of patients that the survival endpoint is persuasive because it accounts for all factors, known and unknown.  For mortality events, unlike Time to New Treatment, the meaning would be clear.   

Critiques aside, this is a study design that could actually help to answer the question – with longer follow up because patient selection (to observation or Rituxan monotherapy) was randomized; however, the study is unable to answer the key question because of the reliance on questionable surrogate endpoints that do not reliably predict a survival benefit.

Karl Schwartz
President, Patients Against Lymphoma


* ASH abstract:

Theory, Observation, and Endpoints

October 6th, 2010


There was once a time in history when doctors prescribed blood-letting, and were convinced that it was effective – and could cite many success stories. In comparison, homeopathy (water with trace amounts of different compounds) along with good hygiene appeared effective!

Each medical practice (disproven by modern scientific methods) was based on a prevailing theory and substantial clinical observation.

There are many such examples of theories that when tested rigorously just didn’t hold up, (such as HRT for women) and yet, clinical observations seems the basis for a good deal of professional opposition (about 50/50) on the recent Advisory committee’s recommendation (12-1) against approval of Avastin for metastatic breast cancer. 

 (See Nine Members of the Oncology Community Speak Out about Bevacizumab’s Role in Metastatic Breast Cancer

So how do you measure clinical benefit, if not by theory (an infinite #) and observation, which is influenced mightily by what we expect and want to see, and our financial interests if any? 

For example, and this could seem harsh, how many professional opinions on Avastin are explained by a natural reluctance to admit to prescribing an ineffective therapy?

Some background:

Today a treatment is proven to provide clinical benefit if it improves survival compared to the natural course of the disease, or the disease treated differently, but also if it improves quality of life (a separate topic). 

… But since we can’t know if any individual would have done better with therapy X compared to Y, the testing must be done on large groups, randomly assigned to one arm of the study or the other.  If one group does better than the other (lives longer or better), we have evidence of clinical benefit that is firm and objective. 

So the randomized controlled trial (RCT) design is a triumph of modern clinical science as it protects us from our own biases. 

However, WHAT and WHEN you measure the effects of therapy  can make even the results of a RCT controversial (as in the Avastin example above), a drug, which was conditionally approved based on measured improvement in progression free survival (PFS) for those receiving Avastin in a prior study.

So what is PFS and why is it used instead of overall survival?  

PFS generally measures time to progression, relapse, and to death from ANY cause.

The rationale for including “death from any cause” – even if not apparently related to the disease or treatment – is that it’s not always possible to know what’s related; and accidental or unrelated causes will balance out when comparing groups treated with different protocols.

In FDA deliberations, PFS is also weighed against offsetting toxicities.  PFS is a surrogate for survival because survival benefit can take too long to measure, particularly for the indolent cancers that have long survival; and because the measure is confounded when patients use additional therapies.   

It appears that in the follow-up Avastin studies, done to confirm the finding of the first, the magnitude of PFS for Avastin was smaller and the toxicities were found to be more significant.  Further, Avastin did not provide a survival advantage at the point it was measured.

 What will be FDA’s ruling?

I expect the agency will remind that an improvement in PFS must be sufficient to reasonably predict survival benefit.  If the PFS advantage is small and the price for that benefit is high in respect to the toxicities, I expect it will go along with the Advisory committee to deny full approval,

 …. but regarding conditional approval, it may simply require additional study.  If so, the task for the sponsor will be to figure out which subgroup of patients may benefit from this drug (find a biomarker) … which is what patients want, and need!

For patients, in effect, the conditional approval remains, because the drug (approved for other indications) can be used off-label and also can be tested further.  

Consider also that for this indication there are other effective protocols, such as the chemo induction therapy used as the control.  So arguments supporting approval  - such as that the small improvements in PFS or response rate have been used as the basis for other approvals  –  I don’t find persuasive.

Actually, I started this piece because I wanted to write about PFS as a composite measure of benefit for indolent lymphomas.  (A composite because it measures time to progression AND mortality.) 

It is clearly a necessary metric for this indication, but I wonder if its meaning is inflated in studies that have low and/or equivalent mortality in the study arms?  In such cases, we could more accurately call it Time to Progression so we don’t assign to it a meaning (the survival part) it doesn’t deserve.

Anyhow, in summary:

Theory and even professional observation are each unreliable as evidence.  The theory-holder is especially vulnerable to selective observation (seeing only what fits his theory); the theory-inventor and commercial sponsor even more so!

Opinion by Karl Schwartz
President, Patients Against Lymphoma

Who “owns” extra biopsy tissue? Why Cancer Patients Must Advocate Vigorously for caHUB

April 15th, 2010


Karl2007How many of us can recall reading the consent document regarding the use of our extra biopsy tissue?  And if we did, how could we be expected to understand its implications, … or our other choices?

Only recently considered “waste tissue,” the evaluation of biospecimen – particularly when correlated with clinical information (response to therapy, etc.) –  is considered the key INFORMATION to making progress against lymphomas and other cancers,  heterogeneous conditions, which can have variable clinical courses and underlying biology – even within the same diagnosis.  

See about the critical importance of high-quality biospecimens for cancer research and patient care, an NCI video on this page:

Presently, pathology departments, the institutions, the investigators, the cooperative groups, even NCI, argue for use of it.   The patient community unaware that it has become so valuable, and that “ownership” of it has become so problematic!

Importantly, with the recent advent of caHUB*, we now have an alternative to a fragmented system where tissue remains unused because of ownership battles,  or the use of it defaults to individual researchers in the center who have access to the refrigerator. Done in isolation, on relatively small numbers sample, without clinical annotation, this use of patient tissue is unlikely to achieve anything of clinical importance.

caHUB is a “national biobank, or biorespository, of human tissue, blood, and other biological materials–collectively known as biospecimens–that can be used for medical research. It will help ensure that an adequate and continuous supply of biospecimens is available to accelerate cancer research and the development of molecularly-based diagnostic and therapeutic agents that will further enable personalized medicine.”   See for details on caHUB:

So I think the cancer patient communities need legal counsel regarding the use of biopsy tissue for research and government regulation to standardize consent and ownership practices — to protect the interests of patients and to save the gifted, well-meaning, human, all-to-human, researchers from themselves.

Proposing a carrot: Institutions that participate in caHUB, should be awarded generous grants and public acknowledgments. 

See Request for Input on the Biospecimen Procurement Program for the NCI’s cancer Human Biobank (caHUB)

And a stick: institutions who do not offer this option to patients, must discard the extra tissue unless they can show its use has a true potential to advance clinical science, and the institutions have provided patients with adequate consenting and knowledge of the alternative.

And to establish trust and best use:  Empower an NCI steering committees with independent experts and STRONG PATIENT REPRESENTATION to determine best use of the tissue for research.   Noting that access to the biological and de-identified clinical INFORMATION will be available to all, including commercial entities – through the caBIG bio-informatics system, so that researchers can COMPETE WITH IDEAS instead of for ”ownership.”  

The reason patient intervention (through legislation) is needed is to make possible what caHUB offers, and apparently what most researchers will not accept in practice, even when they agree with the concept.  To illustrate, I copy comment of an unnamed investigator on the competition for use of biospecimen:

“Doctors who work in the field disagree. Many individual sites disagree with the NCI – e.g. many good centers don’t participate in cooperative group studies because they disagree, don’t like, or have other priorities. Our XYZ lymphoma committee often disagrees with the NCI CTEP staff – so for us to send samples from our patients to the NCI to be used on studies we don’t favor is problematic if we disagree – we will not be motivated to participate – it’s very very challenging.  …
When patients have a  biopsy, the operative consent form generally mentions “waste tissue” – this falls into that category. As I understand it, the patient has no clear rights to “waste tissue”, which would generally not be needed for diagnostic purposes and is therefore discarded. The generic consent form says that this may be used by the institution for research or other purposes (as it is otherwise waste) in a de-identified way.”

What is step one?  First, we need feedback from the NCI and research community to make sure our concerns are legitimate and the proposed remedy is feasible.   Noting that we really don’t care what method is used to get there, only that we do.   

“The patients are waiting.”  The alternative to having reliable biomarkers for cancers is a high risk of unproductive and irreversible toxicities –  the patient all too often receiving no benefit and significant harm from cancer interventions.  

The answer to Who Owns It is that it belongs no one, not even the participants.  Its use must be earned and the results must be shared with the entire research community. 

Who Can Use it Productively?   Productive use requires not only the tissue, but also a robust bioinformatics and clinical annotation system that give meaning to the information in the cells. It is basically worthless without annotation – the clinical history of the participant … which few single centers, if any, are equipped to do.  Example: molecular mutation A found in the cancer cells of hundreds of samples from multiple institutions, correlated with durable responses to Treatment B or, as importantly, failure to respond.   

The patient community has no conflict of interest,  except the use of our tissue in ways that best serves clinical science.   Presently, we have no voice in this matter, despite being the primary stakeholders – and there is little authentic enthusiasm among investigators and individual institutions to receive our input.

~ Karl Schwartz
President, Patients Against Lymphoma

Advance Care Planning Consultation – text of Health Care Bill

March 12th, 2010


We have opted for neutrality in the Healthcare debate, not for lack of heart-felt opinion on it, but to prevent ideological debates from distracting from our MISSION, which is to provide support and evidence-based information for lymphoma survivors no matter his or her ideological beliefs. 

What follow is not OUR opinion on the controversial Advance Care Planning provision in the present Health Care Bill proposal, but the actual text.  The purpose is to allow you to read it and to judge it first-hand.  (The alternative is to form opinion based on opinion.)    Here also is a link to the full text of the proposed bill:

‘Advance Care Planning Consultation  

(1) Subject to paragraphs (3) and (4), the 7 term ‘advance care planning consultation’ means a consultation between the individual and a practitioner described in paragraph (2) regarding advance care planning, if, subject to paragraph (3), the individual involved has not had such a consultation within the last 5 years. Such consultation shall include the following:

 ‘‘(A) An explanation by the practitioner of advance care planning, including key questions and considerations, important steps, and suggested people to talk to.

 (B) An explanation by the practitioner of advance directives, including living wills and durable powers of attorney, and their uses.

 (C) An explanation by the practitioner of the role and responsibilities of a health care proxy.

 (D) The provision by the practitioner of a list of national and State-specific resources to assist consumers and their families with advance care planning, including the national toll-free hotline, the advance care planning clearinghouses, and State legal service organizations (including those funded through the Older Americans Act of 1965).

 (E) An explanation by the practitioner of the continuum of end-of-life services and supports available, including palliative care and hospice, and benefits for such services and supports that are available under this title.

 (F) (i) Subject to clause (ii), an explanation of orders regarding life sustaining treatment or similar orders, which shall include—

(I) the reasons why the development of such an order is beneficial to the individual and the individual’s family and the reasons why such an order should be updated periodically as the health of the individual changes;

 (II) the information needed for an individual or legal surrogate to make informed decisions regarding the completion of such an order; and

 (III) the identification of resources that an individual may use to determine the requirements of the State in which such individual resides so that the treatment wishes of that individual will be carried out if the individual is unable to communicate those wishes, including requirements regarding the designation of a surrogate decision maker (also known as a health care proxy).

 (ii) The Secretary shall limit the requirement for explanations under clause (i) to consultations furnished in a State—(I) in which all legal barriers have been addressed for enabling orders for life sustaining treatment to constitute a set of medical orders respected across all care settings; and (II) that has in effect a program for orders for life sustaining treatment described in 14 clause (iii). ….

 (iii) A program for orders for life sustaining treatment for a States described in this clause is a program that—‘

 (I) ensures such orders are standardized and uniquely identifiable throughout the State;

 (II) distributes or makes accessible such orders to physicians and other health professionals that (acting within the scope of the professional’s authority under State law) may sign orders for life sustaining treatment;

 (III) provides training for health care professionals across the continuum of care about the goals and use of orders for life sustaining treatment; and

 (IV) is guided by a coalition of stakeholders includes representatives from emergency medical services, emergency department physicians or nurses, state long-term care association, state medical association, state surveyors, agency responsible for senior services, state department of health, state hospital association, home health association, state bar association, and state hospice association.

 A practitioner described in this paragraph is—(A) a physician (as defined in subsection 16 (r)(1)); and (B) a nurse practitioner or physician’s assistant who has the authority under State law to sign orders for life sustaining treatments.

 (3)(A) An initial preventive physical examination under subsection (WW), including any related discussion during such examination, shall not be considered an advance care planning consultation for purposes of applying the 5-year limitation under paragraph

 (1). (B) An advance care planning consultation with respect to an individual may be conducted more frequently than provided under paragraph (1) if there is a significant change in the health condition of the individual, including diagnosis of a chronic, progressive, life-limiting disease, a life-threatening or terminal diagnosis or life-threatening injury, or upon admission to a skilled nursing facility, a long-term care facility (as defined by the Secretary), or a hospice program.

 (4) A consultation under this subsection may include the formulation of an order regarding life sustaining treatment or a similar order.

 (5)(A) For purposes of this section, the term ‘order regarding life sustaining treatment’ means, with respect to an individual, an actionable medical order relating to the treatment of that individual that—

 (i) is signed and dated by a physician (as defined in subsection (r)(1)) or another health care professional (as specified by the Secretary and who s acting within the scope of the professional’s authority under State law in signing such an order, including a nurse practitioner or physician assistant) and is in a form that permits it to stay with the individual and be followed by health care professionals and providers across the continuum of care;

 (ii) Effectively communicates the individual’s preferences regarding life sustaining treatment, including an indication of the treatment and care desired by the individual;

 (iii) is uniquely identifiable and standardized within a given locality, region, or State (as identified by the Secretary); and

 (iv) may incorporate any advance directive (as defined in section 1866(f)(3)) if executed by the individual.

 (B) The level of treatment indicated under subparagraph (A) (ii) may range from an indication for full treatment to an indication to limit some or all or specified interventions. Such indicated levels of treatment may include indications respecting, among other items—

 (i) the intensity of medical intervention if the patient is pulse less, apneic, or has serious cardiac or pulmonary problems;

(ii) the individual’s desire regarding transfer to a hospital or remaining at the current care setting;

 (iii) the use of antibiotics; and  (iv) the use of artificially administered nutrition and hydration.’’.


March 11th, 2010

Karl2007As you may know, personalized medicine is therapy that is chosen rationally based on the unique characteristics of the patient or the disease – the alternative being one-size-fits-all medicine, or decision by trial-and-error. Indolent Lymphoma survivors are well acquainted with the latter, evidenced by: “We could try this, or that, or the other. It’s up to you.” (No Standard of Care)

Treatment decisions can be based on Clinical Variables (stage, symptoms, age, and so on), but also on Biological Variables. The latter is based on tests of tissue (blood / tumor) that reveal differences in the underlying disease – such as a mutation that exists in one tumor but not another.

Importantly, clinically meaningful biological variation can exist within the same diagnosis – explaining why the same treatment is not equally effective on all patients with the same type of lymphoma. The jargon for this in the literature is “disease heterogeneity.”

Two recent reports provide evidence for progress based on the identification of biomarkers that appear to predict outcomes for patients independent of clinical variables:

First: the CLL the study comparing CC vs. CF found NO difference between these protocols, but importantly it identified patients who should not do either treatment -based on a mutation in the tumor cell.

Second: A study confirmed that 80% with Classic Hodgkin lymphoma are cured, but that a high number of tumor-associated macrophages (in the tumor microenvironment) are strongly associated with those who are not cured.

When a biological characteristic is found to predict outcomes it’s called a biomarker.

In these instances, patients (with the cytogenetic marker for CLL, or immune signatures for HL) can be spared the unproductive and non-reversible toxicity of these protocols – instead, can try other therapies – either less or more aggressive, depending on the goal of therapy.

With biospecimen-based research, patient outcomes can be compared, not just against other protocols, but also against suspected biological variables – to first identify and then validate biomarkers of response – to the benefit of all patients.

Essential to the conduct of such research is the adoption of STANDARDS for the capture, storage, annotation, and testing of the tissue (blood / tumor) so that the results of such tests can be compared across different studies – to increase the confidence we can have the tests are truly reliable for decision making.

For much more detail, see Biospecimen Research Network

~ KarlS
President, Patients Against Lymphoma

Patients Against Lymphomas

February 8th, 2010


Karl2007Patients Against Lymphoma is a non-profit group founded and maintained by patients and caregivers directly affected by lymphomas, a kind of blood cancer that has risen 4% annually between 1970 and 1990.

We provide direct support in online forums and  evidence-based information on lymphoma and its treatments through our website  

We also engage the research community – providing patient perspectives on the direction of clinical research and the design of clinical trials.

One of our major goals is to help patients understand the critical role of clinical trials in making PROGRESS AGAINST LYMPHOMAS / CLL and to provide also general guidance on when we may reasonably consider clinical trials …that are a good fit for our clinical circumstances and treatment goal. 

See for our ongoing related projects:

Importantly, we maintain our neutrality by accepting only public support.  We have chosen this path in order to provide unbiased perspectives on clinical research and investigational drug approvals … ensuring that our advocacy efforts are driven only by patient needs.

Please check back for perspectives on clinical research and other topics of importance to lymphoma survivors and caregivers.

Best wishes,

President and Co-founder of Patients Against Lymphoma