CLLPAG Niagara Falls Conference and Survey

Paul Henderson and Me

Every Canadian knows Paul Henderson. He is the hockey player who scored the most famous iconic winning goal ever, finding the back of the net in the dying seconds of the Summit Series in 1972 against the Russians, a defining event in Canadian identity.  For non Canadians, think Olympic Gold, the Word Cup, Wimbledon, the Masters, the SuperBowl and the World Series all wrapped into one. His goal surpassed all that. Turns out Paul is a sweet guy who is not shy about using his fame to help others who share his diagnosis of CLL. We met at the CLLPAG conference.

The CLLPAG conference in Niagara Falls was wonderful in so many ways, and not just for meeting a hockey idol.

First it was great to see so many old friends and make new ones in the CLL community.

As I have said before, if it wasn't for the downside, everyone would want cancer.

People may have left with different levels of understanding of their disease, but everyone left with a clear and strong sense that they were not in this alone. It was an enormous group hug for everyone involved.

That said, it was not just about feeling good. The world class and world wide faculty presented both the medical basics and the latest for a crowd of over 200 that included many newbies and more than a few pros.

Patients and patient advocates addressed the cold and complex psychological, social, financial, and political realities of the disease and its cost in the broadest sense of the word.

Still, the overall sense was hopeful. The CLL world is changing very fast, for the better.

Thanks to Deborah and all the volunteers and faculty who all donated their time. Amazing success.

I will leave for my next post an update on the promising new science, my vision for the future, and a reprise of my own presentation. Actually, that will take a few posts.

Before that I need your help.

As part of an effort to bring together an more informed and participatory patient group, I am surveying fellow cancer patients and their caregivers  about what they would want on their smart phone or IPAD or computer in an app to have with them at all times when dealing with their malignancy.

So please, please complete a very brief online form at http://www.virtualcancerbuddy.com/ if you didn't do one already at the conference. You don't need to have been to CLLPAG or even have CLL to share your needs. You just need to be a cancer patient or a caregiver of a cancer patient.

We are truly and eternally all in this together.

Snow

Picture from the road in northern 

 Pennsylvania on April 23. 2012

The CLLPAG conference in Niagara Falls, Canada was amazing, full of promising news and good feelings.

My presentation was warmly received and I have been asked to post it here which I plan do soon.

The drive back to Columbus Ohio reminded me of many roads trips along the "401" from Montreal to Toronto in the Canadian winters in the 70s and one of the reason I now live in southern California.

It is not supposed to snow in late April.

Possible Clarification on the Pivotal Trial of Ibrutinib (PCI-32765) Concerning 17p deletion

Based on some excellent detective work done by some of you who read my blog, it looks like all the pivotal trial is asking for is that you have confirmed your 17 p status.

In other words, you must to know if you are 17 p deleted or not before you start in the trial.

Either way, with or without the deletion, you are OK to enroll if it is otherwise a fit.

That makes more sense. It was a big unclear from reading the exclusion list at Clinicaltrials.gov.

The comments that follow my last post make it clearer

Please read them.

New Clinical Trial for Ibrutinib (PCI-32765): Exclusion Criteria and More

The phase 3 pivotal trial to get ibrutinib (PCI-32765) approved by the FDA is gearing up.

A Phase 3 Study of Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE™)

This is big news.

Let me get personal first.

My prior failed transplant would have knocked me out of any chance at the drug in this and maybe any other trials until approval.

Please read the exclusion criteria for this critical study listed below.

Exclusion Criteria:

• Known CNS lymphoma or leukemia.
• No documentation of cytogenetic and/or FISH results reflecting 17p del status in patient records prior to first dose of study drug.
• Any history of Richter's transformation or prolymphocytic leukemia.
• Uncontrolled Autoimmune Hemolytic Anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP).
• Prior exposure to ofatumumab or to ibrutinib.
• Prior autologous/allogeneic transplant
• History of prior malignancy, with the exception of certain skin cancers and malignancies treated with curative intent and with no evidence of active disease for more than 3 years.
• Serologic status reflecting active hepatitis B or C infection.
• Unable to swallow capsules or disease significantly affecting gastrointestinal function.
• Uncontrolled active systemic fungal, bacterial, viral, or other infection.
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
• Requires anticoagulation with warfarin.

Exclusion Criteria: Prior autologous/allogeneic transplant

I would be out of luck and running low on options, but instead I am so fortunate because I am here at OSU, four weeks away from my first dose of ibrutinib.

I saw that one coming, and so jumped at this opportunity here in Columbus. One of my more prescient moves.

Transplants cuts off many options, especially clinical trials, so if ibrutinib doesn't work for me, then my path is narrowed and obscured.

Exclusion Criteria: Prior exposure to ofatumumab or to ibrutinib.

Please note that any prior ofatumumab also excludes you.

Exclusion Criteria: No documentation of cytogenetic and/or FISH results reflecting 17p del status in patient records prior to first dose of study drug.

The 17p deletion exclusion seems to be a double negative.

The way I am reading it, it seems to say that unless you are 17p deleted, you CAN NOT enter the trial.

If so, that was not a turn I expected. I thought Pharmacyclics (PCYC) would go after the much larger population (market) of all new and old patients with CLL not just those with "Relapsed or Refractory Chronic Lymphocytic Leukemia".

It certainly suggests a great degree of confidence in the drug to handle the nastiest 17p del cohort. The company is betting are betting the farm on that wildest and most dangerous horse and the one most in need of taming. And maybe secretly hoping for the same wide off label use that is seen with rituximab helping to generating seven billion US dollars in annual sales.

I hear the results out the NIH trial on 17p del patients, though very preliminary, are very promising on that tough group.

Exclusion Criteria:

• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
• Requires anticoagulation with warfarin.

The exclusion of those on coumadin and with bleeding in the brain is because of the history of brain hemorrhages (some fatal) that occurred in earlier phase trials. Frankly I am surprised it is not all blood thinners and anyone with a bleeding tendency similar to the exclusion in the MDACC trial with rituximab.

This important phase 3 trial NCT01578707 should be much larger to get the more statistically significant result to gain FDA approval, so there will be many more opportunities to get the drug. Take a look at the trial link, move fast if you qualify and need therapy, and watch for other similar trials if you are interested in what I believe is the best of the new bunch of small molecules.

Clonal Complexity and Prognosis

Nothing in CLL is simple. Or easy to understand. Or consistent.

And it turns out that the greater the complexity, the poorer the prognosis.

It appears that FISH is just the tip of the iceberg. FISH probes only what is programmed to probe. Very focused, very limited.

Massive whole gene sequencing (sponsored by grants from the National Human Genome Research Institute, National Cancer Institute, the Blavatnik Family Foundation, and National Institutes of Health) has discovered much more complexity . There are 9 mutated genes in 5 core signaling pathways namely: DNA damage repair and cell-cycle control (these are our old friends, TP53 or del 17p and ATM or del 11q), Notch signaling (newly discovered FBXW7, and the better known NOTCH1), inflammatory pathways (MYD88, DDX3X, MAPK1), and RNA splicing/processing (two new players, SF3B1, DDX3X).

What is important is that for the first time ever more than half of these of these were discovered in CLL.

In the CLL patients studied, SFB31 was the second most frequently mutated gene occurring in surprisingly high 15%. SFB31 mutations was primarily associated with del 11q (that includes me) cancer already known to have a poor prognosis. This same mutation in SFB31 is founded in myelodysplastic syndromes that is a well recognized and rightly feared complication of CLL and its treatment.

Just the presence of the SFB31 mutation in CLL is an independent predictor of poor prognosis. Just what we need: Another risk factor to worry about. You don't want a bad spliceosome messing up your RNA.

Here is a link to the article in NEJM . This same material has presented at ASH 2011.

I bring it up now, not to add more reasons to worry, but to point to the progress being made in understanding the complexities of the disease.

Remember that PCI-32765 (ibritinib) is a targeted therapy that works in blunting of some of the pro-survival or anti-apoptotic crosstalk done by the BCR or B cell receptor between the cancer clone and its micro-enviroment . This drug and its ilk were not possible without the help of the basic science that elucidated these pathways, their importance, and their possible aberrations.

The good news is that these new mutations are strong clues as to how the cancer develops and what might be new vulnerabilities to be exploited in emerging targeted pharmaceuticals.

I am still clearing up a backlog of news from ASH and important journals and will be bringing you more videos and news soon. There is so much new in CLL that it is near impossible to stay current and not feel overwhelmed. I will try to continue to clarify some of what I believe is the critical new stuff.

My treatment at OSU has taken more out of me than I anticipated, slowing me down, but I hope to up and more energetic and if the stars line up, bring you want I think will be even better news from ASCO.

Forget for a moment all about CLL and look at my cute granddaughter

I have tried not be a stereotypical grandfather, but I am finally giving into temptation and posting posting an adorable video of my talented 9 month old granddaughter.

We who struggle with disease and its therapies, decisions and trials, highs and lows, do so because we have reasons to live, to put up with crap, to reach into the future.

They are different for all of us. I am blessed to have many motivators in my life.

Here is my youngest one. I especially like how she uses her teeth on the keyboards.

That Very Narrow Bridge

Thank you, RABBI JONATHAN OMER‑MAN .

It is well worth reading anything written by the Rabbi but this is a theme close to my heart and one that I have written on before.

Check out his webpage: The Perpetual Pilgrim. He is a gentle, wise transcendent person, an expert in Kaballah, Jewish mediation, and is one of the Rabbi written about in Roger Kamenetz's wonderful book, The Jew in the Lotus, detailing their encounter with the Dalai Lama. Kamenetz tells an instructive tale of the the Jewish Buddhists or Jubu of which I would count myself a lapsed affiliate.

Several years ago, I was lucky to briefly study and pray and mediate with Rabbi Omer-Man. His influence lingers. Our family Passover Seder back in SoCal was Buddhist themed about the push for spiritual freedom, the need to leave behind our our Pharos and places of mental and pyschological enslavement.

Here is the Rabbi Omer-Man's recent post:

That Very Narrow Bridge

“This life’s journey is like crossing a very narrow bridge; the main thing is not to give in to fear.”

Rabbi Nachman of Breslov
The bridge in that well-known hasidic song is not a wooden stucture mounted on a trestle a few inches above the ground, a plank from which any fall would be gentle and uneventful. It is more like a catwalk suspended precariously high over a windy abyss, whose distant depths are occasionally visible but more often shrouded in gloom or fog.

Rabbi Nachman is not saying that the terror below is not real — he knows that it is, and that it is palpable — but rather that there is security in holding firmly onto the handrail of faith.

The abyss is radical doubt, despair in divine providence. The bridge is certainty, trust in divine goodness and truth; it is a pathway to the Infinite.

When abyss and bridge are no longer two, but one, there is no abyss, there is no bridge, and life’s journey is a broad highway to the One.

Give us the courage, H’, to look into the darkness, to find You in your absence. Show us there a radiance that is brighter than a thousand suns.

לֹא-תִירָא, מִפַּחַד לָיְלָה; מֵחֵץ, יָעוּף יוֹמָם

The rabbi says " The bridge is certainty, trust in divine goodness and truth; it is a pathway to the Infinite."

Would that I believed. I don't. I am a bundle of radical doubt, but I push on. What else is there to do? This is not about bravery or faith or even good sense. It is just doing what is necessary. Ram-Dass (another teacher I was lucky enough to meet) said to me that perhaps my path was not through my beliefs nor my theology, but through my simple actions. It remains with me as a generous statement.

As Fritz Perls said: "The only way out is through." or the more prosaic: Fake it to your make it.

So I just keep walking on that very narrow bridge.

Happy Easter and Good Pesach to all my friends.