Friday, November 30, 2012

Visit to Pharmacyclics to Say Thanks for their Work on Ibrutinib

I was delighted to have the unique opportunity, as a patient in one of their trials, to speak to the staff at Pharmacyclics, the people who make ibrutinib (PCI-32765), to express my thanks and to put a face and a personal story to the statistical plots.

As all us CLLers know, every point on a Kaplan Meyer curve is (or sadly was) a living, breathing soul, a mom or dad, a husband or wife, a sister or brother, a friend or co-worker with a story to tell.

I came to tell mine and to say thank you from me.

And to say thank you from my whole family.

This picture was from my daughter Heather's wedding last month in Chicago, by the lake. I am at the far left.

For me it was very emotional. I have been lucky enough to speak in front of thousands of healthcare providers and patients on CLL but now I was talking to the people who make the medicine that, in a significant way, was allowing my very act of speaking possible. Usually my slide deck comes with lots of scientific slides and a few jokes. This time it was, by design, full of personal slides, very little science (my audience was full of scientists who work on the molecule daily) and still a few jokes. 

I told my story and said thanks.

What I wasn't expecting from this small but growing biotech company based in Silicon Valley was the genuine warmth of my reception and the commitment of the team, from CEO on down, to improving the care of patients in general and those with CLL in particular. Scores of employees waited to shake my hand and introduce themselves.

I was humbled and astonished.

I am a very lucky guy.

I need to quote Gilda Radner once again.

"If it weren't for the downside, everyone would want cancer."

Remember, we are all in this together.

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Saturday, November 24, 2012

Clinical Trials: Ibrutinib (PCI 32765), GS1101, ABT199, AVL 292, CAR-T, GA101 and all the Others

At the very engaging, patient education oriented, annual Lymphoma Research Foundation Meeting earlier this month in Manhattan Beach, CLL was among the invited guest, the only leukemia with a place at the table in the three days event, because CLL is at once both a lymphoma and a leukemia. In fact the official name, CLL/SLL or Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, recognizes that dual nature. The clonal fingerprints are identical for both disease. It is just that in SLL none of the cancer has spilled out into the blood stream. Yet. This dual labeling is a good thing as it allows us with CLL/SLL access to more meds (some that are used for leukemias and some that are used for lymphomas) and more importantly, access to more clinical trials.

One of the big pushes at the meeting was to encourage those attending to consider those clinical trials. Pharmacyclics and other pharmaceutical supporters had booths and brochures explaining the trials that they are running.

Speeches from happy patients in deep and durable remissions and from cutting edge researchers told us why clinical should be a dog-eared bookmark on our web browser.

The poster boys for selling the risks and benefits of the trials to all patients with lymphomas were two early studies involving new CLL drugs (Ibrutinib and GS 1101) using the visually powerful waterfall plots that tell you about shrinking tumor burden.

Here is some of the early data on ibrutinib (PCI-32765) similar to what was presented.  I could show similarly impressive data for GS-1101(CAL 101).

Every picture tells a story. It's easy to see at a glance that for the vast majority of the patients their tumor burden shrank dramatically.

For many of the attendees this was their first exposure to both the brave new world of tyrosine kinase inhibitors and to what could a trial do for you. I was approached by a few with questions about what was this magical  medicine and how could they get in on the action.

So here is my take on clinical trials.

Now I am not talking about letting your doctor pull off a few extra tubes of blood at each visit to bank for studies down the line. Everyone should say yes to those research requests. 

I am talking about therapeutic trials.

First and foremost, you must need therapy. No matter how excited you are about a new medication, the guidelines as to when to initiate or resume treatment do not change if the therapy is tried and true, cutting edge, or experimental. Maybe 30% of us will never ever need any treatment and remissions  from standard chemo-immunotherapy such as FCR can be remarkably durable. If we don't need treatment, we don't need treatment.

Let's say we do need therapy and we are doing the research to find our therapy choice. Here is where my advice about picking our team of experts becomes so critical, because without a CLL guru at the helm of our ship, we may never know or have easy access to all our options. Each of the top guns in CLL aspires to be the one who discovers the next big thing, and so expect there to be some bias towards his or her own trials. This is not entirely sinister as it is what they know best, and if we are seeing that doctor already, odds are a trial at his or her facility is going to make a lot more sense than traveling across the country for a similar option with all the risks of infections, and all the expense, stress, and just inconvenience that flying and hotel rooms entails. Ask me, I am an expert with trips from Orange County to Columbus Ohio every 3 and 1/2 weeks (and there are no direct flights). 

Still, there might be a better option at a distance. It is incumbent on us to do our own research on the web and at clinical That was certainly the circumstances in my case where my only option for an ibrutinib trial was across the country. Is it fun? NO. Is it worth it? YOU BETCHA!

When we are considering a trial, understand this is not a DIY therapeutic tour, but a tightly scripted and heavily escorted guided tour. This is important. Our appointments, biopsies, and CT scans are part of a rigid schedule, and if we don't like it, well, we can always leave the trial. We shouldn't enter a trial expecting it to change to meet our particular needs. When change comes though the IRB (Institutional Review Board), it is never quick and is always very conservative. They are watching out for our safety, but are also very sensitive to not corrupt the data by changing the rules midstream.

Understand what our insurance will pay and what it will not. Often the only costs covered by the trial sponsor is the medication and special blood tests that monitor its levels. How they get away with saying that a CT scan every three months is usually and customary care for CLL and that we and/or our insurance are responsible for the costs is beyond me, but somehow they do .

Look at what doors this trial might open, and what it might close. Having had a transplant as I have shuts off a lot of options. Will the treatment in the trial preclude further treatments or trials?

If it is a multiple arm trial, we need to be comfortable with all the possible options. Are they all realistic for our circumstances or is one arm a straw man chosen because it will be easy to best and represents nothing that we would ever consider? Can we live with letting a computer program randomly decide whatever treatment we will get?

Does it offer a cross-over if we don't respond to the arm to which we are randomly assigned? I believe that less CT sans and more cross-overs would go a long way to increasing the dismal rate of enrollment in most cancer trials in the USA. Why these are persistent sore issues will be a topic for a follow-up post.

Remember we are starting with the premise that we need treatment, so we can't compare the trial option to doing nothing. We must compare it to what we would do if we weren't in the trial. And that's the rub.

Honestly, despite these caveats, for many relapsed and most refractory CLL patients and for nearly all those with 17p deletion (like me), a trial is often our very best option. It is what I chose. And I am sure glad that I did. My circumstances would likely be very different if it weren't for Clinical Trial NCT01217749 at OSU and my daily 420 mg of ibrutinib.

Another point. We should not think of trials just as a last resort when we are knocking at heaven's gate. It is sadly so rare that such a miracle save happens. Trials are much more likely to be helpful at earlier stages of the disease.

Let's be honest. If the existing therapies were so great, the pharmaceutical companies, the universities, the NIH and all the researchers would not be trying so hard to come up with new ones and there wouldn't be the 1274 CLL trials listed on For comparison, strep throat is an illness we nailed decades ago with penicillin and there are only 31 trials listed, nearly all dealing with special populations such as HIV. Most of us with CLL need more research to get us better help, but for the vast majority of us with a strep throat, there are already easy cures.

What I am saying here is that is a desperate need to move the therapy ball forward, to improve our story. As Dr. Susan O'Brien succinctly said: "Those who need treatment for CLL will die of CLL."  Maybe not the cold truth we wanted, but if we are ever going to change that reality, it will be through clinical trials. Conventional therapies, as good as they are, will never change that paradigm. New treatments or protocols are our only hope for a cure.

That's why small phase 1 trials, where there has been an encouraging signal from animal and cell line studies, and now we need to know about dosing and toxicities, make more sense in CLL than in CML where options are already pretty good.

Phase 2 trials are great as there is more experience with the new drug, and now the research is looking at efficacy as well as adverse events. Sometimes the new therapies are used on their own or combined with other standard medications and sometimes new dosing schedules or combos of only already approved drug are tried.

The phase 3 trials are usually the ones that compare the new therapy to standard care and often involves hundreds and hundreds of patients from multiple sites. These are the easiest to find and enroll as they are usually big, but there can be very strict inclusion and exclusion criteria.

Truth is that we help with advancing knowledge whether or not the trial brings us any direct clinical benefit. While it's a good feeling to be beneficent, it is a much better feeling to be beneficent and healthy. Choose carefully. Ask for help.

Today, in CLL, they are so many promising choices in trials. The late Dr. Hamblin implored us to think laterally and trials are one of our best way to do that. 

Last point. With the increased understanding of the biology and structure of the cancerous CLL cells, the new targeted therapies that today are only available in clinical trials are often a better bet or at least an equivalent option when compared to the less specific existing chemo-immunotherapies. In other words, while we are lab rats when we enter a trial these days, odds are improving that we will be long lived lab rats.

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Thursday, November 22, 2012

No Bloody Nose is Going to Spoil my Thanksgiving

Acting on the advice of Dr. Byrd, last night I went out and after some research bought a warm mist humidifier for our bedroom. I was already using Bactroban ointment daily in the effected nostril to keep the tissues moist.

This morning, I woke up with yet another nosebleed, minor, easily controlled, but unpleasant, inconvenient, and unpredictable.

Doesn't my nasal mucosa know that I have work to do, patients who are counting on me being at my best, family and friends with whom I want to be fully engaged, and important pending lectures and meetings that are the culmination of weeks of work, months of planning, and years of being aware. 

A stuffy nose is no fun and doesn't help my focus, but my real concern is the unpredictability. Will it reoccur when I  walk into an exam room or onto the stage? 

I preach to anyone who will listen that control is an illusion, that life is random, and that it is how we cope with the challenges that is the measure of our mettle. Maybe I need to pay better attention to my own rants. And maybe I should consult my reassuring ENT specialist to see if there is a nasal vessel that needs to be cauterized.

Will my nose be my Waterloo, my Achilles tendon? I doubt it. More likely it will turn out be just a speed bump  rather than a dead end.

So it was particularly timely that today I received these warm wise words of my fellow CLLer.

"Feeling gratitude can be hard in the face and aftermath of super storms or
the diagnosis of a cancer. Frank evidence that life is fragile and that we
are temporary.

But again and again we see how adversity restores our awareness of the
beauty in the world and the value of our relationships to one another. 

Happy Giving Thanks day to all. 

~ Kar

Patients Against Lymphoma
Patients Helping Patients

Thanks Karl

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Wednesday, November 21, 2012

Growing our Own: Family, Friends, Ibrutinib and Green Tea: Many Reasons to Give Thanks

Our flushing Camellia Sinensis (tea trees)

I have many reasons to celebrate my favorite secular holiday of the year, Thanksgiving. It is a good time to pause with family and friends, perhaps before the festive meal begins, and go around the table and have everyone reflect on all that brings us joy and purpose, all that makes us thankful.

I am blessed with a close and loving and expanding (through marriage and babies) family, amazing friends nearby and on the other side of the world, meaningful and rewarding work, year round access to, and better yet, the ability to grow our own tasty local organic vegan food (and soon make meaningful amounts of my own delicious green tea), the chance to travel and lecture in supposedly pedestrian towns that always turn out to be full of new experiences and friends, teachers and cultural opportunities that expand my vision, and maybe, just maybe, getting my health back, my chance to keep going, to do more, and to grow old.

I am so grateful for the opportunity to be a lab rat. Yes, I complain about the CT scans and all the travel, but honestly because of Clinical Trial NCT01217749 that gave me access to ibrutinib, I am here and well and celebrating with a mind that is not convulsed about my next treatment choice or about a looming unexpected twist in my health. I have a real shot at physical redemption. I am thankful for all the help I got from my case managers and my medical group (St Jude Heritage Medical Group), the entire medical and trial team at OSU, and my family, especially my wife for making this all  happen. 

It is possible to live in gratitude and sickness at once. Some of us with cancer must do this for long chunks of our lives, but it never easy and never the most desirable. Ghandi simply said: It is health that is real wealth and not pieces of gold and silver. While I have posted extensively on living with bad news and sickness, it has always been with an eye on the prize of getting better, of being well.

My next post will discuss the risks and benefits of clinical trials, both from my personal perspective and from what I learned at the Manhattan Beach Lymphoma Research Foundation Meeting a few weeks ago.

But first, I will enjoy a down day of turkey less vegan feasting with my family.

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Monday, November 19, 2012

Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in CLL/SLL Patients and Has Minimal Effects On Platelet Aggregation

Apparently, judging by some of the emails that I received, my epistaxis (bloody nose) generated some general concern, so I am glad to be able to say that I am no longer walking around with a tissue at the constant ready, and more importantly, I have some reassuring research to share from an ASH 2012 abstract.

No less an expert than Dr. Mohammed Farooqui from the NIH did the study titled Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Patients and Has Minimal Effects On Platelet Aggregation without any pharma support that looked at not only at platelet counts, but also how well they actually function or aggregate, a critical step in clot formation, and other measures of their activity. He found what yours truly had suggested in my last post.

Although grade 1 or 2 (mild or moderate and not dangerous or disabling) bruising is a known adverse event seen with an ibrutinib, Dr. Farooqui found in looking at 25 volunteers in the NIH trial who were taking 420 mg a day that " This preliminary report does not identify any significant ibrutinib effect on platelet function." Equally important, platelet counts rapidly improved. He concludes by saying something very similar to what I gathered from the old literature that I referenced in my last post:  A rough day: Bloody nose times two and a tender rash minutes before my CLL and MDS lectures in Chicago. I quote the last line of the ASH abstract: "The apparent functional tolerance of BTK inhibition in platelets is likely attributable to redundancy in the affected signaling pathways." What I said was "there are also clearly redundant pathways and signaling to get a healthy thrombus going in response to an arterial injury."  Like minded, except Dr. Farooqui has the lab data to support his finding.

Here's another thing I really liked about his abstract beside the reassurance on the platelet issue.

"This work was supported by the Intramural Research Program of NHLBI, NIH. We thank our patients for participating in these research studies." 

They not only funded the research themselves because they thought it was important, but they thanked the patients. That is so rare and so welcome. I would have to call Dr. Mohammed Farooqui and his team at the NIH (including my old friend, Dr. Wiestner) mensches (Yiddish for a good people).

Now you might argue that I should have read all the ASH abstracts that mention ibrutinib by now and you would make a good point. I am therefore most grateful to the reader who pointed me to this particular research after reading my last post. In my defense, I have been a tad busy with travel and teaching. I guarantee that all the ASH abstracts that mention CLL will be read with more than a few reviews presented here over the next few weeks.

As my more constant reader can perhaps tell from my upbeat tone, I am feeling much better with not only no more bloody noses or other issues with which to deal, but thankfully with a rested mind and body.

Nothing like a good night's sleep and being home again with my wife and cat.

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Saturday, November 17, 2012

A rough day: Bloody nose times two and a tender rash minutes before my CLL and MDS lectures in Chicago

I am all better now, but yesterday after finally catching up on some desperately needed sleep in my Chicago hotel, in the bathroom in the morning, I had a nasty sudden bloody nose that wouldn't stop until I applied 20 minutes of direct pressure with both hands.

It was reassuring to know that my platelets had just been checked the day before at OSU in Columbus and were nearly 400,000 so I knew it wasn't my ITP returning, but could it be some platelet dysfunction related to one of the many meds that I was taking? Use of coumadin excludes you from an ibrutinib trial due to possible increased bleeding risks, but was there a concern if you weren't on a blood thinner? Aspirin and other anti-platelet drugs are OK so the concern may be very specific. Being the information hound that I am, I reviewed some old articles on the subject. A study in Blood (2000) looked at the platelets in patients with XLA (an X linked congenital lack of BTK) suggested "These results suggest either that the Btk/Tec family kinase activity is dispensable to platelet function or that there is sufficient Btk/Tec kinase functional redundancy to rescue signaling in specific receptor pathways." In other words, BTK inhibition may have some effect on platelet function, but it is not critical. Another article in the same journal (2006) states: "In summary, the data presented here demonstrate the previously undocumented and critical role of Btk in bt/VWF-induced signaling in vitro and GPIb-dependent stable thrombus formation in vivo." This seems to suggest BTK may play a significant role in proper platelet function. Current Biology in 1998 concludes: "Our results demonstrate that Btk is important for collagen signaling via GPVI, but is not essential for thrombin-mediated platelet activation." I don't pretend to understand all the nuances of these reports, all of which are several years old and predate the era of BTK inhibitors and none of which were studying ibrutinib or any other BTK inhibitors. Rather, they were looking at the platelets of patients born without BTK. Still the data seems to suggest there is a definite role for BTK in clot formation. However,  I am not sure that it is clinically important as there are also clearly redundant pathways and signaling to get a healthy thrombus going in response to an arterial injury. 

Every trial visit I am asked about nosebleeds and bruising, so there must a need for some vigilance. But then again I am also asked about a myriad of other possible problems. That's why we do trials, to find out the benefits, and the risks.

I had no other worrisome bruising or bleeding issues, so I practiced my own advice and tried to under react.

After the bleeding finally slowed down, I needed to rush to clean up, shower and dress in a a blood red sweater and black jeans to give my CME lecture on MDS (myelodysplastic syndrome) to about 250 primary care providers in Chicago.

It all went well, but I had to fight the urge to sneeze more than once while on the stage.

My day wasn't done. The next speaker in the line-up, a good friend who is an expert in dementia wasn't feeling that well with stomach issues and asked if I could hang around and perhaps switch times with him and go on in his slot. As it worked out, he spoke as planned, so I went upstairs to my hotel room to rest and to quickly email Dr. Byrd who quite sensibly blamed the dry air of the plane and the hotel heating system and not the meds. He did not think it was a significant issue. Further reassured, I took a very short power nap, woke up early for my CLL lecture with a second milder more easily controlled bloody nose and just made it down to the stage for my final 90 minute presentation.

Ironically, the lecturer-friend on dementia who was at the podium between my two talks had to briefly leave the stage because of his gut issues and the moderator needed to jump in with the save. Fortunately Alzheimer's Dementia was one of her areas of expertise. She however warned me I was on my own, as she was not prepared to talk on CLL if I exited the stage with a Kleenex pressed against my nose.

The lecture was uneventful and well received and I hung around to answer questions including one from a doctor whose husband is enrolling in an ibrutinib trial. Today I am feeling fine. A tender mysterious rash came and went on my nose last night (maybe from all that pinching to control the bleeding), but I have had no other issues.

A bloody nose can be a harbinger of trouble or a false alarm, but in either case, it is startling, annoying, messy and inconvenient. It all made for a dramatic and stressful day, but all's well that ends well and it was ultimately of no consequence. If Dr. Byrd isn't worried about a bleeding issue, either am I.

Still I will be glad to be home tomorrow.

Labs were just great at OSU. My counts are all essentially normal on ibrutinib. No nodes to be felt. Anywhere. Like the vast majority of patients, I am responding well. Without a CT scan or bone marrow biopsy, you could not tell that I have CLL. And maybe soon, even those won't show any evidence of my evil clone.

I will soon be reporting on important issues from the Lymphoma Research Foundation Meeting that took place in Manhattan Beach last week, and I will be going to ASH this year, so watch for some newsy posts soon.

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Monday, November 5, 2012


My daughter Heather was married to Tim Post last week in Chicago and I will posting a bunch of photos over the next several weeks.

I completely and totally forgot about my CLL for the week in the Windy City. For the gift of not only reaching that blissful day, but to be able to do so with no foreboding or malignant shadows but with hope and joy was a double blessing.

But my hope and joy couldn't hold a candle to that of my daughter and new son-in-law.

It was all so wonderful.

Here's a few picture to give you the flavor of what it was all about. The best is yet to come.

There are a ton more by the wonderful photographer at

I highly recommend her.

The ceremony by Lake Michigan

Patty Singing at the Ceremony
                                                         Father Daughter Dance    


Saturday, November 3, 2012

Now a Word from the Creators: The Team who Designed and Synthesized the Molecule now called Ibrutinib

I was thrilled to the marrow to find the following email in my inbox.

I redacted two name as I do not yet have their permission to thank them personally.

I am hoping to talk to the team leader and post more on the history of the drug's birth and evolution. 

It takes more than a village to make a new drug and I am living in gratitude to so many, known and unknown.

Here's the first email (with very minor edits to protect identity):

Dear Dr. Koffman,

A former colleague just posted a link to your blog on his Facebook page. I'm happy to read of your positive response to ibrutinib.

Both of us were part of the team that discovered ibrutinib at Celera in 2005. One of my direct reports, Dr. X1, first designed and synthesized the molecule which we believed would be an inhibitor of Brutons Tyrosine Kinase (BTK). This enzyme plays a signaling role which we hypothesized is important in Rheumatoid Arthritis and cancer. Preclinical testing in animal models of RA and cancer cell culture looked very promising. Several months later, Celera shut down its pharmaceutical program and sold the rights to Pharmacyclics who subsequently advanced it into clinical trials.

My old team at Celera has since widely dispersed. Dr X1 is currently (teaching at a University in) China. Several others are no longer working in drug discovery due to massive lay-offs and changes in the US pharmaceutical industry. I am now with the National Cancer Institute and our former team leader (who posted the Facebook link) now works in Australia.

We are all thrilled to see that our molecule survived Celera's shutdown and has made it to the clinical setting. Words cannot express the joy we feel knowing that our work is positively impacting the lives of people like you. 

I hope for your continued recovery and will follow your blog with great interest.


Paul Grothaus, PhD
Bethesda, MD

Excepts from his follow-up email:

My former boss, Dr. X2, was the one who pointed me to your blog, he also told me that he had written to you as well. X2 was the one who coordinated the overall project and could best inform you about the drug's discovery and development at Celera. I was more directly involved in the chemistry rather than the biology of the compound. Of course, Pharmacyclics really deserves the credit for discovering its oncology applications and pushing it forward to the clinic. Development of any drug is really due to the work of many individuals, many of whom never really receive much credit or compensation. One doesn't go into this field expecting those, it's for the science and the hope that you find something useful. The dream of every medicinal chemist is to find a drug that makes it to the clinic and helps patients. We're all excited to have been part of that.

Best wishes for you and all cancer patients.


It is amazing to think that this molecule did not even exist in the universe until it was manmade only seven years ago, around the time that I was being diagnosed with CLL.

Like most breakthroughs, it began with a risky new idea and will only end with years of hard teamwork.

So many steps could have been missed. This molecule could have been less than a footnote to another company's shutdown and my story and that of so many others might be radically different and most likely less positive. Instead, through a path of fortuitous decisions, it is rapidly traveling forward to FDA approval for cancer treatment. I also hope I can learn more about from Pharmacyclics about how they moved the process on.

I am so lucky to have hitched a ride on part of this journey.

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