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.

ASH 2013: Dr. Jeff Sharman Discusses FCR versus BR in Front Line CLL

In this interview, Dr. Jeff Sharman gives us some understanding of the important trial data presented at ASH 2013 that compares FCR (fludarabine, cyclophosphamide, rituximab), the gold standard chemo-immunotherapy (CIT) to BR (bendamusine-rituximab) the new kid on the block and very popular with community oncologists.

In the excitement and promise of the new era of gentler and more effective oral medications for CLL, there is still a diminishing group of patients that for many reasons will continue to chose a chemo-immunotherapy (CIT) approach.

One possible reason is that for a few patients with excellent prognostic factors, a significant subset of those will reach MRD negativity and for that group FCR produces exceedingly durable remissions, starting to hint a possible cure. A half year of harsh but not the worst therapy, and you're done. Time to get on with your life without any daily pill reminding you that you have CLL.

Professor Hallek discusses this special group in my short interview from iwCLL last year.  I would not be completely dismissive of the value of CIT in those special circumstances.

Sadly insurance coverage and expense will be another reason that we will still see chemo. Older drugs are cheaper than newer drugs.

And even more sadly, patients' and physicians' unawareness of the rapidly changing therapeutic landscape will limit some of us CLLer's option to what our oncologist is most comfortable with it.

A few of us won't be able to tolerate the new oral therapies due to side effects, but as more options and new TKI's are approved I suspect that will be a vanishing small number. There are also the very few patients who have progressed on ibrutinib (the only oral TKI approved for CLL at this time and available by prescription) and an unfortunate group of us who both can not qualify for a trial or who have no access to the new meds because of where they live or their insurance and who need treatment NOW and can not wait for a different option.

That said, the FCR versus BR data welcomed as it is, is hardly the blockbuster news that it would have been a few years ago.

Ibrutinib and idelalisib and ABT-199 and obinutuzumab and others have rightly stolen the spotlight at ASH and elsewhere. Their time has come, and not a moment too soon.

Still CIT is not going to quietly fade away so fast so let's look at this important ASH abstract.

This link gives the data.

This link explains what is meant by the grade of adverse events and reminds us that a grade 3 adverse event is severe or disabling, a grade 4 is life threatening and a grade 5 adverse event is polite medical talk for a side effect that kills the patients. So when we see that on the FCR, we patients had a 90% of a Grade 3 or worst hematologic side effect compared to only two out of three in the BR arm.

The price of this higher that high toxicity and small but real risk of dying from FCR was an impressive 98% overall (ORR) response rate with nearly half of those being CR (complete responses). With BR the ORR is the same but the CR is 38%. MRD (minimal residual disease) negative data was not presented. Progression free survival was better for FCR in those under 65 years old, but not in the older group.

So very impressive results, but significant toxicity. This is an old and too common story with chemo: The more toxic the drug, the better it works. FCR is better in younger patients, but comes with more risks and misery.

New targeted and biological therapies break this paradigm and that is why when we have a choice, we should be putting the emerging therapies high on lists of options.

Remember too that this trial was for front line therapy in fit patients where access to the newer treatments in even more difficult.

Listen to Dr. Jeff Sharman and get his take on this important study. Dr. Sharman is a smart, very busy and compassionate guy who has done much to help the CLL and other blood cancer community and I am grateful for the time he gave for this interview at ASH 2013.



Dr. Sharman has an excellent blog himself where he covers much of the same and even more detail on the trial here.

ASH 2012: Dr. John Byrd and the Dream of Magic Bullets: The History and Science behind the Success of the BCR blockers such as Ibrubinib (PCI-32765) and Idelalisib (GS-1101 or CAL101)

In the first of a four segments of my interview with my own wonderful doctor at OSU, Dr. John Byrd, we hear him discuss every patient's dream of a magic bullet and how the history and science of TKIs in general and BCR blockers in particular lead us tantalizingly close to that magic moment.

Be prepared to hear a progression free survival rate in the trial that Dr. Byrd presented at the ASH press conference that will knock your socks off.

Be prepared for some surprisingly good news on what happens to the adverse events the longer you are on the medication.

If you have visited my site at all in the last few months, you are already prepared for the news of the changing of the guard from old school cytotoxic, collaterally damaging, mutagenic chemotherapy to the emerging gentler targeted biological approaches.

 Dr John Byrd ASH 2012

My wife and I leave for Ireland next week, but I hope to continue to post more of the interview every few days. Even ancient castles have the internet these days, but expect shorter commentaries.

The house, the vegetable garden, the tea trees, and most importantly, the cat will be cared for by my adult children who will be moving in during our absence.

Packing the clothes is the easiest part of getting ready. Many layers, and be prepared for the cold and wet.

I have burned about 4 hours of traditional Irish music to keep as going as we drive from village to village in our little rental car.

Paperwork and boarding passes may be an issue as United Airlines and Aer Lingus don't seem to like to play well together. I am hoping our status with Global Entry and TSA-Prescreen will help, but I am not counting on it. The connection in Chicago is tight.

The real work is getting all my precious meds organized for my daily needs. That takes hours of counting out pills. The idea of schlepping more than 20 bottles of my daily and my just in case medication is overwhelming. Without my meds, I would be in trouble fast, so I always bring extras for a few days' buffer. And I bring emergency meds for sudden infections, especially with the flu making the rounds in the USA and Ireland. My irreplaceable Ibrutinib travels in my pants pocket so it is always with me.

The prep for a trip and the worry over what could go wrong is always the worst part. Once we are in Ireland, no matter how cold and damp, we will love it.

What makes that especially certain is that an internet friend whose wife has CLL is meeting us at the airport for a guided tour of the capital of his country, Dublin and then we will share a vegan dinner together. For a fanciful end to our very long day of travel and time shifts and touring, my wife and I will sleep in a real castle.

We can't wait to hit the road.

I am very lucky, but I got a ton of work to do before we leave for the airport.

One piece of personal medical news. Despite all the bone wasting corticosteroids prescribed with my infusions and other issues, and my stopping calcium, my bone density was unchanged in the last two years. I am still in the no man's land of osteopenia (not quite normal but not an an increased risk of fractures), but have not progressed to osteoporosis. I am crediting my high doses of Vitamin D3 and my weight training.