Polycythemia Vera Letter
A great letter sent by either a medical resident or a medical student to one of our group members:
"...I am very distraught by your news, and wish
you the best of
luck. However, it is quite remarkable and refreshing to find
someone who demonstrates such detailed knowledge and extraordinary
involvement with their treatment. I may not be able to supplement
your wisdom.
Polycythemia may result from diuresis, excessive
erythropoietin production, and elevated clonal expansion of "stem"
cells within the bone-marrow that are the precursor for
erythrocytes (red blood cells), granulocytes (sub-type of white
blood cells), and megakaryocytes (form platelets). I will assume
that diuresis is not a factor, and that your plasma erythropoietin
level has been previously assayed and not found to be elevated.
The specific diagnosis of polycythemia vera indicates that red
blood cell formation from the precursor cells predominates, but all
the above cell types may be excessive in circulation.
This is dangerous for several reasons. An increase in blood
viscosity and volume occurs, which can cause vascular stasis,
hemorrhagic diathesis, thromboses, and infarction. The bone-marrow
may become progressively fibrotic (myelofibrosis). Additionally,
the hyper-replicating "stem" cells in the marrow may undergo
leukemic transformation, resulting in uncontrolled expansion and a
grave prognosis.
As you are undoubtedly aware of; headache, dizziness,
gastrointestinal symptoms, hematemesis, melena, and intense
pruritus are common symptoms. Hyperuricemia from high cell
turnover results in gout in 5%-10% of individuals with PV. The
only known cure for PV is a bone marrow transplant, an extremely
risky and expensive procedure (usually not covered by insurance) at
best, assuming an HLA matching donor can be found.
Enough of the depressing details. There is some encouraging
information. Several treatments in combination with phlebotomy
have proved more effective in reducing the incidence of long-term
complications than phlebotomy alone. Phlebotomy should not be the
only therapy because of common vascular problems and poor clinical
tolerance (no one desires frequent blood letting).
New protocols are usually compared with regular phlebotomy
treatment by itself. Median survival is in excess of ten years
with regular phlebotomy exclusively. After ten years myelofibrosis
is seen in 15%-20% of individuals and the incidence of
transformation to acute myeloblastic leukemia is 2% with phlebotomy
treatment only. Unfortunately, after fifteen years the incidence
of myelofibrosis or splenomegaly complications approaches 50% if
phlebotomy is the only treatment.
Reducing these and other complications has been the primary
focus of combination therapies. Regardless of the protocol
selected, I highly recommend tolerance and persistence with
frequent cell counts and phlebotomy as required, despite the
discomfort. Three complications that indicate a need to
discontinue or substantially reduce phlebotomy treatments are;
cardiovascular complications, platelet counts in excess of
800,000/ul, and splenomegaly.
Hydroxyurea
Hydroxyurea is an antineoplastic compound (inhibits
cellular
growth). A Swedish study reported an increase in the incidence of
leukemic transformation to 10.5% (vs. 2% for phlebotomy alone)
after treatment with hydroxyurea. Normal levels of erythrocytes
and thrombocytes are achieved in 70%-90% of PV individuals.
However, in 15% of individuals, platelet increase was not
controlled during maintenance therapy, and chromosomal
abnormalities eventually develop in approximately one-third of
those managed by this treatment. I don't recommend this protocol
for individuals that are complication free. See pipobroman below.
Chlorambucil, Busulfan
Chlorambucil is an alkylating antineoplastic compound.
It is
also a known carcinogen. An increased risk of cancer is seen with
this treatment, which appears to persist for at least five years
even after stopping the treatment. Other alkylating antineoplastic
compounds are being experimented with currently, but will likely
have similar risks.
P32 (Radioactive Phosphorous)
Whole body radiation treatments generally wreck
havoc with
cellular replication. Single doses of P32 dramatically reduce
platelet and granulocyte proliferation. Red blood cells are also
affected, although the reduction is delayed because of the longer
innate survival of these cells. The duration of reduction is dose
dependent, and generally lasts between three months and three
years. Resistance to this treatment does develop, and there are
multiple side-effects from repeated radiation exposure.
Radiation and chlorambucil treatments to suppress bone marrow
should be used as a last resort in my opinion, as these treatments
are mutagenic. P32 therapy substantially increases the incidence
of acute myeloblastic leukemia transformation from 2% (phlebotomy
only) to 15% of individuals with PV. Targeted delivery of these
agents would be a major improvement (see below).
Cyclophosphamide, Azathioprine
Cyclophosphamide is a potent antineoplastic
immunosuppressive
agent. It is toxic to both replicating and non-replicating cells
and is very effective at suppressing bone marrow. It has been used
successfully in combination with corticosteroids as a treatment for
thrombocytopenia.
Pipobroman
Pipobroman is another antineoplastic agent that
appears to be
superior to hydroxyurea treatment. In addition, with chronic
therapy, less resistance develops to this treatment than to other
forms of treatment, even after twenty years of therapy. It is very
effective at reducing erythrocyte and thrombocyte concentrations,
with complete remission being achieved in 95% of individuals with
PV. It does not eliminate the possible complication of acute
leukemia. Regardless, this compound should be considered as an
alternative to hydroxyurea therapy.
Ticlopidine
Ticlopidine acts as an anticoagulant by inhibiting
platelet
aggregation. It is effective at reducing the risk of thrombotic
stroke in cases of elevated platelet concentration.
Interferon
Recombinant IFN is a cytokine that has
antineoplastic
activity. A chief advantage of IFN is that it is relatively devoid
of harmful side-effects when compared to other treatments for PV.
My recommended dose is 3MU three times/week, and as you are now
quite aware, this is one protein messenger where more is not
better. It is quite likely that a dose of 3MUx3/week will
significantly reduce the amount of a second compound, for example
pipobroman, required to control the elevated cell levels in PV.
While such a protocol would be considered experimental, IFN acts by
an independent mechanism, and in combination with other therapies
may prove synergistic in effect.
Antilymphocytic Antibodies
A specific antiserum can be produced to one's bone
marrow
"stem" cells by repeated injection of these cells into a recipient
(usually a horse) followed by antibody isolation and injection.
This technique has proved effective in the production of anti-
toxins (eg. vs. tetanus, snake toxins). It is also being utilized
experimentally in the treatment of various cancers and in tissue
grafting. Monoclonal antibodies may be used as accurate delivery
systems for potent biological toxins. They may also be kinased
with P32, resulting in specific cell-type targeted radiotherapy.
However, currently response to antiserum treatment is quite
variable, particularly from one batch of serum to the next. This
technology is expected to improve in the future..."
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The letter above is a great overview of PV and treatment options, but with the following personal notations: Pipobroman is not available in the states. Chlorambucil as treatment for PV has been discontinued as leukemogenic. Only a small handful of US hematologists are still using Busulfan as first line treatment. I've never been able to locate a single MEDLINE article indicating Cyclophosphamide or Azathioprine as treatment for thrombocythemia. Ticlopidine is primarily used for heart patients that can not tolerate low dose long term aspirin. It's effect is similar. Antilymphocytic Antibodies are not currently being used for the treatment of PV, nor are they currently listed in any clinical trials for PV or ET (essential thrombocythemia). I have never been able to find any history of research for their being used as treatment for PV or ET. Virtually all of our PV list subscribers are on either interferon (Intron-A) , hydroxyurea (Hydrea), or phlebotomy alone.
Please bear in mind that I am not a physician, nor am I even a health professional. Always work with your hematologist and follow her or his guidelines and direction. With PV or ET you should be under the supervision of a hematology specialist. It is somewhat rare a disease and many hematologists in private practice may see only a few polycythemics or none at all over a long period of time. A university or teaching hospital may be best for you, at least to set a treatment guideline that your local hematologist can follow at home. Traditional treatment has been to immediately get the hematocrit down below 45 as soon as possible after diagnosis by repeated phlebotomies over a period of weeks. There is then a divergence of professional opinion on the best treatment thereafter - as noted by the varying current treatment options our list server members are using.
Robert Tollen