ASCO 2014: Dr. Byrd: Ibrutinib in the Real World of CLL (chronic lymphocytic leukemia)

In this short second half of my interview from the final minutes of ASCO 2014, Dr. Byrd, my clinical trial doctor at OSU, discusses some of the potential  pitfalls in receiving ibrutinib outside of a trial from a provider who perhaps has little or no experience with the drug.

That is one of the reasons I push so hard that we patients be well informed and engaged so we can be be sure we are getting the best possible care.

It is also a push to strongly consider a second opinion, especially when we are considering therapy  with a doctor where the bulk of the practice and research is devoted to the care of CLL patients.

Ibrutinib and some similar other targeted oral medications (kinase inhibitors) are quite safe and easy to use, but do have some unusual characteristic effects.  For example it is common to experience a rapid climb in the lymphocyte count at the start of therapy. You and your doctor need to appreciate that it is not dangerous or a sign of progression or even really an adverse event. It is just a redistribution of the lymphocytes from the nodes to the blood whether there are more vulnerable and more likely to die.

Again, please pardon the pops and hisses in my part of the audio during the interview.

I have several great videos on tap from Greece (ESH International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment) but they are embargoed until after ASH.

And of course, I will be attending ASH 2014 next week with my one man video production team to bring the latest news, commentaries, and explanations.

I go as as doctor, a patient, a reporter and I hope as your advocate. It can get pretty crazy: a scheduling nightmare and long demanding days.

On a personal note, my labs remain stable even though I have been off cyclosporin for my auto-immune platelet issues (ITP) for almost two months. The one fly in the ointment is that my white count and absolute neutrophils are a bit high. That usually means an infections, but I feel well. Could be just stress and lack of sleep. It's happened before and returned to normal, never leaving a clues as to why it bumped it. With CLL, I have learned to accept that things just happen and I may never know why.

Here is Dr. Byrd.



Happy Thanksgiving.

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.

iwCLL 2013: Dr. Byrd Discusses If and When to Stop and the Long Term Use of Ibrutinib

In this last part of my interview with Dr. Byrd from iwCLL 2013 in Koln, Germany, he speculates on the issues of long term risks of using ibrutinib, and the complex concerns about stopping the medication.

This segment's posting was delayed due to some technical issues, so please look back to the prior part one and part two to get oriented.

The updated news from ASH 2013 about the long term safety concerning ibrutinib continues to be encouraging. Most problems, including serious infections, occur most often in the first six months. The longer we take the pill, the fewer the problems.

The data on late relapses is still very thin because they are so few and far between, but it is clear that they do occur, mostly in the usual suspects, those of us who have been heavily treated or have high risk and unstable genomics such as deletion 17p or 11q.

Sadly, the Kaplan Meier curves are not longer straight lines going out towards eternal life, but they are still pretty great. Below are the ones from about six months ago from NEJM. The latest data is little changed.

KAPLAN MEIER CURVES FROM DR. BYRD'S ARTICLE IN NEJM 7/4/2013

Will they continue there downward droop? Will it accelerate? We don't know the answers yet.

Because every step down is a lost life, we are not being greedy when we want the great results to be even greater.

Dr. Byrd does make an interesting and important point about going off meds. Most relapses occurred in those who had only been medication for a short time, and without the selection pressure of ibrutinib blocking the BTK pathway, there is no survival advantage to mutating past it and therefore little likelihood that we will see that resistance develop off med. That's good news and if confirmed in clinical trials and hopefully soon, in real life experiences, could have major implications on how we dose the medication and control the cost.

Here is the video:


Since that meeting, we do have some answers to a few of the questions that were unanswered in Germany.

We know what the pills cost. About $91 each retail. About what was expected.

We are seeing some new interesting late side effects. In contrast to the minor annoyance of brittle nails, some of us are enjoying thicker, curlier and darker hair.

Maybe there is a whole new marketing opportunity for Pharmacylics and Janssen. Insurance may be hesitant to pay that kind of cost for control of cancer, but the price of vanity has no limits.

I will let you be the judge on the effects on yours truly.

Selfie from my Balcony 1/19/14

New Adverse Event for Ibrutinib: Brittle Nails

The Registration Trials that are ongoing are purposed not only to find out if the strong response rates seen in the earlier phase 1 and 2 trials hold up with larger and different populations of patients, but also to look for early signals of unanticipated side effects of adverse events.

But problems with medications can show up very late in the game.

Who would have guessed that pregnant mothers who received DES (Diethylstilbestrol) in what turned out to be a futile attempt to reduce the risk of miscarriage would see a problem a generation later when it was realized that their daughters exposed in utero had an increased risk of a rare vaginal and cervical cancer.

And while a good number of the brave first patients out of the handful that entered the phase 1 trial of ibrutinib are still doing well on drug, at the time of this writing I don’t believe that anyone has been on the medicine for even four years, and most of us for much shorter times.

Therefore we should not be surprised as our experience grows with the new generation of treatments heading rapidly for FDA approval when new possible concerns pop up.

I didn’t get a chance to ask Dr. Byrd when he spoke on the early results with ibrutinib in Stockholm at the same meeting where I too lectured (I gave a patient’s perspective on having CLL and how my life was impacted by both the disease and by my dramatic response to the new medicine) about the incidence or statistical significance of what to me was an unknown adverse event: brittle fingernails.

That explains why my career as a hand model will never get off the ground. My fingernails break easily and I must keep then very short at all times to avoid them tearing. Reaching in and out of my carry-on bag with its computer sleeve and tight pockets where I stuff my papers and medications is like a dance in a minefield for my fingertips, and they are often the worse for wear after my travels.

I also am certain just as we all know that when someone asks us if our nose is itchy, our noses are more likely to itch, awareness of the possibility of any problem increases the incidence of the problem. I will now join the ranks of those ibrutinib subjects reporting brittle nails, though for me the fashion consequences are much less significant compare to the women who enjoy growing and painting their nails and who, I bet, were much more astute and observant than me in pointing out this problem early on.

I just thought it was a consequence of my vegan way. Maybe it is.

In the big scheme of things, jagged fingernails are not a biggie. Sure beats pneumonia or neutropenia. Still could it be a marker of a bigger problem?

What’s next? Split ends? This isn’t so crazy. Many chemo drugs not only cause your hair to fall out, but when it grows back, it grows in curlier due to the broken bisulfide bonds.

Will our future doctors be able to walk into our exam room, check our fingernails, and assess if we have been compliant with taking our medications?

Time will tell, but I am pleased that so far, so few nasty signals are popping up.