MPNforum Magazine

Dr. William Dameshek                                                 Credit:  Tufts  photo archives

Perhaps it is possible to resolve all of these dilemmas, conflicts, antagonisms and confusions by considering, not that the various conditions listed are different but that they are closely inter-related. It is possible that these various conditions –”myeloproliferative disorders’”  — are all somewhat variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undiscovered stimulus. This may affect the marrow cells differently or irregularly with the result that various syndromes, either clear-cut or transitional, result.

  —William Dameshek     “Some Speculations on the Myeloproliferative Syndromes” Blood, 1951 

  The Other Myelofibrosis

By Zhenya Senyak

 Given the current controversy over pre-fibrotic myelofibrosis (pPMF), it no longer surprises me I don’t actually know my diagnosis.  Not with any certainty.

 It’s been 17 years since my first bone marrow biopsy.  I’ve seen four doctors,  consulted with a brilliant and pre-eminent hematologist and had a multi-day work up at a major university’s hematology center.

So how come I’m still stuck between two worlds?

And while some have a clear diagnosis and are on a successful MPN-management program,  how come so many of us are battered by competing therapeutic claims… and living with a diagnosis subject to challenge?

Out of respect for the experience and insight of Dr. Richard Silver and his  chief hematopathologist, Dr. Attilio Orazi,   I know I have myelofibrosis.   Based on the World Health Organization 2008 classification, I definitely have full blown primary myelofibrosis (PMF).

Two other pathologists and Dr. Joseph Moore, my hematologist at Duke, lean toward a diagnosis of essential thrombocythemia.   Makes you long for the old days when ET was known as megakaryocytic leukemia which could apply to a whole range of MPNs.

 The issue isn’t unique…and diagnosis matters. 

Early myelofibrosis can suddenly roar into life and shut us down in a matter of months.  Late ET can amble on until we succumb to a completely different disease or accident of fate.  Early MF could mean we should be on Pegasys now.  Late ET means a daily  baby aspirin and keep an eye on the CBCs.

 All our MPNs, as William Dameshek pointed out in 1951, share enough commonality to be considered a single disease with different expressions, or phenotypes.  They’re caused by one or more mutations that lead to proliferation of one or more blood lines.  There are similarities in bone marrow cellularity and megakaryocytosis, but  in simple terms – and it is never this simple –a diagnosis of essential thrombocythemia results primarily from proliferation of platelets, polycythemia vera from red blood cells, myelofibrosis from deposition of fiber in the course of myeloproliferation.

The advent of better diagnostics, genetic markers, the JAK2 and MPL mutations, and a greater array of available drugs makes the determination of MPN sub-types more significant, and in some cases, critical, today.   Being able to sort out one of the thorniest problems of all – discriminating between late ET and early MF through clinical, tissue, and morphological evidence may contribute to life-saving therapy. –

 How many myelofibroses are there anyhow?

Among the main MPNs are idiopathic or  primary myelofibrosis (PMF) and secondary myelofibrosis, MF resulting from progression from another bone marrow disorder or a myeloproliferative neoplasm like ET or PV.   And for more than a decade now, we’ve had another version slipping between the cracks, pre-fibrotic myelofibrosis, prePMF.

Despite being defined and sanctioned by the World Health Organization, the very concept of pre-PMF has sparked considerable scientific and academic controversy.

On the face of it, pre-fibrotic myelofibrosis (pPMF) —  that is, myelofibrosis without fibrosis – is an oxymoron. It’s a disease that might as well be called myelo.   It’s like calling someone pre-deceased.  Or a virgin, pre-pregnant.  By any measure, the nomenclature is unfortunate.  

“Would you tell me, please,” said Alice, “what that means?”

“Now you talk like a reasonable child,” said Humpty Dumpty, looking very much pleased. “I meant by ‘impenetrability’ that we’ve had enough of that subject, and it would be just as well if you’d mention what you mean to do next, as I suppose you don’t mean to stop here all the rest of your life.”

“That’s a great deal to make one word mean,” Alice said in a thoughtful tone.

“When I make a word do a lot of work like that,” said Humpty Dumpty, “I always pay it extra.”
— (Lewis Carroll, , 1871)

Likely because diagnosis of pre-MF is so subjective this newest MPN sub-type has not developed a strong following among clinical hematologists .  Still, according to the World Health Organization, it’s right up there with the other MPNs as a distinct clinical entity. And with a study published last month (Giovanni Barosi, et al., see below) aligning pre-MF in a continuum with primary myelofibrosis, we can expect renewed interest in this diagnosis.

Why should we care?

If true, it’s likely many of us with semi-benign ET may actually be carrying an early version of MF, an indolent myelofibrosis with thrombocythemia (high platelets) steadily accruing marrow fibrosis, requiring a different range of testing and therapeutic intervention.  Alternatively, those of us with early MF may be presenting only an advancing ET with little threat of imminent progression.

Is the concept of a distinct condition, pPMF, useful or not?

As you can well imagine – this being the Art of Hematology and not automotive engineering or some other precise discipline – there are ferocious advocates for opposing positions.

 When some of the leading MPN clinical investigators, the heavyweights of hematology, line up on opposite sides, some bone crunching power plays are inevitable.  It may be a necessary part of the process of sorting out scientific knowledge but it leaves clinical hematologists,local pathologists and patients on the sidelines, confused. The gold standard for pre-MF diagnosis appears to be solid brass.

In 2009,  Peter Campbell and a largely Cambridge-based English group – including Tony Green, Keith Wheatley,  Claire Harrison and others – published a straightforward paper on the association between bone marrow fibrosis in ET patients and progression of that MPN to myelofibrosis.  (This is about a year after the World Health Organization published its new MPN classifications, enshrining pre-PMF as a distinct sub-type.)

 Jurgen Thiele, from Cologne – an associate of Giovanni Barosi and fellow member of the International Working Group for Myelofibrosis Research and Treatment — and colleagues took exception to these findings. He was joined by Weill Cornell’s Attilio Orazi and  the Mayo Clinic’s Ayalew Tefferi  and others who objected to the English group’s findings  on technical and substantitive grounds. They essentially made the argument that the cohort of ET patients studied by the English group wasn’t made up of ET patients at all but  largely composed of patients at an early stage of primary myelofibrosis (pPMF) since they presented with some varying  levels of  bone marrow fibrosis even though they lacked some of the WHO features characterizing PMF.

It a surprising  objection in a way since it was Thiele who early on challenged the conventional wisdom that PMF necessarily involved bone marrow fibrosis.   As early as 1999, in Leukemia, he argued the case for MF without  fibrosis contributing to the 2001 WHO classification of pre-MF.

Meantime, the Cambridge group, Campbell et. al, which had published its findings on the association between ET fibrosis and MF progression were understandably put off over the objections by Thiele et al..

See here, now, said the English group –– naturally in much more professional, academic terms-   you had a significant role in developing those very same WHO diagnostic criteria we used that you’re now saying aren’t definitive.

For diagnosis of primary myelofibrosis, the 2008 WHO critieria require a patient to meet three major conditions: megakaryoctye proliferation, fibrosis (or if no fibrosis then increased marrow cellularity) and either the JAK2 mutation or some other clonal marker or evidence of bone marrow fibrosis;  PLUS at least two of four minor criteria:  splenomegaly, anemia, leukoerythroblastic blood, and raised LDH levels. (LDH or Lactose dehydrogenase is an enzyme released during tissue breakdown, as in hemolysis, and is used as a measure of disease progression.)

Now it seemed that even though the Cambridge cohort studied by Campbell et al. didn’t meet these MF criteria — and were therefore studied as ET patients — Thiele, Tefferi, et al seemed to be claiming their fibrosis trumped all other combined criteria.

In their response, the Cambridge group  also questioned the new category of “prefibrotic myelofibrois”  as contrasted with “true ET” based on subjective evaluation of blood marrow slides.  “We believe that the diagnoses of primary myelofibrosis and myelofibrotic transformation should be reserved for patients with definitive clinical or laboratory evidence of disease acceleration….who may be candidates for novel or experimental therapies and/or bone marrow transplantation.”  

Finally, the Cambridge group  denied the pre-eminence of fibrosis as a diagnostic sign.  Accumulation of reticulin fibrosis, they said, is a natural enough occurrence in ET and PV patients.

Giovanni Barosi et al — the case for a continuum from pre-MF to MF.

 There are strong proponents of the prefibrotic MF designation.   And in the Barosi Paper published last month researchers from Pavia, Italy’s Centre for the Study of Myelofibrosis make the case for a continuum, with pPMF as a early step on the road to full blown PMF.    It’s a big, retrospective study –683 patients overall, 132 identified as prefibrotic MF —  that looks at data collected over a period of 21 years.  The cohort includes every patient seen in the Centre for the study of Myelofibrosis inPavia,Italy,  Giovanni Barosi and his associates followed a cohort of primary MF (PMF) patients for a median of 43 months after diagnosis, representing 3,848 human years.

Defining pre-myelofibrosis

The investigators sought to sidestep the minefield of pre-PMF definition by re-examining the bone marrow biopsies of all MPN patients and  selecting a pre-MF cohort of 132 patients based on objective bone marrow characteristics: including dual myeloid megakaryocyte dominance, megakaryocyte morphology — shape and clustering —  and a bone marrow fibrosis grade  below 1.   Fibrosis 1+ and above  was classified as PMF. Unfortunately these defining bone marrow elements overlap with the ET phenotype or require an objective bone marrow biopsy analysis that is not necessarily reproducible.  The great majority of the cohort (69% ) were at the  450,000 platelet level,  meeting WHO’s ET classification)

It would be hard to say the study is flawed by its inability to clearly and objectively  distinguish ET from pre-PMF but it certainly adds enough ambiguity to its findings that it would be difficult to base a therapeutic path on its conclusions.

What did they discover?

 Overall, except for the gender dominance of females, the prePMF group  presents as ET patients. But there’s a big difference: 19% of the pre-MF cohort progressed to PMF.

The most significant revelation in the study is the discovery of a continuum for myelofibrosis from pre-MF to fibrotic MF. Barosi and colleagues divided the PMF group into grade one bone marrow fibrosis and advanced (grades 2 and 3) and observed a continuous modification in, among other parameters, hemoglobin, platelet count and spleen size.  CD34+ cells in peripheral blood and LDH concentration increased along the continuum of bone marrow  fibrosis.

In addressing the question of whether or not WHO appropriately classified prePMF with PMF, the authors conclude pre-MF patients were shown to progressively accumulate reticulin fibers in the bone marrow, thus documenting that transformation in PMF-fibrotic type is part of the natural history of the disease.

 By embracing prePMF as a sub-type of MF, survival numbers change dramatically.  Median survival in PMF is from 4 to 10.6 years. By including pre-PMF patients,  survival doubles in the Barosis series to 21 years. The progression of bone marrow fibrosis among 67 pre-MF patients with zero fibrosis was similarly languid . “The 50% cumulative probablbility of progression from fibrosis grade 0 to grade 1 was 9.6 years, and to grade 2 0r 3, 16.4 years. 

 Barosi et al. conclude pre-PMF is a mode of presentation of PMF with an indolent phenotype and a very long survival.  That, of course, describes Essential Thrombocythemia as well.

Pre-Primary Fibrosis, a linguistic slight of hand 

Along with others, I think it may not be helpful to consider myelofibrosis as a separate disease.

Myelofibrosis is a reaction to a disease. The deadly accumulation of fiber in the bone marrow is the outcome of a diseased state, the accumulation of fibrosis impacting hematopoeiesis in the marrow.

As William Damishek said, “It is possible that these various conditions –”myeloproliferative disorders’”  — are all somewhat variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undiscovered stimulus.”

It is, to my mind, one of the strongest arguments against adopting  sub-type diagnosis of pre-PMF.  This is not to deny there is a transitional state between ET and MF, presently undiagnosable under WHO standards.  But at the same time let’s recognize how such sloppy neologisms as pre-PMF,  MR without fibrosis, hobble therapeutic efforts.

So much time, so many hours and brainpower, so much exercise of statistics and writing, editing, commenting and arguing in learned journals over this issue for the past decade and still, to this very day, there is no reliable, reproducible,  useful and actionable diagnosis of the pre-myelofibrosis state.   It still is not possible to assemble a pre-PMF cohort for study that would meet with universal agreement.  And how could there be?

If the line between ET and MF  in May, 2012 appears, at best indistinct. Three years earlier it must have been invisible. 

            I visited Dr. Richard Silver in 2009 in a time of upheaval in the MPD world newly renamed MPN.  I saw him  after the appearance of the Campbell and Thiele et al. exchanges which were  symptomatic of the confusion and controversy in MPN diagnostics post-2008 WHO classifications.

I knew nothing of all that.  I was there to to find out why I was exhausted, losing weight, and suffering inexplicable bone pain and plummeting counts.

Richard Silver is the great eminence of contemporary hematology. His 1970 book, Morphology of the Blood and Marrow in Clinical Practice is an early classic and features a preface by William Dameshek. the doctor who essentially launched this field.

In the forefront of hematological research, Silver was lead investigator in Anagrelide, Intron-A,  Pegasys, and Ruxolitinib, with a robust clinical practice, a medical school teaching load and author of more than 200 journal articles.  For many, on all things hematologic,  Silver has the final word.

After lengthy and through examination, in my case,that word  was myelofibrosis, or specifically, myelofibrosis with myeloid metaplasia.

In the next few days, the bone marrow report from his attending pathologist arrived.” Markedly increased megakaryocytes, atypically large and clustered. 1+ reticulin fibrosis. Findings consistent with essential thrombocythemia.”  (See the article on bone marrow biopsy, this issue.)

On review, the chief pathologist at Weill Cornell looked at the same slides, the same bone marrow aspirate  and concluded,  “The presence of significant bone marrow hypercellularity with granulocytic hyperplasia and the presence of tight clusters of megakaryocytes displaying abnormal nuclear features….are all findings consistent with early stage primary myelofibroiss  This diagnosis is also confirmed by the presence of significant reticulin fibrosis. (Emphasis added.)

The revised report  was signed by Dr. Attilio Orazi, one of the authors, with Thiele, claiming in 2012 that the presence of reticulin fibrosis is a significant indicator of early myelofibrosis. 

Because high platelet readings and low or absent levels of fibrosis are common to both the pre-MF and ET phenotype, diagnostic confusion seems inevitable.  

Back in North Carolina I took my labwork and slightly fibrotic body to  Dr. Joseph Moore, medical director of the Duke Raleigh Cancer Center.  Another round of all day exams and tests, these more extensive and exhaustive, review of BMB slides by the resident pathologist, and consultation with Moore.
The only new discovery was my high  lactose dehydrogenase (LDH) level – one of WHO’s four secondary PMF markers —  but still a baffling lack of splenomegaly and only 1+ early reticulin fibrosis. Moore’s recommendation, “It looks like ET, but wait and see and take hydroxyurea, it’s a good drug, like a wet blanket, calms down your counts.”   I considered it.

On the four hour drive home from Duke,  I tried to sort through all the findings, diagnoses and therapeutic prescriptions.   It was impossible. There were too many variables.   Since my on-going fatigue and low level anemia were problematical regardless of which disease subtype I carried, I thought it might be too early – or too late – for that HU wet blanket

Clearly I had a disease that fell someone along the MF continuum but it was possible I had enough good quality time ahead that I could avoid the toxicity of any drug….for now.

I didn’t fill that Rx either.

 Conclusion….One world, one certainty.

 As MPN patients, we’re forced to rely,  finally, on our hematologists, on each other, and own best judgment.   Polycythemia vera has clearcut markers, JAK2 mutation, unmistakable diagnostics and a limited but effective choice of treatment options.  ET and MF are less clear.  But for all of us, there’s one certainty:   It’s our bodies, our health and our lives.  When our consulting hematologists disagree, when standard diagnostics are unclear, and when argument rages over the very definition of our diseases and the conclusions to be drawn from our bone marrow biopsies, we are thrown back on our own resources.

In the matter of pre-PMF,  so far, no matter how famed and skilled a hematologist or clinical investigator, there will be opposing views, alternate therapeutic paths advanced by equally famed and skilled physicians.

In the matter of advanced MF with splenomegaly, we have world famous hematologists both praising and damning Jakafi in long statistic-laden learned papers and public forums.

As patients and caregivers, we are caught in the middle.

As fast as genetic-based science and biotechnology are progressing, today our MPNs are still largely a medical mystery and a matter of interpretation, of art more than science. There’s unquestionably a time in the progress of our disease that medical intervention is indicated, sometimes urgently required.  For some of, there’s also a time to wait and see.   We simply have to choose….and hope we’re right.

We’re learning. The whole field of molecular biology is exploding and there are good, brilliant scientists in well-equipped labs exploring concepts, options, pathways. Eventually, I have no doubt, they will succeed in reversing fibrosis and stopping myeloproliferative disease.

Meanwhile we can only take it all in and be grateful for the creative thinking, the hard work and even the heated disputes that help light our way along this mysterious path.  And hope for the best.

Take me back to the Contents

©Zhenya Senyak and MPNforum.com, 2012. 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 MPNforum.com with appropriate and specific direction to the original content.