Venetoclax in refractory CLL (chronic lymphocytic leukemia) patients with deletion 17p And News about Upcoming Support and Education Opportunities

Friends,

This week in the 2015 Conference Coverage section of the CLLSociety.org we have posted my final interview with Dr. Stephan Stilgenbauer while we were at the American Society of Hematology (ASH) annual meeting in December 2015 in Orlando. We discussed his late breaking abstract on venetoclax in refractory CLL patients with deletion 17p. You can see a summary and view our interview here. [http://cllsociety.org/2016/03/ash-2015-dr-stephan-stilgenbauer-dramatic-responses-venetoclax-relapsed-refractory-rr-17p-deleted-cll/]

Last Saturday, it was my privilege to speak at The Southern California Blood Cancer Conference sponsored by the Leukemia and Lymphoma Society in Anaheim, California on being your own advocate. The CLL Society team was in attendance at our booth and it was great to meet all of you who were there. It was a super meeting.

Our first satellite support and education group launched yesterday at City of Hope, Duarte CA and I believe the 15 patients and caregivers shared and learned together. We will be meeting the third Monday of each month at 7 PM of every month. For more information, view the flyer. [http://www.cllsociety.org/docs/cohmarch2016.pdf] There is no charge to attend.

We are also forming a new patient and caregiver support meeting in Charlotte, NC. If you are interested, please complete the online survey to indicate your preferences for days and times. [https://charlottegroup.questionpro.com/] We look forward to getting started. 

There is another educational meeting coming up, this time by LRF.

April 2^nd at 7:30 AM: The Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options hosted by the Lymphoma Research Foundation will be held in Manhattan Beach, California. It will be held at the Manhattan Beach Marriott from 7:30 AM to 3:30 PM. You can find out more information and register here. [http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=9357081#location] There is no charge to attend.

In the meantime….

Stay strong.

We are all in this together.

Brian Koffman

Volunteer Medical Director of the 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.

                                            

ASCO 2014: Dr. Susan O'Brien Reviews the 3 years follow-up Data on Ibrutinib in CLL (chronic lymphocytic leukemia)

If you can handle more hisses and pops on an audio recording, you will get to hear some pretty exciting news from Dr. Susan O' Brien who incidentally is leaving MD Anderson after many years of important CLL related research and compassionate patient care to head up a cancer research team  and consult on CLL patients in my backyard at the University of California at Irvine (UCI) starting Jan. 1, 2015

During the interview, Dr. O'Brien shares the three year follow-up data on single agent ibrutinib in relapsed and refractory patients and in the elderly.

In her important ASCO 2014 abstract, published 6 months ago, the data is astonishingly good for those lucky enough to get ibrutinib frontline, the over 65 crowd, a strong argument in favor of moving it and other drugs such as idelalisib or ABT-199 upfront.  In this trial, in the treatment naive arm, there was one early progression with Richter's that was probably there before the trial even began, and the rest of the cohort remains in the happy land of PFS also known as progression free survival.

The data is still very good for the difficult to treat relapsed and refractory group, but the curve is not flat. Relapses happen. This is especial true for those of us like me with the dreaded 17p deletion, where half the patients have started to progress after a little more than two years. While this is clearly much better than anything else out there in this most challenging population, ibrutinib has not hit a home run for this group as it might have for the treatment naive patients.

Despite significant recent progress, effective long term therapies for relapsed 17p deletion still remains one of the more pressing unmet needs in the world of CLL.

Dr. O'Brien discusses what these relapses look like, and mentions a strategy that I would strongly consider, namely that even at the time of relapse, one stay on ibrutinib until a new therapy is begun, as the BTK inhibitor, even it is no longer irreversibly binding, it is still partially braking the disease progression.

Let's listen to Dr. O'Brien.


Again sorry for the audio noise. Once these final ASCO interviews are posted, I promise I will not only be notching up the quality of what you see and hear about CLL here and elsewhere, but with the help of many others, will be expanding into whole new realms of education and support to meet the unmet needs of our community. Stay tuned.

ASCO 2014: Dr. Furman Gives us Perspective on Resistance with Ibrutinib in CLL (chronic lymphocytic leukemia)

More of My Son, Ben's Mural Work

ASCO 2014 was only a few months ago, but happily the CLL world is a fast moving place.

Since this video interview with Dr. Rick Furman of Weill Cornell, recorded and edited by Andrew Schorr and his team at Patient Power, idelasilib has been approved for CLL (see this post for discussion of its labeled indication) as predicted by Dr. Furman, and ibrutinib was approved for frontline therapy in 17p deleted patients (see this post).

YEAH to both!

Also in the intervening months, new mathematical models that consider evolution of resistant sub clones have been published by Dr. Burger out of MDACC and a high powered mathematical team headed by Dr. Natalia Komorova out of UCI. (I plan to interview Dr. Komorova as we are practically neighbors in Orange County, CA). Similar research, but this time using deep genetic analysis of the cancer's evolution over time by Dr. Cathy Wu from Dana Farber was presented at AACR 2014 Hematologic Malignancies Conference last week. (I also plan to post on her important research soon.)

The issue of ibrutinib resistance may be becoming an increasingly important issue. More and more of us are doing great with our BTK inhibited, but we still have residual disease and if you are similar to me with bad markers such as clonal diversity, 17p deletion, 11q deletion, and have a history of having been heavily pretreated (I have the first three for sure and many would say the 4th with my bone marrow transplant), then the fear of a resistant sub clone starting to act out, while still not the case for most of us even with the worst of the worst disease, is based on a growing reality of a droopy Kaplan-Meier (KM) Curve. Below are KM plots from OSU published in NATURE at the start of the year that show the downward drift in progression free and overall survival for those of us that are 17p deleted. As you can see the curves are way better than anything else out there, but they are hardly perfect.

This whole resistance issue might be largely obviated in the future by moving the new therapies up to frontline status. Dr. Furman and I both agree that is the direction we need to encourage with appropriate trials and struggles with insurers to pay for these drugs in all treatment naive patients.

Dr. Furman also mentions two exciting new BTK inhibitors, ACP-196 and ONO-4059. Click on the drugs' names to be linked to their phase 1 trials. We are just in the first chapters, but it is looking that the stories they will tell should have very happy endings. Please consider trials that offer these drugs among your treatment options.

Here is my ASCO 2014 interview with Dr. Rick Furman.



As there is a small but significant cohort of FCR patients that do great for years and years, there is a much much larger cohort of patients taking ibrutinib and other small molecules, now based on more than on more than four years of data, that should continue to do well year after year.

I am so happy for all these patients.

But I worry about the minority who won't do well, who will relapse. I am not giving up on my plea: Don't leave us stranded on 3rd base- Get us to the home plate of a cure with a follow up therapy.

We discuss obinutuzumab and ABT-199 as mop up therapies and I think those are smart choices. Maybe it will be cirmtuzumab, a new ROR1 mAB discussed in my recent post with Dr. Kipps from the very same meeting. We will only find out with clinical trials.

More Good News- Update on My Lab, CT Scans, and General CLL (chronic lymphocytic leukemia) Status

My blog has veered far away from the simple telling of my story to more telling of our stories with much B roll.

I am making plans to maybe bifurcate its content in the future, but for now it will continue its happy and diverse life as a personal health blog, a home for research news and video and audio interviews with leading researchers, and a whole bunch of personal analysis and advocacy on what it all means.

I am back from Ohio State where I am still seeing the research team every 3 months and getting CT scans every six months for my clinical trial on ibrutinib. I have riffed on this being too much radiation before in this prior post that includes links to some of the basic research of radiation exposure and its risks, but Dr. Byrd argues that the few relapses he sees on ibrutinib show up first in the nodes, so he wants to monitor me with the scans.

True enough. When I relapsed post failed hematopoeitic stem cell transplant in 2008, the nodes were my canary in the coal mine showing slight growth months before my lymphocyte counts started to move up and my platelets down.

So twice a year CTs are still the plot line for my clinical trial at OSU.

Since diagnosed in 2005, I have probably had about two dozen CT scans!

Add to that the equivalent of the 20 chest X-rays annually I get from flying over 100,000 miles a year, and my risk of secondary cancer is significant. This link with a NASA produced video tells the air travel part of the story.

If you really want to worry, take a look at this article from Medscape on CT scans in NHL.

But this post is not about the danger of CT scans, but about what my last one showed and happily that was stable disease.

I still have enlarged lymph nodes but they have changed little since October of 2012, or for the last 20 of my total of 25 plus months on ibrutinib. My largest sentinel gut node near my liver was about 10 cm at its peak, 7.3 x 3.3 cm just before starting ibrutinib, 4.4 x 0.7 cm in October, 2012 after about 6 months on the medication, then it shrunk to its shortest 3.9 x 0.7 three months later and when last measured on June 30, 2014 was 4.4 x 0.4 which actually represents its lowest volume. It has been fluctuating and when you account for the difficulty of measuring mobile objects in the mesentery and near the liver, is mostly stable since its dramatic shrinking in the first 6 months of therapy. Its a long hot dog shaped node instead of the more common bean shape. The same early dramatic shrinking in the first six months and slight ups and downs since has been the tale for my other smaller sentinel nodes on the scans.

So I have pretty stable disease.

What does this mean to still have enlarged nodes and a touch of CLL in my blood (see this prior post from last April on my flow cytometry report to understand more about my numbers and disease burden)?

The CLL does not proliferate in our blood, so the disease in our nodes and bone marrow are the source of all our problems and I will ignore the blood for now.

There is good reason to believe that these enlarged nodes are still full of CLL, but that it is not proliferating, thanks to the signal blocking from ibrutinib preventing it from getting the messages from its nurse like cells and others to be fruitful and multiply. So chock full of CLL, but it's dormant.

The other more positive interpretation is that these enlarged nodes are just the scarred down skeletons of the cancerous nodes they once were, and there is no residual disease to be found. Unfortunately, I am skeptical of this more PolyAnna hypothesis, and short of a biopsy which is not going to happen, there is not way to know for sure.

So what to do to avoid waking the Kraken?

Hope my genomic instability as evidenced by my 17p and 11q deletions and my complex karyotype will continue to behave with the ibrutinib aboard and not mutate so that my magical bullet no longer covalently binds BTK and blocks its activity?

Knock down the residual disease by adding a second or even a third agent?

Be reactive or proactive?

That is the question du jour faced by many of us now and more in the future whose CLL is controlled but it is not gone now with the new medications such as ibrutinib and idelalisib.

I have probed this recurring and unanswered question in more detail a prior post, and will soon be updating my thoughts on how to avoid being left stranded on third base and not getting home to a cure.

The rest of my news is also good.

My blood counts are boring and despite dropping my cyclosporin to a token dose of only 25 mgs once a day and stretching my 40 grams of IVIG infusions to every 7-8 weeks, my ITP also remains dormant. I think the possible immune stabilizing activity of ibrutinib and my low disease burden may be the factors  that have given me this long ride with high normal platelet counts. I have not been anemic for many months now and my neutrophils and the rest of the CBC are all copasetic. My blood chemistries are in the normal range and only my very low immunoglobulins, namely IGA, IGM, and IGG give proof to that fact that I still have a B cell leukemia, albeit a very sleepy and well behaved one.

More personal clinical and general CLL news soon, nearly all of it good.

I will be posting some of my interviews from ASCO 2014, plus sharing some exciting advocacy news. Busy times.

ASH 2013: Dr. Byrd Discusses Dinaciclib and the Need for More New Drugs to Treat CLL (chronic lymphocytic leukemia)

ASCO 2014 in Chicago was whirlwind with important updates to all of us with CLL.

Since returning a week ago, it has been an even crazier pace, but over the next few weeks, I will be sharing what I learned and what we CLL patients need to know.

While waiting for the processing of the audio and video material from ASCO 2014, I am finishing up by posting the relevant ASH 2013 interviews.

In the first on a three part interview with Dr. John Byrd, my personal trial physician out of Ohio State, we look at the drug, dinaciclib, a cyclin-dependent kinase (CKD) inhibitor, similar to flavoperidol, that arrests tumor proliferation.

Flavoperidol is a potent but difficult drug to administer with a very nasty attitude. For many with 17p deletion, it was their only chance at a remission.

Dinaciclib is a kinder gentler drug, with a better safety margin or "therapeutic index".

Dinaciclib also works independent of the 17p pathway and so has potent activity in that most difficult to treat population.

The ASH 2013 abstract is available here.  I attended the oral presentation on the last day of ASH 2013 in New Orleans. Dr. Joe Flynn, also out of OSU, was the principal investigator and just one of the nicest guy ever. Another great CLL doctor we patients are blessed to have.

So what did the phase 1 trial data on these 52 most difficult to salvage patients show us with this IV drug.

Its impressive efficacy of 58% is essentially the same (57%) in the 17p and 11q group. Responses were also very durable. Tumor lysis was a small but real risk and there was one case of sepsis. The most common side effects were low blood counts (leucopenia, anemia, and thrombocytopenia). That fits with  how it works as a CKD inhibitor.

Sounds pretty good, but I bet you have never heard of it. And it will probably never become commercially available, even though it helped nearly 6 out of every 10 of the worst relapsed/refractory patients with 17p deletion who until very recently had very few real options.

It likely won't be marketed in part because it's given IV, but more importantly, because the new oral agents such as ibrutinib and idelalisib and ABT-199 and others have similar or better efficacy with fewer risks.

The bar has been set very high.

It's a business decision. Merck who owns the patent on the drug must compare the outrageously high cost to get to this new molecule to market with the shrunken market share when and if does gets there. Makes perfect sense to stop the drug development from a corporate perspective.

While I understand that every company must make decisions that are sensitive to their long term success and viability, these decision are sometimes (such as in this case) not a good thing for us patients.

As we get near the end of this segment of the interview, Dr. Byrd discusses the early research on the causes of resistance in the few patients, especially the 17p patients, that do relapse on ibrutinb. (I will have more on resistance from ASCO 2014)

We patients needs as many options as possible to help us in those desperate circumstances. Dinaciclib could have been a potent option.

I am glad that ibrutinib and ofatumumab are approved and that idelalisib is getting very close.

But we mustn't stop there. The CLL battle is going well, but it is hardly won. This is no time to let up on the research and equally important, the commercial development of these novel molecules.

Don't leave us patients stranded on third base.

Listen to our conversation from Dec 2013 on this and other topics:



There are two more informative interview segments with Dr. Byrd from the last day of ASH 2013 that I will be posting soon.

I was going to write the CLL story is in evolution, but in truth it is in revolution.

It helps me to understand these rapid changes by reviewing all the research steps that lead to progress or to blind alleys .

Due to my lack of funding, technical problems and mostly the antiquated and wrong headed ASCO policy of denying bloggers such as me access to their extensive press resources, much of my material from ASCO 2014 may be audio only recorded off site as required or the video shared through joint efforts with my friend and fellow patient advocate, Andrew Schorr and his team at Patient Power.

Despite these challenges, I am excited to be sharing the developing news from Chicago earlier this month.

ASH 2013: Dr. John Pagel Discusses the Risks and Benefits of ABT-199 and TRU-016 or otlertuzumab in CLL (chronic lymphocytic leukemia)

In the final segment of my interview with Dr. Pagel from ASH 2013, he discusses ABT-199 and TRU-016 or otlertuzumab (yet another mouthful for us to poor patients to learn and pronounce).

We have heard much already about ABT-199. Here is a link to a trial reported at last year's ASCO meeting and I have an interview pending from ASH 2013 with Dr. Seymour from Australia. At ASCO later this week, there will more news on ABT-199 with a new dosing schedule to reduce the risks of tumor lysis syndrome (TLS).

TRU-016 is another under reported therapy, a potent monoclonal antibody (MAb), much like rituximab, that is as of now only available in clinical trials. In my opinion it has not received the attention it deserves. Unlike rituximab or ofatumumab or even obinutuzumab that all target CD20, TRU-016 targets CD37. But like CD20, CD37 is also found on most mature B cells, both cancerous and benign and much less so on T cells making it is a good choice for fighting CLL. That's an important difference from Campath that binds to CD52 and destroys both B and T cells. With no T  or B cells to fight infection coupled with our already wimpy immunity, we are high risk for life threatening infections. TRU-016 did not increase infection risk in this small trial.

Here is the ASCO abstract that compares bendamustine with or without TRU-016. The number were very small, but for those who received TRU-016 there was responses in the two patients with 17p mutations but not in the two with 17p deletions. As expected, there were no responses to single agent bendamustine.

And here is Dr. Pagel:



I am hoping to sneak one or two more post before I take off for ASCO 2014 later this week.

Personal Update on my CLL (Chronic Lymphocytic Leukemia): The Good News

It's been a while since I posted on my personal medical news.

Today in Columbus, it was all good. CBC was happily and boringly normal. My Hgb still shows that I am no longer anemic. My ALC (lymphocytes) is 1.4 which is actually a bit high for me, but certainly a comforting level.

My ANC (neutrophils) was healthy. My platelets are a bit higher than normal again, but that is to be expected due my splenectomy. The spleen gleans the aging and decrepit platelets, so counts are higher when it's missing. I will take high platelets any day over the terrors of single digit counts when my ITP was raging. By the way, the accepted wisdom is that the high platelets associated with a splenectomy do not increase the risk of a blood clot, but ironically ITP which ravages the platelets does. You can both hemorrhage and thrombose with the same disease. Seems inflammation is the enemy. I refer you to the 19th century wisdom of Virchow's triad, a trusted nugget carried in the brain of all medical students. 

More on this particular topic soon with some personal revelations, but that is for another post.

My blood chemistries show my liver and kidneys are happy and healthy. The advantages of a vegan lifestyle.

Dr. Byrd would not agree to skipping my next CT scan in three months. The very few late relapses on ibrutinib that he has seen after 24 months (my two year anniversary of living with the TKI magic of ibrutinib aboard will be at 9:30 AM EST on May 7, 2014) are often subtle and begin in the nodes. With my pesky abdominal nodes, that does seem prudent despite my aversion to more diagnostic "radiation therapy". Getting the scan at the newer CT at OSU's Martha Morehouse may cut the rads by as much 60%.

Most relapses occur between 12 and 24 months, so my period of higher risk is thankfully coming to an end. 

Still my clonal instability and my small subclone of 17p deleted cells keeps me forever on alert.

What we really need is a trial for the many patients such as myself that are doing very well on ibrutinib, but are not in a complete remission (CR). How about adding in a PI3K inhibitor such as idelalisib or one of the newer ones following in its footsteps. Hit the cancer clone on two pathways at once. A pincer move. A classic chemotherapy technique, but instead on chemo, we box off the cancer with focused therapies. Next add a potent third generation monoclonal antibody (mAb) such as obinutuzumab once the rascally clonal B cells have been released from the nodes and marrow out into the open spaces of the blood stream where they are easy picking for the antibody. Finally, we add something to mess with Bcl-2, say ABT-199. All this done in a carefully orchestrated and timed dance to maximize efficacy and dodge tumor lysis (TLS) by adding the ABT-199 as the final coup de grâce to make sure the beast will never rise again, but also when the tumor load is low so the risk of TLS is mitigated.

You can't get to cure without first passing by CR and MRD (minimal residual disease) negative.

For me, this is not a theoretical discussion. This is my blood and marrow and proliferative centers in my node that are at stake.

The same applies to many others that are in similar circumstances with ibrutinib and other TKIs.

It may even make long term financial sense in that it may also be a way to limit the duration of therapy with this initial treatment intensification, but with a predicted end of treatment baked into the plan.

I don't want to wait until it's too late so I am hoping such a trial may come to pass, speedily, in my time.  

These and similar concepts are beginning to percolate out there.

What do you think?

I am wondering about bouncing such a plan off the powers that could make it happen. Right now it is a small population that would qualify for such a trial, but our numbers are growing fast.

Please give me your feedback.

"You may say I'm a dreamer, but I am not the only one."

More news, personal and general soon.

I wish a meaningful Passover to all my Jewish friends. May we all leave our personal Pharaohs behind and cross dry shod into the promised land.

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.

ASH 2013: Dr. Adrian Wiestner Discusses Prognostic and Predictive Factors, the Nuances of 17p deletion and Residual Disease

Merry Christmas.

In the second part of the interview from ASH 2013 in New Orleans, Dr. Adrian Wiestner from the NIH gives us some very carefully considered reflections on the news from the cutting edge changes in our understanding of CLL.

I first asked him to revisit the important issue of predictive versus prognostic factors that I first discussed at iwCLL with Dr. Sharman.

His review of 17p deletion, particularly for those lucky few who are mutated with 17p is very hopeful and nuanced. Listen carefully.

Dr. Wiestner suggested a cut off of 25% to define high risk 17p deletion. The reality is that it depends. While Dr. Tam's research in Blood on de novo 17p del (from the time of diagnosis and not first appearing after treatment) find prognostic significance only when more than 25% of the nuclei are missing the small arm of one of the 17 chromosome, others suggests a lower cut of 20%, some 10%, and some as low as 5% in looking at all cases, de novo and acquired, of 17p deletion. Like many subjects in CLL, consensus is lacking.

My simple take is the less 17p, the better. None is the best.

And we all know that the less disease, the better. Dr. Wiestner points out the obvious but we we need to hear it: You have to get to MRD (minimal residual disease) negativity to get to cure. What does this mean for the new drugs that rarely seem to get to CR, let alone MRD negative? Dr. Wiestner shares some thoughts.

Keep in mind also that 17p is a bad player in that not only does it not allow apoptosis (cell suicide) in response to most chemotherapy and thus rendering common CLL drugs such as fludarabine and cytoxan most ineffective, it also allows the cancer cells to mutate (genomic instability) with no controls on a clone gone bad. Add this clonal devolution to a significant population of residual cancer cells and we begin to understand why initial responses to the new agents such as ibrutinib and idelalsib are excellent, but sadly late relapses are more likely in those of us with a deleted 17p.

This seems to me to be a strong call for dual therapy for the 17p population, but whether that is the answer will only be answered with clinical trials.

Let's listen to Dr Wiestner.



We are so lucky to have a team of doctors working to solve our issues.

More interviews soon.

iwCLL 2013: Dr. Byrd Discusses 17 p deletion with Ibutinib

I need to keep this brief. I am exhausted.

As my flight was canceled, I ended up on a red eye to Baton Rouge, then took a shuttle to NOLA.

Didn't even get to sleep much on the plane. There was a medical emergency in the row next to us so I offered my help. That kept me up.

All turned out well.

Back to iwCLL

In the second part of the interview with Dr. Byrd from Cologne, Germany for iwCLL  2013, we learn his ideas of how to approach patients with 17p deletion.

I am seeing a consensus growing that for the more high risk patients, monotherapy is probably not the way to go.

That said it is important to remember that all 17p were not created equally, and some, especially in mutated patients or those wit ha low percent of cells with the 17p deletion can follow a fairly benign course.

More on that later, but let's hear what Dr. Byrd has to say on the topic.


Though it was less than three months ago, it seems like so much has happened since.

ASH today was amazing. So much to share, with important papers and informative interviews. I want to dissect out a new treatment paradigm that Prof,. Hallek is promoting.

But first I will post most of the iwCLL stuff. It is too good not to share.

Still sick and bit hoarse from all the interviews, but I will survive.

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 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: 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.

Closer to Approval for CLL? Ibrutinib Receives a Third Breakthrough Designation from the FDA for 17p deleted Patients

Here is the first part of the official press release on the third breakthrough designation for ibrutinib. This one is close to home.

The news is important, not only because it means there is another reason to believe the wonder pills will be in drug store near you next year some time, but because insurance, at least at first, will likely only pay for the designated indications, without putting up a fight.

The good news is however limited in its scope. It is only for CLL/SLL with 17p del. I don't know if the percentage of the cells that lack the short (think p for petit) arm of their 17th chromosome has been defined that will be needed to qualify. We know that 17p del tends to play more nicely at lower percentages. Not sure if the FDA gets down to that level of detail and I hope they leave that decision to a discussion between us and our doctors, as we do now when considering therapy.

What we do know is that this does not mean breakthrough designation for all of us with CLL. At least not yet.

Will it be used off label for others with CLL? Most cancer drugs are and one that in the studies so far appears to be as safe and efficacious as ibrutinib should be no exception. Who pays will be the bigger issues.

On a personal note, as one with small population of 17p deleted CLL cells, this is particularly good news, as I would have an option should my trial close or I need to leave it.

SUNNYVALE, Calif., April 8, 2013 /PRNewswire/ -- Pharmacyclics, Inc. (PCYC) announced today that the U.S. Food and Drug Administration(FDA) has granted an additional Breakthrough Therapy Designation for the investigational oral agent ibrutinib as monotherapy for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients with deletion of the short arm of chromosome 17 (deletion 17p). Patients harboring a deletion within chromosome 17 generally have poor response to chemoimmunotherapy and have limited treatment options. The presence of deletion 17p is one of the worst prognostic factors in patients with CLL.

In February 2013, FDA granted Breakthrough Therapy Designations for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) and as a monotherapy for the treatment of patients with Waldenstrom's macroglobulinemia (WM), both of which are also B-cell malignancies. Ibrutinib is jointly being developed by Pharmacyclics and Janssen for treatment of B-cell malignancies.

The Breakthrough Therapy Designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases where "preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development." The designation of a drug as a Breakthrough Therapy was enacted as part of the 2012 Food and Drug Administration Safety and Innovation Act. Pharmacyclics, together with Janssen, is working with the FDA to determine the implications of this Breakthrough Therapy Designation to the ongoing and planned development and the FDA filing requirements for the use of ibrutinib in CLL patients with deletion 17p.

The FDA Breakthrough Therapy Designation for ibrutinib in CLL patients with deletion 17p was based on data from pre-clinical and clinical studies where ibrutinib as a monotherapy was used to treat patients with this disease. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease which has a poor prognosis. In addition, Pharmacyclics and Janssen have recently initiated a Phase II study of ibrutinib in patients with CLL deletion 17p, RESONATE" -17, which is a single-arm, open-label, multi-center trial using ibrutinib as a monotherapy in patients who have deletion 17p and who did not respond to or relapsed after at least one prior CLL treatment (a high unmet need population). The primary endpoint of the study will be overall response rate. This global study opened this year and Pharmacyclics plans to enroll 111 patients worldwide.