ASH 2014: Rough Notes from Dr. Clive Zent and Dr. Wiestner on Prognostic Factors and Resistance in CLL (chronic lymphocytic leukemia)

I found these notes that I had originally planned to use to develop blog posts based on a lecture that I attended at ASH 2014.

I still might do that, but first I am sharing this discovery in its raw form.

I took down all this information live on my laptop as it happened in December 2014 in a lecture hall at ASH, so expect it to be very rough and full of typos and mistakes. 

And don't take it for gospel! I have not done my usual fact checking.

Though it is still mostly unedited, I did try to clean it up a bit. Otherwise it would have been completely indecipherable for most. So I explained a few of the acronyms, improved the grammar, added the occasional punctuation, fixed some of the typos and provided some minimal text to help with context.

I wanted to share a sense of what I try to do at ASH and other cancer meetings. 

I wanted to share the velocity and volume of the information that sometimes comes from the podium. 

This is the raw material that I do my best to unpack, decode, make accessible, explain, contextualize, add relevant references, fact check, and publish here and elsewhere.

So this is hardly my usual blog post. I share it for two reasons:

1. First, it is full of incredibly valuable tidbits of information, albeit in bullet form with almost no explanatory notes.
2. Second, it shares a bit of a peek behind the curtains about what goes on at some of these huge medical conference.

Here goes.

Dr. Clive Zent

In the 1970s, the only testing for genetic testing and prognostic indicators was by karyotype analysis

Major limits- needs metaphase (not that common in CLL), needs BM (bone marrow). Only looks at whole chromosomes

1990s, we get FISH

Limits: can look at specific site only

Now we have a new era of genetic testing

Old school Sanger Sequencing needed 10% of mutation to find it, slow, expensive
PCR amplification needs only 1%
Next generation now look at whole gene- faster, cheaper
SNP arrays (clinical role unclear)
Copy # variations
Loss of heterozygosity

Usually only find 10-20 genes that are mutated
Usually found in " pathways"  controlling DNA repair such as TP53 + ATM
BRC
IGH

DNA damage responses ATM + TP53 related,  eons 4-9 (5-15%)
TP53 usually mono-alelle  5% at time of dx,
11q 10% (exon 68s)

Loss of function

Most common loss of one 17p with 80% of mutation on other gene
In contrast, 11q loss has only about 30% mutation on other gene
Can also have bi-allele losses

What does in mean?

Poor survival

BCR signaling pathways

no known mutations at start (abstract 297 disputes this) but somatic hypermutation, stereotypy

Notch1 10% at dx  in PEST domain
30% of those w RT
up to 20x inc risk of RT
BIRC3 11q22.2  near ATM  6 MB bases from 11q22.3  (asoc w loss of ATM0
significant on its own

RNA editing
SF3B1
splicing factor3 subunit 1
10% at dx
Poor Px dec resp to CIT

Clonal Evolution

No longer believe we develop new clones but start with small one that grow
Freq by FISH  (which is low) 4-5% year, but in next gen 20% after RX
Clinically important for resistance

Does clonal size matter?
Large # of mutations not findable yet, but sub clones of 17p matter even if low #

Comparison of MOLECULAR GENETICS AND PROGNOSIS

13q same as no CLL

TP53 BIRC3  worse

Moving forward

Very high risk-
 P53 and ATM (function testing)
High/intermediate

TP53 - No CIT ( chemo-immunotherapy)

Novel therapies then immune therapies including HSCT or CART1

NOTCH1 targeted theory
SF3B1

Summary Test TP53 and ATM (testing functioning coming soon)

Dr. Adrian Wiestner

Novel therapies in CLL
BCR Pathway
CLL a malignancy of anti-self" B cells
BCR  repertoire is skewed
Stereotyped BCR
often recognizes auto-antigen
Binds self motifs in itself

BCR activation in lymph nodes- CLL dependent on micro-envirnoments

IBRUTINIB NO MTD(maximum tolerated dose)!

RESPONSES WITHIN DAYS

Dramatic shrinkage of nodes but persistent lymphocytosis

With just 1 dose, lymph counts  jumps 50%

Larger patient to patient variability

Different patterns

Unmutated:  high ALC count quick up and downMutated: more SLL like, slower rise and fall- more durable results?

Most of the rise in ALC is from cell redistribution at first, but clear that IBRUT does much more
Measured tumor burden falls by CT and BMB

80-90% reduction: can start with trillion of cells

Cells in peril are not a concern: When you look they have inhibited BCR and NF kappa B and low Ki-67 suggesting no proliferation

Idelalisib PI3K delta  NO MTD!

Unaffected by adverse PX  factors inc 17p especially in first yr

IBR AEs
Diarrhea
AF 5% vs 0.5%  but much longer exposure
Bleeding mostly petechiae- not significant
Grade 3 or higher  no difference in either arm
IDEL AEs
Diarrhea 30%,7% colitis
20% Grade 3 Pneumonia

46% PFS  with 17p deletion

Complex karyotype  are the ones who progress- that is the group that progresses

PFS front line 17p del is >80%

Resistance:

Mutation Cysteine 481 is the problem,- IBRUT can no longer bind covalently (still weakly binds and  has some activity) Two cases of resistance, there was activated in PLC gamma 2 downstream (gain of function)

What about progression due to Richter's transformation?

Q: Is it more or less than without ibrutinib?

In 63 cases of 17p  RT was found in 23% at median of 12 months; risk factor was complex karyotype

Maybe it's actually less risk w Ibrut

Steve Treon

Ibrutinib in WM /LPL (Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma) by 

IGM falls by 75% and Hgb climbs

69% major response in WM

Shared Decision Making, Cancer Risk Assessment, and The Doctor- Patient Relationship

Welcome to my world as a practicing physician. Here is your chance to learn of the secret sacrifices we doctors make in the inner sanctum of the temple of Evidence Based Based Medicine. 

The "joys" of mandated guideline-driven shared medical decision making come to life in a one act play.

Below Dr Kildare will welcome you to his world that we doctors and patients will increasingly inhabit as we worship at the altar of evidence based, cost effective care.

This article is about lung cancer, but the issues it raises apply to all healthcare including CLL: arbitrary guidelines, lies to game the system, the intrusiveness of the computer and electronic medical record, the farce that is "mandated" shared decision making, and the general loss of intimacy and trust in the patient-doctor relation as big government and big insurance and big medicine play a more and more invasive role in the clinic and hospital.

I am no Luddite.

I celebrate the use of technology and big data. I look at cost effectiveness when sharing decisions with my patients (or with my doctors when I am the patient), but we need to remember the human connection and to pay attention to the needs of the real person in front of us and not to some statistical metric.

This is a good read:

Here is the link and below I simply cut and pasted the text.

Thank you Dr. Grannis for feeling our pain.

http://www.cancernetwork.com/blog/lung-cancer-screening-shared-decision-making-session?GUID=4DA9CFB5-590D-4180-AC65-4071506DC6BF&XGUID&rememberme=1&ts=23012015 …

A Lung Cancer Screening “Shared Decision-Making” Session

Blog | January 16, 2015 | Screening, Lung Cancer

By Frederic W. Grannis, Jr, MD

Frederic W. Grannis, Jr, MD

A ONE-ACT PLAY

DRAMATIS PERSONAE

DR. KILDARE, a private practitioner of medicine named Sonny Kildare

PATIENT, a patient named Hiram Wrisque

It is the near future. As the lights come up, a young physician, DR. KILDARE, is seated behind a desk working at a computer in a consultation room. For dramatic emphasis, he is dressed in the white smock, pants, and shoes worn by interns during the mid-20th century. A stethoscope is draped over his shoulders.

There is a knock on the door.

DR. KILDARE. Come in.

The office door opens and PATIENT enters, stage left.

PATIENT. Good morning, Dr. Kildare.

DR. KILDARE. Please sit down, sir. For the record, what is your name and date of birth?

PATIENT. I am Hiram Wrisque. I have been a patient in this medical practice for almost 50 years; a patient of your granddaddy’s until his passing. I am not sure why this visit has been scheduled? I requested to be screened for lung cancer 3 months ago.

DR. KILDARE. Well, Mr. Wrisque…

PATIENT (interrupting). Mr. Wrisque was my daddy; please call me Hy.

DR. KILDARE. All right, Hy it is. We have scheduled this doctor–patient shared decision-making discussion because it is mandated in the Centers for Medicare and Medicaid Services—we call it CMS for short—decision of February 2015 for all patients who ask their doctors to order a screening CT scan.[1]

PATIENT. Seems like a waste of time, I have done a lot of reading on the subject, and given it a lot of thought. But if we must, then let’s get on with it.

DR. KILDARE. First thing is that we need to enter your eligibility information into this computer database. What is your age?

PATIENT. I am 65 years old.

DR. KILDARE types laboriously into his computer.

PATIENT (impatient). Look, doc, I have to get my wife to her chemotherapy, so why don’t you take this sheet of information I have prepared for you, and you can have your secretary type it into the computer later. That way you can make eye contact with me instead of that computer screen. Let me sum up what it says it for you.

First thing, I smoked two packs a day for 40 years, starting at age 10. I quit 15 years ago today, when your granddaddy convinced me that my bullous emphysema and COPD were caused by smoking, and that I was at high risk of lung cancer. I have worked since high school at the nuclear power plant maintaining the asbestos insulation. Mom and dad and my older sis all died of lung cancer. My own lung cancer was resected 7 years ago and the laryngeal cancer was radiated 6 years ago. They tell me there is no evidence of recurrence of either and that I am probably cured of both. I had pneumonia twice in the past 2 years. Almost forgot to mention that I had lots of exposure to second-hand smoke as well.

I am in otherwise good health and can even play two sets of doubles tennis a couple times a week.

DR. KILDARE. Thank you for organizing that risk information for me. It is very helpful and makes it clear to me that I must recommend that you are not a good candidate for screening.

PATIENT. What?

DR. KILDARE. Yes, although you have a number of risk factors, Hy, you don’t meet the Medicare criteria for insurance coverage because you quit smoking 15 years ago.

PATIENT. Well first thing, doc, I asked to be screened 3 months ago, and it took all of this time to get the appointment.

DR. KILDARE (defensive). I am a very busy man and couldn’t get you in earlier.

PATIENT (exasperated). I have just about every risk factor for lung cancer imaginable and very clearly have a high risk of dying of lung cancer and yet you are telling me that I can’t be screened? That’s just plain nuts.

DR. KILDARE (irritated that this discussion is taking longer than anticipated). Here, Mr. Wrisque—sorry, Hy. I would like you to read this copy of an article from Chest by an eminent physician at Memorial Sloan Kettering named Dr. Peter Bach, who also wrote the guideline on lung cancer screening for the American College of Chest Physicians.[2] He explains how you don’t meet the criteria used in the National Lung Screening Trial and that it would be irresponsible to screen you without good evidence.[3]

PATIENT (cutting in). I told you I have read a lot on the subject. I read this article, and it makes no sense to me. Dr. Bach says elsewhere that if I get screened with CT scans and they find a lung cancer, that I have only a one out of five—20%—chance of survival,[4] but all studies, including the National Lung Screening Trial and International Early Lung Cancer Action Program show that the chance of survival with cancers detected by CT screening at 5 and even 10 years and beyond is between 60% to 90%.

DR. KILDARE. Hy, you need to leave this up to the experts.

PATIENT. Don’t be condescending with me, Sonny! I even went to the Web site at Memorial Hospital in New York and entered my personal information into their lung cancer risk calculator—I am told it was written by Dr. Bach himself. It told me that my risk of lung cancer is very high, that I have a 4% chance—that’s one out of twenty-five risk—of getting lung cancer in the next 6 years![5]

What’s more, this calculator didn’t ask if I had a previous cancer caused by cigarettes. Why, Dr. Bach himself has published data that indicates that because I had lung and laryngeal cancers in the past that my risk of lung cancer is at least 20%.[6]

DR. KILDARE (now flustered). Yes, all of that may be true, but since you had the good sense to quit smoking 15 years ago, your risk is now lower.

PATIENT. I understand that, but it’s still high enough that I am greatly concerned for my future. An article I read by Dr. Robert McKenna in Los Angeles, perhaps the busiest lung cancer surgeon in the country, informs me that more than half of the ex-smokers he operates on for lung cancer had quit more than 15 years earlier.[7]

DR. KILDARE. I am sorry that you are disappointed, Hy, but the Medicare rules are very clear.

PATIENT: This shared decision-making sure seems to happen on a one-way street.

DR. KILDARE. I suppose that you could pay for the CT out of pocket.

PATIENT. Look, doc, I am retired on a fixed income and have a lot of expenses for my wife’s medical care. It just isn’t possible for me to pay for screening. What’s more, it isn’t fair to put me in this bind when people with much lower risk will be covered by CMS or private insurance. On top of that, I asked at the hospital and they told me they can’t screen me without your say-so or they might lose their status as an expert center.

DR. KILDARE (whispering). You didn’t hear this from me, Hy, but if you, let’s say, revise your time estimate (he winks) on how long ago you quit, you would be eligible.

PATIENT. You mean if I lie to you. Sorry, but that’s not the way I was raised.

DR. KILDARE (worried). I was certainly not advising you to lie. That would not be ethical on my part.

PATIENT. But it is ethical for Medicare and Medicaid to ration access to a test that can save me and other people like me from suffering and premature death?

DR. KILDARE. Well, Hy, we seem to have reached an impasse, and I certainly don’t see this as rationing healthcare. I see no point in continuing this discussion further.

PATIENT reaches into his shirt pocket and takes out a pack, a brand recognizable by its prominent red logo, strips off the cellophane covering, opens the flip-top box and extracts a filtered cigarette.

OK, doc, you leave me with no alternative.

DR. KILDARE (agitated). Wait…what are you doing? You can’t do that here; it is against the law. Put out that match immediately or I will have to ask you to leave my office.

PATIENT (blowing a smoke ring from the cigarette he has just lit). I had no other choice, Sonny. Now that I am a current smoker again, I meet the damned Medicare criteria, so please just tell your computer to arrange for my screening CT scan ASAP. Now I have to be going. You have yourself a nice day.

DR. KILDARE shrugs resignedly and begins slowly typing the order into his computer as Hiram Wrisque exits stage left. 

REFERENCES

1. Proposed Decision Memo for Screening for Lung Cancer with Low Dose Computed Tomography (LDCT) (CAG-00439N). http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=274. Accessed January 14, 2015. (Scenario assumes that Final CMS decision of February 2015 will be substantially unaltered.)

2. Detterbeck FC, Mazzone PJ, Naidich DP, Bach PB. Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e78S-92S.

3. Mazzone P, Powell CA, Arenberg D, et al. Components Necessary for High Quality Lung Cancer Screening: American College of Chest Physicians and American Thoracic Society Policy Statement. Chest. 2014 Oct 30. [Epub ahead of print]

4. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Intern Med.2012;157:571-3.

5. Memorial Sloan Kettering Cancer Center: Lung Cancer Screening Decision Tool. http://nomograms.mskcc.org/Lung/Screening.aspx. Accessed January 14, 2015.

6. Lou F, Huang J, Sima CS, et al. Patterns of recurrence and second primary lung cancer in early-stage lung cancer survivors followed with routine computed tomography surveillance. J Thorac Cardiovasc Surg. 2013;145:75-81

7. Mong C, Garon EB, Fuller C, et al. High prevalence of lung cancer in a surgical cohort of lung cancer patients a decade after smoking cessation. J Cardiothorac Surg. 2011;6:19.

- See more at: http://www.cancernetwork.com/blog/lung-cancer-screening-shared-decision-making-session?GUID=4DA9CFB5-590D-4180-AC65-4071506DC6BF&XGUID&rememberme=1&ts=23012015#sthash.sHKKeEg2.dpuf

Experience with Idelalisib (Zydelig) in CLL (chronic lymphocytic leukemia)? A chance to can help fellow patients in Canada.

I received this email today with a link to a survey for those of us who have had experience with idelalisib. It is a chance to help our fellow patients with CLL in Canada. 

The email speaks for itself. Please help if you can.

Hello Dr. Koffman,

My name is Elizabeth Lye and I am the Scientific Advisor with Lymphoma Canada. I am reaching out to you to see if you can help put us in touch with patients who may have experience with idelalisib (Zydelig) for CLL. This treatment is not currently available in Canada and Lymphoma Canada is working to help Canadians gain access to this treatment. 

If you are not familiar already, the pan-Canadian Oncology Drug Review (pCODR) makes recommendations to the provinces and territories to help them decide whether they will provide funding for new cancer drugs in Canada. Understanding the experiences of patients is a key element in the pCODR review process and pCODR allows patient groups to do this through "patient submissions".

In order for Lymphoma Canada to have a strong submission, we really need to have patients who have direct experience with idelalisib (Zydelig) to complete an online survey or to participate in an interview with one of our staff. To ensure patient privacy and confidentiality, individual responses will not be identifiable.

I am writing to see if you would be able to help us find patients to participate in our survey.  Given that not a lot of people in Canada have had experience with idelalisib, we are seeking input from patients internationally to complete our survey to support our government submission. 

Would it be possible to post the link to the survey on any of the patient forums you post to? Or perhaps you have some other ideas that may help us locate patients who have experience with idelalisib (Zydelig) for CLL.

As always, the timelines are very tight. The closing date for the surveys is April 7th. The link to the survey is: http://www.lymphoma.ca/news/idelalisib-cll-survey

Thank you in advance for your consideration of our request.

Kind regards,

Elizabeth

///////////////////////////////////////////////////////////////////////////////////////////////////////

Elizabeth Lye

Scientific Advisor

Lymphoma Canada

7111 Syntex Dr., Suite 351, Mississauga

ON, L5N 8C3

Phone 905.822.5135 x 3

Toll-Free 1-866-659-5556

/////////////////////////////////////////////////////////////////////////////////////////////////

ESH 2014: Dr. Cathy Wu Explains TUMOR HETEROGENEITY and CLONAL EVOLUTION in CLL (Chronic Lymphocytic Leukemia)

This is taken from the first of a two part interview with Dr. Cathy Wu in Greece where I spoke on the patients' perspective at a meeting of the Greek Hematology Professional Congress.

It is also a teaser of what is to come in the new website of the nonprofit The CLL Society. That CLL specific education and support site should launch in the next few weeks. It will offer much deeper and broader information and be more searchable than is possible with a blog. 

Be assured that my blog is not going away but may revert back to more of a personal blog and the place where I continue to host my candid and occasionally combative opinions and commentaries. 

Truth is that the plethora of news and emerging therapies in CLL have outgrown the capacity of my time linear blog to keep up. This new format also will offer the chances to hear other patient voices in what will be the only patient driven physician curated place on the web for CLL support and education.

I and the team of fellow volunteers are pretty excited. It's been a ton of work, but our mission is to address the unmet needs of the CLL community and we believe this new website will be a helpful piece of that effort. There is great information out there and we want to help everyone find it and explain it in our soon to be born strong and friendly CLL focused website.

Honestly, my efforts to help launch our nonprofit 510c3 and its website has consumed me, leaving less time to post here.

While we are still building phase 1 of the new website, I plan to continue to post news and interviews like this one here modified for this blog. The website will offer more links, a glossary, some surprise, and a whole lot more.

Stay tune, but I digress.

This clonal heterogeneity discussion is very important stuff on how our cancer evolves and what it means when we consider therapies.

TAKE AWAY POINTS:

·     Cancer by its nature is genomically unstable.
·     Over time it acquires more mutations.
·     New clones and sub-clones can arise over time.
·     Therapy can influence the balance and evolution of the clonal and sub-clonal populations.
·     Those changes may have significant implications for how to best manage our cancer.

PREFACE:

Hematology in general and CLL specifically are full of jargon and acronyms that can be both overwhelming and daunting.  With time and experience, you'll become familiar with the terminology and acronyms.  We will try to explain each medical term the first time it appears in an article, but we will use the true terminology so that you gain comfort and familiarity with the medical terms that you will see in your lab reports and in medical articles. We will also provide a glossary for your reference.

CLONAL HETEROGENEITY:

Dr. Cathy Wu out of Dana-Farber starts at the basics.

In the first of our two part interview from the International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment in Greece in November 2014 she reminds us that while the concept that any cancer is made of multiple populations of different cells dates back to the 70s, it is our recent ability to look deeply and quickly at the genome with next generation genetic sequencing that has really cracked open our understanding of how huge a factor this is in one’s particular CLL aggressiveness and its ability to become resistance to therapy.

We now know that questions about the presence or absence of a good or bad prognostic indicator often should not be answered with a simple yes or no.

More importantly we know that our population of our cancer cells evolves over time. Hence the need to repeat FISH and other tests when the contemplating therapy.

An analogy: In most good movies the lead protagonist has an arc to his or her character. We see how he or she changes and evolves in response to the support received or the challenges faced.

So too it is with our cancer. Unfortunately CLL is much more like a movie than a snapshot. Dr. Wu explains our cancer may evolve over time in response to therapy and other selection pressures.

Please enjoy our video interview with Dr. Cathy Wu.

If you want to dig deep, take a look at this Blood Journal abstract or this abstract from ASH 2014 or this older full text from the Journal of Clinical Oncology or this on the evolution of resistance to BTK inhibitors such as ibrutinib as just a few of the many examples of the explosion of research in this field.

Our understanding of this complicated concept is itself evolving.

I believe it is critical research with enormous implications for how we should treat our cancer. 

More to come.