TITLE: CRC 2015: Dr. Neil Kay on Prognostic Indicators and Standard Early Care for CLL

This week’s new post on the CLL Society’s website brings us practical advice from Dr. Neil Kay out of  Mayo clinic on  prognostic indicators and how to manage early stage CLL. He also  discusses MBL or monoclonal B cell lymphocytosis a precursor to CLL.

Dr. Kay’s lecture and my commentary from the robust but accessible CLL Research Consortium (CRC) Patient Empowerment and Education Conference in April 2015 in San Diego at UCSD can be found under conference coverage here.

If you haven’t already seen Dr. Kipps’ incredible overview of CLL and the work the CRC does, please catch it here.

Brian Koffman (flying home after two weeks in Poland)

Volunteer Medical Director CLL Society

ESH 2014: Prof. Stephan Stilgenbauer Discusses Prognostic Factors, FCR and Implications for Therapy in CLL (chronic lymphocytic leukemia)

In part two of my interview from ESH in November 2014 from Greece with Professor Stilgenbauer of the University of Ulm, Germany we go deeper on the topics we cover in part one and introduce new subjects. I recommend you take a look at that post if you haven't already. That prior post also has links to even earlier reviews of some of the same areas of discussion.

In this segment, the doctor starts by using the examples of 11q or 17p deletion that help explains some of the subtleties of the difference between prognostic and predictive factors.

It is a nuanced subject, but one worthy of our efforts to understand as it can help guide our therapeutic choices.  His examples clearly outline the differences. Hopefully my brief introductory notes that follow also help.

The best known bad player found by FISH or interphase fluorescence in situ hybridization is deletion of 17p.

When the short arm of the 17th chromosome (17p) is deleted, gone with it is TP53 that is important in maintaining genomic stability when our DNA is reproducing itself. Because of its critical role in guarding the fidelity of each copy of the genome when our cells are replicating, it is considered a tumor suppressor. The doctor explains how it also fosters resistance to most chemo-immunotherapies.

The number two bad boy is 11q deletion.

The 11q arm carries ATM that is also involved, those less critically, in the same pathway protecting the stability of our genome. But the new discovery is that 11q deletion may also lead to loss of BIRC3 that leads to the jamming on of the pro-survival and anti-apoptotic NF-κB signaling pathway. More on this in later posts.

It's complicated, but the pieces are coming together.

Dr. Stilgenbauer points out that in those of us with 17p deletion with the relatively good news of having a positive mutation status, our CLL may be slow to progress. This combination of + mutation status and 17p deletion is an example of a prognostic factor- prognosticating about how we will do in the future.

He next points out that when patients with that same combo eventually do need treatment, it will most likely not respond to conventional chemo-immunotherapy (CIT) such as FCR. This is an example of a predictive factor, representing a "prediction" of the likelihood of a given therapy working.

If we are both unmutated and 17p deleted, sadly odds are we will both progress quickly and do poorly with traditional therapies. A double whammy. Bad prognostic and predictive factors. That's me.

He correctly points out the good initial response rates to CIT for those with 11q deletion (I am in this group too), but he neglects to point out that while we might get a deep response, it is not durable, possibly due to our cancer's ability to mutate more freely. He is right in highlighting the strong correlation between unmutated status and 11q deletion, which raises the questions about which is these two gives us the bad prognostic.

The professor's take on the possible "cures" with FCR is also instructive. Please give a critical listen.Much to ponder.

We also talk about the need for deep sequencing to search for 17p deletion or to check for TP53 function. He explains the new versus old ways to look at the chromosome.

Dr. Stilgenbauer outlines the sinister consequences that happens when the selective pressure of CIT is applied to even the smallest subclone population of 17p deletion cells. They can rise up and take charge when the cancer returns.

I believe that FISH is important but only a first step. Today we need to look for both deletions missed by FISH and smaller but critical subclones that are beyond the resolution of FISH. CLL management needs to move in this direction.

I don't want this post to be too much of a downer. While all statistics and cellular biology are important for predicting what happens to different groups, they do not determine individual destiny. And many of the new therapies' responses are blissfully blind to FISH status. I myself am unmutated, 11q deleted, 17p deleted, ZAP 70+, CD38+, have a complex karyotype and I am doing fine, thank you, but knowing this helped informed my decisions.

He closes with the familiar clarion call of the twin needs of having a CLL expert on our team and for more research.



More from ESH, Greece coming soon, including Dr. Wu on clonal heterogeneity and Dr. David Porter of U. Penn on CAR-T in CLL.

Many interviews to share from ASH last month in San Francisco are on the way.

Stay strong. We are all in this together.

ESH 2014: Prof. Stephan Stilgenbauer Reviews Predictive and Prognostic Markers in CLL (chronic lymphocytic leukemia)

I was asked to present the patient's perspective in CLL at a satellite symposium to the annual congress of the Hellenic Society of Hematology held in Thessaloniki in northern Greece near the birthplace of Alexander the Great last month. The sponsors took a risk in inviting a patient to speak to a group of hematologists but my reception was warm and enthusiastic despite my inability to speak in the native language.

As a result of the positive response I received for my 30 minutes on the podium, I was asked if I could shoot a series of monologues that address various aspects of why it is so critical that our voices be heard by the professional community that treats us. I will posting those here and later our CLL website soon.  Check out the first monologue here filmed soon after I flew home. More monologues to follow on other topics.

The Hellenic hematology congress was co-incident with another valuable meeting in Thessaloniki organized by the European School of Hematology (ESH), ESH 2014: International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment so I stayed in town for an extra few days to attend the CLL sessions and shoot some videos for the blog.

On a personal note, on my one half day free in Macedonia, I did rent a car and drove in the rain to see the amazing underground museum that includes the unspoiled grave of Philip II, father of Alexander the Great. Don't miss it. I loved my much too brief return visit to Greece.

 

Grave of Phillip II

My ESH videos were embargoed until after ASH, so I am only able to share them now.

The first video interview is with Prof. Dr. med. Stephan Stilgenbauer of the University of Ulm.

We revisit the topic of prognosis and predictive factors. Here is a link to an earlier post on another aspect of this subject with Dr. Bill Wierda from MD Anderson. Dr. Jeff Sharman gets into some of the same material in this helpful post from iwCLL 2013.

The first message that I gathered from Prof. Stilgenbauer is that the significance of all these factors must be reassessed in this era of novel therapies and that process has only just begun. How they may have predicted and prognosticated about treatment with FCR is not always going to match up as to their relevance for therapy with ibrutinib or idelalisib. 

This should be an active area or reassessment and research. One possible example seems to be that patients with 17p deletion respond differently when treated upfront with ibrutinib versus when treated after they have relapsed with 17p deletion. More predictive and prognostic factors will emerge if we look. 

My next take way: It is no longer sufficient to test only only for the deletion of the short (p for petite) arm of the 17th chromosome (17p deletion), but we also must ask our hematologists to check the function of the TP53 gene. TP53 has been called the guardian of the genome because when it is functioning well, it protects our genetic information from being miscopied and thus spawning a malignant offspring. When it is missing or dysfunctional, cancers are both meaner and harder to kill. Here is a nice overview on TP53 from the NIH. Dr. Stilgenbauer discusses the relation between TP53 and 17p deletion.

Finally we touch briefly on some of the new prognostic factors found in CLL with the advent of deeper probing of our cancer's genetic makeup with next generation sequencing. These include mutations in NOTCH1 (a signaling pathway between adjacent cells) and SF3B1 (a surprise finding, a important in gene splicing). Here's the original article from the NEJM that goes into much greater detail.

Here is Dr. Stilgenbauer.




More soon from ESH and ASH.

As I write and edit these recent blog posts, it has become increasingly clear to me that the scope of what needs to be done to teach about CLL had grown beyond the capacity of this meager blog.

That will be a major part of the mission of the nonprofit CLL Society Inc., to inform and support both the newbie and the cognoscenti of the CLL community through a new dedicated and more robust CLL specific website.

Please complete our survey to let us know what are your unmet needs by clicking this link: https://cllsociety.questionpro.com. It closes at the end of the week.

And thanks so much to the many of you that have already finished the survey and a big thanks to those of you that have generously supported us already with a tax deductible donation. It will all be used to extend and deepen our reach with more knowledge and support.

                                            

Forbes says: "With So Many Terrific New Drugs For Chronic Lymphocytic Leukemia (CLL), Why Worry?" I say it's a Tempest in A Teapot

Hydra (mythical monster that grows two heads when you cut off one)

Elaine Schattner wrote a provocative and helpful editorial in Forbes: With So Many Terrific New Drugs for Chronic Lymphocytic Leukemia, Why worry? I recommend we all read it, but that we also read it critically.

It has to do with her concerns about the dangers of unnecessary treatment.

My friend and fellow cancer advocate Andrew Schorr wisely reminds of us a friend with CLL who has done very well without treatment for nearly 18 years.

We know that about three out of every ten of us diagnosed will follow a very indolent (slow) course and never need treatment.

And so the author cautions us to avoid unneeded therapy. Good counsel. Never take a treatment that's not needed. All drugs and I mean all drugs have side effects. 

Her concern and motive for her editorial is that thousands of us will rise up demanding that our hematologists offer us the new expensive therapies just because they are so darn safe and effective when we would be better off doing nothing, just watching and waiting. Hordes of CLL patients will ignore the carefully tuned 2008 iwCLL guidelines on treatment, and demand an immediate prescription NOW before we are in troubled waters.

I believe it's a false concern. 

A powerful and practical reason that Ms. Schattner is worrying over nothing is that these expensive drug are not yet approved frontline  with the notable exception of ibrutinib in 17p deleted patients as detailed in this recent post). It is highly unlikely our medical insurance is going to pay for an off label use of a pricey therapy when there is ZERO data to support it. And of course, there are vanishingly few of us that could afford the out of pocket cost of at least several thousand dollars per month for any of the new star therapies (in order of appearance on the CLL stage): ofatumumab, obinutuzumab, ibrutinib and idelalisib. And of course, even frontline approval is not the same as approval (and insurance coverage) when there is no indication to treat.

That said, I am sure that there will be a few patients among us who will think it is the height of craziness to sit on our hands. We should strike the cancer while is still in its infancy well before it has the time to achieve its typical mature persistence and wily ways, making it such a formidable foe, making a cure still a dream for almost all of us. Kill it before it grows into a multi headed hydra.  

But a quick review of the facts should dissuade us from this tempting but false path. There is absolutely no evidence that early intervention helps. In this oft quoted article from 1988, Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation, and this one from the NEJM in the same year show we learned that there was no survival advantage to early intervention. And there are certainly risks. Studies such as these reinforces the importance of knowing the data and also knowing where there is no data.

Wait you say: Chlorambucil may have been state of the art in 1988, but today we have better therapies. Might not the results be different if we looked again using today's drugs? 

Good question. The same sort of trial was set up with FCR, but died on the vine due to lack of enrollment.

That is why trial such as this closed trial on using lenalidomide or this new one using ofatumumab are so important and need our support.

Although prognostic factors such as FISH and ZAP 70 and mutation status tell us much about a group of individuals and little about the individual members of that group, wouldn't we all want to jump out of the high risk frying pan and get far far away from the heat in the kitchen to a calm and cool place of low risk if we could do so by intervening early?

That's is exactly why we need more studies to answer if it is possible to save more lives by using the new mAbs such as ofatumumab and obinutuzumab and the new TKIs such as ibrutinib and idelalisib and others in the pipeline before we traditionally need treatment. There is good reason to believe it just might be so, but without data…. it's only conjecture.

So what do I recommend?

I believe all these drugs should be moved towards more frontline therapy for all patients with the help of well designed trials,  not just those of us with high risk prognostic factors.

I believe these drugs should be studied in those of us with high risk unstable disease BEFORE we need treatment. 

And maybe I am about to sound like a doctor when I say this: I also believe that outside of a clinical trial, there is absolutely no role for these drugs for patients who don't meet criteria for treatment.

The Forbes editorial ends with some sage advice:

“As with other malignancies, the best way to prevent overtreatment is to assure that doctors are current in their education, knowledgeable of “lesser” treatment approaches, and not motivated by financial incentives to give therapy. And for patients, the best prophylaxis is to know that not all conditions carrying a malignant label warrant treatment. Patients might ask, “What’s the least toxic therapy you can give, so that I’m likely to stay alive with the quality of life I want, with this particular form of cancer?”

That's precisely what we are trying to do here. Educate doctors and patients about low toxicity options.

IF YOU WANT A PERSONAL RESPONSE OR TO JUST STAY IN TOUCH, PLEASE SEND YOUR EMAIL ADDRESS TO BKOFFMANMD@GMAIL.COM AS I OTHERWISE DO NOT RECEIVE THEM.

iwCLL 2013: Dr. Jeff Sharman Discusses the Practicalities of the New Prognostic Factors

In this short but rather technical discussion of the new diagnostic tests that is a follow-up to part one of my interview from iwCLL 2013 in Cologne, Germany, Dr. Sharman shares what he actually tests for in a patient who is considering therapy.

I started by challenging him that we have heard of these novel disease markers such as BIRC3, Notch 1 and SF3B1, but they are not discussed much outside of academic research, and even then, they are not tested for in most trials

Most of these new prognostic markers have just not yet made it from the research studies into the hematologist's office.

One important point that I want to linger on for a moment is the difference between a prognostic and a predictive marker.

Though the terms are often used rather loosely, and many markers are clearly both, there is a difference.

A predictive marker tells us patients how likely we are to respond to a particular therapy. A 17p or BIR3 or CYP2B6*6 warns us that our chance of a response to FC is markedly diminished.

Mutation status prognosticates how likely we are to need therapy and die too soon from our disease. Remember that all prognostic markers are prognostic for groups, not for individuals

While there is frequent overlap, it is a helpful distinction to keep in mind when considering our  workup in advance of therapy. Obviously a marker that predicts that we won't do well with traditional chemo-immunotherapy carries with a bad prognosis if that is the only therapy our docs could offer.

But as you have heard over and over again, that dangerous bottleneck is rapidly expanding with the new treatments coming into use. Accordingly, the distinction becomes increasingly important and predictive tests may soon help guide choice of our therapy.

Here is Dr. Sharman:



One more sad note: I just found out that another CLL warrior lost the fight. George Martinez, whom I met and connected with in Columbus, Ohio, a fellow charter member of Team I (ibrutinib) who like me, flew to Ohio from his home in SoCal to join Byrdland, came to that drug after being badly beaten up by his CLL, its treatment, and multiple horrific infections.

I will miss his kind, funny, warm and generous ways.

We need to be looking at more than kicking the cancer down the road. We need to looking at reconstituting our immunity and preserving our marrow.

I hate this disease and want to see it vanquished!

Rest in peace, George.

iwCLL 2013: Pharmacogenetics and Dr. Jeff Sharman Discusses New Prognostic Factors

In this interview from iwCLL 2013 with Dr. Jeff Sharman, a very clear teacher and community based cancer researcher, we learn about what I call the coming third generation of prognostic testing.

The first generation was staging, Rai in the USA, Binet in Europe, plus describing how the bone marrow looked liked under a microscope (degree and pattern of CLL infiltration), and some simple blood tests such as monitoring the rate of the rise in the lymphocyte count (doubling time), and B2M, a marker of disease burden.

Then we got more sophisticated (and expensive) with FISH testing, ZAP 70, CD38, and mutation status.

Dr. Sharman tells us what is coming next. An abstract of the Blood article that reviews some of this topic can be found here.

And the progress is not stopping.

Here's a new word we should all learn: pharmacogenetics or our unique genetic nature or phenotype that is concerned with how we metabolize medications. As we might easily infer, our individual pharmacogenetics has significant consequences on how well we respond to some therapies.

An article published last month in Blood, describes for the first time how this aspect of our genetic make up, specifically the subtype or allele of CYP2B6 that we carry, determines how well we convert a certain chemotherapeutic agent, in this case cyclophosphamide into its active form which in turn influences our response to that chemo. Not unexpectedly, those who have a low conversion rate not only do more poorly, but also have less adverse toxic events.

This  whole new area of medicine, pharmacogenomics is already important in cardiac disease where we can measure markers that tells us how and when we doctors should, but sadly too often are not, properly using certain blood thinners based on the patient's measurable genetic make-up.

UPDATE: More on the  gathering importance of pharmacogenetics from today's (11/19/13) New England Journal of Medicine (NEJM) here and here and here with an editorial here.

When the conservative and prestigious NEJM devotes most of an entire issue to a topic, we know that is an emerging hot topic. I am certain that this ill become an increasingly important arena in research in oncology precisely because so many drugs have such a narrow range of safety, and how we metabolize them might just determine the difference between toxicity or efficacy or no activity.

Let us return to listen to Dr. Sharman clearly explain some of these new prognostic tests that are emerging. I am particularly interested in his discussion of directly measuring the functionality of p53, rather than just look for a deletion. What matters to us patients is not the presence or absence of part of a single chromosome , but whether the anti--cancer gene is working or not.

Here's Dr. Sharman:



Part 2 soon.

ASH is coming so I want to be get most of the iwCLL posted here before.

ASCO 2013: Dr. Wierda on Prognostic Factors in CLL (Chronic Lymphocytic Leukemia)

The whole arena of prognostic factors in CLL is constantly evolving, but a few principles have remained constant over the years.

1: Most, if not nearly all the data is retrospective.

2: Dr. Wierda and many others are refining algorithms that will weight the many variables to better predict our future including such helpful information as the expected time to first treatment or our chances of a durable remission or ultimately our chances to live long and prosper.

3: The markers predict for groups, not individuals, but that doesn't mean we should be therapeutic nihilist and ignore what our FISH tests tell us about what options improve our odds.

4: Bad prognostics are not in themselves an indication for treatment (outside a clinical trial).

5: Good prognostics doesn't always mean that our CLL will be a non-event.

6: New prognostic factors are being discovered all the time, but few will be of much clinical import.

Here is the second part of my interview with Dr. Wierda from ASCO 2013.

I will let him fill in the details on all these topics and other aspects of this moving target.

Again my thanks to  my friends at Patient Power for sharing the work and supporting the effort to get the important news about CLL from ASCO out and available to all those of us who need it to inform our choices about how we handle our disease. Check in on their website on a regular basis as Andrew Schorr is frequently update his informative site.



In fairness, I must add that other researchers have published data supporting a possible relationship between Notch1 and Richter's Transformation (or Syndrome),

I quote from a letter in the British Journal of Haematology, 2012, 158, 415–429


"NOTCH1 mutations were associated with a ~5·8-fold increase in the crude hazard of transformation into a clonally related RS (Richter's Syndrome) "

This is from an editorial from haematologica | 2012; 97(3)

"In fact, the first studies reported a high frequency of NOTCH1 mutations in .... disease progression towards transformation into Richter’s syndrome."

Now this is not the same level of evidence as in a full article, and as such might not pass mustard for Dr. Wierda and others as proof positive of the correlation, but it convinced me that it is worthy of further study.

There is just too much data out there for anyone of us to be aware of it all.

And that's OK.