Short and Sweet News: Less CLL (chronic lymphocytic leukemia) cells in my blood than 90 days ago

Good news. 

The absolute number of my B cells where my cancer lives dropped by almost 1/5 in the last 3 months from 246 to 216 after slowly climbing over the last year and 1/2. 

This is a very welcome and somewhat unexpected finding.

I am planning on it being the start of a new trend in the right direction.

4 plus years on PCI-32765 AKA ibrutinib and counting. 

Only time will tell if my resistant sub-clone and with it my CLL is truly shrinking, but the climb has stopped and that is reason to be celebrate.

Three Year Anniversary on Ibrutinib for my CLL (chronic lymphocytic leukemia)

A Man and his Pills

On May 7, 2012, I swallowed my first three battleship grey pills of PCI-32765, later to be known as ibrutinib and finally Imbruvica when approved by the FDA for relapsed/refractory CLL in February, 2014. For us early adapters, most of whom like me, are still doing well in the subsequent extension trial, it is still the same grey pill and it is still called PCI-32765.

Clinical Trial NCT01217749 or PCYC-1109-CA out of Ohio State University (OSU) was a phase 1b/2 trial mixing the then very new BTK inhibitor with the then newest antibody, ofatumumab. I was in the last of three cohort. My group received the monoclonal antibody first so I actually started the trial a few months before I got to the ibrutinib. Details are described here.

Turns out that my cohort did the poorest as a bunch. Better to use the oral signal blocker first or even simultaneously to empty most of the cancer cells out of the marrow and nodes where the antibody can pick them off with no interference from their microenvironment enablers. That's why we do trials: do figure this stuff out.

But statistics predict for groups and here I am three years later in a deep deep remission. My absolute lymph count is at the low end of normal at 1000 and only 0.8% of those cells are clonal. If we do the math with just a few calculations we figure out that I only have 8 cancer cells in each microliter of blood. That not bad for someone who has a complex karyotype, 17p and 11q deletions, ZAP 70+, unmutated, CD38+, and a failed transplant.

Excellent disease control and a very deep remission, but not MRD negative. And certainly not cured.

For that elusive cure, I and most CLL patients will need a cocktail, preferably of target therapies. Fortunately some researchers agree and such trials are opening up.

During these last three years my blog has morphed from talking about my ups and downs in managing my CLL into a more universal story about the changing research and treatment paradigms in our disease.

Our newly launched nonprofit's CLL Society website: http://cllsociety.org will increasingly be taking on that educational role and my blog will return to being more my personal journey and the place for me to vent and pontificate.

Just this week, our website has several new articles: an article on the WHO statement on clinical trials, the news about the breakthrough therapy designation for ABT-199 or venetoclax for my fellow 17p deleted patients, and two cool interviews with Professor Roberts from Melbourne, part of our conference coverage,  which were done at ASH 2014. Dr. Roberts talks about the mechanism of action of and the early result with venetoclax or ABT-199, a drug that he helped develop in Australia.

Every Monday, Wednesday, and Friday we will be adding new videos and articles, so check back frequently. Already on some days, the one month old http://cllsociety.org is helping more folks affected by CLL than this venerable blog.

I have been asked by pessimists and worriers: How long and deep will the CLL Society's efforts at education, support, news, and advocacy continue? 

The answer is: As long as there is the need and the support for what we are doing, we will keep going.

Realistically, we desperately need to staff up in order to keep going at this pace and to expand what we are already doing. We have big plans that demand more than any one or two people can do, but we are just starting up and I am confident we will soon have the resources we need.

Stay strong.

We are all in this together.

Brian

Personal Good News on the CLL (chronic lymphocytic leukemia) Front at OSU

Selfie with Roy Lichtenstein's wonderful sculpture at the Columbus Ohio Airport 

Perfect weather in Columbus, Ohio and a lovely walk in the woods with OSU friends the day before my OSU clinic morning with Dr. Byrd.

The Columbus airport is in the throes of construction so they have moved the marvelous structure by Ohio State University alumni, Roy Lichtenstein to a more accessible site where I could snuggle up to his flying brush strokes.

At the James Cancer Hospital, my vital signs were all good with my usual healthy low end of normal blood pressure, no fever, slow pulse, and stable weight.

Physical exam revealed no surprises (no enlarged nodes or  organs), and my lab was rock steady. Red blood cells were just the tiniest bit low, platelets were stable in the high 300's, neutrophils were good and my absolute lymphocyte count was 1.2.

My immunoglobulins are still very low except for "my" IGG level. The "my" is in quotations as the source of my normal IGG on the blood test is from many other generous souls whose blood donations were pooled to produce my every seven weeks infusion of IVIG that boost only that one antibody. As of today, there is no known way to raise my poor IGA and IGM levels.

Blood chemistries were all perfect with my happy healthy liver and renal function tests, electrolytes, and blood sugar. Clean living has its rewards. And ibrutinib is less likely to inflame the liver compared to many other cancer therapies.

Everything tested really hasn't changed much in over a year. Rock steady. I like it.

My only complaint is that appointment was at 9 AM and it's 12:30 now and I am still waiting for my magic grey pills (PCI-32765 AKA ibrutinib) to be dispensed so that I can skedaddle. I was hoping to catch a 12:30 flight out, but that is sure not going to happen. There's another flight in a 90 minutes, but it is fully booked. Miss that I will be sitting at the airport for several hours.

Tomorrow, due to a quirk of scheduling, I do it all over again in San Diego at UCSD with Dr. Kipps.

It's all OK, especially when the news is so good.

PS: I  did nab the very last space on an earlier flight (that left late of course) to Chicago from Columbus, then had to race from one side of the airport to the other at O'Hare to snag my standby seat to LAX just as they were announcing the flight was closed, waited forever for the shuttle to my offsite cheaper parking, discovered too late that the 405 freeway home was stopped dead due to a car fire, so I snuck off going around a barrier as I missed the last possible off ramp, and finally made it home  using surface streets for a great vegan dinner and a short refreshing swim. Now time to sleep. Traveling is not for wimps, but life is good.

Approval of Imbruvica Frontline for 17p deleted CLL (Chronic Lymphocytic Leukemia) and Important Trials

It's old news (July 28, 2014), but worthy of some reflection that ibrutinib ( PCI-32765 or Imbruvica) was approved frontline in CLL for those of unfortunate enough to have a deletion of the short (petite or p) arm of chromosome 17.

The p53 gene lives on the 17p arm so when it's deleted, there's missing p53. Without functional p53, cancer cells don't die very easily of apoptosis, the programmed death pathway built into all cells that allows them to suicide when they get too old to function, or in the case of our leukemic cells, become increasingly aberrant and dysfunctional. Without  the tumor suppressing p53 gene, the "guardian of the genome", protecting and repairing our DNA and if that fails, then starting to fire up the self destruction pathway, our cancer continues to grow and mutate and get weirder and more aggressive and difficult to treat.

Most chemotherapy works with the help of p53, first damaging the DNA itself, but then needing the p53 to take it from there by recognizing the overwhelming damage and then persuading the injured cell to die. No p53, and we get just the  chemo induced DNA damage, but the cell can live on and even reproduce faulty clones of itself. That is one reason 17p deletion carries such a bad prognosis.

Until we had ibrutinib (and now also idelalisib or Zydelig), our choices for treating 17p deleted CLL were poor- There were and are a few other therapies that do their killing independent of p53 induced cell suicide. Campath works if you don't have any big nodes, but comes with high infection risks. HDMP (high dose methylprednisolone) + R (rituximab) and flavoperidol and even lenalidomide helped some.

No great choices, until now.

I quote from the press release about the trial that lead to the ibrutinib approval:

At baseline, the median age of these patients was 67 years, 58% of whom had at least one tumor  >  5 cm, and 32% of whom had the del 17p mutation. Patients receiving IMBRUVICA demonstrated a statistically significant improvement in progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) as compared to patients treated with ofatumumab. The median PFS and OS has not been reached on the IMBRUVICA arm. There was a 78% statistically significant reduction in the risk of progression or death as assessed by an independent review committee (IRC) according to the modified IWCLL criteria (HR 0.22, 95% CI, 0.15 to 0.32). In addition, the analysis of overall survival demonstrated a 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA arm (HR 0.43; 95 CI, 0.24 to 0.79). This was observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive IMBRUVICA prior to the analysis. For previously treated del 17p CLL patients, there was a 75% reduction in the risk of progression or death as assessed by an IRC (HR 0.25, 95% CI, 0.14 to 0.45).

Ibrutinib seems to do well on all the folks like me with a missing 17p chromosome on our FISH test, and probably even better for the treatment naive 17p deleted patient. Here is another abstract from the NIH on the subject.

This is good news, right now for just those 17p deletion frontline, but I hope it is only the beginning.

I believe these drugs and others in the pipeline need to be available to all appropriate treatment naive patients, not just those with 17p deletion.

It shouldn't be that most of us have to fail chemo first before being offered less toxic options. The ibrutinib data from the earliest trials suggest those who get ibrutinib upfront before any chemo do the best.

That is why there are some really important clinical trials out there to consider for those who will soon be needing their first treatment for their CLL. Here are a few of my favorites.

With ibrutinib or Imbruvica:

Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

With idelalisib or Zydelig or CAL101: 

A Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously Untreated CLL/SLL

A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL

Efficacy and Safety of Idelalisib in Combination With Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia With 17p Deletion (Havasu)

Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia

With ABT-199 or GDC-0199:

A Study of GDC-0199 (ABT-199) in Combination With Obinutuzumab in Patients With Chronic Lymphocytic Leukemia

This is by no means a complete list. There are at least 222 trials when you search untreated CLL on Clinicaltrials.gov.

These trials are critical so we can finally prove, as I suspect, that moving these drugs upfront and avoiding chemo all together, is our best course for a long and healthy life.

There are a few other exciting early trials using ROR1 for relapsed disease that Dr. Kipps will be discussing in my next post, an interview from ASCO. ROR1 may prove to be the holy grail of a marker that is truly unique to the CLL cells, making it the perfect target for an anti-cancer drug.

UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia

This is with a very exciting and very specific antibody developed by Dr. Kipps' team at UCSD. It should be opening very soon.

Autologous ROR1R-CAR-T Cells for Chronic Lymphocytic Leukemia (CLL)

This is from Dr. Wierda's team at MDACC and CLL Global Alliance, building on the promising work out of U. Penn with CART-T cells directed at the much less specific CD19.

Both these are phase 1 trials with all the risks and possible breakthroughs that come with being early to a new therapy. My ibrutinib trial, though later in development, was still a phase 1/2 trial.

There are growing choices out there for those of us facing therapy for the first time, and for those who have relapsed. 

Clinical trials are the only way our knowledge can grow, and the only way these drugs will ever become widely available.

And clinical trials are for many of us, especially in frontline settings, the only path to getting these new agents. 

Speaking of new drugs being available, July 28 was also the date that the FDA gave final approval for Ibrutinib for those who have received one prior therapy. The accelerated conditional approval six months ago had been based on phase 2 data, the final approval looked at the big phase 3 RESONATE trial data.

More from Dr. Kipps on ROR1 soon from our interview at ASCO 2014.

Celebrating My Two Year Anniversary Today on Ibrutinib for My CLL (chronic lymphocytic leukemia)

Much has happened in the last two years, most of it very good.

On a personal note, I swallowed my first 3 battleship grey capsules of PCI-32765 (it wasn't even called ibrutinib yet) on May 7, 2012 in a Phase I/II clinical trial at OSU with Dr. Byrd.

Two years later my lymph nodes have shrunk to less than 1/2 their size with the possibility that all that remains on the CT scans is the scarred shells of what used to be cancerous nodes.

Today, to find any CLL in my blood, you can no longer rely on the standard bloods test but must do the vey sensitive flow cytometry to find the < 0.3% of cells that are still clonal.

My latest bone marrow biopsy was 15 months ago in Feb. 2013 and even back then it showed only 4% CLL by flow cytometry down from between 10%-20% a year earlier.

I am clearly in a very deep and deepening remission.

I am very grateful.

On a community note, ibrutinib, the first in class signal blocker (BTK) for CLL, received breakthrough approval in the USA for anyone who has tried at least one prior therapy based on its outstanding safety and efficacy data in all patient groups, including those with 17p deletions and other hard to treat clones. But it is broadly available to any of us who have tried but not necessarily failed just one prior therapy.

Obinutuzumab, a potent 3rd generation monoclonal antibody (mAb) is now on the market and is getting complete remissions with the wimpy help of a touch of chlorambucil in clinical trials. Clearly it is this new mAB that is doing the heavy lifting.

Idelalisib, another  exciting targeted oral medication, should be approved later this year based on its stellar efficacy results in pivotal trials with few adverse events.

ABT-199 is proving to be perhaps the most potent oral agent yet in difficult to that patients.

ONO (ONO 4059) and Infinity (IPI 145) and others have very promising signal blockers well into development.

ROR1 trials are just beginning and should offer laser like focusing and very little off target damage.

CAR-T therapy has pulled a handful of patients from near death to deep remissions.

I was revising a 2012 CME (continuing medical education) on CLL program that I will be giving in Baltimore in June and realized just how far we (and I personally have) have come.

I am very grateful.

After  all, we are all in this together.

I think I''ll enjoy some  home made coconut milk yogurt to celebrate the amazing progress.

iwCLL 2013: Dr. Michael Hallek Discusses Clinical Trials in Germany versus the USA and BR versus FCR

Happy New Year.

I am in Alameda, enjoying babysitting my 7 month old and 2 1/2 year old granddaughters. Needless to say, finding a second to get any work done is tough, but the joy of being with them makes my inefficiency a small price to pay.

Today, I am returning to share additional relevant interviews from iwCLL a few months ago.

In the first part of my interview on September 11, the last day of iwCLL 2013, Professor Hallek first discusses some of the differences in clinical trials on either side of the pond.

One subject Prof. Hallek does not mention is the greater willingness of European patients to be randomized in a trial. Canadians and Americans prefer more control in deciding their therapy, and that helps explain the generally lower accrual in North American studies that have two or more randomized arms. I admit that one reason I was drawn to my trial, the official title being,  An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia, was that I was assured that I would be getting PCI-32765, AKA, ibrutinib, AKA, Imbruvica. Phase 3 trials rarely offer that certainty, unless there is a cross-over and that is a big ongoing issue.

Keep in mind that the  calculus of accrual is entirely different when we are looking at the new non-chemo agents, where trials offering some of the exciting new drugs have filled at record rates.

Also don't miss the professor's definition of young.

I like it.

Next, Prof. Hallek, presages with great accuracy what was going to be announced a few months later  in at an abstract presented in New Orleans at ASH 2013, namely that BR is gentler on the marrow, but less effective than FCR. His take on what to do with that data is the real gem in our conversation. Listen to how he describes tailoring of the therapy to the individual patient.

Dr. Jeff Sharman whose interviews have and will continue to pop up here, has a nice review of the ASH data on his excellent blog.

Here is Professor Hallek, who was very busy chairing iwCLL, so I very much appreciate his time.  Sadly when my flight to New Orleans was canceled, I had to also cancel my follow-up interview at ASH, but we get the full story here and from the abstract.

Many, myself included, wonder if the whole question of BR versus FCR is moot as the era of chemo-immunotherapy may be ending in CLL. We have spent many blog posts discussing this issue, and we aren't finished yet.

Here is Professor Hallek:



More soon.

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 trials.gov 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 trials.gov. 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 clinicaltrials.gov. 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.

Heartburn: Ibrutinib (PCI-32765)

Well I guess I am getting a taste of the full spectrum of GI issues associated with ibrutinib.

While the lower intestinal issues have calmed down, and the nausea is gone, I am having some nasty heartburn for the first time since I can't remember when. Vegans usually don't get heartburn.

I am confident that this well recognized side effect of the drug will also pass, as have the other issues.

It is hard to report on my palpable nodes day to day is kinda like watching the grass grow. You don't notice much difference from one morning to the next, but after a week there has been a real perceptible changes. My nodes are slowly melting away.

Generally I am feeling well otherwise. More details in future posts.

Canoed six miles down the Darby Creek just south of Columbus today. It was wonderful.

Has a great meal with new friends. Vegan flour-less chocolate cake may be the source of my gastric issues. That was wonderful.

Watched the LA Kings win game three against Phoenix. That too was wonderful.

Only the heartburn is not so wonderful.

Very bad and irrelevant news: Ibrutinib (PCI-32765)

Soon after I first arrived here, I hinted at some bad news that I needed some time to digest.


As circumstances developed, I didn't see Dr. Byrd for several weeks to get the proper perspective and then I had to digest what he said.


The good thing about CLL is even with bad news, you almost always have time to analyze your circumstances, adjust to the new realities, under react, and move forward. 


I also wanted to wait to share with you until I had more distant from the shock


Let me set up the story.


Just before I came to see Dr. Bryd at OSU to assess whether I was a good candidate for his trial, I had a bone marrow biopsy with Dr. Kipps to show that I  had recovered my CD20+ after all my rituximab, an inclusion requirement for the clinical trial with ofatumumab and ibritinib and to assess my status.


That bone marrow biopsy done two months early showed slightly less than 10% CLL (with CD 20 positivity), and my old friend 11q deletion back in 11.5% of the the cells analyzed. The marrow was pretty healthy. No big surprises.


I tried to talk them out of another biopsy at OSU, but they insisted. 


It told a different story.


They use mitogens or stimulants that makes cells divide and thus make it easier for the pathologist to find genetic abnormalities.


And they sure did.


The FISH testing found over 50% of my cells as being 11q deleted.


For the first time 13q14.3 (D13S319) and l-3q34 (LAMP) were both positive.


And:


17p1-31 (TP53) which should be 0-6% of the background population was positive at 7.3%. Not a strong signal, but not a signal I wanted to see at all.


And worse yet, the cytogenetic studies showed that I had not one but two evil clones with "complex karyotypes" that confirmed the FISH findings and re-enforced my bad prognostics and suggested likely resistance to most therapy.


My cancer apparently consisted of two clonal populations, both nasty and both pretty bizarre. Bizarre is bad. Bizarre is aggressive and unresponsive. 


This was very dark news indeed. 17p deletion is usually a clarion call for a transplant. Nothing else reliably stops its often furious and fast fatal march. Complex cytogenetics may make any decision, transplant or other therapy more problematic. Clonal evolution is itself a very poor prognostic indicator. Zap 70 +,  unmutated, CD38+.  I had just about every bad omen.


Things were not looking good.


Now before I proceed, I must point out that comparing the sudden change to a much more aggressive and hard to treat cancer in the 60 days between Kipps' and Byrd's biopsies is not fair because the two labs were using very different techniques.


The mitogens employed by the team at OSU are used precisely because they powerfully stimulate cell division, and thus can demonstrate and some would say artificially inflate genetic abnormalities.


The two methods are looking at very different raw material. Comparing apples and rabbits. Static and active. Most research and data you see in the journals and at conferences still asses their findings the way Kipps' lab did with the static FISH studies. That is the existing standard when a paper says that 20% of the patients were risk risk 17p or 11q. 


So there may be much less change in the 60 days than the numbers suggest.


But the realist in me, says it is still some kind of devolution.


And Dr. Byrd said that these low level findings may not be accurate, as the 17p is the most difficult probe to nail against the background noise. It may mean nothing. It may be a false positive.


The skeptic in me says it must mean something.


Moreover, Dr. Byrd (and Dr. Keating agreed) reassuringly stated that he has seen these low levels of 17p disappear. 


The worrier in me wonders if they are really gone or just hiding? 


But what makes all this speculation and grim foreshadowing and ruminating moot and irrelevant is that I am responding to the ibrutinib.


The proof is in the pudding.


It's working. 


IT'S WORKING!


Some data generally suggests that, at least at first, low levels of 17p del are not as a important factor in response to most therapies as are high levels.


Most importantly, as I have posted before, there is little difference in the response to ibrutinib of 17p deleted patents compared to this with those with more favorable FISH. The depth or durability of the drug's activity seem blind to 17p deletion status. And there are theoretical reasons to believe that being the usual lousy ZAP70 + as I am might be actually be an advantage as PCI-32765 blocks B cell signaling and ZAP70 is all about signaling.


It is all irrelevant as long as the pills work their magic. So far, so good.


What it does tell me, is that it was one of my more prescient and fortuitous moves to push to get into this trial when I did. It's closed now.


If I had not, I would not  had a second biopsy and would not have known of my clonal evolution and the sinister loss of a 17p. 


When it came time (sooner rather than later)  that I needed treatment, my options would have been very limited as most therapies are inactive or pretty toxic or both when you don't have a working P53 pathway (usually found on my missing 17p) to tell the cells to die. Making matter worse, many trials with ibrutinib or other tyrosine kinase inhibitors would exclude me because of my prior transplant.


Of course, there still exists a few scary "what ifs" and "what nexts". Planning for them has become much more difficult and constricted. But that can wait.

Right now, the overwhelming sense I have moment to moment and week to week is just I how fortunate I am to have made the jump to Columbus, Ohio when I did.


I am very lucky and very blessed and very thankful to be here. Now.

More Good News at the end of the first week of Ibrutinib (PCI-32765)

The exam at clinic today at the James by Gretchen, my PA, and Dr. Byrd confirmed my lymph nodes were much smaller.

My white blood count and lymphocytes doubled but only from six to twelve and from two to four respectively, but everyone seemed happy with those numbers.

Dr. Bryd says the rise in the lymphocyte count is not a prerequisite indicator of the ibrutinib working. Not at all. I had expected a much higher jump up in the ALC (lymphocytes) with my nodes shrinking so much and the unanchored clonal B cells needing to go somewhere, but Byrd said that in those such as me with ofatumumab already aboard, may not get as big an inflection in the counts.

Hgb is stable but still a touch low, eosinophils are up a bit again, and neutrophils and platelets are all good.

My GI issues are manageable and should gradually improve. Apparently they are more common on those of us like me with big abdominal nodes. They usually decrease over a few weeks. Makes sense.

And Dr. Byrd says he reads my blog. I feel honored.

The news is very very good. Still tired and muscle pains, but happy. More soon.

I Gotta to Admit It's Getting Smaller

The nodes are continuing to shrink. Smaller today than just a few days ago.

No secrets in the showers. A palpation reality is that soapy hands makes the skin disappears and the nodes easier to find. They are still there, but on they are getting hard to find.

More GI issues with cramps and pain and nausea and diarrhea.

Clinic appointment tomorrow.

It's working already: Ibrutinib (PCI-32765)

My nodes are definitely smaller after only five days. Not nearly gone, not softer, but undeniably shrinking.

Also getting waves of nausea and feeling plain lousy and diarrhea so I know the medication is for real, but it is nothing that I can't manage.

Monday I am at the clinic and will see if the less biased examining fingers of my treatment team confirm my findings of diminishing nodes that I discovered when I showered this morning.

I also expect that those nasty B cells had to go somewhere, so my absolute lymphocyte count should be quite a bit higher when they do the blood work. That's a good thing.

Maybe, just maybe, this is the beginning of the end.

This is very promising news.

Now I must remember to enjoy but under react.

My first 36 hours of life on Ibrutinib (PCI-32765)

I took the first 3 specially prepared by the pharmacy gray capsules of ibrutinib 140 mg each for a total of 420 mg yesterday at 11:15AM at the infusion center, except I had no infusion. That was a treat. To go to the cancer center and sit in an infusion chair, but get no IV.

I did have blood drawn, and except for another mild blip in the liver function tests and my mild anemia, all remains normal. I was examined and questioned repeatedly (do you have rashes, fevers, GI issues, fatigue, pain, neuropathies and so on?) and issued instructions and given a diary to complete and waited around for about 2 hours. The PA (I didn't see Dr. Byrd again) had said almost nothing negative about ibrutinib and proffered glowing reports of all the successful patients in the trial. Seems like almost everyone responds and almost no-one has any major problems.

Then I was out of there with the magic pills in my stomach and on their way to by blood stream and into my cancerous B cells to block their malignant communications and begin the process of healing.

The earth didn't shake, bells didn't ring, and angels weren't heard singing, but it was still pretty special. Had a wonderful meal and a long nap.

Took the next three pills this morning, and I have nothing to report. No missing in action lymph nodes, no sudden surge of health, but no diarrhea or rashes or bruises or any of the side effects I was told to possibly expect. Nothing positive or negative. If there was a placebo control, I would think I got it.

A non-event and I am just fine with that.

Many people get a very fast response with ibrutinib, so I hoping and expecting by the time of my appointment next week, my nodes will be at least less firm, if not significantly smaller. My white count will likely have climbed as all those clonal B cells leave the protection of the germinal centers and enter the dangerous freeway of blood where their life expectancy is much shorter.. That is what the PA seems to be anticipating. That would mean I am one of the many responding.

But for now, the game changing ibrutinib, like the actual infusion of my transplant, was a bit anti-climatic. Wonderful, satisfying, but not very dramatic.

The real positive excitement will happen soon enough.

What doesn't kill you makes you stronger: NOT

It has often been said what doesn't kill you makes you stronger.

THAT IS SO NOT TRUE!

When you are fighting for your life, be it cancer or heart disease or major surgery or any of a myriad of chronic grinding illness, the flare-ups and complications and relapses and the aggressive therapies needed to steady the ship usually leave you weaker, more tired, more stressed, more vulnerable and often more disabled and depressed.

Sure it was good to have survived measles as a kid (proud to part of the last generation who got the disease and not the shot), or learnt from a failure in college or a lost job or love in your 20s, but most stuff that hits those of us over forty years old, leaves us wounded and weakened. Our immunity or our bone marrow or our psyche all can take a hit, becoming less resilient.

It can wear us down, beat us up. We can rise again, but like the boxer who beats the count, we might be wobbly and need to be extra cautious to avoid a career ending injury.

I don't say this to depress or discourage, but rather to urge us to act wisely and to do what we can to avoid damaging choices. Make choice with our eyes wide open. Risks and adverse events are not always just part of the package insert for the drug or the over protective counsel from an elder or an expert . They are real life occurrence that happen with cold statistical certainty. 

We need to do what we can to improve our odds and avoid the slings and arrows or outrageous fortune. Stay out of the line of fire if we can.

Sometime it is not possible and as is the rightful order, the rampant disease is worse than the treatment. Still the treatment, while preferable and the wiser course to the morbid state it treats, can be pretty noxious. 

We do what we must do. I just don't buy the belief that we are all supposed to thankful somehow for the "experience" we have gained from all these punches to the gut.

This rant just came over me in a rush- a sudden insight that I wanted to share.

Tomorrow I start ibrutinib-PCI-32765- the raison d'être for my moving to Ohio over 8 weeks ago.

I can't wait. Partially because it is so effective and partially because it is so non-toxic. 

Such a perfectly lovely combination.

I am so lucky and grateful to be here.

Virtual Cancer Buddy and brief update on Clinical Trial NCT01217749 (PCI-32765 and ofatumumab)

Well I am  finished my final weekly infusions of ofatumumab and so I now can put some energy into some projects dear to my heart.

This http://www.virtualcancerbuddy.com/ is near the top of the list.

Please go to the link and spend the two or three minutes letting me know what are the most important health data and web support tools that you would want to have with you at all times.

As some of you know, I like Chris D, and many others with CLL or cancer have a thumb drive in my pocket that has some medical history, but it would take a dedicated doctor or nurse to find it and open it and root through it if I wasn't able to guide them. And if I am able to guide them, they don't need it.

The idea is that this would be more accessible, simpler and more robust, but because it could contain more that just the dry spreadsheets and contact information it would be something that you would be constantly consulting and would be regularly updated.

It would be your boon companion, virtual cancer buddy.

Your feedback will help to design it.

Do you want easy access to the latest clinical trials?

Do you ache for a calming MP3 to help manage the stress?

Do you long for tools to aid on the difficult decision processes?

Do you wish you had easy access to reliable research information?

Would an integrated appointment reminder be important?

Do you want your advance directives accessible?

Would it help if it could Skype to others with cancer?

Where do want it? On your phone or ipad or computer or everywhere?

Please check out http://www.virtualcancerbuddy.com/ and see the whole list.

The plan would be to provide this as a free service to cancer patients and their caregivers as a value added service from their treating hospital or oncologist.

Thanks a bunch for your help.  The survey only takes a few minutes at the very most.



Next week I finally start PCI-32765 or ibrutinib. These last 8 weeks of ofatumumab have been a long prelude with only very modest results on my nasty but not enormous nodes. Truth be told, probably all the benefit came in the first two weeks. Not so the advisers events. The persistent and humbling myalgias that have me limping around the apartment at times are my only side effect now. That and a completely mucked up circadian rhythm that has me up to 3 or 4 AM most days.

I am glad for a the five week break from "ofa".

I am ecstatic that I get to taste the magic sauce next week.

I am looking forward to being home again with my family and friends and cat and showing off my shrunken lymph nodes from ibrutinib.

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.

PCI-32765 and Ofatumumab Trial Update: Sirens blare and more rashes and sore muscles

I beat the storm back from shul where I said Kaddish for my father. The severe weather sirens wailed a few minutes after I enter the house. Right now, the thunderclaps are right overhead and the lightening is like a 60's strobe show and the rain is falling in torrents.

This time I knew what those sirens meant and what to do to be safe.

Wish I could say the same about my new rash on my left arm.

My left elbow has been sore since I worked out at the gym three days ago with a sweet college student as my trainer. It got a bit worse when I returned again yesterday, but with the dexamethasone aboard for my third infusion from one day earlier I was feeling no pain.... until last night. Been swimming, and enjoying the jacuzzi and sauna too.

Late last night, my elbow stated to swell a little especially up into my medial triceps where my muscle was so sore. It was bright fire engine red with sharp borders, like a welt or hive. And the pain in my arm increased.

The flaming redness faded over a few hours, but a faint flat confluent pinkish rash now reaches from nearly to my wristband more than half way up my triceps and is spreading.

Dr. Byrd's very kind and smart PA, Margaret thought it might be a skin infection. Heck, my immunity is zilch after the steroids suppress everything and the ofatumumab decimate my B cells. And oh yeah, I have CLL.

I don't think the culprit was the IV. It doesn't look or feels like that kind of inflammation. But a micro abrasion at the college gym, a known popular gathering place for germs, could have lead to a staph or strep infection. The sauna and jacuzzi are suspect too.

Like a good patient, I started on the prescribed dicloxacillin, an old school narrow spectrum oral penicillin that has enhanced activity against staph, but not MRSA.

Better to be safe. That is if the dicloxacillin will make me safe. If we are treating the right thing.

After initially resisting the diagnosis of cellulitis, I am now pretty convinced and worried that if it doesn't turn around soon, I may need IV antibiotics.

I saw Dr. Byrd last on March 19, got bad news later that day after he had left, and will not see him again until April 11 at the earliest to discuss what it all means.

Frustrating, but I understand he may want to sit down and talk face to face in a non rushed setting to give me his experienced perspective.

This is no fun.

Update on the trial of ofatumumab and Ibrutinib

Friends,

Here is an update on ofatumumab first part of my ibrutnib trial at OSU. I do this for for 5 more weeks the on the 9th week of the trial, I finally get my first taste of ibrutinib (PCI-32765). Can't wait.

Bad news:

I don't have common mouth numbness and tingling after three doses of ofatumumab, but my liver function tests have climbed a bit. The ALT is worst at 98 (almost 3x normal), but the AST and LDH are also up but not even twice normal . These are relatively mild changes and only found this one time. I was screening for hepatitis of course before starting, I don't drink anything stronger than green tea, and I avoid tylenol. Heck, I avoid everything. I am on a ton of meds that can effect the liver, but nothing has changed in years.

Even after my transplant, my liver tests stayed boring, in fact toward the very low end of normal. There was a much smaller rise in only was AST when I returned from China, but that was short lived and was trivial. Hopefully the same adjectives apply to this too. Maybe I don't take well to "foreign " foods.

The package insert doesn't mention it. But there isn't much on the common oral neuropathy either.

Generally side effects in drugs are not discovered until they get used by a lot of sick people.

Hence the morbid joke: Alway use a drug when it' s new while it still works and before we find out all that is wrong with it.

Lab next week's lab with see if it's a nothing blimp or perhaps a trend.

Good news:

Eosinophils are falling, almost back to normal (700). CBC is pretty normal, and the rest of the chemistry panel is good to go.

CLL is one weird disease. Full of blind spots and unexplained good and bad twists and turns.

Very good news:

Nodes are smaller. Definitely not gone, but definitely smaller, and my GI symptoms are better.

Could the tumor kill and the cleansing action of the liver be the cause of the increases in AST, ALT and LDH? My white count was normal going into the trial and still is now.

Any other CLLers seen a bump in the liver tests with ofatumumab?

Disappointingly, I did not get to talk with Dr. Byrd so I don't have his take on this or on some much bigger and impactful issues and decisions that I am facing.

So I am still chewing on it and trying to round its corners as I move forward.

And I keep my mantra going: Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react, Under react.

Slowly and with awareness.

Nice n' easy does it every time (with thanks to BERGMAN, ALAN / BERGMAN, MARILYN / SPENCE, LEW and of course Frank Sinatra).

Please enjoy the linked video. I sure did: the chairman of the board and Gene Kelly together.

Ah, that's better.