Dr. Jeff Sharman on some interesting clinical trials for CLL, an important Canadian survey, and much more

This week in the Clinical Trials/The Basics section of the CLL Society website, we’ve posted an interview with Dr. Jeff Sharman where we talked about how clinical trials are developing. We also reviewed some very important things that patients should know and do regardless of whether they are being treated within a trial.
You can read a summary of our discussion and watch my interview with Dr. Sharman here. http://cllsociety.org/2016/06/dr-jeffrey-sharman-best-practices-new-cll-trials/
For Patients Who Have Been Treated with Venetoclax: Lymphoma Canada is preparing a submission for the pan ­Canadian Oncology Drug Review (pCODR) for Venetoclax for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have received at least one prior therapy; this includes patients with 17p deletion.You can help by completing their survey, which will provide us with the patient input required for the submission. pCODR uses this information to help them make recommendations to the provinces and territories regarding funding for new cancer drugs.You do not need to live in Canada to complete this survey. You can access the survey here. https://www.surveymonkey.com/r/PSPKRHK Consider taking the time to help out your fellow CLL patients in Canada. Thanks.
NEXT WEEK: We will be publishing the next issue of The CLL Tribune. You can look forward to:
· Reading/viewing an interview with Dr. Jeff Jones about Venetoclax from the recent EHA meeting in Copenhagen in Conference Coverage
· Read answers to reader questions by Dr. Rick Furman in Ask the Doctor
· Learn about what bone marrow does in The Basics Section
· In Beyond the Basics, find out about the ASCO sponsored TAPUR trial which is looking for new creative uses for already approved targeted therapies
· Learn new facts about CLL in the Did You Know section
· View some data from our most recent Reader Poll and share with us your opinions on CLL experts and whom you might recommend to other patients in our Ask & Tell section
In Living Well with CLL, you can read about:
o  WhyYou Should See a CLL Specialist
o  How my Support Group Saved my Life
o  I Don’t Have CLL. Yes, I Do. Now, I Don’t.
o  On Being a Novice Patient
o  May I Remember Never To Forget
Stay strong.
We are all in this together.
Brian Koffman, MD
Volunteer Medical Director of the CLL Society
http://cllsociety.org

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

ASCO 2014: Dr. Sharman Reviews the Results and Implication of a Single Agent Obinituzumab Poster in CLL (chronic lymphocytic leukemia)

Another audio interview from ASCO 2014, this time with the ubiquitous Dr. Jeff Sharman, who with his work heading up a large national CLL/NHL research group, has brought us several important clinical results that has advanced our understanding of treatment options and provided directions for further research.

Here he is part of a group with Dr. Joe Flynn as the lead author, studying two different doses of the  fully humanized monoclonal type II antibody directed against CD20 (same target used by rituximab and oaftumumab) known as obinituzumab, also known as (AKA) GA101and AKA Gazyva used in this trial as single agent.

The abstract shows a strong trend to a better response with the higher dose, especially as regards complete responses. This is not surprising when we know from a dose escalation trial of rituximab published in 2001 from Dr. Susan O'Brien (mentioned in the interview by Dr. Sharman), that when it comes to antibodies, more is better.

Makes sense based on what we know about how these antibodies work. There are billions of B cells and only so much antibody. When they are all "bound up", there are none left.

There is also research now looking to see if there is similar dose response relation with CAR-T therapy: the more chimeric T-cells, the better, though the story here is much more complicated as it seems CAR-T cells are serial killers.

Dr. Kipps and I also discussed this same paper and the difference between Type 1 and Type 2 antibodies here. Dr. Jennifer Brown discusses earlier research on GA101 at ASH 2013 and the different types of antibodies here. And here are the details of its FDA approval and some of my comments only published only a little more than a year ago.

And if that's not enough background, here is an editorial from Blood 2012.

What a great year it has been for those of us touched by CLL! We are all on a fast moving train and while cure is still a distant light in the tunnel, long lasting low toxicity disease control for most of us may be a whistle stop that we blown past some time without even noticing some time last year.

Here's hoping.

Enjoy the audio interview with Dr. Sharman.


Thank you for putting up with all the pops and hisses again. I promise that they will be a thing of the past once I finish uploading the audio from ASCO 2014 and move forward to ASH 2014 and beyond.

Stay tuned as we have big plans that I will be announcing here soon that will improve our options for education and support for all of us with CLL and related B cell lymphomas in the near future.

FDA Approval of Idelalisib (or CAL-101 or GS-1101 or now Zydelig) for CLL (chronic lymphocytic leukemia), SLL (small lymphocytic lymphoma) and FL (follicular lymphoma)

ME AND A GIANT TREE

SEQUOIA NATIONAL PARK

It was another good week for those of us with CLL/SLL and our friends with Follicular Lymphoma (FL).

CAL-101 AKA GS-1101 AKA idelalisib AKA Zydelig (See Dr. Sharman's post on the name game and his positive early experience with the drug) was approved last week by the FDA for relapsed CLL patients who would be consider candidates for rituximab (R) and for FL and SLL patients who have had 2 prior therapies.

I quote from the label:

----INDICATIONS AND USAGE---------------------------

Zydelig is a kinase inhibitor indicated for the treatment of patients with:

            􏰅  Relapsed chronic lymphocytic leukemia (CLL), in combination with 
rituximab, in patients for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities. (1.1)

            􏰅  Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients 
who have received at least two prior systemic therapies. (1.2)

            􏰅  Relapsed small lymphocytic lymphoma (SLL) in patients who have 
received at least two prior systemic therapies. (1.3)

Let’s pause and consider this.

A few things should catch our attention and this post is about parsing this first part of the label..

First idelalisib is approved as mono-therapy for SLL or small lymphocytic lymphoma (and FL), but not CLL. With CLL it is only approved for use with rituximab. Moreover, for CLL we can use it on label if we have relapsed after one treatment, but for SLL (and FL), idelalisib must be at least our third therapy.

But aren’t CLL and SLL essentially the same disease? Though we may be starting to tease apart the biology of this pairing (see this article expectedly from Serbia: (Possible role of CD22, CD79b andCD20 expression in distinguishing small lymphocytic lymphoma from chroniclymphocytic leukemia; Danijela Jovanovic, Predrag Djurdjevic, Nebojsa Andjelkovic, LjubicaZivic Contemp Oncol (Pozn) 2014; 18 (1): 29–33 DOI: 10.5114/wo.2013.38570), in almost all practical circumstances, there is no distinction between CLL and SLL and we treat the two diseases as one entity. Until now, with perhaps the one exception to consider possibly curative surgery and/or local radiation for SLL when it is only found in a single node, treatment was the same whether our malignant B cell clone was strictly nodal or it had spilled over into the peripheral blood and marrow.

Now, if we are going to strictly follow the language on the Zydelig label, we will have for the first time both a different indication for treatment and a different treatment protocol for CLL and SLL.

While this is an interesting point, it is probably of little clinical import as SLL recurring three times as strictly nodal would be rare. Idelalisib might be a good choice, but ironically this is exactly where I personally would want to use it in combination, likely with antibody or even chemotherapy.

Next point.

For those of us with CLL, idelalisib is approved after our first relapse. This is different than the CLL indication for ibrutinib, where we only need to have received a single prior therapy and due perhaps to an adverse reaction or intolerance, are now looking for another treatment options but may not have relapsed. (The label says: IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.) Although the most common circumstance leading to a prescription of Imbruvica would still be relapse, it is possible that some of us couldn’t tolerate FCR or Chlorambucil or other treatments and then still needing some sort of therapy for our progressive CLL, but not having relapsed, would now qualify for Imbruvica but not for Zydelig.

This too would be a rare but possible occurrence.

The last item to be considered in the “Indications and Usage” of Zydelig quoting the label again is indicated, for relapsed CLL in combination with Rituximab:

….in patients for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities.

Who are these patients? What relapsed patient would ever be offered single agent R? Hard to imagine mono-therapy with rituximab where the response rate as a single agent in relapsed disease is dismal, ironically confirmed in the idelalisib pivotal trial where only 13% of those in the rituximab plus placebo arm got any benefit from treatment.

Before dismissing out of hand this possibility, there are several realities to consider.

First and foremost, the FDA approved the drug based on the trial data it was presented.

The FL and SLL gang were two subpopulations of a larger pool of patients with Non Hodgkins Lymphoma (NHL) that were studied. The data that the FDA used was from that lymphoma patient trial where everyone had to have received at least two prior therapies to be included. Of all those studied, these two subgroups, FL and SLL, responded very nicely to single agent idelalisib, hence the language of the approval.

For the CLL trial group, the phase III study was for patients who were considered too frail based on their co-morbidities (chronic kidney disease and others) for chemo-immunotherapy and thus would be considered for rituximab alone. The results of idelalisb with rituximab versus rituximab alone were, as we all would expect, very impressive.

Are the “Indications and Usage” starting to make sense?  This is the same reasoning that that explains why we have Gazyva only approved for use with Chlorambucil.  That's the way it was studied.


The FDA approvals tend to stick pretty closely to the exact way the drug was studied and thus the pharmaceutical companies tend to reap what they sow.

This is not as crazy as it seems on first blush. It can be dangerous to extrapolate data and the FDA has been burnt too often not be conservative. I am in fact impressed with the speed and the use of the new breakthrough pathways has allowed these important novel drugs to get to market so quickly.

In fact the Zydelig label also adds:

Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

As to the actual reasons for the pivotal CLL trial design, I discussed with Dr. Sharman and Dr. Furman in this and this past post about the strong trial data that lead to approval for CLL published in the NEJM and presented at ASH 2013. There are times when single agent rituximab might be considered for relapsed disease in the elderly or frail “slow-go” patients that could not tolerate chemo-immunotherapy. While most if not all CLL gurus that you see interviewed here on my blog and quoted elsewhere on the web, would rarely, if ever use single agent R, it is the real world treatment of choice for about 8% of all relapsed patient in the community. Rituximab maintenance which I discussed a few years back in this post, is also frowned upon by most experts, but is used 9% of the time. 

So again, what seems at first to be a strange qualifier on the relapsed CLL indication label, I suspect won’t prove to be much problem to us patients.

Moreover, how the doctors prescribe them and how insurance pays for them is a whole other topic.

Once it is approved, remember that a doctor can use it however he or she wishes.

Which is a good segue to my final subjects for this post.

Before I finish on this very good news, I wanted to share even more good news by means of this link to the Gilead website that will assist any one considering this important new drug. As does Pharmacyclics, Gilead is offering to help commercial and uninsured patients with practical and generous financial support to make this expensive breakthrough drug more affordable. It is also priced a full $1,000 lower per month that ibrutinib, but that doesn’t consider the additional cost of rituximab. Still cheaper is better.

Unfortunately, like all pharmaceutical companies, even if they wanted to, Gilead cannot directly help Medicare Part D patients. They do nice job explaining the financial hit a Medicare patient faces on their website here.

What they can do is support independent non-profit organizations such as LLS that can then offer financial assistance for both eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs. On the LLS site, the income must be below 500% of the federal poverty guidelines, but for a family of four, that is anything below $119,250. 

For more details from Gilead and a number to call on how those of us with government insurance might qualify for financial aid, check here: There is of course no guarantee that help will be provided. Resources are limited, but it is certainly worth investigating.

And here is a link to active idelalisib trials. The expanded access program closed for new enrollees in the USA with Zydelig's approval, but will continue for those already enrolled. 

So in the end, good news. We all need more options, and now we have two great oral medications, both with strong help for most of us from their manufacturers to offset the considerable cost.

I will post more soon on how I see Zydelig fitting in, the the black box warnings and its strength and weakness, but for now I am just so happy we have this new weapon in our arsenal.

Thanks to all of you who volunteered for the trials that helped speed its approval. If appropriate, don't forget to consider trials for these two drugs and for several others existing antibodies and TKIs in the pipeline.

It is a good time in the CLL world and it will only continue to get better, quickly.

Only a few days later after this good news, Imbruvica was approved for front line therapy for those of us with 17p deletion. That is giant. More on that important expanded indication in another post soon. 

Much reason to celebrate as we now have two new powerful oral medications to help us live longer and better.

ASH 2013: Dr. Jeff Sharman Discusses FCR versus BR in Front Line CLL

In this interview, Dr. Jeff Sharman gives us some understanding of the important trial data presented at ASH 2013 that compares FCR (fludarabine, cyclophosphamide, rituximab), the gold standard chemo-immunotherapy (CIT) to BR (bendamusine-rituximab) the new kid on the block and very popular with community oncologists.

In the excitement and promise of the new era of gentler and more effective oral medications for CLL, there is still a diminishing group of patients that for many reasons will continue to chose a chemo-immunotherapy (CIT) approach.

One possible reason is that for a few patients with excellent prognostic factors, a significant subset of those will reach MRD negativity and for that group FCR produces exceedingly durable remissions, starting to hint a possible cure. A half year of harsh but not the worst therapy, and you're done. Time to get on with your life without any daily pill reminding you that you have CLL.

Professor Hallek discusses this special group in my short interview from iwCLL last year.  I would not be completely dismissive of the value of CIT in those special circumstances.

Sadly insurance coverage and expense will be another reason that we will still see chemo. Older drugs are cheaper than newer drugs.

And even more sadly, patients' and physicians' unawareness of the rapidly changing therapeutic landscape will limit some of us CLLer's option to what our oncologist is most comfortable with it.

A few of us won't be able to tolerate the new oral therapies due to side effects, but as more options and new TKI's are approved I suspect that will be a vanishing small number. There are also the very few patients who have progressed on ibrutinib (the only oral TKI approved for CLL at this time and available by prescription) and an unfortunate group of us who both can not qualify for a trial or who have no access to the new meds because of where they live or their insurance and who need treatment NOW and can not wait for a different option.

That said, the FCR versus BR data welcomed as it is, is hardly the blockbuster news that it would have been a few years ago.

Ibrutinib and idelalisib and ABT-199 and obinutuzumab and others have rightly stolen the spotlight at ASH and elsewhere. Their time has come, and not a moment too soon.

Still CIT is not going to quietly fade away so fast so let's look at this important ASH abstract.

This link gives the data.

This link explains what is meant by the grade of adverse events and reminds us that a grade 3 adverse event is severe or disabling, a grade 4 is life threatening and a grade 5 adverse event is polite medical talk for a side effect that kills the patients. So when we see that on the FCR, we patients had a 90% of a Grade 3 or worst hematologic side effect compared to only two out of three in the BR arm.

The price of this higher that high toxicity and small but real risk of dying from FCR was an impressive 98% overall (ORR) response rate with nearly half of those being CR (complete responses). With BR the ORR is the same but the CR is 38%. MRD (minimal residual disease) negative data was not presented. Progression free survival was better for FCR in those under 65 years old, but not in the older group.

So very impressive results, but significant toxicity. This is an old and too common story with chemo: The more toxic the drug, the better it works. FCR is better in younger patients, but comes with more risks and misery.

New targeted and biological therapies break this paradigm and that is why when we have a choice, we should be putting the emerging therapies high on lists of options.

Remember too that this trial was for front line therapy in fit patients where access to the newer treatments in even more difficult.

Listen to Dr. Jeff Sharman and get his take on this important study. Dr. Sharman is a smart, very busy and compassionate guy who has done much to help the CLL and other blood cancer community and I am grateful for the time he gave for this interview at ASH 2013.



Dr. Sharman has an excellent blog himself where he covers much of the same and even more detail on the trial here.

ASH 2013: Dr Jeff Sharman Discusses the Ideal Design of Phase 3 Trials with Novel Agent versus the Reality in the Community

As a patient, it is easy to be critical of study design.

Case in point: The phase 3 trial of rituximab (R) plus idelalisib (I) versus rituximab plus placebo presented at ASH 2013 in New Orleans.

Wait a minute, we patients scream. One arm of this trial is offering us a monotherapy option that is not recommended by most CLL experts because it produces a lousy response rate in the middle single digits. In the trial, lymph node response rate was a meager 4% for the R+ placebo versus 93% for the arm with the two active agents. And the duration of the response for the R alone is less that six months.

In comparison, in the R+I arm, median progression free survival has not been reached, and remarkably, even overall survival was improved, something unheard of in CLL just a few years ago when FCR was shown to be the first drug combination to add years to our lives.

All the data from the late breaking abstract can be accessed here. It is powerful, but one must ask, does idelalisib look so good because it was being compared to a straw man?

Is this an ethical way to conduct a trial?

Dr. Jeff Sharman, a regular on this web site, is both a community based oncologist and the medical director of hematology research for The US Oncology Network.

He points the pros and cons of the controversial trial design.

Watch the video and form your own opinion before I give you my bottom line.

First Dr. Sharman does a good job reminding us the difference between a phase 1, 2 and 3 trial.



So what do you think?

At first,  I was dismayed by the trial, from a patient's perspective, but when we have a trial design where we are pretty much guaranteed that we will get idelalisib if we need it, and in either arm we  can avoid chemotherapy, on further reflection I am more sanguine about this kind of trial.

The science bothers me more than the ethics. In the study, the results with idelalisib are very impressive and would likely have stood up to a much more active comparator arm, but in this case it was a massive mismatch as evidenced by the unheard of gargantuan P number (p = 1.3 x 10^-30 ). In other words, the odds of getting this result by chance alone was not one in a million or one in a billion or one in a trillion, but about one in 10 followed by 30 zeros.

So what is my take away message?

First, I am OK with most trials that have a cross-over built in from the get-go, and especially fond of those that offer us a chance to avoid chemotherapy.

Second, idelalisib is clearly going to be a powerful addition to our armamentarium for treating CLL. 
In this study it took on a tough bunch of patients.The median number of prior therapies was three. The test subjects were all considered too unhealthy to get traditional chemotherapy. Nearly half were 17p deleted and 17 out of 20 were unmutated. We are told that all the risk groups responded better to the idelalisib arm, but the abstracts doesn't give us much detail.

So, bottom line, unless my need to get my disease under control was so acute that I could not risk the delay in getting a response if I was randomized to the R+ placebo arm, I wouldn't hesitate to enroll in a similar trial if I needed therapy.

Based on this and other positive studies, I hope and suspect idelalisib will be approved for CLL in the USA before the end of the year. And that will be a good thing for the CLL community.

iwCLL 2013: Dr. Jeff Sharman Discusses Two Issues: 17p deletion and Residual Disease in CLL

In Part 6 of my iwCLL 2013 interview with Dr. Sharman who has a lot of experience with several of the promising new CLL agents, we look at some more unknowns.

He reminds us about how thin and immature the data is when looking at 17p deleted patients treated with either idelalisib or ibrutinib, but, and it is a big but, how encouraging it is compare to the historical data. In other word, how much much better it is than standard therapy such as FCR.

Another take away message is when we are comparing studies, make certain we are comparing apples to apples. Results with treatment naive patients will be much better than that with a group of patients who had been a round the block a few times.

And sometimes the enemy of good is better. His advice is sound and I echo it. Most of these new drugs are a great leap forward in CLL therapy. At least for now when not one of the new oral meds is yet approved for CLL, don't be too picky about which one you can get. Do your homework, follow the literature (or my blog and other reliable online sources), check clinicaltrials.gov, and make the jump if appropriate.

Dr. Sharman also raises the question implicit in the observation that those treated earlier, before we are badly beaten up by chemo-immunotherapy or by the disease itself, do much better. Should we treat with these new agents earlier?  Only more trials will tell.

And he has an interesting historical take on the issue of the residual disease.

Here I might respectfully differ with the doctor. These drugs work so differently than traditional chemo or even monoclonal antibodies, that we may need to radically rethink our assumptions about what residual disease means in terms of prognosis.

I personally hope so. My next CT will be 21 months after I first swallowed a bruton tyrosine kinase inhibitor named at that time PCI-32765, soon better known as ibrutinib or now as Imbruvica. My nodes have changed little in the last few CT scans with gut nodes hanging around 4 centimeters, so the risks associated with residual disease are not a theoretical problem for yours truly. I may have reached my "maximum response", but maybe that is not such a bad thing. Again, only long term follow up with inform us.

Here is Dr. Sharman. Please see his other videos if you haven't already. Lots of good stuff in this segment.



Part 7 soon, and more interviews to come.

On a personal note, thank you all for your kind thoughts and prayers as I battle this nasty respiratory infection.

I think I have hit bottom, and am clearly getting better, albeit slowly with levaquin 500, a broad spectrum antibiotic, aboard. I am hardly well, but I am no longer getting worse. My fear of pneumonia is fading.

iwCLL 2013: Dr. Jeff Sharman Outlines Options if You Need Treatment NOW

In Part 5 of my interview from iwCLL 2013, Dr. Jeff Sharman outlines what factors go into deciding  how to manage our disease NOW with these new drugs coming, but not here yet.

He lists many of the available trials for both treatment naive and relapsed refractory patients, focusing mostly on the two leading oral CLL drugs, idelalisib and ibrutinib.

As always your best source of finding out about the latest on the status of any clinical trials is visiting clinical trials.gov and don't be afraid to email the trial co-ordinator if you have questions. They want to hear from us. That's how they fill their trials. It is a very user friendly web site and should be part of your life.

There are some great options out there, and we need to know more. Our work is not done. We are not cured with any of these therapies. There are relapses late and early.

We need more clinical research to tell us what works best and most safely, but without us patients enrolling, all research halts.  No doubt the lightning fast FDA approval of ibrutinib, going from test tube to prescription pad in under 8 years, was facilitated by the dazzling rapidity of accrual in many of the important trials.

Please carefully consider investigating some of the promising trials of combination therapies with the better known novel agents or one of the newer less studied but very promising novel agents such as ABT-199 and IPI-145 or ONO-4059 and others.

Here is Dr. Sharman. If you haven't seen Parts 1-4 please scroll down or search under Dr. Sharman on my blog.



Part 6 and 7 are on their way.

And so are my interviews with Drs. Kay, Byrd, Kipps, Pagel and Hallek.

On a personal note, I am a touch sick again or still: a deep chesty cough and fatigue. We will see what the morning brings. If I am not better, time to break out for my "just in case" antibiotic.

iwCLL 2013: Dr. Jeff Sharman Discusses Why We Feels so Lousy with Cancer

In Part 4 of my conversation with Dr. Sharman at iwCLL 2013, we start by discussing the lousy tired feeling that sadly so many of us are all too familiar with. And even more sadly, that too many community oncologists seem not to be familiar with or in total denial about our truth that CLL could be the primary source of our achy tired feelings.

When we understand about the cytokines released by our rogue cancer cells, we begin to understand why decreasing our tumor burden with standard therapy such as FCR, or better yet, blocking those cytokines with idelasilib or ibrutinib and others, can give us back out lives.

Many questions. No cookie cutter answers.

Do the new therapies change the threshold to treat?

Dr. Sharman touches on the dilemna of mono therapy with rituximab?

If you have not seen Parts 1-3, take the few minutes to acquaint yourself with the first segments of this wide ranging interview.

Start here with Part 1 where we discuss among other things, the emerging importance of pharmacogenetics in medicine in general and cancer in particular.

In Part 2, we move on to prognostic and predictive factors and the difference

Part 3, Dr. Sharman managing high risk disease.

And a heads up, Parts 5- 7 are very quickly on their way.

And more from Drs. Byrd and Kipps and Kay and Pagel.

And then on to ASH.

Dr. Sharman was incredibly generous with his time in Germany. I am very grateful and lucky that I get to do this work.

Enjoy listening to a thoughtful expert. I did.

.

Blessings to all my American friends for Thanksgiving. There really is much to be thankful for in the CLL community this year, but until we all have a seat at the table of deep and durable remissions, we have much hard work ahead of us.

And to all my friends from the Regina and surrounds, how bout them Saskatchewan Roughriders winning the 101st Grey Cup in North America's oldest professional sports league.

iwCLL 2013: Dr. Jeff Sharman Gets Down to Discussing How He Treats Patients with High Risk Disease

In Part 3 of our conversation from iwCLL 2013, Dr. Jeff Sharman talks about how he approaches a patient with 17 p deletion.

This touches on the thorny issue of clonal evolution and the concern that treatment might lead to a Darwinian selection of the fittest, in this case the most resistant and probably the nastiest sub-clone of the CLL bunch.

Still, Dr. Sharman points out how the new biological treatments may force us to reexamine (and I do mean examine in a formal one) our long held beliefs about the inadvisability of early treatment.

Some of the new kinase inhibitors such as ibrutinib and idelalisib seem to have less of this risk, as they seem nearly as active on the high risk clones as in the more wimpy cancer cousins.

But there remains too many gaps in our knowledge to know what is the right thing to do, but we are moving forward at a rapid clip. And what may seem the best choice today, will certainly be different tomorrow.

Here's Dr. Sharman in part 3 from Cologne, Germany. If you haven't seen part 1 and 2 of the interview, please scroll down to the two prior posts.



More to come soon.

PS: I love the comment that my tie looks like gene sequencing. That made my day.

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. Jeff Sharman on Mantle Cell Lymphoma (MCL) and Coffee and Road Map.

Dr. Sharman is a great educator with a super blog on CLL and NHL (Non-Hodgkin's Lymphoma) talks about MCL.

He points out the specific challenges with MCL and why the changes coming to treatment for other B cell lymphomas such as CLL might be even more helpful in this particular nasty cancer.

While not speaking specifically on CLL, the drugs he discusses should be familiar and his explanations of mechanism of action are both clear and creative- like coffee and road maps.

I will be interviewing Dr. Sharman and many others at iwCLL, a CLL specific conference in Cologne, Germany in a few weeks, so stay tuned. Please let me know if you have any burning questions.

Here is the short ASCO interview:

Again my thanks to the team at Patient Power with whom I worked at ASCO. Andrew Schorr and his team do important work for the CLL and cancer community, and it has been a pleasure to pool our energies and resources.

ASCO 2013: Dr. Sharman on The Biology of CLL being Cracked with a Therapeutic Renaissance Underway

At the ASCO 2013 in Chicago, I had a chance to catch on camera some of the enthusiasm and optimism of Dr. Sharman.

Dr. Sharman is the director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, and a very creative and visionary doctor and a great blogger. His posts are always worth reading.

In this  interview, he clearly outlines the rationale of using the new small molecules that blocks BCR (b-cell receptor) or Bcl-2 (b-cell lymphoma-2).

He shares some of the development of third generation mAbs (monoclonal antibodies) such as obinutuzumab to turn on the immune system.  We learned in my earlier ASCO post with Dr. Wierda, immunotherapy, namely an allogeneic stem cell transplant is the only proven cure on CLL. And we have strong data from the German trial and others that adding a mAb such as rituximab to FC makes the chemotherapy better, so building a better antibody is an important step forward .

The swelling number of promising new molecules and treatment options needs to be met with an reciprocal swelling number of volunteers for clinical trials to keep the renaissance alive.

Are we already in a therapeutic renaissance for CLL?  I believe we are just in the very earliest stages of the coming change to the treatment paradigm, but we need many more bright lights to guide our way and that will only be produced by the hard work of the bench scientists and the valour of the volunteers  who enroll in well designed and patent friendly clinical research. Only then will we able to say that we have turned the corner on the "dark ages" of CLL

Thanks again to Andrew Schorr and the great team at Patient Power for helping make these interviews possible.

More soon.

ASH 2012: 10 Minute Break from the Excitement of the End of the Chemotherapy Era in CLL

Since I last posted I have interviewed Dr. Wiestner and Byrd, two of the most important researchers in moving ibrutinib forward. I also taped a long discussion with Dr. Wierda about CAR-T therapy among other things. Dr. Furman who did the phase 1 ibrutinib trial is next, then meeting Dr. Jeff Sharman.

This afternoon more lectures on ibrutinib, lenalidomide, and the first one on CAR-T.

Squeeze in the poster sessions and exhibit halls. And a visit with my sister-in-law.

Let me just summarize the news from ASH on CLL. You may not have heard it here first, but let me shout it out loud and clear.

The days of chemotherapy for CLL are ending. 

Details to follow.