"Spent" phase in PV
From: Norm Freeburg <nfreeburg@CYBERUS.CA>
Subject: Re: PV/spent
At 12:55 PM 03/02/97 EST, you wrote:
>dear alorie
>I am also a Pver who worries about spent phase. Does anyone
>know for sure? I think not. The most promising data indicate
>perhaps 12% pv will go to spent, but I fear that has lots to do
>with people dying before they get there, so the % could be much
>higher for young pv patients. On the other hand, one hopes that
>data suggesting 30% and more were based partly on medications that
>are now out of favor. But there's little agreement, including on
>whether phlebotomies accelerate move to spent, or at least don't
>slow it as opposed to medications that arguably might. Dan
>
>
Dan and Alorie,
Actually the Najean data is less optimistic - 20% at 10 years, 32%
at 12 years, 52% at 15 years, and 80% at 20 years. These are stats from
Najean that Silver uses for those who did NOT get leukemia. In
phlebotomy-only, Najean had 12 of 37 patients in myelofibrosis before the
tenth year - over 33%. (Silver also references this.) By the 12th year, ALL
patients still treated by phleb-only had myelofibrosis, BUT there were only
6 patients left on phleb-only.
The other 31 had either died, had a serious thrombotic event, developed
early signs of MF, thrombocytosis, etc., so that they were not being treated
by phleb-only any longer.
(This data is found in "The very-long-term course of polycythaemia: a
complement to the previously published data of the Polycythaemia Vera Study
Group" publ. in British Journal of Haematology, 1994, issue 86, by Najean,
et al.)
Date: Fri, 24 Jan 1997 21:43:05 -0500
From: Norm Freeburg <nfreeburg@CYBERUS.CA>
To: Ralph, Procrit
Ralph and Pat,
Welcome to the group! My husband has polycythemia vera; he also
posts at times. I trust the group can be a help to you both as you seek
answers.
Procrit is the brand name for erythropoietin - a hormone released by
our kidneys to stimulate blood production in the marrow. The erythropoietin
can now be made in the lab, and is being used some for
myelodysplasia/myeloproliferative diseases (also apparently by athletes!).
You can get more info on this (studies, etc., where it's been used) by doing
a Medline search with the terms "erythropoietin myelodysplasia." Try the
Medline at <http://www.ariessys.com/> - you'll have to register first; it
will give you the 200 most relevant articles for however many years to
choose to look. Or you may also try the free Medline search at
<http://www.healthgate.com/> Again, use "erythropoietin" with
"myelodysplasia" as your search terms, not "myeloproliferative" (not as many
articles with MPD). If you have any trouble getting this, please let us know
- the articles are there and most have abstracts available on line for you
to view.
The end stages of polycythemia vera can have many facets -
post-polycythemic myeloid metaplasia or "spent phase" is not necessarily
accompanied initially by significant myelofibrosis. The enlarged spleen
(splenomegaly) and, sometimes liver (hepatomegaly), is usually present, but
this can progress slowly also. The anemia (red blood cell cytopenia) occurs
eventually (sometimes white cells and platelets remain high). Some questions
you may want to ask the hematologist - does your wife have immature white
blood cells and nucleated red blood cells in her blood tests? (a
leukoerythroblastic blood picture) - does she have tear-dropped shape red
blood cells? (teardrop poikilocytosis) - is her spleen and/or liver
enlarged? - what is her red cell volume and plasma volume at this time? What
are her platelet and white blood cell counts?
A leukoerythroblastic blood picture, teardrop-shaped red blood
cells, and anemia is consistent with what the literature calls
post-polycythemic myeloid metaplasia even if there is not significant marrow
fibrosis. If this does not fit your wife's blood picture, myelodysplasia
sometimes follows myeloproliferative disease (one recent article describing
this is "Mixed myelodysplastic and myeloproliferative syndrome" in Leuk Res,
Sept 1996 by Neuwirtova, et al.). I'm not sure that the specialists find it
that easy to tell them apart (bone marrow is hyercellular in most
myeloproliferative disease, but also frequently in myelodysplasia).
Besides various hormone therapies, interferon and different growth
factors have been used as treatment. Surgery (splenectomy) is sometimes done
with enlarged spleen. We have a number in the group with PPMM. Harriet S.
(does not usually post on the week-end) is more current on the latest
research. The Fred Hutchingson Cancer Centre in Seattle has sent us
information on their bone marrow transplant protocols for myeloproliferative
disease.
If you need help getting the actual articles on erythropoietin/
myelodysplasia (for submitting to the insurance company), please let us know.
We wish you both the very best.
Ruth
Date: Tue, 20 May 1997 13:08:03 -0400
From: Norm Freeburg <nfreeburg@CYBERUS.CA>
Subject: Re: For Ruth - response to Robert
Robert,
I think the question that you are asking, stated in different terms, is:
"Does increased erythropoiesis present the same risk as increased
megakaryopoiesis in progression to fibrosis?" (For explanation to some of
our "new comers" reading this - erythropoiesis is the production of the
erythrocyte - the red blood cell, while megakaryoctyes are the precursors
of platelets.)
For starters - though we use and read the terms "increased
megarkaryopoiesis," perhaps a better phrase would be "abnormal
megakaryopoiesis." Messinezy (citing other sources as well) theorizes that
perhaps all myelofibrosis had a prior state of high platelets. Perhaps,
this was also Najean's theory - if myelosuppression was used early enough
in PV- preventing any platelet rise - fibrosis would be prevented.
Clearly, this is not the case. Whether most cases of primary myelofibrosis
had an unrecognized proliferative stage, I don't know, but there ARE other
disease besides MPD which produce marrow fibrosis (and presumably not just
with high platelets); Najean has discovered that MF STILL occurs even when
platelets have always been kept under control; Silver states that high
platelets in ET do not appear to routinely lead to MF; AND, on a personal
basis, Norm has gone from a very hypercellular marrow with NO evidence of
fibrosis and no abnormal cells (few large platelets) - in what we know was
a good biopsy sample - to myelofibrosis, confirmed in biopsy and peripheral
blood. Neither at diagnosis 4 1/2 years ago, nor since have Norm's
platelets ever been above 400,000.
So, perhaps, the better phrase is "abnormal megakaryopoiesis" - sometimes
"increased" and "abnormal" being one and the same. Does the increase cause
the abnormality, or does the abnormality cause the increase? Can it be
both? Does it vary from one individual patient to another?
So, what are some other things that we KNOW? As you mentioned, PDGF and
TGF-beta are KNOWNS involved in fibrosis. We KNOW that there is a
relationship with PDGF, platelets, and marrow fibrosis. We THINK we KNOW
that TGF-beta is a major player in this development. (TGF-beta has been
released in high levels from "abnormal" or "increased" megakaryoctyes.
Also, some of the characteristics of MF - fibrosis, angiogenesis,
osteosclerosis, and hypoplasia can be induced by TGF-beta.) HOWEVER,
TGF-beta is not the only player; studies show that there must be other
cytokines involved. Are these other cytokines released by abnormal
megakaryopoiesis or might abnormal hematopoiesis, in general, be involved?
In addition, in one study TGF-beta has been found released NOT just from
mekaryocytes, but from other leukemic cells. These patients had reduced
marrow megarkaryocytes, but still had high TGF-beta deposits.
Thrombopoietin (Tpo), as you are aware, is another growth factor that some
studies have found linked to fibrosis. Tpo has particularly interested me
- actually since reading the article you brought to our attention that I
subsequently reviewed. Tpo affects, not just megakaryopoiesis, but ALL
hemapoiesis. I was further intrigued to discover that iron MIGHT act to
inhibit Tpo - with Tpo, therefore, being one of the possible players
(major?) in reactive thrombocytosis (increased platelets) caused by
iron-deficiency.
So what does this all come down to? I think it's fair to assume that
abnormal hematopoiesis, whether megakaryopoiesis or erythropoiesis, puts
the PV patient at risk for fibrosis.
The question then might be, "What are your options? What can you do
differently?" These are the same questions that Norm and I looked at when
we faced the concern that perhaps the IFN was not going to control his
RBC's. (And we're aware that Silver had stated IFN may not be effective in
controlling erythropoiesis if there is extensive fibrosis.) Norm was
adamant that phleb-O was not an option; we talked about HU; we were really
interested in pipobroman (Vercyte). (Yes, a leukemia risk, but no MF so
far.) But, all of this has become sort of academic since he had the repeat
biopsy which (with his smears) confirmed secondary myelofibrosis. For
various reasons, we are not excited about moving to a myelosuppressive
(other than IFN) now that he has MF.
You know that if you really want to know what is happening in your marrow
- well, it would have to be a biopsy or perhaps the scintography. (In
Norm's case, the peripheral blood gave good indicators, though,
particularly in respect to his WBC's - the IFN has normalized this.) Norm
has a question for you - could you have scintography done in the States -
then send the results, data, pictures, etc., to Najean for analysis?
However, in your case, Robert, since you have hypertension - this really
may still be your greatest threat, even though you were diagnosed young.
Wishing you the very best,
Ruth