Friday, March 29, 2013

Why to Avoid Iron if We Don't Really Need It: Anemia in CLL

I was asked what is the risk of getting too much iron.

Here is an extended version of my answer.

Hi Bill,

Iron overload is a difficult issue should one become transfusion dependent.  That means we can not longer maintain an adequate hemoglobin without the help of getting someone else's blood.

But too much iron can seriously damage the liver, the heart and other organs. It needs to be prevented when possible and treatment should be considered when the iron (or ferritin) is at a level that can cause damage. Yet the treatment with the new chelation agent, EXJADE or deferasirox, while admittedly very effective, is fraught with risks, especially if you have any pre-existing renal or liver impairment.

In the absences of anemia, we treat patients with too much iron by bleeding them, not by chelating them.

Yes, we doctors still bleed patients for some conditions, we still use leeches for some wound treatments, and we still occasionally trephine skulls.

Back to the subject at hand.

Iron overload happens when multiple transfusions are needed because the marrow is impacted with CLL and we are not  making enough red cells, or if there in a rapid and severe drop from auto-immune hemolytic anemia or AIHA where we rapidly destroy our our red cells (though benefits from blood transfusions are very temporary and are best avoided), or if one develops a damaged bone marrow such as in secondary myelodysplastic syndrome or MDS.

After a transfusion, the red blood cells counts climbs quickly and generally feel more vigorous. Unfortunately, then the hemoglobin starts to fall quickly or slowly depending on the underlying problem that created the need for more blood. The iron, however, remains in the body, and it hard to get rid off.

I would not take an iron supplement unless you are certain that iron deficiency is the cause of your anemia. Most anemia in CLL is NOT from low iron, but from bone marrow failure and iron will not help. Not a bit.

There are inexpensive blood tests to nail the diagnosis. Measuring serum iron, total iron binding capacity, and ferritin can usually sort this out. There are other tests and information included in the CBC itself that can be helpful with the diagnosis.

If indeed there is iron deficient anemia (IDA), you need to find the source of the blood loss. Barring any recent trauma, it is almost always from either heavy menstrual flow (not a common problem due to the age of most with CLL, but certainly a possibility in some younger female CLLers) or the more worrisome concern of bleeding from the gastrointestinal tract. Colon cancer can present with anemia and no other symptoms and we are at higher risk for all secondary cancers including the ones in the gut.

A strict vegan diet may also result in IDA after many years, but the data is conflicting.

Even too many blood draws from the vampires at the labs can lead to IDA.

Diagnosing IDA is just the first step, it demands its own work-up.

Take a look at this very cool anemia app that I put together with Dr. Steensma, a world expert in MDS,  for practicing healthcare providers. It is pretty simple and clear.

Here's the link to the free Iphone and Ipad versions.

Stay strong


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Tuesday, March 26, 2013

Live from the Infusion Center: Anemic Again

My blood draw at the cancer center for my IVIG infusion showed that I am mildly anemic again. Hgb was only 13.2 which is the lowest it has been since last August. 

This almost certainly not a big deal unless my counts continue to fall. 13.2 is a value many with CLL aspire to reach.

The white count, neutrophils and lymphocytes were all fine and platelets were 381,000.

However, I am clearly iron deficient based on lack of iron stores seen on my bone marrow biopsy, a low iron saturation of 14% and a borderline ferritin of 22.

My marrow was making adequate red cells so that is not the issue, and there is nothing clinically or in my lab to suggest an auto-immune problem (AIHA), so the nutritional deficit is the likely culprit. B12 is fine, daily I eat a ton of leafy greens with high levels of foods with folate, so that leaves the finger pointing at iron. 

Doctors Kipps and Forman agreed that there was no need for iron replacement a few weeks ago as I was not anemic when my blood was last checked a month ago, but the sharp eyed Dr. Kipps did notice that my MCV, a measure of the red blood cell size, was drifting down. My erythrocytes tend to be too big and funny looking due my splenectomy, but lately they have been more normal size, consistent  with a mixed picture of multiple influences on their size and shape, as low iron stores will shrink cell size.

Vegan like me are at higher risk for iron deficient anemia as the iron found in veggies is not as easily absorbed as the iron in blood. There is some controversy on this, but it makes sense. Heme iron is found in animal proteins, while non-heme iron is found in plant-based foods and has a different molecular structure than heme iron.

All the green tea I drink doesn't help either, as it interferes with absorption.

I am not too worried about a GI bleed as my last colonoscopy was only 3 1/2 years ago.

So why not take iron?

First iron overload is a much bigger problem and harder to remedy down the line in blood cancers.

Second, there is some controversial data (in dialysis patients) suggesting that iron supplementation may be associated with increased infection risks and low iron may be protective. Again, there is conflicting data.

Finally iron is constipating and can cause other GI issues.

I think I will just start taking more blackstrap molasses. And check for my stool for blood. And watch the trend. 

All in all, not a bad picture. Much better than the numbers that too many friends need to contend with.

Still one time, I would love to have a blood count with no numbers in the red. I haven't seen that in 8 years. Not once since I was diagnosed.

BP is 107/68 and I need a nap.

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Monday, March 25, 2013

ASH 2012: Dr. Rick Furman Discussed the Very Early Experiences with Idelalisib and Ibrutinib

This video is a real treat as it shows us the recent history of the small molecules that are changing our future.

And the narrator, Dr. Richard Furman, the head of the CLL and Waldenstrom's Macroglobulinemia program at Weill Medical College was not only there at the beginning, he was the investigator for these phase 1 trials for ibrutinib and idelalisib.

He tells of the broken promises of a prior generation of small molecules. He reminds of the bravery of the volunteers who entered the unknown world of these new drugs with little more than hope that these pills would be different than all the rest that preceded them. He points out how the amazing changes that lead to the record fast accrual for the follow-up phase 2 trials. He explains why the climbing lymphocyte count was not a big concern and how it is so different than the rising counts encountered with the tumor flare seen with lenalidomide.

So much has changed in the last few years. What a brave new world we have entered. A place chock full of both hope and unknowns.

This was filmed at ASH 2012 in December.

I have nearly caught up on all my other non CLL medical writing so I can soon turn my attention to more on non-chemo answers for CLL, but this interview should help those looking more than my musical interludes when they tune in on my CLL adventure.

Part 2 with Dr. Furman to follow, then a long interview with my friend, Dr. Adrian Wiestner.

And I will be going to ASCO in May in Chicago though at this point it is uncertain whether I will be  bringing my video staff.

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Friday, March 22, 2013

Leonard Cohen: Like any dealer, he was watching for the card that is so high and wild he'll never need to deal another.

Leonard Cohen, Isle of Wight 1970
Stranger Song

More nuggets that inform my life came out of this plaintive song and from that whole first album than it is healthy to admit. I still remember the small apartment in Montreal where I first heard his music with a bunch of other angsty teenagers.

A sample of the sound bites that constantly rattle in my brain from that one song:

Reaching for the sky just to surrender.

Please understand I never had a secret chart, to get me to the heart of this or any other matter.

You hate to watch another tired man lay down his hand like he was giving up the holy game of poker. 

And of course, I am still to this day:

...watching for the card that is so high and wild (I'll) never need to deal another.

The card that is so high and wild I'll never need to deal another.

Does it really exist?  I am still watching. And waiting.

Watching and waiting in CLL has a whole other meaning.  It is a wait and see stance: how is the disease behaving, and then ignore it or respond to it depending on whether it is being nasty or nice. I am long past that pleasant interlude of plausible denial. All my chips are in the game now and I grabbed what I believe to be my best card on the table. In a trial. And even it's only advertising one more shelter I can live with that.

On the Isle of Wight, Leonard performed infront of 600,000 in the early morning of August 31, 1970 not long after the final live performance of Jimi Hendrix. Talk about a change of pace. Are you experienced?

And 43 years later, the self proclaimed grocer of despair is still delivering.

Sorry for another brief diversion but where would I be without music. Cohen's song are always humming in the back of my head, and this is one of the most persistent.

Back to work. Will be blogging again this weekend.

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Monday, March 18, 2013

St Patrick's Day with The Fenians

The Grove in Orange County (the squeezebox player looks right at home in his kilt)

Orange County's own local Irish rock band, the Fenians. Such fun. Celtic Rock. A crowd that covered at least three generations Irish dancing and wearing silly green beads and shamrocks on their heads.

I took a much need break from writing a paper on thyroid disease to catch their show.

No Guinness or Irish coffee or green beer for me, but green tea to celebrate St. Patrick's Day. Does that count?

Cabbage, but no corn beef for this vegan.

I should have been working, but I can only stare at my computer screen so long.

Posts and video interviews on CLL will be more forthcoming here real soon when I finish what I must on thyroid, gout, anemia, and post trauma stress disorder. I won't even dare to share what wonderful tales of organ dysfunctions and disease states that I got off my to do do list last week.

Who said my life wasn't interesting?

Should be all finished soon. Until the next batch.

Here's a sense of what I enjoyed tonight instead of doing my homework or writing a post with gravitas.

"Won't you take her in your arms and tell her that you love her."

Won't ya?  I think you should.

Am I turning Irish? No, but I am married to a bonny lass with Irish blood and green eyes.

And I believe in being fully ecumenical when it come to celebrating holidays, especially the ones that are such fun and include live music.

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Sunday, March 10, 2013

Saying No to Chemo: Non -Chemo Options for CLL, Part 1

This is probably the most common question that I am asked.

"I know that I need therapy, my CLL is taking off, but I don't want any chemo, so what are my options?"

The answer used to be "not much", but not so anymore. Today there are many choice and soon there will be even more.

But before I give my answer, let me give an important preamble and discuss what we are taking off the table when we veto the chemo option.

When fellow CLLers says no chemo please, I take it to mean that they don't want cytotoxic drugs that work by preferentially killing rapidly dividing cells.

For CLL in the USA, we are mostly taking about two classes of medications.

Number one and the backbone of most chemo cocktails is fludarabine that is a classic purine analog that kills by blocking DNA synthesis. Pentostatin and clardribine are similar adenosine analogs that work the same beat. What these cleverly designed drugs do is pretend to be purine, get themselves incorporated into the dividing DNA and completely gum up the work of replication. Nice.

The other class of pure chemo drugs we see a lot of are the direct descendants of the now banned World War I poison, mustard gas or nitrogen mustard. (The story of how its antileukemic powers were accidentally discovered is worthy of its own post). They destroy by attaching an alkyl group to any and all busy DNA, causing aberrant cross links and preventing it from making copies of itself. The more active the DNA, such as in a fast growing cancer, but also in our fast growing gut and skin, the more damage and the greater the kill. This is how the old standard therapy chlorambucil (AKA Leukeran) works. So too cyclophosphamide  (Cytoxan) the big C in FCR, and bendamustine (Treanda) an old communist drug but a new kid on this side of the Berlin Wall.

There are many many others cytotoxic drugs in oncology that play lesser roles in our disease such as vincristine (Oncovin), the V in CVP occasionally used for refractory CLL and just to confuse us, the O in R-CHOP used for Richter's Transformation and many lymphomas.

Oncologists carefully concoct these toxic cocktails with several goals in mind.

First they want to add to the killing power. Cancer is famously adaptive and will rapidly mutate itself right past a block on its road to lusty growth. Blocking it when it turns to either the left or right is a smart strategy. So too is capturing it in a pincer move with the lengthening lists of the toxic chemicals that make up the alphabet soup that we and others get IV to knock the socks off our cancer, and sometimes (but probably never in CLL) kill it for good.

But doesn't adding one drug on top of another inevitably lead to unacceptable toxicities?

Not necessarily so says our clever oncologists. They look for more than just complementary killing. They look for non-overlapping toxicities. CHOP is the poster boy example, a potentially curative cocktail for some lymphomas, where each of the chemo drugs interferes with the DNA in different synergistic ways AND where each drug has a different toxic target (the marrow or nerves or the heart).

Of course, it is never black and white, and dosing and individual sensitivities widely vary.

Hippocrates famously said that the difference between a medicine and a poison is the dose.

Never was this more true than with chemotherapy. Low dose oral chlorambucil is remarkably well tolerated, even in the elderly, but at the proven price of not doing much to extend the life of the patient.

Some chemo drugs are routinely used at low doses for relatively minor skin problems or auto-immune issues.

But the issue is more than the dose. It is also who is getting the dose.

Is there co-morbid heart disease or nerve damage from uncontrolled diabetes? Has the marrow been beaten up and is having a tough time rising again?

That is why it is so important that we stay well otherwise. Cancer is a hard enough fight without the handicap of a bad heart or bronchitic lungs.

Chemotherapy is not "targeted" in the strict sense, but it does preferentially cull the rapidly dividing cells and that is a good thing. In some cancers, it does such a strong job, it can cure. In CLL, while there are no chemo cures, it can and does give many of us years of healthy happy remission.

The majority of us that end up sitting in the infusion chairs for hours and hours report that while CLL chemo is annoying, it was much gentler that expected. No hair loss, little nausea. FCR or BR are wimpy protocols compared to some of the more potent stews used for more aggressive cancers. I know a surgeon who continue to operate all through his treatments with FCR.

Still cytopenias (low blood cell counts) are all too common including anemia, neutropenia with its high serious infection risk, and low platelets. So hand in hand with the chemo might come a partnering dose of a bone marrow stimulant for either red cells (EPOs), white cells (G-CSFs) or platelets (TPO mimetics) each carrying its own set of side effects and worries. Some of us even need transfusions to just keep going. More decisions. More risks. More time. More expense. More worries.

Long term, there also may be a price to pay. The marrow can only take so much before it gives up the ghost. When our marrow stops making enough of the three lineages of our blood cells, we are in dire straits and the only durable way out may be importing a new one AKA an allogeneic hematopoeitic stem cell transplant.

Chemo wallops our immune cells short term, risks of infections shoots up and may stays up for more than a year after fludarabine which is particularly nasty to our T cells.

Insist that your doctor offers you appropriate antimicrobial prophylaxis.

These drugs by design are mutagenic so we hold our breathe when we get our regular PAPs or mammos or PSAs or colonoscopies. We are getting them aren't we? Please see my earlier post on secondary cancers and do the right thing by yourself.

Infections and secondary cancers are the handle and the blade of the our grim reaper's scythe. So anything we can do to keep it reach short and its edge dull is good.

Eating right, exercise, love, sleep, and avoiding chemo are part of that prescription.

Still, when we face a clear and present danger, we must focus on our imminent needs and worry about tomorrow, tomorrow.

And until very recently, the best tools we had for staying alive when our cancer started to rage was a chemo cocktail, and I for one am grateful that these drugs were and are there in our time of need.

It was only a few years ago that we showed that for the first time a combination of chemo and immune therapy in FCR could prolong our lives. We know that those diagnosed with CLL in the 90s live longer than those diagnosed in the 80's, and much of the credit rests at the doorstep of chemotherapy and the modern management of its side effects.

So before we wave goodbye to chemo as some sort of poison concocted by the a cabal of international pharmaceutical companies, the military and medical industrial complex to keep cancer as a big profit center at our expense (believe me I encounter this line of thinking almost daily), let us calmly look at its risks and benefits.

Let's not throw the baby out with the bathwater.

If you have read any of my posts over the last few years, you have seen me vote with my feet and my blood. You know that I am a fan of the emerging small molecules and have tried to avoid chemo in my own personal journey.

All I am asking for is that we have some balance and keep our eyes wide open as we enter this brave new "post-chemo" world.

"Targeted therapies" while they might be compared a smart bombs or drone, they too like their battlefield equivalents, can pick off innocent target either that look like the enemy or are in the wrong place at the wrong time.

As I said, it isn't black and white.

More on non-chemo choices soon.

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Thursday, March 7, 2013

ASH 2012: Dr. Wierda and Practical Advice on CAR-T Trials

In part two and final part of my interview from ASH 2012 with Dr. Wierda from MD Anderson (please  see part one first to get oriented) talks about some of the practical issues, upcoming trials, and possible role of CAR-T in conjunction with the new TKIs (tryosine kinase inhibitors).

In effect, Dr. Wierda is painting a picture where a small molecule such as ibrutinib or idelalisib or ABT-199 or AVL-292 or others in the pipeline is being used to reduce the amount of disease (cytoreduction) and then adding CAR-T therapy instead of the riskier allogeneic transplant to get rid of the nagging residual disease that seems to be left by all these drugs, and with that two step chemo-free process  offering the real possibility of a cure for our CLL.

As he stated, this are still many active area of research. Here's some issues that are near and dear to me.

Why the small molecules seem to move so slowly at ridding the body of all traces of disease- maybe we are just not waiting long enough or maybe it doesn't matter? It doesn't seem to matter in many patients with CML treated with imatinib (Gleevec). Will it be the same with CLL?

Can CAR-T therapy replace allo-transplants and become a practical, affordable path to a cure? A one-two knock out punch?

What about the rare relapses in CAR-T therapy with the cancerous clonal evolving to express no CD-19 and thus are no longer targets for the the engineered T-cells?

What are the bridges to these new therapies while we are waiting for answers?

Let's here a surprisingly practical discussion with one of the doctors who is not only discussing but creating this new future.

Dr. Wierda had to run off after this segment, so there is no part 3.

But Drs. Furman and Wiestner still have important things to teach us from interviews at ASH 2012 that I will be posting soon.

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Wednesday, March 6, 2013

The Great Big Sea

Enough CLL for moment.

Tonight, I was at genuinely fun unpretentious folk-rock-celtic-trad concert from the best band to ever sail from the cold and rocky shore of Newfoundland, namely the Great Big Sea.

Newfoundland has always been a special place for me. Lived there for 3 months as a medical student in a fishing village that could only be reached by boat. Or helicopter if there was a real emergency. The road came decades after I had left. Worked at a tiny hospital in town and traveled up and down the foggy coast to tiny fishing hamlets where we held clinics in a classroom or someone's bedroom.

It was there that fell in love with being a family doctor.

That medical school elective changes my life forever. I was hooked by the scope and depth, the variety and the intimacy of a general practice.

And so that has been my path for the last 40 plus years.

The concert tonight was a total escape for me and an echo of some dormant memories, time off from work and sleep that I can hardly afford, and yet could hardly afford not to take. Hope these CBC videos gives you a reasonable facsimile of being there.

Catch them in concert if you can. They are on their 20th anniversary concert right now.

Enjoy a video or two that take less brain and more heart than my usual fare.

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Monday, March 4, 2013

ASH 2012: Dr. Bill Wierda on CAR-T Therapies and "Off the Shelf" T-Cells

Dr. Bill Wierda out of MD Anderson Cancer Center (MDACC) is doing important cutting edge immunological research in CLL and looking to improve and make CAR-T therapy a safer and more generic treatment option.

In the first part of my interview from ASH 2012, he explains how he is moving forward in engineering T- cells to target the CLL clone and spare the normal B-cells.

These are early days, but there is surely a vision of an exciting future that is becoming clearer and brighter. Think of these souped-up T-cells doing the work of an allogeneic transplant without all the associated risks. Imagine them seeking and destroying our cancer cells and passing harmlessly by our normal cells.

Dr. Wierda does not minimize the risks or the work left to be done, but the journey has begun. There have been startling successes at U. of Penn and MDACC and UCSD and collaborating on finding better targets to attack and quicker and cheaper ways to engineer these killing machines.

Take a look at my recent post with Dr. Kipps on ROR1 to set the stage.

This work is particularly important because since it was recorded, it has been revealed that some patients with CAR-T directed against CD19 are relapsing because the clone is losing its CD19. Clever nasty cancer.

Poor patients now not only have an aggressive CLL relapsing, they also have no B cells and next to none antibodies, probably forever.

More to come soon.

Exciting and promising and challenging times.

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Friday, March 1, 2013

ASH 2012: Dr. Tom Kipps ROR1

In this short final segment from my ASH 2012 interview, Dr. Kipps explains an exciting new target for CLL, ROR1 that seems to almost exclusively exist on cancer cells, making it an extremely attractive target for a vaccine, a monoclonal antibody, or CAR-T therapy.

Please excuse the bursts of static.

Soon I will be ASH 2012 interviews with Drs. Wierda on CAR-T,  Dr. Furman on his experience in the early trials with the TKIs, and an overview with Dr. Wiestner.

Pretty exciting stuff.

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