Questionable Online Advice from a Physician about CLL (chronic lymphocytic leukemia): Yet Another Reason Why We Need the Best Information

OK, class. What is wrong with the advice this syndicated doctor is giving to his inquiring patient? Here is the link to one paper's column so you can read the whole question and response.  CLL is disease of the bone marrow April 2, 2015

"DEAR DR. ROACH: I have been diagnosed with chronic lymphocytic leukemia at stage I, and I am experiencing swelling in my lymph nodes under my arms and in my neck..... — N.H. ANSWER: Chronic lymphocytic leukemia is a disease of the bone marrow, an indolent (slow-growing) type of cancer. It is called CLL when the cancer cells are mostly in the blood, and small lymphocytic lymphoma (SLL) when it is primarily in the lymph nodes. These are just different manifestations of the same disease. However, if the disease is mostly in the lymph nodes, then radiation treatment usually is used, even in asymptomatic early disease. In stage I CLL, the condition typically is watched for progression." Actually Dr. Roach is mostly correct in his definitions. CLL and SLL are the same disease with different presentations. The cancer cells are essentially identical phenotypically and immunologically. The WHO say the cancers are identical. It is a nuanced difference, but I would argue that while CLL is usually found mostly in the blood and marrow, occasionally in patients such as myself with 11q deletion, we may have near normal lymphocyte counts and little bone marrow involvement, but may present or develop massive lymph nodes, so our CLL may be "primarily in the lymph nodes".  For us, our cancer is a leukemia that behaves more like a lymphoma.  In contrast, SLL presents in the nodes and when it spoils over into the blood with excessive lymphocytes (greater than 5,000 that are monoclonal) or the blood counts drops or the marrow is heavily involved, then it is becomes CLL.  Take a look at this link for more on diagnosis. This is a subtle point and Dr. Roach is for the most part correct as are nearly all the similar online definitions by such reputable sources as LRF, so I have no fight to pick on this point. His admonition to watch (and wait) with Stage 1 disease is also sound counsel. And the rest of his discussion that I didn't excerpt on herbal therapy was thoughtful and well considered. My real concern is the statement about SLL that radiation therapy "usually is used even in asymptomatic early disease". This simply isn't the case and would come as a big surprise to many SLL patients who have happily dodged any therapy for years. There can be an argument made in the rare patient who present with a single cancerous node or cluster of nodes in the same tight anatomical location that removing it or sterilizing it with radiation is potentially curative, but this patient already has nodes in two anatomical locations, so a curative treatment is less likely. In fairness to Dr. Roach, there was one small (14 patients in stage 1 or 2) retrospective study from 1989 that showed an impressive 80% progression free survival at 10 years in stage 1 disease with the authors recommending early radiation therapy.  The results were less impressive with Stage 2 disease (two locations on the same side of the diaphragm) and not significant with more advanced disease. Radiation therapy in the absence of symptoms is certainly not routine "standard of care", especially with the demonstration of more than one site involved. If considered, it certainly needs to be carefully reviewed with a CLL/SLL expert. Moreover I suspect that the role of radiation in SLL will be decreasing rapidly with the options of new targeted therapies now available that are so darn quick and effective in shrinking our nodes. I present this case as a cautionary tale of the danger of not being abreast of the latest research and guidelines whether you are the patient or you are the doctor. Understanding the details and nuances of our disease is critical for our survival. CLL/SLL is a relatively uncommon, but complex disease that is different in each and every one of us. We all need to be treated as individuals. And the treatment options are changing very fast. Many well meaning general oncologists may be badly out of date and we need to be ready to ask for a second opinion from a CLL expert.  We all need to be our own best advocates.  We all need to be informed. That is why I and other CLL patients, caregivers, and experts have been working so hard and long to put together the only active patient driven, doctor reviewed, CLL educational and supportive website based in the USA. The nonprofit 501(c)3 CLL Society Inc. website has just been launched to meet the unmet needs of the CLL community. We aim to be the hub for all helpful reliable and valid CLL information on the web either on our website itself or through selected links to other reputable sources. Here is our Mission and Vision statement: Mission: The CLL Society Inc. is a patient-centric, physician-curated nonprofit focused on patient education and patient support. Dedicated to addressing the unmet needs of the CLL and related blood cancer communities, it explains the rapidly changing therapeutic landscape and the importance of clinical trials, supports and builds patient networks, and educates providers and patients alike. Vision:  We act to help shape a smarter, brighter future for those with CLL and related B cell blood cancers by encouraging and supporting smart patients, smart providers, smart clinical trials, smart healthcare delivery systems, and smart therapies. We are careful not to replicate the fine work of many other organizations and patient forums, but looked to fill the  gaps with searchable information, with supportive articles, with interviews with experts, with news and the latest research from all the major meetings and journals, with carefully vetted links to our reliable sites, with many useful tools such as glossaries and spreadsheets for labs and updates on clinical trials and so much more. And we are only just beginning. With the continued support of the CLL community of patients, caregivers, providers, and industry, we have big plans to fill in gaps in our information and grow in response to what the community wants.  It will be a vibrant growing site. New material will be added regularly. Please consider signing up for alerts and the newsletter.  Email us with feedback. Your support and comments will guide our future development.  Let us know if you want to write for us and we will help with editing and fact checking. After all we are all in this together. You know who I am so I think you what you will find at http://cllsociety.org robust gritty explanations of what we need to know to win in our struggles. Complex topics unpacked and explained in accessible but not simplistic terms. I will share all the news and research, good and bad. No sugar coating.  My blog will continue, but may gradually morph back to being more about my personal ongoing CLL journey. For the foreseeable future, there will be some overlap with my blog and http://cllsociety.org but eventually the website for the nonprofit 501(c)3 CLL Society will be the main source of all the new information and my blog will be where I tell my story and share my candid opinions. Stay strong. Stay in touch We are all in this together.

Dosing of Ibrutinib and Other Oral Agents

"Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy."

PARACELSUS

Recently there has been some discussions among those of us who hang out at online at CLL forums such as ACOR and CLLSLL Yahoo Groups about the dosing of ibrutinib.

I am a strong believer in the power of these online communities to help us cope with our disease.

The problem inherent in peer to peer counsel is not the inaccuracy of the advice given as that also sadly too often occur in professional to patient counsel. The problem is more the lack of authority afforded any particular response. That said, if respect is earned, several regular contributors have earned my respect with their well reasoned and researched frequent comments online.

Often, especially with cutting edge therapies, the patient community is better informed about their rare disorder than the community healthcare professional who must handle the full spectrum of illness his or her chosen specialty demands.

For more on this subject see this article in BMJ  provocatively titled: What happens when patients know more than their doctors? Experiences of health interactions after diabetes patient education: a qualitative patient-led study

Case in point: Dosing of ibrutinib.

The only approved dose for ibrutinib is four tablets a day for mantle cell lymphoma (MCL), which by the way is usually a nastier disease than CLL. The Imbruvica dosing is right on the package insert.

So the community oncologist dutifully looks up what the dose to use for CLL, and finding no FDA sanctioned guidance, recommends using the MCL dose. After all,  the somewhat arbitrary dose of rituximab is the same across a wide spectrum of illness.  Arbitrary because, according to legend, the original dosing was based upon how much rituximab was available, divided by how many trial patients needed it. That worked out to be 375/M² and the rest is history.

The circumstances are less arbitrary with ibrutinib. We know that ibrutinib works by irreversibly blocking BTK through covalent binding to cysteine-481. We know that the sweet spot for getting that site fully saturated is somewhere between two and three 140 mg. capsules a day.

Moreover we know that mutation of cysteine-481binding site is an important cause of late resistance. Ibrutinib no longer fits, and the BTK pathway, and thus BCR signaling continues unabated. Not a good thing.

One sure way to increase the odds of that sinister development is to start with a low dose of ibrutinib that only partially blocks the site, but allows a significant population of lymphocytes to continue to express BTK. That is the last thing we want in cancer therapy. What we want is a SHOCK AND AWE approach to cancer. We don't want the cancer cells retreating, regrouping, and later coming back to get us by probing our weak points.

Worse yet, the up and coming second generation BTK inhibitors also seem to bind at the exact same site, so if we become resistant to oneBTK inhibitor, we may be resistant to them all. A strong incentive to get the full dosing the right from the start.

So when a doctor suggests slowly going from one to two to three or more capsules a day, it is OK for a patient to say: Can we please get a second opinion from someone with more experience with the particular drug? (Of course, there is always the possibility of the individual's extenuating circumstances that we just don't know).

Some drugs for good reasons such as allopurinol in gout needs very slow upward titration to prevent increased painful flares, but ibrutinib and most of the other TKIs should almost never be dosed that way.

Bottom line: The standard dose for CLL is three 140 mg. capsules once a day, for MCL four 140 mg. capsules once a day. Sometimes those doses can be adjusted due to adverse events or hepatic disease or concomitant medications that effect its clearance (more on that topic, specifically on the CYP3A4 pathway in another post). Short of end stage renal disease or dialysis where there is no data to go by, no dose adjustments are needed as less than 1% of the drug is excreted unchanged by the kidneys.

The right dose is more than important, it is mission critical.

"Tell me why it is hard to make arrangements with yourself" Neil Young

Communication breakdown,

It's always the same,

I'm having a nervous breakdown,

Drive me insane!

Led Zeppelin

What's new you've been asking?

You've heard it before. 

Nothing. Nada. Rien du tout. Bupkahs. 

Stillness is not my strength. 

Add to that a communication breakdown and it makes for a frustrating frozen moment. My insurance authorization for my appointment at UCSD was fumbled on the two yard line. In the fourth quarter. With one second left on the clock.

My scheduled appointment for a second opinion on a second transplant is suddenly on hold after office hours on the day before the appointment, waiting for a last minute paperwork reprieve that would allow me to keep the hard to get chance to see the double agent, Dr. Castro, who moves with grace in both the world of CLL and transplant medicine. A rare man in deed. I need his take on the advisability and timing and risky details of second dose of a stranger's stem cells. Or goosing my immune system with lenolidomide, the princely stepchild of thalidomide. That certainly would be entering unknown territory. Or other options I haven't even considered.

There is still a chance I will get the go ahead tomorrow.

In reality, nothing will be decided until the computer that controls an x-ray unit is used to slice through my gut, and using complex algorithms reconstructs my interior geometry. Moving nodes that are less than a half an inch across to begin with will be scanned for any change.  Not by inches, but by millimeters will my future be decided. That CT scan won't happen for another month.

In Vegas, I would be a card counter. I want all the edge I can get.  I want to know what is knowable. I want some to time to compute the odds and then make my move. 

I should still get the information and time I need. 

I am just not good at waiting.