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. Jan Burger Discusses the Role of the Micro-environment in CLL: Part 1

On the first day of iwCLL 2013 in Koln, Germany, Dr. Jan Burger presented important basic science lab based research on how our CLL cells survive and grow in their protected niches and why it is so difficult to rid us of all the cancer calls, especially those hiding deep in our marrow and nodes.

His strong research along with the pioneering work of Dr. Tom Kipps and others helps us better understand the power of the new small molecules such as ibrutinib and idelalisib, and why we sometimes see the wild rise and slow fall of the absolute lymphocyte counts with treatment, particular with mono-therapy.

Without understanding the factors that influence the vulnerabilities and strengths of the evil clones that we are battling, we would never be enjoying the promise of the emerging targeted therapies. Instead. like the chatter for so many years at past ASH and iwCLL meetings, we would still be studying the best mix of chemo cocktails, admittedly often extremely effective, but coming packaged with all their collateral damage and long and short term risks.

We owe a great debt to all the bench scientist who are finding biological answers with potentially revolutionary clinical implications.

Here is the first of my three part interview with Dr. Burger from MD Anderson, Houston, Texas.

On a person note, today I saw Dr. Steve Forman, my transplant doctor from City of Hope for my twice a year follow-up. He agrees with the plan to taper the IVIG to every eight weeks and we have a plan to reduce my cyclosporin. More on all this later, after I get Dr. Byrd's sign off next week when I am back in Columbus.

Immunotherapy for Metastatic Melanoma

The big news out of ASCO 2013 was not about CLL, but about metastatic melanoma.

ASCO is well known to be more of a solid tumor meeting and it lived up to its reputation.

The big buzz is that now oncologists are using a new class of immune therapies that takes the brakes off the immune system so that it can aggressively attack the cancer.

Harnessing the immune system has long been an elusive goal in cancer therapy.

Until recently the best durable response rate in advanced melanoma was about 5% with a very difficult interleukin 2 protocol that made patients feel just awful.

Now it is over 70% and quite durable with simple combination of two separate immune therapy. And with a manageable side effect profile.

Moreover, the breakthrough PD- L1 antibody drugs discussed may have potential in a broad range of cancers, including blood cancers. It is important that those of us with CLL follow the developments in other tumor therapy so that we can be aware of any possible application or parallel research for our particular malignancy.

Exciting and hopeful times for those of us with cancer.

I am grateful to Andrew Schorr and the dedicated professional team at Patient Power for providing the support to do these fun interviews with these pioneering doctors. Please check out Patient Power over the next few weeks for more interviews from ASCO 2013.

Here's a link to Patient Power for the the first part of this same interview on the tremendous parallel progress in targeted therapy for advanced melanoma with a specific mutation that until recently had been well known as a fast working assassin for most victims.

Targeted therapy.

Immunotherapy.

Logical and complementary drug combinations.

This is the future not just for the treatment of melanoma, but for all of oncology.

Soon I will be posting my interviews with several CLL experts done in partnership with Patient Power.

Dr. Lynn Mara Schuchter on the Latest News on Immunotherapy for Advanced Melanoma from ASCO 2013