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.

Zydelig: The Black Box Warnings for use in CLL (Chronic Lymphocytic Leukemia), SLL (Small Lymphocytic Lymphoma), and Follicular Lymphoma

Before you get very far into the Zydelig (CAL 101 or GS 1101 or idelasilib) label,  you come across a big bold black box warning.

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION

See full prescribing information for complete boxed warning.

• Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig- treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig. (5.1)
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig. (5.2)
• Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig. (5.3)
• Fatal and serious intestinal perforation can occur in Zydelig- treated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected. (5.4) 
  
  
  

That kind of warning should and does give most patients and doctors pause before proceeding. And that's a good thing. But we also need some perspective.

While black box warnings are the strongest language that the FDA can put on a label, it is focused on the worst of the worst and not necessarily on common problems.

Our old friend, the rather gentle giant in the CLL world, rituximab has multiple black box warnings (as it should):

From the Rituxan label:

WARNING: FATAL INFUSION REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
See full prescribing information for complete boxed warning.

•   Fatal infusion reactions within 24 hours of Rituxan infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor patients and discontinue Rituxan infusion for severe reactions (5.1).
  
•   Severe mucocutaneous reactions, some with fatal outcomes (5.2).
  
•   Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death (5.3).
  
•   Progressive multifocal leukoencephalopathy (PML) resulting in death (5.4).

Each one of those problems can kill us (PML has a 90% mortality rate, worse than Ebola) and if it doesn't cause our demise, leave us badly shaken and permanently damaged. But those concerns are thankfully relatively rare and it hasn't stop me or many others from enjoying the real benefits of rituximab.

Black boxes are found on many labels. Even common antidepressant medications come with a black box warning for the rare but obviously critically important issue of increased risk of suicide in those patients younger than 24.

For Zydelig, the serious liver issues and severe diarrhea and colitis occurred in one out of every seven patients in their trials. Not so rare. Colitis is miserable and can be fatal. Fortunately, the other, generally more life threatening, adverse events are less common.

Gilead have instituted a FDA mandated REMS (Risk Evaluation and Mitigation Strategy) program. Using this link and further links found on that webpage, you can see how serious the FDA and Gilead are about staying ahead of these potential problems for us patients.

They are being proactive. The fine print in the package insert gives strict guidelines on monitoring and what do based on what the patient's conditions and the lab test are telling the doctor. And most problems can be reversed if the patient and clinician are on their game and respond quickly and appropriately when there's a signal of an emerging problem. After a period off the drug, many of us can safely restart it at a reduced dose and continue to do get the benefits.

This is yet another reason to be choosy about who is managing your CLL. Please pick a doctor who is experienced with CLL and with the new medications so that he or she is on top of all the good and all the possible bad associated with them.

CLL is itself risky. Doing nothing is not an option for many of us.

FCR is no cakewalk. BR is not much better. Lenalidomide comes with a host of its own unique nasty issues.

But all of these drugs and and other drug combinations have saved lives. We can not afford to be therapeutic nihilists because we have no guaranteed safe choices.

Carefully read the label. Ask your doctor. Insist on the correct monitoring. Report any and all problems promptly.

Odds are heavily in our favor. Have perspective.

One place I do see as an advantage for idelalisib at this time is that there it has no warning on the label about bleeding in association with anticoagulants as there is with ibrutinib. By the way, Imbruvica has no black box warnings. The bleeding issues with Imbruvica are being studied more as they are not presently fully understood. Time will tell, but there is reason to believe that most of the bleeding/bruising problems may be simply increased bruising that is more a cosmetic than a health issue. Still, at this time, Zydelig has no such caution and Imbruvica does.

As I said in my last post, we are so lucky to have this choice of two new potent oral medicines that are targeted at our cancer.

To borrow from my dear friend and patient advocate, WWW: May our paths be well chosen.