Sunday, January 09, 2011

And now, the bad news

“Laws are like sausages,” Otto von Bismarck once said. “It is better not to see them being made.”

The same could be said of treatments for chronic lymphocytic leukemia, especially with experimental drugs like Revlimid, aka lenalidomide.

Not long ago, I wrote about some of the positive aspects of my Revlimid experience in a piece entitled "First, the good news." Now it’s time for the promised bad news, which happened in October while I was trying to increase my daily dosage from 10 mg to 15 mg and then 20 mg.   

Actually, the first sign of trouble was back in June, when I was taking 10 mg. One night, all of a sudden, I had trouble forming sentences. I could talk or write, but as I did I realized that I wasn’t saying the words I meant to say. Language is usually reflexive, but I found myself having to concentrate very hard to find the right words to form even simple sentences. I was not always successful. This lasted for about 10 minutes and stopped almost as suddenly as it had started.

I think many of us experience some loss of mental agility with age, an effect of which can be occasionally searching for words (as well as standing in front of the pantry blankly and saying “Now, why did I come over here?”). Revlimid can further (temporarily) reduce this agility by adding a layer of dullness or lack of mental swiftness. In the past I have described the drug as the enemy of multitasking.

My ten-minute word hiccup seemed similar to things I had experienced as part of aging, but also different enough and intense enough to cause me concern. I took myself off the drug immediately and looked at the list of side effects that the drug's maker, Celgene, provides. I also read up on side effects reported in CLL and Revlimid studies. Nothing obvious seemed to explain the situation, so I chalked it up to “chemo brain,” a medical catch-all that is not unlike that famous Victorian malady, “the vapors.” I resumed the Revlimid after a few days, and all was well. By the time I next saw my oncologist, I had almost forgotten about it, mentioned it in passing, and went on my merry sausage-making way.


Until it happened again, on the night of October 5, four days after I began taking 20 mg. Again with the language problem, again for about 10 minutes. Marilyn said it sounded like I was trying to say two things at once. I recalled getting words almost right; for example, I wanted to say “tea” but ended up saying “Ted,” which is my father’s name. Hey, both start with a “T” and have three letters!

This time I didn’t shine it on. While on 15 mg for two weeks, I had begun to hear a periodic heart beating sound in my right ear. This got worse at 20 mg. Before the language problem hit, I had already decided to stop the Revlimid that night and have a CBC the next day. In the past, whenever I had heard a heart beating sound, it had signaled hemolysis, or an attack of autoimmune hemolytic anemia (AIHA), in which the body destroys its own red blood cells. This sound was different, though, and I wasn’t getting any other telltale signs of AIHA, such as orange urine or feeling winded while walking up stairs. Still, I didn’t want to take any chances, and a CBC seemed a logical place to start.

The CBC came out fine. All I knew for sure is that the severity and frequency of the beating sound had increased with the dosage of Revlimid and that the sound went away when I was off the drug. And, of course, I had that disturbing language thing again. I made an appointment to see my oncologist, Dr. Belle, ASAP.

Dr. Belle told me that Revlimid increases the viscosity of the blood and that the sound was probably my heart working harder to pump blood into my brain. This explained why the sound got worse with the higher dosages.

And this also explained the language trouble: Dr. Belle said I had almost assuredly had a TIA.

A what, I asked?

“Transient ischemic attack,” she said. Also known as a mini-stroke.

“I’m quite concerned about that,” she said.

I was, too. Later, after making use of Google to find out everything I could about TIAs, I was in something of an information-induced panic, after which I calmed down to a level that might be described as “heightened concern.” 

I learned that TIAs, like full-fledged strokes, are caused by a blood clot in the brain. The difference between a TIA and a stroke is that a true TIA lasts less than 15 minutes and causes no permanent damage.

TIAs can affect vastly different areas of the brain, including language (leading to expressive aphasia in my case, where I can understand what is being said but have trouble expressing myself). TIAs are considered to be warnings; about one third of people who have them go on to experience a full-fledged stroke within a year.

Should the ischemic attack drag on for more than an hour, you enter the realm of official strokedom and potentially severe harm. I had narrowly missed a situation in which I might have ended up bawking bike kiss for the guest of by wife.


Before these incidents, I had never had a stroke or a TIA. The literature on Revlimid and CLL indicated that blood clots in the lungs and legs could be an issue, but I could find no evidence of TIA in CLL, although it was reported at least once in  patients taking Revlimid for myelodysplastic syndrome.

Apparently, a TIA is a rare event, although clots are not. One patient information document for a Revlimd-CLL clinical trial classifies clotting -– defined as “formation of a blood clot that breaks loose and is carried by the blood stream and plugs another vessel” -– as one of a secondary group of possible side effects of Revlimid, occurring in 3% to 20% of patients. 

The trial, using Revlimid as a single agent, is being conducted at New York’s Roswell Park Cancer Institute, arguably the country’s leading center for CLL-Revlimid research. They have been dealing with CLLers for years and have the clinical experience to know what’s what.

And guess what?

All patients in the trial -– yes, ALL–- are required to take 2 mg of the blood thinner Coumadin each day.

This, my friends, is not commonly known, and it’s not even commonly practiced in most other CLL-Revlimid trials, from what I can gather. Nor is your local oncologist likely to know about it. So consider it a public service when I say that it is a wise precaution for all CLLers, even those with no history of clotting problems, to take Coumadin (generic warfarin) with their Revlimid!

As the patients in the study are told in writing: “It is important that you take the Coumadin every day that you take the study drug lenalidomide.” (Here's an interesting little abstract.)

Obviously, those who are at high risk for clotting stand a better chance of running into trouble. But how do you know if you’re high risk?

I had no history of clots. My blood pressure is excellent, I don’t have diabetes, arterial disease, or high cholesterol. High risk? Me?

Then I had a grand “D’oh!” moment, worthy of Homer Simpson at his worst.

Back in 1977, my mother, who was only three years older then than I am now, died of a pulmonary embolism. She had a long history of thrombophlebitis, or veins being blocked by clots. My older half brother, her other son, had two strokes about ten years ago -– when he was the age I am now -– after using Vioxx. He had assumed that Vioxx, later recalled by the FDA, was the cause. But did heredity play a part, especially since he had another stroke just a few months ago? Even Homer Simpson could probably get the right answer to that one.


I’ve been back on 5 mg of Revlimid, as well as some Coumadin, for awhile now. A carotid ultrasound ruled out any problems with plaque in the neck, so the odds of another TIA (or worse) really seem dependent on the dose of Revlimid I take, as well as the dose of Coumadin.

After two weeks of 2 mg of Coumadin daily, I had a PT/INR test, which measures clotting time. Mine came out normal. In other words, I was clotting like a person who wasn’t on Coumadin. That’s just not a good sign. So now my doctor is fiddling with increased dosages, which is typical with Coumadin, trying to get my blood suitably thin.

Until that’s done, I’m sticking with 5 mg of Revlimid. I may never go higher, and I may end up using the 5 mg intermittently -– say three weeks on, one week off, or 5 mg every other day.

The 5 mg seems to be working fine, judging by how I reacted when I resumed the drug after a three-week treatment holiday. I got a good amount of tumor flare, which lasted about two weeks before reducing, and my B2M is high, indicating that a whole lot of cell kill is going on. My CBCs continue to be normal and I have so far been spared the low neutrophils and low platelets that are fairly common to CLLers on Revlimid. 

Needless to say, I’m going to watch for symptoms very carefully. Should I experience a third TIA, despite the blood thinner, my Revlimid career will probably come to an end.

Why take a chance at all, you might ask? Well, I don’t really have a choice. That's a short sentence but a big concept. Sometimes we take risks because we have no better alternative. Revlimid is the only thing out there that appears to be able to give me long-term stable disease without the curse of AIHA.

Other therapies also come with potential for great harm, just in different form, in case you hadn’t noticed. I'd rather take my chances with carefully managing Revlimid at lower doses -- which may get me to the next drug that can control my disease but might be easier on the system (CAL-101?) -- than jump on the transplant bandwagon. Given the difficulty I would face in getting a good donor match, as well as the inherent risks that can lead to fatality, I am in no rush to go that route. 

With CLL treatment, we are always playing with fire. At least I now know what I need to watch for and plan for. The only thing worse than having to manage potentially serious side effects is to suffer them without warning.

I’ve been warned.


Anonymous said...

Thank you for this heads up. v

Paul Zamecnik said...

Thanks David. I'm in a clinical trial with FCR for 6 months, 4 months off, and then Len for 6 more months. Oh yeah -- and my mother has had several blood clots. You can bet that I'll be asking for the coumeden.

Anonymous said...

I have been a part of Rosewell L study since March & been on the C drug from the beginning. Knock on wood no stroke type issues so far. I peaked at 25mg of L in July but could not tolerate. Been on 15mg since, platelets are fine, RBC & HG are low, WBC are within range.


Anonymous said...

Thank you for this generous heads up. . . literally. Thank you for your thoughtful, helpful and well written posts. I always look for them and I am always helped by them.

Anonymous said...

Why is it that David has to give us a heads up? Something is fundamentally wrong here.

Good warning to all: take nothing for granted in this world!

Anonymous said...

The potential risk of blood clots with lenalidomide therapy - especially if it is combined with any kind of steroid therapy such as dexamethasone or prednisone etc - is well documented. Most responsible clinical trial protocols call for regular monitoring of PT time (time for blood to clot) and patients are given prophylactic coumadin if they have out of range PTT or if they have prior history of blood clots.

I am amazed Dr. Bella was not more aware of this risk factor and needed this adverse effect to develop fully before she acted. Does not speak well of her level of experience.

50s something professional in recovery said...

I have been thinking of signing up for the Continuum trial, one of my oncos mentioned aspirin but I know that warfarin (Coumadin) is better in general in clot prevention (I am a semi-retired doc). Seems though that 2 mg of warfarin is low, to get your blood adequately anticoagulated ("thinner") most patients start at 5 mg and many need 10 mg....there are newer safer anticoagulants coming on the market, however.

Anonymous said...

There are several issues here:

Coumadin use is not w/o risk and the risk rises as the dose increases to increase the INR

It is possible that low dose Coumadin or ASA may be effective in protecting patients on L... we need to know what the experience has actually been.

The newer drugs referred to above have been tested in other circumstances (atrial fibrillation, post knee surgery) so it isn't clear that they would be helpful in this circumstance.

Anonymous said...

Rev is commonly used for multiple myeloma (MM) and it is known to produce DVTs and subsequent PEs in that setting. I found TIAs listed on one MM site as a possible side effect but no incidence data. Since there is strong evidence that you have had TIAs, I am wondering if you would be better off with low molecular weight heparin (lovenox) or the newer warfarin substitute, pradaxa.
Regards, TomD

Anonymous said...

It bothers me that docs are so clueless. Who knew?

When I was on my first-line trial (HDMP+R) I was not warned about neutropenia, nor put on any prophylaxis that I can remember. I flew home on a completely full Southwest flight, and caught something that landed me in the hospital two days later, with a ANC of 0.0. Not good.

Now they do a better job, but c'mon!

Anonymous said...

David I am a 48year old female from Scotland. Found out in Sept 2009 that I have CLL (counts then ALC 7.2, WBC 12). June last year went to London got my prognostic markers done, I am 11q del, CD38 20% and unmutated. Counts yesterday ALC 22, WBC 28, still on watch and wait. There is a trial for Revlimid in England for early stage CLLers with bad prognostic markers tempted to apply for it but on there schedule no mention of warfin to be given. Don`t know what to do!

David Arenson said...

Hello, Scotland.

I'd bring up the issue to the trial investigators. They might put some stock in the abstract I linked to, and also in the fact that Dr. Chanan-Khan's trial of chemo-naive patients requires 2 mg of warfarin per day. It may be optional for you to take it; perhaps it would not prove contradictory to the goals of the trial. You don't know until you ask!

Anonymous said...

Hi, David. I'm on one of the lenalidomide/rituximab trials. My protocol calls for 2x28 day cycles of 10 mg. L before starting rituximab. My tumor flare has been quite dramatic: starting within a few hours of taking the first capsule and becoming unbearable by the third consecutive day of the drug. After almost 2 full cycles (with and without prednisone) I can only tolerate 5 mg. of L every other day. My oncologist doubts L will ever be widely accepted outside of medical centers because of the difficulties predicting patients' reactions (I had him on the phone on Christmas Day) and adjusting dosages and prophylaxis. Counting down the days until my first rituximab infusion. Best wishes on your lenalidomide journey.

David Arenson said...

"My oncologist doubts L will ever be widely accepted outside of medical centers because of the difficulties predicting patients' reactions (I had him on the phone on Christmas Day"

Interesting thought. I hope my posts have helped convey how tricky L can be. This isn't an easy or predictable drug. I think it is best used by patients who are willing to take risks and stay on top of symptoms, people who are active in their own care. And by doctors who, even if they haven't dealt with every variation of L and CLL, are willing to take calls on Christmas. I have my doc's cell phone number and I have had to call her when she's been on vacation.

DebraLynn said...

Hi, David. Great writing. I am a former newspaper reporter, and still a columnist for McClatchy Newspapers. You can google me at debra-lynn b. hook. My web site is I have a FB page, too. I also have &*% CLL, unmutated. Ta-da. I was diagnosed a year and a half ago. So far so good. WBC holding steady at 17. Last week, WBC spiked, lymph nodes starting feeling like tiny pepper shot, spleen "slightly enlarged." This, luckily ? was right before I got a nasty cold. So that might have been the reason. Anyway. Thanks. Headed to the doctor in an hour to find out IF I need to do anything with this nasty cold. It's all so confusing. Your blog like the proverbial breath of fresh air. I keep thinking of starting one, too. Meanwhile, I am grateful to you for your writing and for your details. I hate to say, but it's good to find someone with longevity AND unmutuated. This really freaks me out sometimes. In fact, that's how I found you. I googled unmutated CLL forum. Helps to know you are there. Rambling, sorry. Debra-Lynn Hook, 55 years old, diagnosed at 53.5 in 2009

David Arenson said...

"I hate to say, but it's good to find someone with longevity AND unmutuated."

Dr. Terry Hamblin of the U.K., one of the world's CLL experts, has a huge patient database. He reports that one unmutated CLLer lived for 25 years -- and that was before the improvements in treatment and new drugs of recent years.

So don't give up hope. The longer I live with this thing, the longer I expect to live longer with this thing. But it is only natural to search for encouraging stories. One of the very first things I did after diagnosis was to troll the internet for examples of longevity. I even made a list. It was important to know that it could be done. And it can be.