Science & Medicine

by Zhenya Senyak

What power lies coiled in a single word.

On the phone, my grand-daughter told me she was running the Boston Marathon. “I have your name pinned to my jersey,” she said. It was an honor, my Alex running a race with a black ribbon fluttering on her jersey in memory of a fallen hero. But why me?

Then it came to me. Her mother told her I was diagnosed with myelofibrosis, MF. That’s the power of a word. When you move from ET to MF. you get your name pinned to a jersey.

For a few weeks that word hung over me like a dark cloud. Myelofibrosis. After extensive tests at a prestigious Eastern medical center, review of my bone marrow biopsy, and direct clinical examination, the consulting hematologist, backed up by the pathology lab, introduced me to this word that would now describe what was happening to me. He prescribed a course of Pegasys.

Back home in North Carolina, at a famed university hematology clinic, my doctor reviewed the findings, conducted two days of lab tests. His conclusion: Essential thrombocythemia. He prescribed hydroxyurea.
ET! With a single word, an ocean of time opened up before me. I moved from the near death experience of MF to the sunny indolence of ET, a disease for which marathon runners rarely pin names on jerseys.

What happened? What’s going on? These are all good people, brilliant and hard-working. One is an investigative research scientist with a long but limited practice, the other is a deeply experienced clinical hematologist with a heavy patient load. Neither they nor their respective pathologists agree on the diagnosis nor, naturally, can they prescribe the same course of treatment.

What’s the diagnosis?
Both diagnoses depended almost entirely on definitions derived from conventional clinical and pathological observations. I presented, after a 15 year history of ET, complaining of sudden weight loss and fatigue. Line charts based on my CBC history looked like real estate stocks after the crash. I was anemic. My BMB showed some age appropriate reticulin fibrosis and my spleen may or may not have been palpable depending on whose fingers were digging under my rib cage.

They may disagree about some key critical points of my diagnosis but my doctors agree I unquestionably suffer from A Disease Formerly Known as MPD.

The new name, MPN, or myeloproliferative neoplasm, was yet another word that would define my condition and treatment options.
As long as the World Health Organization had officially changed the noun that is the object of all this confusion, I thought it was past time to look a little deeper into the words that defined our conditions and therapeutic options.
For that, I found an excellent guide in Dr. Claire Harrison’s recent article, published in Hematology, “Rethinking Disease Definitions and Therapeutic Strategies in Essential Thrombocythemia and Polycythemia Vera.” (The complete paper with tables and charts is available for download.)*

Therapeutic options, a short menu
In a sense, there shouldn’t be that much to say about therapeutic strategies since, on the surface, you’d think they’re fairly limited. Front line drugs, the first thing to come out of the medicine cabinet, are generally limited to hydroxyurea (hydrocarbomide) for PV, to cool off blood counts, maybe substituted or reinforced by busulfan. Phlebotomies, or venesections, are done when hematocrit levels get worrisome. For ET, beyond an aspirin and HU if age and/or thrombosis are additional risk factors, little treatment is generally available until platelet levels reach alarming levels. Then there’s anagrelide. Some doctors reach for the anagrelide a lot earlier, some not at all. The interferons in various forms are usually held in reserve until needed. Pretty much that’s been it for more than a decade.
Beyond thrombosis, the danger, of course, is that one of these chronic or less lethal MPNs will progress to myelofibrosis or an acute leukemia. While there are drugs that do seem to demonstrably increase the risk of such progression or contribute to the development of fibrosis, it’s questionable that anything, beyond stem cell transplant, can reliably forestall an MPN from taking its natural course

The introduction of a new class of genetically derived agents to inhibit the proliferation of the janus kinase clone – the JAK2 V617F – a point mutation found in the janus kinase of nearly every PV patient and present in more than half ET and MF patients – has broadened the spectrum of palliative options. This is no small achievement since life with a swollen and painful spleen or severe itching or persistent exhaustion can be torture. All the results are not in, however the JAK2 inhibitors, so far, seem not to affect the progress of the disease.
And then there are a range of even more experimental drugs in clinical trial or on their way to trial, all of which are designed to disrupt or modify at the molecular level biochemical processes associated with MPNs. It is far too early to say any of this really works beyond improving the quality of life.

So what’s there to rethink?
Only everything, if one adopts the continuum model, a global and dynamic view advanced by Dr. Harrison. At one level, the continuum model breaks the rigid divisions among the various phenotypes of MPNs – particularly the ET. PV, and MF triumvirate that led William Damishek to first lump these diseases together as MPDs. We can consider them as a continuum of conditions with different phases. This could impact both the way we as patients think of our MPNs and drug companies as corporations calibrate their research designs.
Simply put, in the continuum model MF and acute myeloid leukemia (AML) lie in the advanced phase of the spectrum, ET and PV, the chronic.

“The continuum model is about getting people to think outside a rigid box,” Harrison told MPNForum, “to realize that everyone’s MPN is in a state of flux and that it can be important to look for evidence of other MPNS or transformation. You don’t change straight from PV one day to post-PV MF the next. It happens with time.”

One application of this kind of thinking is to refocus research efforts. “It does help JAK inhibitor companies (consider) their treatment in ET and PV may be worthwhile as, in part, a way of testing an earlier phase of MF.”
Harrison makes the case for the continuum model by drawing parallels between JAK2 positive ET and PV, such as shared higher hemoglobin levels and neutrophil counts, higher incidence of venous thrombosis. Significantly, “the rate of thrombotic complications in JAK2V617F positive ET patients was significantly higher than in wild-type patients but not statistically different from PV patients.” (“Wild” is a medical term of art that actually means natural or unmutated.) Translation: If you’re a JAK positive ET patient your chances of suffering thrombosis are about the same as every PV patient. Welcome to the club,

Another word to know: allele
The JAK2 mutation is unlikely to be the “cause” of MPNs since it is not necessary to have the mutation in order to have an MPN. But whatever has caused the mutation to occur and the mutant clone to proliferate has been closely correlated with outcomes of MPNs. That proliferation causes a genetic preponderance of the mutant, the measure of which is the allele burden. Normally, we are heterozygous. And it’s lucky we are. Heterozygosity is the normal genetic balancing act that occurs when two slightly different copies of a gene – one from each parent – provide insurance against pernicious dominance.
We’ve got two alleles, two copies of each gene, one from each parent. If in the course of reproduction, one gene mutates and becomes dominant its daughter cells increase the allele burden until, in the end, we can become homozygous for a trait. If that trait is linked to the JAK2 mutation the dominant mutated gene is given unfettered access to stimulate blood producing cells. Our allele burden becomes a factor in the progression of our MPN.
“There is a significant body of evidence to support the view that the JAK2 allele burden is consistently higher in patients with PV, PF or post-PV MF than in those with ET,” says Harrison. What is unclear, like so much in our MPNs, is whether this phenomenon is causative or simply indicative. Determining, for example, that patients with high fevers have higher mortality rates doesn’t really tell us that fever is the basis for their deaths. However what does emerge from the determination of allele burden is the relative place one is on the MPN continuum and, perhaps, a clearer target for therapies.
Harrison next turns her attention from the continuum model and the implication of the JAK2 mutation in the progression of the MPNs from chronic to acute, to an overview of therapeutic options. It’s here we should sit up, sharpen our pencils and start taking notes. Because this section of her paper has direct application to our next consult with our hematologists.

An overview of therapeutic options
Discussion of three therapeutic options make up the bulk of the paper:, Cytoreduction to reduce disease symptoms and retard disease progression; the interferons to modify disease impacts and achieve molecular response; and the JAK2 inhibitors and, in passing, other novel therapies like histone deacetylase (HDAC) inhibitors.
The list is by no means complete nor is it intended to be. Her focus is on current therapeutic options and when our physicians take out their prescription pads they do, in fact, have just these three options.
The election of cytoreductive therapy is dependent on disease definitions and risk stratification. But when we get down to it, short of deploying more risky hypertensives or a statin for aggressive treatment, the front line option is the old stand-by, hydroxyurea . In that connection two findings revealed in this paper fly in the face of conventional wisdom.
HU is not going to lead to leukemia. Well, maybe not, but significant research produces a caveat; “It is important to consider,” writes Harrison, ” that hydroxyurea, when used with or succeeded by agents such as busulfan with leukemogenic potential, will significantly potentiate leukemogenicity of either agent alone.”
High platelet levels will lead to stroke or thrombosis. Don’t reach for that bottle of HU pills so fast. Since cytoreductive therapy has successfully reduced platelet levels and the incidence or thrombosis many practitioners associate thrombosis with high platelet readings. Harrison cautions: “…current data suggest that platelet number may not be directly correlated with the incidence of thrombosis and data from the PT-1 trial suggest that additional factors such as reduction of hematocrit, leukocyte count or endothelial factors such as nitric oxide production may be important.”
Harrison, like the BCSH guidelines, suggests no treatment for young patients, beyond aspirin, if the sole risk factor is high platelets.
Since the primary purpose of cytoreduction in ET and PV writes Harrison ” is to reduce the risk of thrombosis, control disease-related symptoms, and to reduce where possible….disease progression,” it’s critical to determine the extent of that risk before prescribing a therapeutic option.

Risk stratification
The risk stratification tables in the paper present entirely conventional criteria for assessment of risk. JAK2 allele burden, for example, is not considered, nor are some of the more current molecular markers.
Primarily, risk factors include age >60, prior thrombosis, high platelet levels, the presence of diabetes, hypertension or significant splenomegaly. Patients presenting with any one of these fall into the high-risk category. Those who don’t have any of these risk factors are considered lower risk.

Therapeutic strategies
Therapeutic options presented, unsurprisingly, are the Current British Guidelines. For all patients with PV and ET, low dose aspirin is recommended
unless contraindicated. Additionally, for PV patients at any risk level, venesection to 0.45 Hematocrit (or Packed Cell Volume).
High-risk PV patients over age 60, HU and under 60, interferon. Second line agents for each are reversed, interferon and HU.
The front line drug for high-risk ET patients over 60 is HU, followed by a second line choice of AG and interferon. The youthful high-risk ET patients are started on either HU or interferon with interferon and AG, alone or in combination, available as second line backup.

Why AG

Having experienced the ravages of anagrelide, the pounding tachycardia and blinding headaches that accompanied that early trial, and learning a bit about the contribution of AG to fibrosis, I wondered about its deployment as a second line drug for older, high-risk ET patients. “If you add an agent after HU such as busulfan or pipobroman,” responded Harrison, ” the risk of leukaemia soars. Interferon is not well tolerated by everyone so it’s important o have additional second line agents…my philosophy is very much that the therapy must suit the patient and not vice versa. Cardiac complications and myelofibrosis risks are present with AG but can be managed and may have to be balanced against quality of life and coping with other side effects for other medications.”
Interferon After discussing uneven results from HU and AG therapies, Harrison turns her attention to the interferons as agents that have shown good clinical results in controlling myeloproliferation and relieving clinical symptoms in PV.
Since Richard Silver first began publishing his finding on interferon in 1988, various formulations of IFN have been tested in clinical trial.
. Harrison summarizes the findings from the recent pegylated IFN-alpha2a (Pegasys) trials. One study demonstrated Pegasys targets the malignant JAK2 clone and achieves a 94.7% complete hematological response in all patients and strong molecular responses such as decrease in the JAK2 clone, over periods ranging from 1 to 3 years. A complete molecular response – no detectable JAK2 clone – was achieved in seven of the 37 patients who completed the trial. The second study, with roughly 40 each PV and ET patients produced similar results. While promising, IFN is still being intensively evaluated.

JAK2 inhibitors The JAK2 inhibitors, says Harrison, have demonstrated some ability to reduce symptomatic splenomegaly, itching and fatigue “There are data supporting the ability of JAK2 inhibitors to control myeloproliferation in patients with PV and ET but no data are available in terms of their ability to prevent thrombosis or affect the probability of accelerated/more aggressive disease …. Considering the downside of currently available proven therapeutic agents, there is simply the need to study these agents more thoroughly along with the histone deacetylase inhibitors (HDAC) like vorinostat and givinostat and consider combination therapies to evaluate their safety and efficacy.”

Doing nothing Wandering between the acute and chronic MPN worlds, personally balancing therapeutic options, I set my fibrotic foot firmly on a therapeutic path favored by the confused and the lazy. I decided to do nothing, fill no prescriptions, walk the Blue Ridge Mountain trails, eat well and live my life while awaiting further developments.
Supporting words for this course of action came from an earlier work of Claire Harrison. Writing in a newsletter of MPD Voice, an educational and support non-profit she set up in London (, Dr. Harrison suggested doing nothing, beyond taking a low dose aspirin, as a viable option for some low-risk ET patients.
“It may…be less beneficial to take a medication which involves more side effects and unknown long-term risk…And remember that taking medication is not the only way to fight your condition. Regular exercise reduces fatigue, improves circulation and can help combat unpleasant symptoms.”
First, do no harm.

Dr. Claire Harrison is a consultant and lead hematologist at Guy’s and St. Thomas; Hospitals. A central focus of her clinical practice is MPN diagnosis, risk definition and therapy. Widely published in major medical and scientific journals, Harrison was chief investigator for Europe’s COMFORT II, Incyte’s massive INC424 JAK inhibitor trial. She is currently active in launching two Pegasys studies in 35 centers worldwide. She is the founder of MPD Voice.

* For a copy of Dr. Claire Harrison’s “Rethinking Disease Definitions and Therapeutic Strategies in Essential Thrombocythemia and Poycythemia Vera,” published in Hematology:

© Zhenya Senyak and, 2011. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and with appropriate and specific direction to the original content.

Comments on: "Dr. Claire Harrison: Rethinking ET and PV" (7)

  1. Susan Telford said:

    The scary part of this disease is that it is rare and hence most GPs and members of the general public have no idea of what it means for the sufferer. You look normal but you are not. The side effects of itching and fatigue are hugh. My sister has been recently diagnosed with MF and is full of anger as she feels perhaps this could have been prevented had the doctors informed her from the early stages of PV. All the counts and what they mean were
    never explained so she too could feel in control of this already enigmatic disease. When you are alone and having to make decisions about your future you would like to feel at least the medical profession has your back. My advise to anyone who has PV is to talk to different people and do your research. I wish you all well in this journey.
    Although this social media vehicle can be scary as you see and hear stories of people at different stages we can develop compassion and a sense of community. Susan T

  2. margaret kay said:

    I have post ET-MF diagnosed in 2005 with ET platelet level over 1oooml asprin plus HU then also AG then in 2009 stopped taking mediation. 2010 had my third bonemarrow byop told i,ve developed MF at presenonly on asprin awaiting blood test to see if i will start mediation.fighting fatigue having transfusions .

  3. Robbert van der Vlerk said:

    I have been diagnosed ET since 2008. Had high blood pressure and suffered two minor tias. Therefor I m treated with HU, ascal and a pill to diminish high blood pressure. Luckily I suffer hardly any of the Side effects; only my (intellectual) brain functions are suffering; I cannot work anymore. I think this comes more because of THE disease then because of THE treatment. Anyone comment on this?

  4. Hi, John…I think, as Dr. Harrison points out, the first issue to address is the danger of thrombosis. The Current British guidelines she refers to apply to ET and PV. I’m roughly in your position right now, still taking aspirin only. Interferon was prescribed for me two years ago and still, I think, is seen as a preferred therapeutic approach for early stages of MF. I also think Pegasys and the interferons are only investigational in the United States but there are patients on the MPN Lists who have had insurance approvals for the drug for treatment of MF. By all means, with my hematologist’s close monitoring and advice I would elect a palliative drug regimen and introduce agents that have proven to have good response rates rather than opt for a SCT. There are many new drugs emerging as genetic targets clarify. Ruxo is only the first to emerge from clinical trial. We have every right to be hopeful…and wary.

  5. Thank you for sharing this story. I have been diagnosed with myelofibrosis for a year, and so far have taken nothing but the aspirin. I am at stage two of four which means my blast count is not too high. My spleen is enlarged and often uncomfortable but I have been assured there are many worse cases of enlarged spleen compared to mine. My platelet count was 1M+ since 2006 but I was not diagnosed.

    I may be starting interferon soon if my insurance agrees. I am 57. BMT has not been strongly recommended, but I have had a brother donor matched regardless. Am I right in reading your analysis above to indicate that interferon is a low risk low harm alternative in for early stage MF patients less than 60 years? Is the consensus that for myelofibrosis the possible benefits outweigh the possible negative factors for such patients?

  6. HW Mueller said:

    Reply to the article

    J.- A. Andersson in J Clin Oncol, 2011, May 2, does not see HU in the role of causing conversion to AML/MDS. This paper was not out when C. Harrison´s paper appeared, but now has to be included in discussions on that matter. One is beginning to wonder whether some treatments, like HU, extend life such that conversions to other illnesses become visible/possible. Certainly, HU does not prevent such conversions even if it does not cause them.

    This leads to the use of the word “palliative”. My Webster´s dictionary of 1995 reflects the meaning of this word as I have learned it:

    Palliative . . . . \adj: serving to palliate

    Palliate . . . . \vt 1: to make (as a disease) less intense or severe. 2: to cover by excuses and apologies [late Latin palliere “to cloak, conceal”, from Latin pallium “cloak”]

    Nowadays one sees this word used to indicate that a treatment does not cure. That is unfortunate, as it is possible, even now, that measures taken against MPD can lengthen life such that people die from getting old (or whatever). In cases like that it is mute whether MPD was cured or not, whether a treatment was palliative (in the “modern” meaning) or not. The word “palliative” can now become meaningless, while in the old meaning it clearly and permanently indicates helplessness, no ambiguity.

  7. Zhen, this popped up in my inbox as ‘new’ a couple of days ago and I much appreciated the reminder to reread your excellent résumé of Claire Harrison’s article, recently published in Hematolgy. I confess an ongoing inability (and perhaps reluctance) to make sense of anything pertaining to MPNs. I should at the very least be able to intelligently question whatever treatment is suggested on Wednesday as a result of ET diagnosis review. Manuela

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