ITP In CLL (Chronic Lymphocytic Leukemia): Personal And Clinical Reflections

Another great discussion courtesy of ONCLIVE with 4 top CLL experts, from left to right: Drs. Byrd, Furman, Ma, and Kipps.

This time they discuss immune thrombocytopenia (immune mediated low platelet count) or ITP.

ITP is where our immune system attacks our platelets. Just our luck, our wimpy inadequate immune system that can't alway respond to an infection or a vaccine or a secondary cancer, whips into high gear to attack its own cells.

In extreme cases it can lead to live threatening bleeding. It is well recognized complication of CLL occurring in < 5% of us, but as the doctors imply, I suspect many mild cases go unrecognized.

When the same process attacks our red blood cells, sometime leading to a dangerous anemia, it is called AIHA for the auto-immune hemolytic anemia. ITP is the platelet version of the same issue. Attacks on the neutrophils and multiple blood cells lineages also occur, but are more rare.

ITP is a subject near and dear to my heart.

About one year after my diagnosis with CLL, I remember being on call for my medical group and waking to the phone in the middle of the night. It was my exchange. I had asked my family doctor to order a CBC that morning because I had noticed some easy bruising and petechiae (tiny red dots caused by small hemorrhages often associated with low platelets) on my legs.

MEDICAL EXCHANGE: Dr. Koffman please.

ME: Yes. It's me.

MEDICAL EXCHANGE: We have a critical lab result ........ on Brian Koffman. A platelet count on 9.

ME: Thanks. I will definitely follow-up on this.

And I did. It was 6 they next morning and I was hospitalized for IVIG and steroids. It bounced up in 48 hours but because of my recurrently dangerously low platelets I would go on to five emergency admissions in the next year,  multiple outpatient infusions, and an urgent laparoscopic splenectomy where I lost half my blood. I failed steroids, rituximab, IVIG, cyclosporin and the splenectomy.

What finally worked post splenectomy was a combination of cyclosporin (an immune suppressing drug used today mostly to prevent rejection of kidney and other transplants) and rituximab that was recommended by Dr. Byrd. The combo's effects were nothing short of amazing, especially  considering that both drugs on their own had had no benefit in raising my counts. On the combo my platelets climbed from single digits to above normal (not uncommon when you have no spleen).

And the combination of cyclosporin and rituximab had the surprising and joyous bonus of reducing my bone marrow involvement with CLL down from 90% to 3%.

There are some case reports in the medical literature of cyclosporin having antileukemic activity, but it generally avoided due to the fact we are already immune suppressed and it can cause significant problems including renal disease, hypertension and aggressive gout.

It was my dangerous and refractory ITP more than my CLL that drove me to a first remission transplant.

That didn't work either, and my ITP was back one year post HSCT.

That were difficult times.

Despite the risks and side effects, it was only about none months ago, after almost two years on ibrutinib and with years of normal platelet counts under my belt, that I finally had the courage to taper off my cyclosporin. I feel it had helped save my life and I worried about stopping it.

But I did and I have done great since.

A few comments from one who's been there and done that. Yes, I know that one case is not data, but it can be a cautionary and instructive tale.

For obvious reason and because it is part of some of the guidelines, I would ask the doctors in the panel to add cyclosporin to their list of second line options for ITP. I would certainly use it well before the extremely immune suppressive alemtuzumab (CAMPATH) that knocks out both T and B cells for a very long time or splenic radiation that has a host of short and long term complications.

I would also remind us all that the surgery does not always go well, though laparoscopic is clearly the way to go. The research tells us that the best predictor of outcome is the experience of the surgeon. Though it didn't work for me, I have no regrets about my surgery.

I would also ask my colleagues to comment on just how difficult it can be to get us off steroids and not have the ITP return.

The data on ibrutinib is encouraging and makes sense from a biological point of view, but it is not 100% effective.

Overall, a very helpful and well considered discussion on a very important and scary topic. As we might expect, while there is much consensus, there is significant polite disagreement on how to proceed.



It is such a blessing to not have to live in fear of what my weekly or twice weekly blood test would reveal.  Showing up at the lab,  not  knowing whether I was OK or I was headed to the hospital.

That's all in my distant past now.

Still, as all of us with cancer know, we are always looking over our shoulder, wary of the return of our past tormentors,

More Good News- Update on My Lab, CT Scans, and General CLL (chronic lymphocytic leukemia) Status

My blog has veered far away from the simple telling of my story to more telling of our stories with much B roll.

I am making plans to maybe bifurcate its content in the future, but for now it will continue its happy and diverse life as a personal health blog, a home for research news and video and audio interviews with leading researchers, and a whole bunch of personal analysis and advocacy on what it all means.

I am back from Ohio State where I am still seeing the research team every 3 months and getting CT scans every six months for my clinical trial on ibrutinib. I have riffed on this being too much radiation before in this prior post that includes links to some of the basic research of radiation exposure and its risks, but Dr. Byrd argues that the few relapses he sees on ibrutinib show up first in the nodes, so he wants to monitor me with the scans.

True enough. When I relapsed post failed hematopoeitic stem cell transplant in 2008, the nodes were my canary in the coal mine showing slight growth months before my lymphocyte counts started to move up and my platelets down.

So twice a year CTs are still the plot line for my clinical trial at OSU.

Since diagnosed in 2005, I have probably had about two dozen CT scans!

Add to that the equivalent of the 20 chest X-rays annually I get from flying over 100,000 miles a year, and my risk of secondary cancer is significant. This link with a NASA produced video tells the air travel part of the story.

If you really want to worry, take a look at this article from Medscape on CT scans in NHL.

But this post is not about the danger of CT scans, but about what my last one showed and happily that was stable disease.

I still have enlarged lymph nodes but they have changed little since October of 2012, or for the last 20 of my total of 25 plus months on ibrutinib. My largest sentinel gut node near my liver was about 10 cm at its peak, 7.3 x 3.3 cm just before starting ibrutinib, 4.4 x 0.7 cm in October, 2012 after about 6 months on the medication, then it shrunk to its shortest 3.9 x 0.7 three months later and when last measured on June 30, 2014 was 4.4 x 0.4 which actually represents its lowest volume. It has been fluctuating and when you account for the difficulty of measuring mobile objects in the mesentery and near the liver, is mostly stable since its dramatic shrinking in the first 6 months of therapy. Its a long hot dog shaped node instead of the more common bean shape. The same early dramatic shrinking in the first six months and slight ups and downs since has been the tale for my other smaller sentinel nodes on the scans.

So I have pretty stable disease.

What does this mean to still have enlarged nodes and a touch of CLL in my blood (see this prior post from last April on my flow cytometry report to understand more about my numbers and disease burden)?

The CLL does not proliferate in our blood, so the disease in our nodes and bone marrow are the source of all our problems and I will ignore the blood for now.

There is good reason to believe that these enlarged nodes are still full of CLL, but that it is not proliferating, thanks to the signal blocking from ibrutinib preventing it from getting the messages from its nurse like cells and others to be fruitful and multiply. So chock full of CLL, but it's dormant.

The other more positive interpretation is that these enlarged nodes are just the scarred down skeletons of the cancerous nodes they once were, and there is no residual disease to be found. Unfortunately, I am skeptical of this more PolyAnna hypothesis, and short of a biopsy which is not going to happen, there is not way to know for sure.

So what to do to avoid waking the Kraken?

Hope my genomic instability as evidenced by my 17p and 11q deletions and my complex karyotype will continue to behave with the ibrutinib aboard and not mutate so that my magical bullet no longer covalently binds BTK and blocks its activity?

Knock down the residual disease by adding a second or even a third agent?

Be reactive or proactive?

That is the question du jour faced by many of us now and more in the future whose CLL is controlled but it is not gone now with the new medications such as ibrutinib and idelalisib.

I have probed this recurring and unanswered question in more detail a prior post, and will soon be updating my thoughts on how to avoid being left stranded on third base and not getting home to a cure.

The rest of my news is also good.

My blood counts are boring and despite dropping my cyclosporin to a token dose of only 25 mgs once a day and stretching my 40 grams of IVIG infusions to every 7-8 weeks, my ITP also remains dormant. I think the possible immune stabilizing activity of ibrutinib and my low disease burden may be the factors  that have given me this long ride with high normal platelet counts. I have not been anemic for many months now and my neutrophils and the rest of the CBC are all copasetic. My blood chemistries are in the normal range and only my very low immunoglobulins, namely IGA, IGM, and IGG give proof to that fact that I still have a B cell leukemia, albeit a very sleepy and well behaved one.

More personal clinical and general CLL news soon, nearly all of it good.

I will be posting some of my interviews from ASCO 2014, plus sharing some exciting advocacy news. Busy times.

Pills, Pills and More Pills: A Serious and Sometimes Humorous Look at Adherence

I have blogged extensively on the serious problem with adherence with oral cancer medications in past posts. Check out my interviews from ASH 2013 if you haven't seen them before.

Pills don't work if we don't take them.

Many factors play into how faithful we are about following our doctors' and pharmacists' orders.

Let me get personal.

I need to take way too many medications. And with way too many twists and turns in how they are taken.

It is so bad that when I travel, I carry a note from my doctor so I don't get stopped by security for all the pills and potions, many of which are unlabeled including the precious unmarked grey capsules that form my trial supply of ibrutinib.

How many pills do I take?

I take so many pills that I could skip breakfast and still have a full stomach.

How many pills do I take?

I take so many that the pharmacy asks me if want help carrying my prescriptions to the car.

How many pills do I take?

I take so many pills that I could reproduce a decent pointillist copy of Seurat's A Sunday Afternoon on the Island of LA Grande Jatte with a week's worth of the medicine in my bathroom.

OK, I am exaggerating, but you get the idea.

My carry on is mostly drugs, both my regular daily doses and my "just in case" meds.

Let's start with the "emergency" meds first.

I always travel with Levaquin for respiratory infections, Cipro for all other bacterial infections, and Tamiflu for influenza. These are like my talismans used to ward away the very infections they are designed to prevent. I cling to the magical thinking that if I bring them, they won't be needed, and if I don't, then watch out.

The magic has worked so far. My same old box of Tamiflu has been irradiated by airport security around the world 100s of times by now.

I may bring ginger and meclizine for nausea and also Imodium and Culturelle (a probiotic) for diarrhea when I travel to exotic lands, topical voltaren, arthritis-acetaminophen, Celebrex, and a few very old stronger pain pills just in case. Over the counter Pepogest (peppermint oil) is my go to for most GI issues.

I don't bring anything for sleep or anxiety. I am lucky that way.

I do bring herbal teas with mullein, slippery elm, and marshmallow root in case I get a sore throat or hoarse voice when I am scheduled to speak.

I pack several cold and allergy remedies too for my longer trips out of the country. Otherwise I can just buy them as needed.

I bring a whole different list of meds for my wife when she travels with me.

My regular daily meds overflow their AM and PM plastic pouches. And when I travel more that 10 days, I need large two pill cases. And I always take at least three extra days of everything.

Getting my meds ready for travel is a more time consuming, exacting and high stakes chore than packing my clothes or my paperwork.

At home or on the road, the daily routine is killer too. I am thankful that I don't take any mid day meds, but in the morning I have ibrutinib 1/2 hour before eating or taking all my other meds. Those include one that I must remember to take only three times a week and one sublingual that I wait to dissolve under my tongue just once a week, and finally one where my dose is variable depending on my activities that day. One must be taken daily after  the same meal daily. One is pill is cut in half and another one in quarters. This all takes a ton of time.

The cyclosporin that is a twice daily medication comes in a bulky thick foil individual wrapper that defies my feeble fingernails in their bumbling attempts to open the packaging, so I often need to cut out each individual capsule. But scissors are a no no in carry-on, so I always bring extra cyclosporin when I am on the road (or in the air)  in case I can't open some of the packets. And what's worse is that me being a vegan and having to gulp down so many capsules made with gelatin, an animal protein obtained by boiling skin, tendons, ligaments, and/or bones with water. 

I don't want to even think about it.

Another complication is that a couple of my regular supplements must live in the fridge. They get forgotten the most. (Left out in the cold)

Another is a tart and fizzy powder that is mixed with first hot water and then cold water, twice a day.

I haven't mentioned all the topical creams my dermatologist wants me to use and the ophthalmic ointment needed nightly to prevent painful corneal abrasions that I self apply with a mirror and a flashlight and that effectively blinds me throughout the whole night.

Until the parade of pills starts all over the next day.

We can understand why oncologist like infusions. They can be sure that the precious medication is delivered.

Still, I am grateful that these oral and self administered medications exist, that I have the insurance and resources to afford them, and the freedom and health to complain about the whole twice daily rigamarole.

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.

Lots to write about but I don't feel like writing

Got back from Canada on Sunday after the memorial service for my father. It's been a rough time.

Monday I was at City of Hope and Wednesday I was at the infusion center for my first rituximab (R) in over 6 months.

Despite only using oral Claritin and Tylenol as pre-medications, I had no reaction to a full dose of 500 mg/M2. The infusion was a non-event, even with the IVIG chaser that kept me in the chair for a total of about eight hours

I cheated a bit and briefly upped my cyclosporin (CSP) back from 75 mg twice a day to 150 mg twice a day, as I believe (with no hard proof) that its antileukemic effects are more apparent at the higher dose, especially in combination with R. That's been my story so far. With that increase comes the increased toxicity, so I added a low dose of a long acting form of nifedipine, a calcium channel blocker, favored by transplant docs and nephrologists for blunting the hypertensive and nephrotoxic side effects of CSP. I am now on three drugs to protect my kidneys and control my BP, and before I started CSP I was on none. It ain't chemo, but it ain't benign either.

I will taper back down on the CSP starting tomorrow, but will repeat the same dance again next week and over all six cycles if my BP and renal function behave.

This is, of course complete voodoo, making up my own idiosyncratic treatment protocols, but there is a raw logic to it, so I am taking the slight risk. Plus it fits with what researchers like: Do an intervention and measure the results.

It is also self diagnosis and treatment, which is a fool errand, but I accept the folly and the responsibility of my acting out my plan. Besides, it is a rather trivial move. The big deal is the use of the rituximab for my >6 cm mesenteric nodes, and preventing my ITP from re-flaring, and really no other reason, just keeping the CLL, the tumor load, in check- dare I say maintenance therapy? That is the real blazing of new territory.

So far, only one day post R, many of my nodes are palpably smaller, but none of them are gone. This is the necessary prerequisite but no guarantee for getting the needed response in the pesky gut nodes. That story will need to wait until my follow up MRI two months after my last cycles. Nevertheless, it will be silly not be happily encouraged by my brisk response to such a gentle treatment.

Though "happy" escapes me these days. That will happen, but I will be patient and fake it for awhile.

I can't wait until Friday night services tomorrow to recite Kaddish for my dad. I promised myself to say that ancient prayer every Sabbath for the next year. It is a son's duty, even for a father who shared with me a healthy skepticism for all things religious. It feels right. It feels healthy, and maybe healing.

Lots of healing going on here.

Lots of healing still needed.

It's Always Something: High Uric Acid

My uric acid or UA level shot up to 9.4 over two weeks from 7.9. It should be under 6, but up to 8 is rarely an issue.

This jump is a recognized complication of my miraculous cyclosporin or CSA that has greatly helped me hold onto my platelets.

In fact, aggressive, destructive gout is a well known risk of CSA. My personal risk of getting that pleasant malady unless things change is about one in four. Besides pain and joint destruction, it can damage kidneys.

Like it does to many others, cyclosporin has also pushed up my blood pressure. That lead to a slight increased dose of my thiazide diuretic to control the pressure. That too can raise the uric acid.

Cyclosporin also is tough on kidneys itself. My kidney function is still normal, but not as good as it was before I started the CSA this time. Last time I took it for this same problem, I had to reduce the dose as my kidney function was compromised. The reduced dose continued to work just as well for my ITP and my renal function normalized.

So I am rechecking the lab in two days, stopping the thiazide, adding losartan for BP control, an ARB that tends to lower UA while it blocks renin receptors that tell the blood vessels to constrict. It is not only good for BP, it is protects the kidney, and it just went generic. Still, I had to get a prior authorization to get the insurance to cover it.

And I will be drinking lots of water. That is easy and should help all the issues.

None of my docs seem keen on reducing the cyclosporin like last time, but rather want to fuss with my other meds to lower the UA while controlling my blood pressure.

The consensus is no allopurinol yet. No gout symptoms, so why add another complicated drug to the mix.

I also got my flu shot today, before I restart rituximab in two days. Normal dose. Don't trust the pharmacists to give me the shot (I am not over 65) and they seem to be the only ones to have the high dose vaccine. Started on the unproven ranitidine trick (300 mg. 2 x a day for 6 weeks, then repeat the flu vaccine) to see if I can boost my response that way. Honestly, I doubt I will mount much of an antibody response, but I am 100% certain that I won't get any after all my vitamin R wipes up the the remnants of my antibody forming B cells.

And just to add another twist, rituximab may raise the uric acid as it goes about the business of killing my cancer cells. This is not very likely as most of my cancer is my nodes and marrow and not in my bloodstream (my lymphocyte count is already suppressed from my last rounds of R) where the kill rate is much slower, so the chance of a tumor lysis leading to another jump in UA is extremely remote.

So many balls in the air for such minor issues.

As Roseanne Roseannadanna said: It is always something.

337,000

My platelet count has increased 11 fold since starting the rituxumab (R) and cyclosporin (CSP). I must saying it is working better than I or any of my doctors predicted for my unorthodox therapy. Now if only my pension plan would do the same.

337,000 is more than double what it was last week, and last week it was already normal. This is the highest level since they crashed when my ITP came back last July.

This unusual but not too toxic med mix is unknown territory, so the length of my first course of R or the dosing and timing of R maintenance is stuff that needs to made up as we move forward.

Moreover CSP has a mixed rap sheet. It helped my CLL and there are a few case reports of its anti-leukemic effects, but it is immune suppressive and could and has taken the brakes off cancer growth for others.

Maybe the true hero of my present story is the sesame oil one tablespoon twice a day that the herbalist recommended for low platelets even though the medical literature, while not silent on this, is also not screaming out the proof of its efficacy.

Maybe it's the Beatles watch that I have taken to wearing to bed with me. Everyone knows how good the Beatles are for platelets.

Yes, I am expecting a long and easy course, and a healthy happy pause before I must change course again.

If the family can work it out, maybe I will finally go hang gliding this weekend.

Back to Normal

My platelets were 154,000 this morning so my new treatment is working. And working fast.

I got some time on my side again, but not now, as I have been away from the beach from 7 this morning. It is 9:15 PM now and they lock the gates at 10:00 PM and I am still doing chores at home.

At the infusion center all day, then a workout, then chores.

I was in the right place

The Night Tripper

But as the good Dr John said: It must have been the wrong time

My cyclosporin(Cs) level (the immuno-suppressive drug I restarted with rituximab for my low platelets) was 1011 two hours after my AM dose. Normally we want to see the level between 100-300.

This is a very toxic drug, but the rest of my lab, especially the sensitive renal function tests as Cs is a notorious kidney puncher, were all boringly within nomal limits. My blood pressure was up a bit which is another comment adverse event, but still quite safe.

What should I do? Hold a dose which I did while waiting for an answer, and restart at a much lower level? Dr Sharma was not sure. me either, so we turned to Dr Forman who uses this drug for protecting transplanted marrow.

And why no side effects? Not that I was complaining.

Turns out my peak level is meaningless. The trough levels are the whole story. measured at the end of the last dose, generally in the morning BEFORE the first dose that day. When taken by mouth, it is a twice daily med.

Cs with it's more measured modulation of immunity, is THE drug that opened the door to solid organ transplants. Before it burst on the scene, the only player in that arena was the infamous carpet bomber of the immune system, high dose steroids, and outcomes were not good.

The theory is that in order to prevent the beginning of the rejection of a transplanted organ (heart, kidney) it is critical to not let the Cs level dip below a certain safe threshold that is adequate to turn off the natural immune triggered rejection response.

I would guess the same principle applies to shutting down the immune modulated destruction of my platelets, but I don't know that for sure.

It is an off label, though not uncommon, use of this medication to treat ITP, so I bet pounds to peanuts that the guidelines are based on historical consensus and not on well designed studies.

So the peak levels meant nothing to anyone, and I am back on the same dose, waiting to get a trough level next week.

Lessons relearnt:

Timing is everything.

Details matter.

I miss stuff, so ask for help and keep fact checking.

And finally,

Not every result that looks scary, is scary.

PS Dr. John is performing at the Coachhouse next week. Very tempting.

91,000

That was the platelet count, a nice climb, likely all from the Ivig 5 days earlier, so it is still getting the job done, though with rapidly diminishing potency and duration of action.

The cyclosporin wouldn't likely have worked this quickly.

The rituximab infusion today was a non-event, but I have the hiccups. BP is till OK, but lymphocytes may be climbing slowly. The steroids in the premeds are keeping me up.

Stay the new course I say. May tweak the IVig- higher dose, different brand.

I am more optimistic, but I have a big lecture on gout to give in Las Vegas, and that will be my focus for the next two days.

That and being there for two friends heading to transplant before the end of the month.

I now have some breathing room again.

CYCLOSPORIN AND RITUXIMAB

CYCLOSPORIN AND RITUXIMAB

That's the plan. The title says it all.

Redux.

Wallop the immune system so I don't destroy my own platelets. Hopefully the combo will also hit the CLL like it did so successfully three years ago. It really should.

Add Septra so I don't die from PCP in the process and maybe add an antifugal.

Watch the BP and renal function. Lots to drink to keeps the kidneys tip top.

This is all doable and pretty simple and usually pretty safe, but will it work? Will it be durable?

The next step is giant. Danger looms closer. That is the nature of this disease.

Know your enemy. Plan ahead. Be prepared. Be on guard. This is my world, again.

The long break from the daily tension was great. Back to work.