ADH 2014: Dr. Sharman on Cell Death in CLL (chronic lymphocytic leukemia), a patient meeting, a newsletter and iwCLL

Friends,

This week on the CLL Society website, in our Conference coverage section, we share the second part of an interview from ASH 2014 with Dr. Jeff Sharman with a discussion of the life and death pressures on our B cells and how that relates to ABT-199. We also cover the latest research on idelalisib and rituximab, and what research in general is still needed.

I'm heading off to the International Workshop on CLL in Sydney, Australia today and will be attending sessions and doing interviews while I'm there. I'll be posting new information upon my return. Stay tuned. We are also co-sponsoring a small patient meeting with Lymphoma Australia.

Also, we will be sending out our inaugural newsletter, the CLL Tribune at the end of September. Don't miss this special collection of research news, basic CLL information, fun facts and a wealth of wisdom and shared experiences from our fellow patients. If you are receiving this information through a CLL Society Alert email, you are already signed up to receive it. If you are reading this through another source, sign up to receive it here.

For those of you in the Seattle area, we just became aware of a patient meeting that will be held on Saturday, September 26, 2015 starting at 9:30 AM at the Sheraton Seattle Hotel. Two CLL patients will be sharing their personal stories, and Dr. John Pagel from the Swedish Hospital will be providing a talk on the basics of CLL. You can call 844-482-6815 to register. Complimentary breakfast and parking are provided and you are welcome to bring a guest. You can view the flyer for the event here.
Stay strong.

We are all this together

Brian Koffman

Volunteer Medical Director of the CLL Society

http://cllsociety.org
http://bkoffman.blogspot.com

ASH 2014: Dr. Jeff Sharman Discusses the Biology of the CLL (chronic lymphocytic leukemia) Cells

I am posting here the video and comments that can also be found on the CLL Society website.

In the first of a two-part interview recorded at the 2014 American Society of Hematology annual meeting with Dr. Jeff Sharman, an important CLL researcher and helpful blogger (see http://www.cll-nhl.com), we take a step back and listen as Dr. Sharman explains how our increased understanding of the biology and lifecycle of the CLL cell has resulted in the breakthrough therapies we are enjoying today.

Take Away Points:

• Unlike some cancers, CLL is not driven by one particular activating mutation.
• B cell receptor signaling is an important driver of CLL proliferation.
• The behavior and biology of the CLL cells inside the lymph nodes and the bone marrow is very different than that of the same cells in the blood stream.
• CLL cells grow in the nodes and the bone marrow, not the blood stream.
• The differences between the biology of the cells in and out of the blood stream have profound implications for therapy.
• About 1% of our CLL cells are born and die each day.

Introduction

Dr. Sharman is a good educator and takes the time to carefully explain what is happening in the lifecycle of our cancer cells.

My more colorful and simplistic analogy comes at the end of the presentation.

Here is the video:

Brian Koffman

8/24/15

Dr. Wiestner on Novel Therapies for CLL (chronic lymphocytic leukemia), Oral versus IV therapies, Idelalisib plus Chemo-immunotherapy Update and my Lingering Cold

Our very thin CLL Society team is busy preparing for the ASCO (American Society of Clinical Oncology) 2015 Annual meeting which starts at the end of this week in Chicago, but we still found time to bring three diverse and instructive new topics to our website http://cllsociety.org for this week.

Today, Monday, May 25, 2015, we posted Dr. Adrian Wiestner's thoughtful and well-considered interview from ASH (American Society of Hematology) 2014 on what is known and unknown about novel therapies. You can find that here.

Expect more video interviews and commentaries from ASH 2014 over the next several weeks.

On Wednesday, the camera is turned on yours truly for my personal take on CLL topics of interest. We include the short video and an updated transcript on this week's topic of oral versus IV medications. I think you might be surprised at some of the issues and non-issues in what would seem at first glance to be should be a simple choice. I have posted extensively about the tragedies that were associated with potent oral medications before we knew about the risk of tumor lysis with ABT-199 now known as venetoclax or in the case of lenalidomide (Revlimid), where there is also the risk of tumor flare. These risks have largely been mitigated now with new dosing protocols. Please see this prior blog post for part of the story.

 This new section on the CLL Society website using monologues and text will roll out here.

And this will be only the first in a long series of instructional postings on the various CLL therapies.

On Friday, we will post an up to the minute review of and link to an important ASCO 2105 abstract about the latest data on combining idelalisib with chemo-immunotherapy. You will find it here on Friday.

Please let us know what you think, especially about my reading and the transcripts of my monologues. You can contact the CLL Society here or email directly, but the 1^st method is preferable.

We are constantly working to respond to the unmet needs of the CLL community, so we listen carefully to what you write us and try to respond as best we can.

We don't have a big production budget and team or large institutional backing, but we keep going to offer up the most robust and recent, yet still accessible information with no gloss and no agenda other than to inform our community.

Because we believe that SMART PATIENTS GET SMART CARE™

Switching to a personal update, my wife and I are stilling struggling with a lingering upper respiratory infection aka a cold that my beautiful granddaughter shared when visiting from Chicago. No fever or cough for me. With the frequent use of a Neti pot, normal saline and steroid nasal sprays and a single shot of a decongestant (and no antibiotics), I have managed to control the symptoms and survive the pressure changes in the first of several air flights.  Both of us remain “under the weather” after a full week of symptoms, but we are slowly improving.

For most of my immune-competent patients, I would never recommend an antibiotic in such circumstances, but I am not most patients and either are any of my fellow CLLers. We are all immune comprised. Our immune systems are as dysfunctional as hyperactive adolescents who are asked to focus on a single boring multi-step math problem while the rest of the vibrant world pours on around them. Like those teenagers, my immunity’s focus is weak and easily diverted to the wrong target, having lead in the past to my nasty autoimmune problem of ITP.

Tomorrow I am at Ohio State for my three-month follow up on my ibrutinib trial.

Expecting another good lab report. Usually my neutrophils jump up when I am sick at all, even with a viral illness.

I wonder if Dr. Byrd will add an antibiotic and chide me for treating myself, always an ill-advised choice.

Personal confession: I worry about my admittedly relatively mild added illness. Worrying is already too easy to do with CLL, and even more so when we are sick. URIs can lead to chest infections and pneumonia is still the leading cause of mortality in CLL.

I will be much happier when this infection is gone.

I will be home one day this week, long enough to get my every 6 week dose of IVIG.

Late in the week, I will be Orlando for less than 24 hours to lecture on anemia and gout to some 400 primary care providers. Then I fly onto Chicago for the very busy ASCO (American Society of Clinical Oncology) Annual meeting.

Rest is not in the picture. But it is a good busy and I will be with friends everywhere I travel.

I may even get to see the little girl who gave me the cold in Chicago. If we are both well.

Thanks

Stay strong

We are all in this together.

Brian Koffman

Volunteer Medical Director of the CLL Society

ASH 2014: Professor Hillmen Discusses the Trials Acceleration Program for CLL (Chronic lymphocytic leukemia)

In this week's new postings on the CLL Society website on Monday, Wednesday, and Friday (May 11th,13th, and 15th), Professor Peter Hillmen from Leeds, England outlines the sorry state of traditional trial design and the problems it creates, or more accurately the problems that it doesn't solve, for us CLL patients. Professor Hillmen heads up CLL research in the United Kingdom.

There are so many new CLL drugs and so many more possible combinations that need to be explored. And that can take a long, long time. Sadly, too long for some of us.

But Dr. Hillmen offers a practical, agile solution that is now happening in the United Kingdom.

During the three-part interview, Professor Hillmen outlines a consolidated strategy called TAP (Trials Acceleration Programme) to get us the answers we need more quickly. Trial design, surrogate markers and how well they translate with novel therapies, and statistics are explained during the course of our interview done in December 2014 at the ASH (American Society of Hematology) Annual Meeting in San Francisco.

I understand if your eyes begin to glaze over when we start to discuss trial design and statistics, but just as it is important that we know about the drugs we are getting, it is equally important that we know about trials we are getting. Proper trial design and proper rendering of the results can change and save lives.

But I will let Professor Hillmen explain it here in a direct link. His excitement and pride are palpable. Please check the CL Society website again on Wednesday and Friday for the 2nd and third parts of our interview.

As we have discussed extensively in the issue of equipoise and crossovers, trial designs must reflect the needs of the patients.

ASH 2014: Dr. Kipps Explains ROR1 and how CLL (chronic lymphocytic leukemia) is really treated in the Community

When I had a chance at ASH (American Society of Hematology) 2014 to interview my doctor, Dr. Tom Kipps, he first talked about the ROR1 trials that has recently opened at UCSD. This has been his research passion for years and is finally in trials. So far, so good. ROR1 holds the promise to be the perfect cancer target: found on our cancer cells, including possible CLL stem cells, and not on much else.

Keeping in mind that in all likelihood, a curative therapy is going to include a biological or immune approach, so it is important to know about ROR1. I have included links to more background and the clinical trials in the article.

In the second segment of the interview, Dr. Kipps discussed the findings presented at ASH on how CLL is actually treated in the real world. Guess what! It is not according to the latest guidelines. Another reason to add a CLL expert to our team.

These two interviews can be found in the conference coverage (past years) section of the website: http://cllsociety.org

Expect video updates on the website every Monday, Wednesday and Friday for the rest of the month.

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

ASH 2014: Interview with Dr. Susan O'Brien and Dr. Bruce Cheson on CLL (chronic lymphocytic leukemia)

There is much to report from ASH 2014, and this sweet interview from Medscape offers a short synopsis of some of the highlights.

Over the coming weeks I plan to fill in the details with more comments and videos, but this is a nice and succinct place to start.

There are some priceless moments, thanks to the wise and dry humor of Dr. Cheson and the honest and patient centric attitude of Dr. O'Brien.

First, right up front, I really appreciate that Dr. Cheson points out just how out of date are even the most recent CLL guidelines that were developed only a few years ago.

Are you listening, community oncologists? The published CLL guidelines are out of date.

I am glad he also asked about the secondary malignancies with chemo-immunotherapy, a question too often swept under the carpet in many presentation on CLL treatment. We know there is a small but real risk of MDS or myelodysplastic syndrome (for an explanation of the relationship of MDS and CLL from Dr. Steensma, click here), a difficult to treat form of cancer that presents as bone marrow failure, that may come along as a late and serious complication with FCR (fludarabine, cyclophosphamide, and rituximab), but we don't have much data yet on the risk with BR (bendamustine and rituximab).  Because bendamustine is a DNA damaging alkylating agent similar to chlorambucil (Leukeran) and cyclophosphamide (the C in FCR), it is likely that MDS will also present as a late, but hopefully infrequent ugly complication after BR.

What we do know already is that now that we are living longer with our CLL, we are getting more secondary cancers (click here for a reminder of our risks), especially blood cancers.

Don't miss Dr. Cheson's hand gesture when Dr. O'Brien talks about the minority of patients that do so very well on FCR, a topic that we have visited here more than once (click here to hear Dr. Hallek at  iwCLL discuss who gets the most benefit from FCR).

Another highlight comes right after the honest discussion of the follow up important trial of the two old school chemo-immunotherapies that are duking it out for supremacy in the CLL world, namely the  FCR versus BR (for more on this trial from Dr. Sharman click here). After Dr. O'Brien's honest and upbeat response, Dr. Cheson asks her, quite properly in this era of new treatment options: Do we care?

Yet another interesting moment occurs when he asks Dr. O'Brien to choose between ibrutinib, idelalisib, and ABT-199: If they were all available: Which one would you pick?

She refuses to answer.

Their discussion on the meaning of minimal residual disease or MRD negativity in the era of novel therapies is both informative about what we know but even more so about what we don't know.

Only time and trials will help sort al this out.

Dr. O'Brien has her own hand gesture when she describes just how much above 50% was the progression free survival curve for ABT-199 at 18 months. We need more data. And more time to sort this all out.

I wish I had produced this video. I don't usually see the role of my blog to share what is already available on other websites, but this is good stuff and there was much in it that cried out for commentary and context. I wanted everyone who reads my blog to have the link with it here.

Please enjoy this Medscape Interview:

CLL: It's the Best -- and Most Confusing -- of Times

Thanks for your help and support.

                                          

Good News from OSU About my CLL ( Chronic Lymphocytic Leukemia)

It is no fun to travel on Thanksgiving weekend across the country to OSU, spending hours in busy airports full of long lines of irritable flyers, but I am know that I am one lucky patient and I am grateful for my good care and my good drugs, even if it means crossing 3 time zones and leaving sunny beachy California for cold and wet Columbus, Ohio.

When I started on my ibrutinib trial two and half years ago there was a definite buzz about this new oral med that might change everything.

Well the game has changed, or more accurately is changing, and it is only going to get better with new non-chemo combos and second and third generation kinase inhibitors and monoclonal antibodies  (mAbs) offering us more and more options.

We aren't there yet, but we are moving fast (but not fast enough for those of us who need answers now) in the direction of long term disease control. Cure is still elusive, but there is now an active area of research on curing CLL, sometime inconceivable a few years back.

I am an example of the early changes.

Before ibrutinib and idelalisib and ABT-199 and now the second generation kinase inhibitors and the new mAbs came along in trials, someone like me with a failed transplant and a clone of 17p deleted bad boys had fewer choices than a vegan at a Texas BBQ stand.

Now 30 months into my ibrutinib adventure, I have a boringly healthy blood chemistry, and a mundane CBC (complete blood count) with a normal numbers of my red blood cells, my neutrophils, my platelets, and an absolute lymphocyte count of only 1.04

If you dig deep enough with PCR or sensitive flow cytometry, I suspect my cancerous clone is still lurking in the less that one percent of my B cells that still carried the signs of being part of the nasty cancerous clone gang when checked three months ago at OSU.

But as I said much to happy about it. And many reasons to give thanks.

Now with my personal good results locked in for another three months until I return for my next OSU clinic visit, I am off to ASH 2014 to bring the broader good news and to push the CLL researchers and pharmaceutical industry no to take their foot off the gas until we have a cure for us all.

Let me know if you have any burning questions for the researchers at ASH.

Life is good.