The Biggest Mistake Patients Make

The Biggest Mistake Patients Make

This is a link to an interesting post.

Even doctors are not immune to thinking anecdotally. Our personal mistakes and successes inform our future decisions and the advice we offer more than we might admit. It can be easier to remember a particular patient than a bunch of statistics.

One caveat: statistics are always blended data. Rare indeed is the CLL study on 57 year old females with exactly two prior chemo-immunotherpies who now needs treatment for enlarged nodes, but whose counts are good.

More likely we will see a study that takes all comers whatever the age or gender or indication for therapy. Maybe the trial only accepted those who have relapsed or who are under 65, but whether is a statistic or an individual, we need to assess carefully how similar their situation is to ours, and then discount or value the information accordingly.

We are always making decisions with imperfect knowledge. Knowing how to weight the value of what we do and don't know can help.

Delays

OK, it is not about CLL or cancer survivorship, but I am delayed again for hours at an airport. Second time to or from Chicago in two weeks. Hours of sitting around.

Hours in planes, hours in airports, waits at train stations and subway stations, days in hotels, long cab and bus and tram and not so express train trips to and from. More security lines and custom checks, though with my Global Entry and TSA Pre-Check, the process is pretty short and sweet.

I am tired, but at least I am not sick and tired.

Can't wait to be back in California. Only one more cross country trip in June, and then I am done until I fly back to Columbus in July.

Turns out even my landing today was delayed because Air Force Two (with the VP) was on the tarmac at SFO.

IVIG: FDA Demands More Prominent Notification of the Risk of Blood Clots

I get IVIG for my ITP. It used to be every three weeks, but now I have been able to stretch it out to every six and my counts are still great. No one is really sure how it works for ITP, but there are theories that it coats my platelets and protects them from premature destruction. I also enjoy the added benefit of protection against infections.

But it comes with risks. I have discussed some before including infusion reactions and allergies, and renal disease. It is an expensive pooled blood product, so there is always the theoretical risk of an occult infection, but there is such extensive safety measures in place that I don't worry much about that one.

Now the FDA is highlighting the risk of blood clots (thrombosis) in a boxed warning.

Ironically those of us with ITP already have a simultaneously higher risk of both bleeding and clotting. How lucky can you be?

I don't plan to stop getting the infusions, though there is a good chance my ITP is no longer active, but why take the chance. Instead I will try to avoid hopping on a plane the day after an infusion as has been in the case many times in the past. Hydration, being active, and my omega 3 rich diet might also help mitigate risk. So would aspirin, but that's not for me with all my platelet problems in the past.

This is the communication directly from the FDA:

Vaccines, Blood & Biologics FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products. Date: June 10, 2013 Purpose: FDA has analyzed recent data that has strengthened the association between the use of intravenous, subcutaneous and intramuscular human immune globulin products and the risk of thrombosis. Additional caution regarding the use of these products is warranted. Summary of Safety Issue 1 Recommendations for Patients 2 Recommendations for Health Professionals 3 Summary of Safety Issue The U.S. Food and Drug Administration (FDA) is requiring manufacturers to add information on thrombosis to th current boxed warning in the labels of all intravenous human immune globulin products and to add a boxed warning to the labels of all subcutaneous and intramuscular human immune globulin products to highlight the risk of thrombosis and to add information on its mitigation. A retrospective analysis of data from a large health claims-related database, as well as continued postmarketing adverse event reports of thrombosis have strengthened the evidence for an association between the use of intravenous, subcutaneous, and intramuscular human immune globulin products and the risk of thrombosis. This information necessitates a boxed warning for the entire class of products. Human immune globulin products are used in a variety of conditions, both on and off-label, by healthcare professionals who may not be aware of the thrombosis risk and measures that could be taken to mitigate this risk. Although all human immune globulin products already contain some information related to the risk of thrombosi in the current WARNINGS and PRECAUTIONS sections of their labels, FDA recognizes that the communication of this risk and its mitigation are not standardized. FDA proposes that for thrombosis a more prominent placement of risk information and a uniform approach for communicating the risk and its possible mitigation will help to reduce the occurrence of these serious adverse events. The information on thrombosis in the boxed warning states: Thrombosis may occur regardless of the route of administration. Risk factors include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer at the minimum concentration available and at the minimum rate of infusion practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Recommendations for Patients Patients should be aware of this risk and discuss this risk with their healthcare professionals. Be aware that thrombosis is associated with human immune globulin products. Talk to your healthcare professional about any risk factors or concerns you may have with human immune globulin products. Contact your healthcare professional if you develop any signs or symptoms of thrombosis during or after receiving human immune globulin. Signs or symptoms of thrombosis may include: pain and/or swelling of an arm or leg with warmth over the affected area discoloration of an arm or leg unexplained shortness of breath

chest pain or discomfort that worsens on deep breathing unexplained rapid pulse
chest pain
numbness or weakness on one side of the body

Recommendations for Healthcare Professionals

Healthcare professionals should be aware of the risk for thrombosis with human immune globulin products and ensure appropriate patient selection and monitoring.
Discuss with your patients the risk of thrombosis associated with these products.
Carefully consider risk factors when selecting patients for treatment with human immune globulin products
Monitor patients carefully for signs and symptoms of thrombosis both at the time of infusion and after infusion and encourage patients to report any signs or symptoms.
Report adverse events involving human immune globulin products to the FDA MedWatch program.

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.

ASCO 2013: The increasing numbers with Ibrutinib

As many of you know I have done very well on ibrutinib for the last year. When I started on PCI-32765 on May 7, 2012, there had been just a little more than a hundred patients who had been on the exciting new oral drug. Many of those early adapters are well known members of the CLL online community. Many are friends.

Personally, I am continuing to do great with near normal counts and no palpable nodes. CT next month in Ohio. All good. Off to Stockholm next week before EHA and just home from ASCO.

Now the community of ibrutinib users including those taking it for other B cell cancers including MCL, WM, and others now exceeds 1500 brave volunteers. Remember that the first trials were only begun in 2009. Many of those phase 1 trial patients are still on drug that tells us something about the durability of the responses, albeit in very small numbers. Still that makes the longest experience with ibrutinib something short of 4 years.

And as with many other biological treatments, the longer we stay on ibrutinib, the more responses, the more complete responses.

One of the nice problems is that when over 200 patients from the early trials were consolidated to look for those who had relapsed after more than a year on therapy, there was only a handful patients to study in more depth. Leaving aside the expected number of Richter's Transformation, about  only 1 out of 20 patients had relapsed with CLL. Most were 17p deleted but one was 11q deleted with a history of nasty auto-immune hemolytic anemia. I refer you to Dr. Sharman's nice review of the subject.

Whenever ibrutinib is approved (and hopefully that will be soon), the number of patients taking the medicine will swell. Other oral drugs may quickly follow. We will need to remain vigilant to see if rarer side effects become apparent post approval. And watch for long term surprises.

Many questions unanswered, but we have come so far in so few years.

And this is just the beginning of a new wave of targeted therapy. Ibrutinib and idelalisib and ABT-199 and GA101 are just the beginning of new wave of game changing therapies. Second and third generations of mAB and TKIs are following on their heels. We patients are needed for the trials to maintain the forward progress.

But let's celebrate the progress that we have made.

These are good times.

ASCO 2013: A Call for New Ways of Thinking

LIVE from ASCO 2013

It's huge.
It's crazy.
It's crowded.

But boy is there a ton of new research to share.

While ibrutinib and idelalisib have kicked open the door to explore new less toxic pathways to control not just CLL, not other B cell cancer, they did not close the door behind them.

Novel pathway inhibitors beyond PI3K and BTK and BCL-2 are being explored and being explored in novel ways with more open access.

New and potentially potent BTK and PI3K inhibitors are in trials now.

Combinations are being considered.

Dr. Wiestner said these new drugs offer us the opportunity to think in new ways.

Hence my disappointment when I hear speakers rightly celebrate the lack of bone marrow suppression with these new targeted therapies, but then got all excited about how that allows them to pile on the old school  bone marrow damaging chemotherapy. Maybe we do need to go in that direction, but can't we try to leverage the low toxicity of these drugs but adding other low toxicity agents to them, offering patients like us gentler and less risky control of our disease.

I like the idea of adding together more than one TKI or adding a monoclonal antibody or an IMID.

In my book, adding in bendamustine or fludarabine or chlorambucil or their ilk should make a significant difference in outcomes to justify the additional downside risk.  

I understand the temptation to revert to tried and true paths. And it might turn out to be the best call. Medicine must be both conservative and progressive.

But we have a sea change, a paradigm shift, happening in CLL. Let's try to keep innovating and exploring using the kind of thinking that got us the breakthroughs with  ibrutinib and idelalisb and ABT-199.

That is the next stage of research that has me excited.

That is the future that I want for all of us.

Live from ASCO 2013: Targeted B cell therapies

Raw review of the first session on targeted B cell therapies.

Typing fast. May have made errors but wanted to get this out

After my bad karma of a weird 35 miles and 16 minute diversion from Orange County to Ontario and then another three hour delay due to weather, I arrive in Chicago four hours late.

Today my karma was good: the hotel and shuttle were perfect. At the meeting 10 minutes early.

ABC diffuse B cell lymphoma DLBCL

NF(kappa)B signaling
Ikk(beta)kinase??

Stuck in the on position

Message from BCR- turns out that BTK is turned on upstream

Ibrutinib binds to site only found in 10 kinases covalent binds to cysteine 481, lasts all day

Inhibits BCR signaling and works other ways when BCR not turned on

Failed in primary refractory disease, worked better in relapsed/refractory

Works great in ABC type as expected Small #s

CD79B mutation 70% response rate, without still 31% response rate-
MYD88 +CD79B 4 of 5 response
MYD88 resistant Poor response??
CARD 11 downstream no response as expected

Pre-clinical trials

Ibrutinib synergizes w PI3K (inhibitor maybe alpha) mTOR, lenalidomide, steroids, chemo

IRAK4 inhibitors???- selective. Works with ibrutinib

BCR Signaling

Other Targets:

• mTOR
• SYK non receptor fostamanib 

BTK inhibitor (ibrutinib)

Little cumulative toxicity- marrow and elsewhere counts stay good

CLL

PFS 96%?  in RX naive (Byrd from ASH 2012) abound 60% in R/R 17 p at 2 yrs

MCL

high response rates 70%
like other biologicals improves the longer patient stays on drug

Other BTKs

CC292 (used to be AVL-292)

Didn't mention but ONO has a BTK inhibitor in early trials that  pre-clinical is strong

More Targets:

PI3K Idelalisib

CLL  significant nodal reduction including those with 17p
Also MCL and others
Little marrow toxicities, some liver enzymes up, pneumonia

Another PI3K
IPI-145 Phase 1 study  Good responses including response in Hodgkin's and T cells!

Dumping of cells from nodes and marrow into the blood (evidence from the marrow is thin- I asked)

Don't get the high WBC when mixed with chemo

EPIGENETICS (Dana Farber)

IN THE NUCLEUS that the actions happens

Sequencing cancer genomes

600,000 events altered, at least 486 important??? ( not sure of #)

Only 15 drugs that targets somatic mutation

Also progression- Need to get to master regulator in nucleus

Histone is critical

HDAC removes markers (placeholders)
Binds zinc  -removes reminder cap
Early w cardiac toxicity


Topical T cells treatment that breaks down when absorbed into blood so less toxicity

Bromodomain inhibitor JQ1

? turns off master growth MYC genes in MM

XANX  bromodomain inhibitors

Dana Farber open-source model of drug discovery.

Questions about how to control cost

That's it for now. I am sure there are mistakes in this. Please forgive. I just wanted to get this out fast in this unedited form to give you a sense of the barrage of information, but later I will of course return to my more editorial style. And videos too soon.

So much happening. So much info. This is all good.