Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in CLL/SLL Patients and Has Minimal Effects On Platelet Aggregation

Apparently, judging by some of the emails that I received, my epistaxis (bloody nose) generated some general concern, so I am glad to be able to say that I am no longer walking around with a tissue at the constant ready, and more importantly, I have some reassuring research to share from an ASH 2012 abstract.

No less an expert than Dr. Mohammed Farooqui from the NIH did the study titled Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Patients and Has Minimal Effects On Platelet Aggregation without any pharma support that looked at not only at platelet counts, but also how well they actually function or aggregate, a critical step in clot formation, and other measures of their activity. He found what yours truly had suggested in my last post.

Although grade 1 or 2 (mild or moderate and not dangerous or disabling) bruising is a known adverse event seen with an ibrutinib, Dr. Farooqui found in looking at 25 volunteers in the NIH trial who were taking 420 mg a day that " This preliminary report does not identify any significant ibrutinib effect on platelet function." Equally important, platelet counts rapidly improved. He concludes by saying something very similar to what I gathered from the old literature that I referenced in my last post:  A rough day: Bloody nose times two and a tender rash minutes before my CLL and MDS lectures in Chicago. I quote the last line of the ASH abstract: "The apparent functional tolerance of BTK inhibition in platelets is likely attributable to redundancy in the affected signaling pathways." What I said was "there are also clearly redundant pathways and signaling to get a healthy thrombus going in response to an arterial injury."  Like minded, except Dr. Farooqui has the lab data to support his finding.

Here's another thing I really liked about his abstract beside the reassurance on the platelet issue.


"This work was supported by the Intramural Research Program of NHLBI, NIH. We thank our patients for participating in these research studies." 

They not only funded the research themselves because they thought it was important, but they thanked the patients. That is so rare and so welcome. I would have to call Dr. Mohammed Farooqui and his team at the NIH (including my old friend, Dr. Wiestner) mensches (Yiddish for a good people).

Now you might argue that I should have read all the ASH abstracts that mention ibrutinib by now and you would make a good point. I am therefore most grateful to the reader who pointed me to this particular research after reading my last post. In my defense, I have been a tad busy with travel and teaching. I guarantee that all the ASH abstracts that mention CLL will be read with more than a few reviews presented here over the next few weeks.

As my more constant reader can perhaps tell from my upbeat tone, I am feeling much better with not only no more bloody noses or other issues with which to deal, but thankfully with a rested mind and body.

Nothing like a good night's sleep and being home again with my wife and cat.

A rough day: Bloody nose times two and a tender rash minutes before my CLL and MDS lectures in Chicago

I am all better now, but yesterday after finally catching up on some desperately needed sleep in my Chicago hotel, in the bathroom in the morning, I had a nasty sudden bloody nose that wouldn't stop until I applied 20 minutes of direct pressure with both hands.

It was reassuring to know that my platelets had just been checked the day before at OSU in Columbus and were nearly 400,000 so I knew it wasn't my ITP returning, but could it be some platelet dysfunction related to one of the many meds that I was taking? Use of coumadin excludes you from an ibrutinib trial due to possible increased bleeding risks, but was there a concern if you weren't on a blood thinner? Aspirin and other anti-platelet drugs are OK so the concern may be very specific. Being the information hound that I am, I reviewed some old articles on the subject. A study in Blood (2000) looked at the platelets in patients with XLA (an X linked congenital lack of BTK) suggested "These results suggest either that the Btk/Tec family kinase activity is dispensable to platelet function or that there is sufficient Btk/Tec kinase functional redundancy to rescue signaling in specific receptor pathways." In other words, BTK inhibition may have some effect on platelet function, but it is not critical. Another article in the same journal (2006) states: "In summary, the data presented here demonstrate the previously undocumented and critical role of Btk in bt/VWF-induced signaling in vitro and GPIb-dependent stable thrombus formation in vivo." This seems to suggest BTK may play a significant role in proper platelet function. Current Biology in 1998 concludes: "Our results demonstrate that Btk is important for collagen signaling via GPVI, but is not essential for thrombin-mediated platelet activation." I don't pretend to understand all the nuances of these reports, all of which are several years old and predate the era of BTK inhibitors and none of which were studying ibrutinib or any other BTK inhibitors. Rather, they were looking at the platelets of patients born without BTK. Still the data seems to suggest there is a definite role for BTK in clot formation. However,  I am not sure that it is clinically important as there are also clearly redundant pathways and signaling to get a healthy thrombus going in response to an arterial injury. 

Every trial visit I am asked about nosebleeds and bruising, so there must a need for some vigilance. But then again I am also asked about a myriad of other possible problems. That's why we do trials, to find out the benefits, and the risks.

I had no other worrisome bruising or bleeding issues, so I practiced my own advice and tried to under react.

After the bleeding finally slowed down, I needed to rush to clean up, shower and dress in a a blood red sweater and black jeans to give my CME lecture on MDS (myelodysplastic syndrome) to about 250 primary care providers in Chicago.

It all went well, but I had to fight the urge to sneeze more than once while on the stage.

My day wasn't done. The next speaker in the line-up, a good friend who is an expert in dementia wasn't feeling that well with stomach issues and asked if I could hang around and perhaps switch times with him and go on in his slot. As it worked out, he spoke as planned, so I went upstairs to my hotel room to rest and to quickly email Dr. Byrd who quite sensibly blamed the dry air of the plane and the hotel heating system and not the meds. He did not think it was a significant issue. Further reassured, I took a very short power nap, woke up early for my CLL lecture with a second milder more easily controlled bloody nose and just made it down to the stage for my final 90 minute presentation.

Ironically, the lecturer-friend on dementia who was at the podium between my two talks had to briefly leave the stage because of his gut issues and the moderator needed to jump in with the save. Fortunately Alzheimer's Dementia was one of her areas of expertise. She however warned me I was on my own, as she was not prepared to talk on CLL if I exited the stage with a Kleenex pressed against my nose.

The lecture was uneventful and well received and I hung around to answer questions including one from a doctor whose husband is enrolling in an ibrutinib trial. Today I am feeling fine. A tender mysterious rash came and went on my nose last night (maybe from all that pinching to control the bleeding), but I have had no other issues.


A bloody nose can be a harbinger of trouble or a false alarm, but in either case, it is startling, annoying, messy and inconvenient. It all made for a dramatic and stressful day, but all's well that ends well and it was ultimately of no consequence. If Dr. Byrd isn't worried about a bleeding issue, either am I.

Still I will be glad to be home tomorrow.

Labs were just great at OSU. My counts are all essentially normal on ibrutinib. No nodes to be felt. Anywhere. Like the vast majority of patients, I am responding well. Without a CT scan or bone marrow biopsy, you could not tell that I have CLL. And maybe soon, even those won't show any evidence of my evil clone.

I will soon be reporting on important issues from the Lymphoma Research Foundation Meeting that took place in Manhattan Beach last week, and I will be going to ASH this year, so watch for some newsy posts soon.

More Good News

I stopped my diuretic (water pill) that tends to raise uric acid. Replaced it with losartan, an ARB that blocks renin from the kidney that constricts blood vessels and raises pressure. In the blockage, the pressure drops and the kidney does better. I am also aware that it can modestly lower uric acid. This is one of the benefits of doing so much lecturing. This little known beneficial side effect of this common blood pressure pill is something I learned when teaching about gout. I am very lucky to have such access to such helpful esoterica.

The magic worked. Uric acid fell in a week to 7.9 from 9.4 suggesting either:

1: I heal fast

2: My medication changes were magical

3: The prior test was a lab error

4: My uric acid has a mind of its own

Moreover, my blood pressure is back in the normal range, though it could be better. My kidney function remains normal and stable.

On the hematology front, my platelets were a remarkable 344,000. The rest of my CBC is all good, though my Hbg (hemoglobin) was down a bit at 13.7 and my MCV (mean cell volume) up a bit at 100. More on that later if it turns out to be an actual worrisome trend. Right now I feel very secure in ignoring it. Or at least just monitoring it.

Had my first rituximab of six weekly infusions (500mg/M2) last week, and happy to say it went off without a hiccup. My small neck nodes and even smaller, but not gone so that suggests I am still sensitive to its effects and still need more. It is probably busy shrinking my critical mesenteric nodes as I am typing away.

This is all good news.

That's good because I am scheduled to be in 7 cities for lectures or meetings over the next 4 weeks.

Included is a visit with Dr. Kanti Rai in Long Island, while I am lecturing nearby, also Chicago, then St Charles and Springfield, Missouri, another visit to my daughter and son-in-law in San Francisco, and a very short drive to speak in Anaheim.

I am already tired before the first flight.

As it Happens

Live from the Virginia Crosson K. Cancer Center.

Real time sharing through Twitter and Facebook are de rigueur for the hipsters today. I prefer to use my blog.

This instant connectivity offers up an unvarnished, unfiltered, direct communal experience with no commentary, no spin, no insights, no imaginings.

Happening at a laptop near you.

Taking the electron machine out of the loop my BP was 120/82 which is great. Much better than it has been. The RN took it about four minutes ago the old fashion way, pumping up the cuff, and listening for the change in the sounds of my pulse with her stethoscope.

So why the terrible headache last night - clearly not from my BP being sky high. I should know better than to scare myself like that. More likely it was a skipped meal and a busy day with too little sleep the night before.

Now I am waiting for my all important CBC and platelet count. The results should arrive any minute.

The metabolic panel, uric acid, and trough cyclosporin level won't be known for a day or two.

And the answer is.........

is.......

WBC 6.o

RBC 4.27

Platelets 309

Wonderfully normal. Shared while the ink from the printed report is still wet.

How real and immediate is that.

Platelets good enough for a road trip

I am very happy to report that my platelets today, a full 17 days after my last IVIG, were a very healthy 216,000, down from 308,000 a week earlier.

This means that surely I needs the IVIG, or the fall would continue. But how low would it go? Who knows? I don't plan to find out.

But more importantly, it is pretty safe for me to travel to Israel and I should be safe for at least a few weeks from a platelet point of view. To add a margin of safety, I am getting a higher dose of IVIG to safeguard my journey.

The rest of the CBC was WNL though my HGB dropped a bit from 14.6 to 13.7. I won't worry about that unless it looks like it's the start of a trend.

The IVIG seems to be doing a better job post transplant and post splenectomy. My platelets have been much more responsive to the protein coating from the immunoglobulins since my scavenging spleen was removed more than a year before my transplant.

I will gingerly try to stretch out the infusions to 3 weeks when I return. I could live with that non remitting life style for a long long time. And I mean that literally.

We leave for Israel tomorrow afternoon. Patty and I are so excited. We are having Sabbath dinner with my donor and his 11 younger siblings.

I hope to see the details of my BMB before I take off and will share the news here.

Seasonal Myths

Friends,

I hope your holiday celebration was joyous. We all could you use a little joy in this crazy world, especially my friends and their families struggling with heavy health issues.

While the powerful myths surrounding CLL seem most often like the sword of Damocles or the rock of Sisyphus, this season reminds of us that it instead can be the myth of the impossible: the virgin birth, the oil lasting 8 days.

Let me spread (strange verb) a little personal joy.

My platelets were a resounding 249,000 today, 2 weeks exactly since my last IVIG.

I am going to try to stretch my good fortune out to 16 days before my next visit to the infusion center.

My time off last week to do some serious writing was a qualified success in that I am clear that is important and difficult work I must do. I can share so much more on the bigger canvas of a full book. The tough part is that it is tough. It is slow and methodical. I enjoy no divine connection with the universal truths with words just flowing through me as guitar riffs did through Jimi Hendrix. " 'Scuse me while I kiss the sun". 'Scuse me while I type on the MAC just doesn't have much of a transcendent ring.

Like Tom Robbins says, I need to show up whether the muses do or don't. And work.

Off tomorrow to visit my daughter and son-in-law tomorrow in Berkeley at their new place.

Platelets are rock solid, Yea Yea Yea (remastered)

You've heard the tune before. G-d willing you will be hearing it over and over again for a long time coming. Boring is good, change is bad when it comes to platelet count.

Platelets were a happy 223,000 yesterday. Two weeks ago the count was 226,000.

Can't say it enough. Flatline is good news when we are talking platelet counts.

Dr. Rai suggested I keep it simple, and so I will. He said and I am listening: Stay with the simple safe IVIG until it isn't doing the job.

In this situation concerning treatment, less is more. No need to add a more toxic chemical to the mix until my hand is forced.

The only change I am considering is stretching out the interval between infusions.

Happy and Sleepy

We received a call from our daughter and son-in-law in Paris late last night, regaling us with stories of trips to U boat bunkers with 8 foot thick cement roof in northern France, and fabulous meals by the campfire with mussels and crusty bread. They told us how my best friend's daughter is so closing to making him a grandpa, they pushed her gravid form on a razor scooter to a Parisian restaurant as walking induced contractions.

When I had finished responding to the "urgent" emails, it was 2 AM, and though I set the alarm for 5:30 to drive to San Diego for an optional but interesting medical conference on sleep disorders, I decided, it was better to walk the walk , or in this case, sleep the sleep, than listen to the talk on sleep.

Platelets were good yesterday: 224,000. That is only half the rise as compared to my first IVIG, but it is still a very healthy and safe level. I can always find a way to worry or not.

A friend is debuting his new romance novel at a book fair with Dean Koonz and other big writer, so we are heading off to congratulate him and get an autographed first edition.

Overall, I have a good feeling that things are going to work out. Lots of great possibilities.