Download POLYCYTHEMIA VERA: DIAGNOSTIC WORK

•
1
Polycythemia Vera
Running head: POLYCYTHEMIA VERA: DIAGNOSTIC WORK-UP AND TREATMENT
OPTIONS
POLYCYfHEMIA VERA:
DIAGNOSTIC WORK-UP AND TREATMENT OPTIONS
By
JOANNE TUTHILL EDDINGTON
•
A manuscript submitted in partial fulfillment of
the requirements for the degree of
MASTER IN NURSING
WASIllNGTON STATE UNIVERSITY
Department of Nursing
May 2000
3
Polycythemia Vera
ACKNOWLEDGEMENT
I wish to thank: my husband, Gordon, for his unwavering support and understanding over
the last 3 years. Without his assistance this manuscipt would have never been completed. I also
wish to thank Amy Roth and Peggy Baldwin, library staff at Providence Portland Medical Center,
for their assistance in obtaining resources used in the development of this manuscript.
4
Polycythemia Vera
POLYCYTHEMIA VERA:
DIAGNOSTIC WORK-UP AND TREATMENT OPTIONS
Abstract
by Joanne Tuthill Eddington, R.N., B.S.N.
Washington State University
May 2000
Polycythemia Vera (PV) is a chronic myeloproliferative disorder characterized by
excessive proliferation of erythrocytes, leukocytes and thrombocytes (Means, 1998; Broudy,
1996). Undiagnosed patients may present to their primary care providers with an elevated
hematocrit. A thorough diagnostic work-up is essential in differentiating PV from secondary and
relative polycythrnia. Treatment options for PV includes phlebotomy and myelosuppressive
therapy. A good understanding of the diagnostic tests required to diagnose PV are necessary to
appropriately refer patients to a hemotologist for treatment. With a thorough understanding of
treatment options, primary care providers can counsel and supported their patients. This
manuscript reviews the diagnostic tests required to accurately diagnose PV and reviews over 20
years of research evaluating treatment for PV.
.
5
Polycythemia Vera
TABLE OF CONTENTS
ACKNOWLEDGEMENTS
Page
3
ABSTRACT
4
LIST OF TABLES
6
LIST OF FIGURES
7
MANUSCRIPT
8
REFERENCES
23
APPENDIX
SUMMARY OF SELECTED PUBLISHED RESEARCH ON POLYCYTHEMIA
VERA
.
32
6
Polycythemia Vera
LIST OF TABLES
1. Diagnostic Criteria for Polycythemia Vera
29
2. Clinical and Laboratory Criteria for Diagnosis of Polycythemia Vera
30
3. Treatment Recommendations by Age
31
7
Polycythemia Vera
LIST OF FIGURES
1. Peripheral Blood Smear
27
2. Algorithm for Evaluation of Elevated Hematocrit
.28
•
8
Polycythemia Vera
Introduction
Polycythemia Vera (PV), also known as Polycythemia Rubra Vera, is a chronic
myeloproliferative disorder characterized by excessive proliferation of erythrocytes, leukocytes
and thrombocytes (Means,
1998~
Broudy, 1996). This abnormal cell production appears to occur
at the level of the pluripotent stem cell in the bone marrow, therefore PV is classified as a
•
hematologic disorder (Means,
1998~
Messinezy & Pearson, 1997). There are three classifications
of polycythemia: (1) primary polycythemia or PV, (2) secondary polycythemia which is due to
increased erythropoietin production and (3) relative polycythemia which is due to decreased
plasma concentration (Berlin, 1975). Proper treatment ofPV requires distinguishing this
hematologic disorder from non-hematologic polycythemias.
Epidemiology
The incidence ofPV is very low. There is little recent epidemiologic data on the incidence
ofPV because it is an uncommon disease that occurs in low frequency. The most recent
epidemiologic study ofPV was done in Olmstedt County, Minnesota. This community's medical
care is primarily self contained within the community and lends itself to population-based
epidemiological research. Over a 55 year period from 1935-1989, the age and sex-adjusted
incidence rate ofPV was 1.9 per 100,000 person-years (Ania, Suman & Sobell, 1994).
The Gruppo Italiano Studio Policitimia (1995) is recognized as a leading reference based
on a retrospective cohort study of 1213 patients with PV in Italy. These patients were followed
for 20 years. Prior to this study, there was little research evaluating the natural history ofPV.
This study demonstrated that PV is slightly more common in men than women, with a male
•
9
Polycythemia Vera
/female ratio of 1.2: 1.. PV is more commonly diagnosed in those individuals who are between the
ages of 50 and 75. For patients who are treated, the cumulative median survival is greater than 15
years and the overall mortality rate is 2.94 deaths per 100 persons per year (Gruppo Italiano
Studio Policitimia, 1995).
Pathophysiology
PV or primary polycythemia results from an overproduction of erythrocytes, leukocytes
and platelets which is independent and unregulated by the body (Broudy, 1996). Erythropoietin
(EPO) is a hormone secreted by the kidney for primary regulation of erythropoiesis (Biligrami &
Greenberg, 1995). Granulocyte macrophage stimulating factor (GM-CSF), Interleukin-3 (IL-3)
and stem cell factor (SCF) are hematopoietic growth factors. In PV, erythrocytosis occurs
despite low or normal erythropoietin levels and it is theorized that leukocytosis and
thrombocytosis occur from hypersensitivity to GM-CSF, IL-3 and SCF (Weinberg, 1997).
Staging of Polycythemia Vera
PV usually evolves through specific stages which include the proliferative stage, the stable
phase, and the spent phase (Dickenstein & Vardiman, 1995). The diagnosis ofPV is usually made
at the proliferative stage of the disease process. This stage is characterized by a significant
increase in red blood cell (RBC) volume. Figure 1 shows a typical peripheral blood smear seen in
patients with PV. It shows erythrocyte overlap demonstrating an increase in red cell volume, as
well as an increase in the number of platelets. This increased volume leads to hyperviscocity and
thrombosis, as well as other circulatory problems including tissue infarction and hemorrhage
(Means, 1998; Dickenstein & Vardiman, 1995; Broudy, 1996). Patients who develop PV may
10
Polycythemia Vera
initially be asymptomatic and some may have a thrombotic event prior to the diagnosis (Gruppo
Italiano Studio Policitemia, 1995). If patients with PV survive the proliferative stage, they may
stabilize and enter what is known as the stable phase. During this phase, red blood cell counts
normalize and the patient may not require regular treatment. Some patients may progress into the
spent phase. This final stage is characterized by anemia, leukopenia, thrombocytopenia, marrow
fibrosis and progressive hepatosplenomegaly. The spent phase is often called Post Polycythemic
Myeloid Metaplasia (PPMM) (Broudy, 1996; Dickenstein & Vardiman, 1995).
According to the Gruppo Italiano Studio Policitimia's retrospective study of 1213 patients
with PV, the most frequent fatal complication was thrombosis. Death from cancer was the
second most frequent fatal complication ofPV and 15% of these deaths were from acute myeloid
leukemia (Gruppo Italiano Studio Policitimia, 1995).
Clinical Manifestations
During the proliferative stage the patient usually becomes symptomatic. The patient often
presents with a variety of nonspecific complaints that may include headache, dizziness, visual
disturbances, weakness and pruritus (Berlin, 1975). Some patients may be completely
asymptomatic and PV is initially suspected by elevated hematocrit alone (Knoop, 1996; Means,
1998). A detailed history, physical exam and laboratory evaluation is important in differentiating
PV from secondary and relative polycythemia.
Since treatment for PV is very different from other types of polycythemia, it is important
to ensure that the patient is carefully evaluated for causes of erythrocytosis. A history of cardiac
disease, pulmonary disease, high altitude, smoking, and renal disease could be a cause of
•
11
Polycythemia Vera
secondary polycythemia (Linker, 1997). A careful history must be taken in order to identify any
secondary causes. Some patients may have both secondary polycythemia and PV.
On physical exam the patient with PV may have skin plethora (ruddy cyanosis),
conjunctival plethora, engorged vessels of the fundus, systolic and/or diastolic hypertension,
hepatomegaly and splenomegaly (Berlin, 1975). A patient with secondary polycythemia may have
bluish cyanosis that is noted on physical exam (Berlin & Wassennan, 1997). A palpable spleen is
one of the most significant findings on physical exam. A palpable spleen is usually seen only in
PV patients and not in other polycythemias. However, patients with PV may not have a palpable
spleen (Berlin, 1975).
Diagnostic Studies
Laboratory studies are essential to the accurate diagnosis ofPV. A thorough diagnostic
evaluation must be perfonned since a misdiagnosis could have dire consequences. Care must be
taken to avoid indescriminent testing, because evaluation could be extremely costly (Hoffinan &
Boswell, 1995). A complete blood count (CBC) with a differential count usually identifies
Polycythemia by an elevated hemoglobin (> 18g1dL in males and > 16g1dL in females), an
elevated hematocrit (> 54% in males and > 49% in females) and an increase in the red cell count
(> 6,000,000/ mm3) indicating erythrocytosis. These elevations require further evaluation. Figure
2 contains the pathway to evaluate an elevated hematocrit. A red blood cell (RBC) mass should
be drawn. If the RBC mass is nonnal then the patient is thought to have relative polycythemia
and should be evaluated for a possible cause. If the RBC mass is increased
(~36
ml/kg for males
and ~ 32 ml/kg for females) then further testing is indicated to differentiate PV and secondary
•
12
Polycythemia Vera
polycythemia.
The next step in the diagnostic evaluation of an elevated hematocrit is to measure the
arterial blood oxygen saturation. A low arterial oxygen saturation tends to support a diagnosis of
secondary polycythemia with erythrocytosis likely being compensatory. If the arterial oxygen
saturation is normal and the patient has a history of smoking then a measurement of
•
carboxyhemoglobin (carboxy-Hb) concentration is indicated. An increase in carboxy-Hb indicates
smoker's polycythemia where there is a compensatory increase in native hemoglobin in order to
maximize oxygen transport (Berlin & Wasserman, 1997). If the carboxy-Hb concentration is
normal and the patient is not a smoker, then an evaluation of serum erythropoietin production
(EPO assay) should be considered. If the EPO assay is elevated then radiographic studies are
needed to establish possible sites of ectopic erythropoietin production. If the EPO assay is
normal, a measurement of the partial pressure of oxygen at which hemoglobin is 50% saturated
(hemoglobin P so O 2) maybe helpful. This test is used to identify individuals with high-oxygen
affinity hemoglobinopathy. If the saturation is normal, the patient likely has long standing
myocardial failure. If the saturation is shifted to the left, then the patient has a hemoglobinopathy
with high oxygen affinity (Berlin & Wasserman, 1997). If the EPO assay is reduced or
nonexistent or all ofthe tests described exclude other diagnoses, then the diagnosis ofPV can be
made (Berlin & Wasserman, 1997; Frenkel, 1997). The presence ofleukocytosis (WBC
~
12,000/ nun3) and thrombocytosis (platelets ~ 400,000/ nun3) also supports the diagnosis ofPV
(pearson & Messinezy, 1995). If there is any question in the diagnosis ofPV, additional
evaluation of bone marrow can be helpful.
•
•
13
Polycythemia Vera
The Polycythemia Vera Study Group (PVSG) was created in 1966 with support from the
National Cancer Institute (Berlin & Wasserman, 1997). This group was responsible for
performing a, prospective, randomized, controlled clinical trial to evaluate the best treatment for
PY. The PVSG developed a set of criteria for the diagnosis ofPV in order to assure that
participants in the trial actually had PV (Berlin, 1975). Table 1 outlines the PVSG criteria. This
criteria contains two categories. Category A, requires that the patient have AI: an increased red
cell mass of2: 36 rnl/kg for males and 2: 32 rnl/kg for females, A2: an arterial oxygen saturation of
2: 92% and A3: splenomegaly. Category B is used if the patient did not have splenomegaly. This
category includes a platelet count of 2: 400,000/ nun3 , WBC count 2: 12,000/ nun3, a leukocyte
alkaline phosphatase level> 100 and a serum vitamin B 12 level 2: 900 pglml, or a serum vitamin
B 12 binding protein> 2,200 pglml. The diagnosis ofPV is made if the patient has Al+A2+A3
or Al +A2+ any two criteria from category B. These criteria are strict. Although the specificity is
very high (false positive rate is less than 0.5%), some patients with PV may not fulfill the criteria
(Berk et al., 1989). The criteria were established prior to the technological ability to determine
serum erythropoietin levels and perform endogenous erythroid colony assays, therefore, they were
not included in the PVSG criteria.
With new technology available, more recent criteria have been developed that include
evaluation of serum erythropoietin levels, and bone marrow for endogenous erythroid colony
(EEC) assay (Hoffinan & Boswell, 1995). Criteria suggested by Hoffinan and Boswell is
outlined in table 2. For patients who do not meet the PVSG criteria these proposed additional
criteria may provide supporting evidence for the diagnosis ofPV (Broudy, 1996). Revisions to
•
14
Polycythemia Vera
the diagnostic criteria for PV continue to evolve as more is learned about bone marrow
histopathology (Michaels & Juvonen, 1997).
The patient being evaluated for an elevated hematocrit should be informed that the
diagnostic work-up requires a large battery of tests. They will usually experience repeated blood
and laboratory tests to establish and confirm the diagnosis ofPV. A bone marrow biopsy is
•
considered the most invasive test in the diagnostic work-up. Prior to this test, they will be
required to sign a separate consent form giving permission for this procedure to be performed.
The patient should be informed ofthe probability of pain or discomfort during this procedure.
They should be reassured that they will be given pain medication and sedation.
Treatment
The patient diagnosed with PV must be educated in the chronicity of the disorder and
informed that treatment will be required for life. It is important for the patient to understand that
ifPV is left untreated, life expectancy may be as short as eighteen months from diagnosis (Gruppo
Italiano Studio Policitemia, 1995). The treatments selected for PV may, however, put them at
increased risk for other problems such as thrombosis and cancers including acute myelogenous
leukemia (Hoffinan & Boswell, 1995; Means, 1999).
According to Means (1999), the goal in treating patients with PV is to reduce the RBe
mass with the least amount of complications possible, in order to provide increased survival ,
maximum quality of life, low cost of treatment and convenience for the patient. Treatment can
extend the median survival for PV patients to greater than 10 years. Treatment-related
complications have caused debate regarding the best way to treat PV.
•
15
Polycythemia Vera
As previously mentioned, one of the goals of the Polycythemia Vera Study Group
(PVSG) was to determine the best way to treat PV. There were seven protocols studied by the
PVSG that looked at a variety of treatment issues related specifically to PV (Berk, Wasserman,
Fruchtman & Goldberg, 1995). Three of these studies, PVSG 01, PVSG OS, PVSG 08, and an
update on data from PVSG 08 which provide the clinical data that support therapeutic
recommendations made by the PVSG, will be reviewed in more detail.
The first study by the PVSG, PVSG 01, was a prospective randomized phase III clinical
trial that compared treatment with phlebotomy alone to either treatment with radioactive
phosphorus
ep) or treatment with the chemotherapeutic agent chlorambucil.
2
32p
and
chlorambucil were selected as they were standard treatment for PV during the 1960's when this
study was conducted (Berk, Wasserman, Fruchtman & Goldberg, 1995). In order to ensure that
the patients were in the active, proliferative stage of the disease, they were phlebotomized and
then observed for rapid elevation of hematocrit. If the patient demonstrated active proliferative
disease, they were randomized to one of the three treatment arms. Patients were enrolled into this
study from 1967 to 1974. During this time period, a total of 431 patients were randomized to one
of the three treatment arms.
One of the strengths of this study was the length offollow-up. Surviving patients that
were enrolled in this study have been followed for more than 19 years. However, during this time,
modification of treatment occurred. Patients who had been randomized to the chlorambucil arm
were found to have an increase in the development of leukemias and were switched to other
treatments (Najean & Rain, 1997). The results of this trial demonstrated that each of the
.
16
Polycythemia Vera
treatment arms of PVSG 01 were related to a significant increase in complications. Those that
were treated with phlebotomy alone were at a significantly increased risk for life threatening
thrombotic events during the first 3 years of treatment. The incidence of these events were highest
in those who had a history of previous thrombosis, those that needed frequent phlebotomy or the
elderly. The patients who received chlorambucil or 32p had an increase risk of leukemia,
•
lymphocytic lymphoma or carcinoma of the skin or gastrointestinal tract. However, patients
developed this risk after at least 5 years of treatment (Berk, Wasserman, Fruchtman & Goldberg,
1995). The overall survival was found to be shorter for those who were treated with chlorambucil
and longer for those who received 32p or phlebotomy.
Because of the risk of thrombotic complications with phlebotomy alone, the PVSG
examined the possibility that the use of aspirin and persantine would decrease the incidence of
thrombotic complications in patients receiving phlebotomy. PVSG 05 was a randomized
controlled phase III clinical trial evaluating the use of aspirin and persantine in patients with PY. It
was initiated in 1977. There were 178 patients who were randomized to one of two treatment
arms. One group received phlebotomy with 300 mg of aspirin and 75 mg ofpersantine three times
a day. The other group received 32p. 32p served as the control arm due to the risk of thrombotic
events in patients receiving phlebotomy alone (Berk, Wasserman, Fruchtman & Goldberg, 1995).
PVSG 05 was stopped in April of 1981 due to the significant increase in gastrointestinal
hemorrhage in the group receiving phlebotomy, aspirin and persantine. Despite early termination
of this study, results failed to demonstrate a decrease in the incidence of thrombotic complications
in the patients who received phlebotomy with aspirin and persantine. In fact, an increase in
17
Polycythemia Vera
thrombotic complications was seen compared to the control arm receiving
32p.
There was no
difference in thrombotic complications compared to those in PVSG 01 who received phlebotomy
alone (Berk, Wassennan, Fruchtman & Goldberg, 1995).
The third therapeutic trial that the PVSG sponsored was PVSG 08. This trial originally
was designed to evaluate the efficacy of hydroxyurea in patients with PV. Hydroxyurea was
known to be a potent nonalkylating myelossupressive agent. In addition, it was not known to
cause leukemia. It had been successfully used before in other hematologic malignancies (Donovan
et al., 1984). This efficacy trial by the PVSG and reported by Donovan et al. (l984),was designed
so that patients received hydroxyurea and supplemental phlebotomy. The goal was to show that
hydroxyurea could be used successfully to achieve and maintain a hematocrit of < 50% and a
platelet count of< 1,000,000 mm3 with minimal use of phlebotomy. The number of phlebotomies .
were restricted to six or less per year. Patients were evaluated for their clinical response and long
tenn disease control.
There were 118 subjects enrolled in this PVSG efficacy trial. Of this group, 59 patients
had received no prior treatment. The other 59 patients had received previous myelosuppressive
therapy. Of the patients with a pre-treatment platelet count of >1,000,000 mm3 , 88% responded
with platelet counts < 600,000 mm3 by twelve weeks. In patients with elevated pre-treatment
hematocrits, 800/0 achieved nonnal values by twelve weeks. The cumulative I-year failure-free
survival in patients who had not previously been treated was 73%. This was reduced to 590/0 in
those who had received prior myelosuppressive therapy. Only two patients developed acute
leukemia by the time of the initial analysis of this study. Two patients who had never received
.
18
Polycythemia Vera
prior treatment experienced thrombotic events (Donovan et al., 1984).
This study by PVSG, reported by Donovan, et al. (1984), demonstrated that for
hydroxyurea to be effective it must be given continuously at doses of 500 mg to 1000 mg per day.
If the drug was discontinued, patients could not maintain normal blood counts for long. In
addition, a severe rebound thrombocytosis was seen in patients with pre-treatment high platelet
counts. This rebound effect often occurred within 7-10 days of the discontinuation of
hydroxyurea.
Soon after the PVSG 08 met its initial goals of establishing the efficacy of hydroxyurea,
the PVSG lost significant funding for additional randomized trials (Berk, Wasserman, Fruchtman
& Goldberg, 1995). The PVSG made the decision to continue following the patients who were
already enrolled in PVSG 08 and evaluate the long-term effects and complications of chronic
prolonged use of hydroxyurea.
Kaplan, et al. (1986), published a report that updates previous observations reported by
Donovan et al. (1984) on the efficacy of hydroxyurea and the incidence of complications. His
report focused on the patients enrolled in PVSG 08 who had not previously been treated prior to
therapy with hydroxyurea. These previously untreated patients in PVSG 08 were compared to a
historical control group from PVSG 01. This historical control group was made up of patients
with PV who had been treated with phlebotomy alone.
There were 51 patients who had not previously been treated with myelosuppressive
therapy who continued to received hydroxyurea and supplemental phlebotomy as of December,
1984. Of these, 31 patients continued to experience long-term disease free control. They were
•
19
Polycythemia Vera
compared to the 134 patients enrolled in the control arm of PVSG 01 who had received only
pWebotomy as treatment for pv. These two patient groups were very similar and were believed to
have the same initial prognosis. The patients were diagnosed using identical diagnostic criteria and
recruitment was structured to avoid selection bias. There were some slight differences in age and
sex distributions in the two groups and some differences in the initial mean hemoglobin and
•
hematocrit values between both groups. There were some protocol changes over the years that
reflected a change in desired hematocrit level on therapy and some differences in treatment escape
clauses allowing treatment of patients with dangerously high platelet counts. While this study has
been criticized for the use of a historical control arm, Kaplan et al (1984) believes that despite
these exceptions the comparison is valid.
According to Kaplan et al. (1984) comparison of the two groups demonstrate that fewer
thromboembolic complications occurred in patients treated with hydroxyurea and supplemental
pWebotomy than pWebotomy alone. In addition, there was not a statistically significant difference
in the incidence of acute leukemia between the two groups. Tatarsky & Sharon (1997) have
published data looking at a subgroup of patients enrolled in the PVSG 08 trial who were treated
by the department of hematology at Rambam Medical Center. This center was an active member
of the PVSG from the start. Their findings support the results reported by Kaplan et al. (1998).
Because of the significant side effects and risks associated with pWebotomy and
chemotherapy, the search continues for a treatment for PV which is both safe and effective in
controlling myeloproliferation. Recently, there has been a great deal of interest in the use of
Interferon alpha (INF-a) for the treatment ofPV. Interferons are cytokines which are involved in
•
20
Polycythemia Vera
a variety of biologic mechanisms which include antitumor, antiviral, immunomodulary activity and
alteration of cell surface protein expression (Fruchtman et aI., 1997). INF-a therapy has been
evaluated and has been found to be effective in inhibiting excessive myeloproliferation controlling
the thrombocytosis, leukocytosis and erythrocytosis seen in PV (Silver, 1997; Stasi et al., 1998;
Elliot & Tefferi, 1997).
Studies by Stasi, et al (1998) and Silver (1997) have shown that human leukocyte
interferon-a (hlIFN-a) or recombinant interferon-a (rIFN-a) given subcutaneously can
effectively control myeloproliferation, reducing the need for phlebotomy. IFN-a can also reduce
accompanying thrombocytosis, leukocytosis and splenomegaly. The side effects are mainly flulike symptoms which were tolerated by most of the patients studied (Stasi, et al, 1998; Silver,
1997).
Stasi, et al (1998) prospectively evaluated 18 patients with PV who were given hlIFN-a.
Seventeen out of these 18 patients showed at least a partial response and 11 showed a complete
response after 3 months of therapy. However, since the mean follow-up of these patients was only
19.5 months the end points of this study did not include evaluation of long term treatment with
hlIFN-a.
Silver (1997), studied the long term effects ofrIFN-a. This prospective nonrandomized
clinical trial followed 28 patients for more than 5 years. It demonstrated that in over six years of
follow-up, no patient developed any malignancy or thrombohemorrhagic complication from using
rINF-a. Current recommendations for INF-a therapy include: rIFN-a starting at 1 million units,
subcutaneously three times per week with gradual dose escalation to a maximum of 5 million
•
21
Polycythemia Vera
units, subcutaneously three times per week. In addition, phlebotomy should be used to maintain a
hematocrit between 40% and 45%. Phlebotomy requirements should decrease over time (Silver,
1997).
Based on PVSG 01, PVSG 05 and PVSG 08, Bilgrami & Greenberg (1995), propose
recommendations for treatment ofPV based on age. Table 3 outlines these recommendations.
Treatment should, however, be tailored to each individual by taking into account the patient's age
and their risk for complications. This information should be weighed against the known risks of
each treatment strategy (Broudy, 1996).
Antiplatelet agents have recently been re-examined as an effective way to control
myeloproliferative thrombocythemia and prevent thrombosis. Because of their antiplatelet
activities, low dose Aspirin and Anagrelide are being evaluated for their control of
thrombocythemia and thrombotic complications seen in PV (Landolfi & Marchioli, 1997; Petitt,
Silverstein & Petrone, 1997).
Petitt, Silverstein & Petrone (1997) prospectively evaluated 942 patients with
myeloproliferative thrombocythemia. Out of these patients, 113 had PV. In this study, the use of
Anagrelide demonstrated a reduction in the platelet count in patients with myeloproliferative
thrombocythemia. It also appeared to slow megakaryocyte maturation. Further evaluation of
Anagrelide is required before it is considered as a first-line agent to control thrombocythemia in
patients with PV.
The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) has
recently published their protocol which is a randomized trial evaluating the risks and benefits of
•
22
Polycythemia Vera
low-dose aspirin in PV (Landolfi & Marchioli, 1997). The plan is to enroll approximately 3500
patients and follow them for three to four years. Using a double blind study method, patients will
be randomized to receive 100 mg of aspirin daily or a placebo (Landolfi & Marchioli, 1997).
In summary, no therapy for PV is without risk. There have been published
recommendations for treatment of PV (Berk et al., 1986; Hoffman & Boswell, 1995; Bilgrami &
Greenberg, 1995; Fruchtman et al, 1997). These recommendations will continue to change and
evolve as prospective randomized trials are developed to evaluate the long-term effects of
standard treatments compared to new innovative therapies (See Appendix for summaries of
selected published research).
Conclusion
PV is myeloproliferative disorder that requires accurate diagnosis. It is important to rule
out other causes of an elevated hematocrit and erythrocytosis prior to the initiation of treatment.
IfPV is treated promptly the mean life expectancy of an individual is more than 10 years.
Treatment for PV should be individualized for each person based on age at diagnosis, presenting
symptoms and comorbid conditions since there are risks associated with each specific type of
therapy. Life long treatment is necessary to control the symptoms of erythrocytosis and prevent
complications. IfPV progresses, therapy will need to be adjusted and palliation and supportive
care may become the treatment goal .
•
•
23
Polycythemia Vera
References
Ania, B. 1., Suman, V. 1., Sobell, 1. L., Codd, M. B., Silverstein, M. N., Melton III, L. 1.
(1994). Trends in the incidence of polycythemia vera among olmsted county, minnesota residents,
1935-1989. American Journal ofHematoloiY. 47.89-93.
Berk, P. D., Wassennan, L. R., Fruchtman, S. M., & Goldman, 1. D. (1995) Treatment of
•
polycythemia vera: a Summary of clinical trials conducted by the polycythemia vera study group.
In L. R. Wassennan, P. D. Berk, N. I. Berk, (Eds.). Polycythemia Vera and the
Myeloproliferatiye Disorders. (166-94). Philadelphia: WB Saunders
Berlin, N. I. (1975). Diagnosis and classification of the polycythemias. Seminars in
Hematoloi)'. 12 (4), 339-351.
Berlin, N. I., Wassennan, L. R. (1997). Polycythemia vera: A retrospective and reprise.
Journal ofLaboratOl)' and Clinical Medicine. 130.365-373.
Bilgrami, S., & Greenberg, B. R. (1995). Polycythemia rubra vera. Seminars in Oncoloi)'.
2.2 (4),307-326.
Broudy, V. C. (1996). The polycythemias. In D. C. Dale, & D. D. Fedennan (Eds.),
Scientific American Medicine 1978-1999. New York: Scientific American Medicine.
Dickstein, 1. I., & Vardiman, 1. W. (1995). Hemotopathologic findings in the
myeloproliferative disorders. Seminars in Oncoloi)'. 22 (4),355-373.
Donovan, P. B., Kaplan, M. E., Goldberg, 1. D., Tatarsky, I., Najean, Y., Silberstein, E.
B., Knospe, W. H., Laszio, 1., Mack, K., Berk, & P. D., Wassennan, L. R. (1984). Treatment of
polycythemia vera with hydroxyurea. American Journal ofHematoloiY, 17.329-334.
•
24
Polycythemia Vera
Elliot, M. A., & Tefferi, A. (1997). Interferon-a therapy in polycythemia vera and
essential thrombocythemia. Seminars in Thrombosis and Hemostasis, 23 (5),463-472.
Frenkel, E. P. (1997). Approach to the patient with an elevated hemoglobin level. In W.
N. Kelley, MD. (Ed.), Textbook ofInternal Medicine (3rd ed., 1315-1318). Philadelphia:
Lippincott - Raven.
•
Fruchtman, S. M., Mack, K., Kaplan, M. E., Peterson, P., Berk, P. D., & Wasserman, L.
R. (1997). From efficacy to safety: A polycythemia vera study group report on hydroxyurea in
patients with polycythemia vera. Seminars in HematoloiY, 34 (1), 17-23.
Gruppo Italiano Studio Policitemia. (1995). Polycythemia vera: The natural history of
1213 patients followed for 20 years. Annals of Internal Medicine, 123,656-664.
Hoffinan, R., & Boswell, H. S. (1995). Polycythemia vera. In R. Hoffinan, M.D., E. 1.
Benz, Jr., M.D., S. 1. Shattil, M.D., B. Furie, M.D., H. 1. Cohen, M.D., Ph.D., L. E. Silberstein,
M.D. (Eds.), HematoloiY Basic Principals and Practice (2nd ed., pp. 1121-1141). New York:
Churchill Livingstone.
Kaplan, M. E., Mack, K., Golberg, 1. D., Donovan, P. B., Berk, P. D., & Wasserman, L.
R. (1986). Long-term management of polycythemia vera with hydroxyurea: A progress report.
Semjnars in hematoloiY, 23 (3), 167-171.
Knoop, T. (1996) Polycythemia vera. Semjnars in OncoloiY Nursina. 12 (1), 70-77.
Landolfi, R., M.D., & Marchioli, R., M.D. (1997). European collaboration on low-dose
aspirin in polycythemia vera (ECLAP): A randomized trial. Seminars in Thrombosis and
Hemostasis, 23 (5),473-478.
•
25
Polycythemia Vera
Linker, e. A., (1999). Blood. In Tierney, L. M., Jr., M.D., McPhee, S. 1., M.D.,
Papadakis, M. A., M.D., (Eds.), Current Medical Diaanosis and Treatment 1999 (38th ed., pp.
484-585). Stamford, CT: Appleton & Lange.
Means, R. T., Jr. (1999). Polycythemia vera. In G. R. Lee, M.D., 1. Foerster, M.D., B.Se.
(Med), F.R.C.P.(C)., 1. Lukens, M.D., F. Paraskevas, M.D., 1. P. Greer, M.D., & G. M. Rogers,
•
M.D., Ph.D. (Eds.), Wintrobe's Clinical HematoloiY (10th ed., pp. 2374-2389). Baltimore:
Williams & Wilkins.
Messinezy, M., Westwood, N. B., Woodcock, S. P., Strong, R. M., & Pearson, T. e.
(1995). Low serum erythropoietin - a strong diagnostic criterion of primary polycythemia even at
nonnal hemoglobin levels. Clinical & Laboratory HaematoloiY. 17.217-220.
Messinezy, M., & Pearson, T. C. (1997). ABC of clinical haematology: Polycythemia,
primary (essential) thrombocythemia and myelofibrosis. BMJ. 314 (7080),587-590.
Michiels, 1. 1., & Juvonen, E. (1997). Proposal for revised diagnostic criteria of essential
thrombocythemia and polycythemia vera by the thrombocythemia vera study group. Semjnars in
Thrombosis and Hemostasis, 23 (4),339-347.
•
Najean, Y., & Rain, 1. D. (1997). The very long-tenn evolution of polycythemia vera: an
analysis of 318 patients initially treated by phlebotomy or 32p between 1969 and 1981. Seminars in
HematoloiY, 34 (1),6-16.
Pearson, T. e., & Messinezy, M. (1996). Investigation of patients with polycythemia.
PostiTaduate Medical Journal, 72 519-524.
Petitt, R. M., Silverstein, M. N., & Petrone, M. E. (1997). Anagrelide for control of
26
Polycythemia Vera
thrombocythemia in polycythemia and other myeloproliferative disorders. Seminars in
HematoloiY. 34 (1), 52-54.
Silver, R T. (1997). Interferon alpha: Effects of long-term treatment for polycythemia
vera. Seminars in HematoloiY. 34 (1), 40-50.
Stasi, R, Venditti, A., Del Poeta, G., Conforti, M. Brunetti, M. Bussa, S., Amadori, S. &
•
Pagano, A. (1998). Role of human leukocyte interferon-a in the treatment of patients with
polycythemia vera. The American Journal of Medical Sciences. 315 (4), 237-241.
Tatarsky, I., & Sharon, R (1997). Management of polycythemia vera with hydroxyurea.
Seminars in HematoloiY. 34 (1), 24-28.
27
Polycythemia Vera
FiiWre 1. Peripheral blood smear shows erythrocyte overlap demonstrating an increase in red cell
volume and an increase in the normal number of platelets (> 10 per high power field).
28
Polycythemia Vera
Red Blood Cell Mass
.
Normal
Increased
1
Relative polycythemia
/1
Arterial Blood Gases and Carboxy-Hb
~
Increased (CoHg)
Smoker's polycythemia
Decreased (pO/02 Sat)
Secondary polycythemia
Normal
Epo assay
Elevated
CT scan of the abdomen
1
Low/Absent
Normal
High affinity Hb
Chronic
Inappropriate
Epo secretion
Polycythemia Vera
mYOidiai failure
I
Pso O2
"
Shifted
I
\t
Normal
High affinity Hg Pump failure
Fii"re 2. Algorithm for Evaluation of Elevated Hematocrit
* ~. From Internal Medicine (p. 1317), by Frankel, E. P., 1997, Philadelphia: LippencottRaven. Copyright 1997 by
Lippencott-Raven Publishers. Reprinted with permission.
•
29
Polycythemia Vera
Table I
The DiaiJlostic Criteria for PolYGythemia vera developed by the PolYGythemja Study Group
(PVSG)
Catagory A
Al TRed cell mass
Malt2 36 mIlkg
Catagory B
B 1 Thrombocytosis
Platelet count> 400,000/ mm3
Femalt2 32 mIlkg
A2 Arterial oxygen saturation 2: 92%
B2 Leukocytosis> 12,000/ mm3
(no fever or infection)
A3 Splenomegaly
B3 Leukocyte alkaline phosphatase
score >100
B4 Serum vitamin B 12 > 900pg/ml or
Serum unbound vitamin B 12
binding capacity> 2,200 pg/ml
~
Diagnosis ofPV is confirmed if either combination is present: Al + A2 + A3 or Al + A2 +
any two from category B. From "Diagnosis and Classification of the Polycythemias," by N. 1.
Berlin, 1975, Seminars in HematoloiY. 12 (4), p. 342. Copyright 1975 Grune & Stratton, Inc.
Reprinted with pennission.
•
30
Polycythemia Vera
Table 2.
Clinical and Laboratory Criteria for DiaiUJosis of Polycythemia vera
Criteria
Elevated red blood cell mass of2: 36m11kg for males and 2: 32 m1Ikg for females.
Normal arterial oxygen saturation, 2: 92% in the presence of erythrocytosis as defined in
criterion 1.
Splenomegaly
Thrombocytosis (platelet count of2: 400,0001 mm3 ) and leukocytosis (white blood cell
count of2: 12,0001 mm3 ).
Bone marrow hypercellularity associated with megakaryocytic hyperplasia and absent iron
stores.
Low serum EPO levels «30mU/mI) in the presence of an increased red blood cell mass as
defined in criterion 1.
Abnormal marrow proliferative capacity as manifested by formation of erythroid colonies in
the absence of exogenous EPO.
~ The presence of four of these criteria indicates that the patient's hematologic disorder is
polycythemia vera. From "Polycythemia Vera", by R. Hoffinan and H. S. Boswell, 1995, In
HematolQiY Basic Principles and Practice, (2nd ed. p 1133), edited by R. Hoffinan, M.D., E. 1.
Benz, Jr., M.D., S. 1. Shattil, M.D., B. Furie, M.D., H. 1. Cohen, M.D., Ph.D., L. E. Silberstein,
M.D. New York: Churchill Livingstone. Copyright 1995 by Churchill Livingstone. Reprinted with
permission.
•
31
Polycythemia Vera
Table 3.
'"
Treatment Recommendations by Aie*
Age (yr)
Treatment
> 70
32p + supplemental phlebotomy **
Busulfan, IFN
50-70
Busulfan, IFN
<50
~*
Phlebotomy. Add hydroxyurea if
high phlebotomy requirement
or history ofthrombosis**
Alternative
Phlebotomy. Add hydroxyurea if
high phlebotomy requirement
or history ofthrombosis**
Modified from recommendations ofPVSG. **Goal is to maintain hematocrit at < 45%.
Platelet anti-aggregating agents only for patients with transient ischemic attacks or peripheral
ischemic attacks or peripheral digital ischemia. From "Polycythemia Rubra Vera" by S. Bilgrami
and B. R. Greenberg, 1995, Seminars in Oncoloi)'. 22 (4), p. 319. Copyright 1995 W. B.
Saunders Company. Reprinted with permission.
•
32
Polycythemia Vera
Appendix
Summary of Selected Published Research
on Polycythemia Vera
•
•
•
•
•
33
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments and
Analysis
Ania, Suman &
Sobel (1994)
Olmsted County
residents. Those
with PV who were
part of the final
data set had to have
lived in the county
for at least 1 yr
prior to diagnosis,
meet the diagnostic
criteria for PV as
set by the PVSG,
and be diagnosed
between 1935 and
1989.
Population basedepidemiologic
research.
For incidence rates
the entire county
population was
considered to be at
risk. Sex and agespecific personyears of residence
between 1935-1089
were used as the
denominators. This
was determined
using linear
interpolation from
decennial census
data.
Survival was
calculated
according to the
Kaplan-Meier
product-limit
estimator.
*50 residents met
diagnostic criteria
for PV between
1935-1989.
*Overall age and
sex-adjusted
incidence rate was
found to be 1.9 per
100,000 personyears.
*The incidence rate
showed an increase
between 1970-1989
compared to 19351969 however this
was not statistically
significant.
*Of the 50 cases
62% were males
and 38% were
female.
*The age- adjusted
incidence for men
was more than
*Small number of
cases makes" it
difficult to evaluate
the full range of
adverse outcomes
because the small
incidence of
leukemias and other
myeloproliferative
disorders.
*Epidemiologic
data is difficult to
come by for PV due
to its low incidence
rates.
*These studies
must be performed
in a large isolated
community where
there are few places
to receive medical
care so that all
information can be
obtained and
•
~
•
•
34
Polycythemia Vera
Author & Year
Berk, et al. (1995)
PVSG protocol 01
Sample & Size
Patients diagnosed
with PV within the
past 4 years
between 1967 and
1974. They had to
Design
Prospective
randomized, non
placebo controlled,
after only phase III
clinical evaluation
Measurement of
Variables
First occurrence of
major thrombotic
event, the
development of
acute leukemia or
Key Findings
Comment/
Analysis
twice that for
women (2.8 vs 1.3).
*The median
duration for
survival was 7.2
years. There was no
significant
difference in
survival between
men and women.
*The most common
cause of death was
myocardial
infarction or
ischemic heart
disease.
it is not lost to
other health care
systems.
*As ofJanuary 1,
198750.8% of the
initial randomized
cohort had died
while on the study.
Length of followup and the
prospective design
of this study adds
strength to the data
•
~
~
~
35
Polycythemia Vera
Author & Year
.
Sample & Size
Design
Measurement of
Variables
Key Findings
Comment/
Analysis
meet the PVSG
diagnostic criteria
for PV in order to
be eligible. A total
of 431 patients
were fully eligible.
of three treatment
modalities. Patients
were randomized to
receive phlebotomy
alone, 32p
(2.3mCilm2) with
initial phlebotomy
to achieve normal
hemoglobin:S 45%,
or Chlorambucil
with initial
phlebotomy to
achieve normal
hemoglobin:S 45%.
lymphoma, the
development of a
nonhematologic
malignancy, or
death.
*Median survival
for those receiving
chlorambucil was
9. 1 years, for those
receiving 32p it was
10.9 years, and for
those receiving
phlebotomy it was
12.6 years.
*The most common
cause of death
reported was
thrombosis.
*Thrombosis
occurred more
frequently in the
phlebotomized
patients during the
first three years of
treatment.
* Leukemia and
non hematologic
malignancies
provided in this
study. However,
long term follow-up
was affected in this
study by the
necessity of
stopping the
chlorambucil
treatment arm. The
advantage of long
term follow-up is
that long term
effects can be
evaluated and may
change previous
early
recommendations.
If the study had
only followed
patients for 3 years,
the adverse effects
of chlorambucil
may not have been
seen.
•
•
•
•
36
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
occurred more
frequently in
patients who had
received 32p and
chlorambucil after 5
years of treatment.
*The incidence of
developing acute
leukemia in patients
,
recelvmg
chlorambucil was
found to be
statistically
significant and in
1981 this treatment
arm was
discontinued.
Patients who had
been treated with
chlorambucil were
followed.
*The incidence of
acute leukemia was
increased in
Comments/
Analysis
•
•
•
•
37
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
patients receiving
32p over those
recelvmg
phlebotomy alone
but it was not
statistically
significant.
*Overall survival
was shorter for
those treated with
chlorambucil.
Berk, et at. (1995)
PVSG protocol 05
Patients older than
21 years of age
who had the
diagnosis ofPV.
This diagnosis had
to have been made
in the preceding 4
years. They could
not have received
any other therapy
other than
phlebotomy. In
Prospective
randomized, non
placebo controlled,
after only phase III
clinical evaluation
of two treatment
anns.
Patients were
randomized to
receive phlebotomy
(to maintain their
hematocrit :s
Incidence of
thrombotic
complications and
incidence of major
hemorrhagic
complications
requmng
hospitalization and
transfusion of at
least 2 units of
blood.
*The study was
stopped in April of
1981 due to seven
severe thrombotic
complications on
the phlebotomy,
aspirin and
persantine ann
compared to 2 on
the 32p ann.
*There was also a
significant increase
Although this study
did not show a
reduction in the
incidence of
thrombotic
complications in
patients treated
with this specific
anti-thrombotic
regimen it does not
prove that antithrombotic therapy
does not work.
.
•
•
•
'
38
Polycythemia Vera
Author & Year
Sample & Size
Design
addition, they could
not have any
chronic disorder
requiring long-term
aspirin therapy .
They also could not
be planning to have
additional children.
In addition they had
to meet the PVSG
PV diagnostic
criteria.
178 patients were
enrolled into the
study, 88 were
randomized to
receive
phlebotomy, aspirin
and persantine and
90 were
randomized to
receive 32p.
45%), aspirin 300
mg three times a
day and persantine
75 mg three times a
day, or to receive
2
32p (2.7 mCi!m ) as
often as every 12
weeks.
Measurement of
Variables
Key Findings
Comments!
Analysis
in severe
hemorrhagic
complications in the
phlebotomy,
aspirin and
persantine arm
requmng
hospitalization and
transfusion. There
were not any
hemorrhagic events
in the 32p arm.
*The overall
cumulative failure
rate was eight times
greater in the
phlebotomy, aspirin
and persantine arm
than the 32p arm.
Other studies need
to be under !aken
to further evaluate
an effective
regImen.
•
•
.,
•
39
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
Donovan, et al.
(1984)
PVSG08
All patients who
had been diagnosed
with PV per the
PVSG criteria were
eligible. If they had
been previously
treated, they had to
wait 4 months after
the last treatment
before they could
begin hydroxyurea.
118 patients were
enrolled. 59
patients had
received no prior
myelosuppressive
therapy. The other
59 had been treated
with either 32p and/
or other
myelosuppressive
agents.
Phase III nonrandomized, noncontrolled after
only efficacy
clinical trial evaluating the efficacy
of hydroxyurea in
treating PY.
Patients were
started on
hydroxyurea
30mg/kg/day x 1
week as a loading
dose. It was then
reduced to
15mg/kg/day.
Initial response to
hydroxyurea and
long-term control
ofPV.
Patients were
considered to have
failed treatment if
their hematocrit
was> 50% for
more than 12
weeks, if they
required more than
six phlebotomies in
any consecutive 52
week period or if
they experienced a
major disease
related
complication:
thrombosis,
leukemia, solid
tumor or death or
when a drug
reaction caused the
*Due to the fact
that most patients
had received
phlebotomy prior to
entry into the study,
only 21 patients
\vith an elevated
hematocrit and 26
patients with an
elevated platelet
count could be
evaluated for initial
response.
*Of the 26 patients
with a pretreatment
platelet count of>
1,000,000,65%
had a reduction in
platelet count to <
600,000 in 3 weeks.
88% responded by
12 weeks. *Of the
21 patients with
elevated
*This study did
determine that
hydroxyurea is
effective in creating
an initial decrease
in platelet counts
and/or hemoglobin
levels. The
incidence of acute
leukemias and
thrombosis were
low.
*Due to moderate
and severe
cytopenias the
recommended
dosage was reduced
to 15-20mg/kg/day.
.
.
•
•
40
Polycythemia Vera
Author & Year
.
Sample & Size
Design
Measurement of
Variables
Key Findings
discontinuation of
treatment.
hematocrits, 80%
had normal values
and 51% of the
previously treated
patients remained
controlled on
hydroxyurea.
*Major toxicities
were seen in both
previously treated
and previously
untreated patients.
They included
thrombocytopenia,
leukemia, anemia,
rash, fever, GI
problems and
malaise.
*There were 2
leukemias reported.
One was in the
previously treated
group and the other
in the
Comments/
Allalysis
•
•
•
6
41
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
previously
untreated group.
*Previously
untreated
individuals
experienced
thrombotic events.
*Moderate toxicity
usually was seen in
the first couple of
weeks of therapy.
*It was found that
the treatment must
be administered
continuously in a
regular basis for it
to remain effective.
*The average daily
dosage should be
500-1000mg per
day.
*Iftreatment is
stopped, remission
did not last and a
Comments/
Analysis
.
.
•
•
•
42
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
rebound
thrombocytosis
occurred.
Fruchtman et al.
(1997)
51 patients with PV
who had received
no prior treatment
and who were then
treated with
hydroxyurea were
compared to 134
patients with PV
who were treated
with phlebotomy
alone.
Retrospective
comparison of
patients who were
entered into the
efficacy trial of
hydroxyurea
(PVSG-08) to PV
patients entered
into the phlebotomy
arm ofPVSG-OI
Comparative
incidence of acute
leukemia,
comparative
incidence of spent
phase, comparative
incidence of spent
phase and acute
leukemia and
overall survival.
*5.9% of
hydroxyurea
patients developed
acute leukemia
compared to 1.5%
of the phlebotomy
patients at the same
point in time (795
weeks)
*7.8% of the
hydroxyurea
patients developed
spend phase by 795
weeks compared to
11.2% of
phlebotomy
patients at 795
weeks.
*Combining the
incidence of spent
*The use of
historical controls
may have
compromised the
studies
internal validity.
*This study
indicates that
although there is an
increase in the
incidence of acute
leukemia in the
patients taking
hydroxyurea, the
increase is not
statistically
significant. Overall
survival (though
not statistically
significant)
•
•
•
&
43
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
phase and acute
leukemia over 795
weeks the two
groups were
similar.
*Overall survival
was not statistically
different between
the patients treated
with hydroxyurea
or phlebotomy
(although there is a
trend for improved
survival with the
hydroxyurea
patients due to the
decrease in lifethreatening
thrombosis).
improves when
hydroxyurea. is
used.
.
•
•
•
44
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
Fruchtman et al.
(1997)
Additional longterm update on the
PVSG08 data
compared to a
historical control
51 patients who
were enrolled in
PVSG 08 who had
not received prior
myelosuppressive
therapy prior to
being enrolled into
the trial and had to
received
hydroxyurea. They
were followed for
an additional
maximum 795
weeks.
These patients were
compared with 134
patients who were
assigned to the
phlebotomy arm of
PVSG Oland had
been followed for a
maximum of 795
weeks.
Phase III nonrandomized
controlled after
only efficacy
clinical trial with
results compared to
a historical control
group for PVSG
01.
Comparative
incidence of acute
leukemia,
comparative
incidence of spent
phase, comparative
incidence of spent
phase or acute
leukemia and
overall survival.
*At 795 weeks the
incidence of acute
leukemia in onstudy hydroxyurea
treated patients was
5.9% and in the
phlebotomy alone
patients it was
1.5%. However,
this was not
statistically
significant.
*At 795 weeks,
7.8% of the onstudy hydroxyurea
patients had
developed spent
phase compared to
11.2% of patients
treated with
phlebotomy.
*The incidence of
spent phase and
*In this very long
term analysis of
two patient groups
there appeared to
be no statistical
difference in the
incidence of acute
leukemias, the
development of
spent phase or
difference in overall
survival in patients
treated either with
long term
hydroxyurea or
phlebotomy. This is
likely due to the
natural history of
patients with pv.
*The control arm
which was a
historical group of
patients treated
with phlebotomy is
•
•
•
~
45
Polycythemia Vera
Author & Year
Groupo Italiano
Studio Policitemia
(1995)
.
Sample & Size
1213 patients with
PV from 11 Italian
hematology
institutions.
Design
Retrospective
cohort study of
patients with PV
who had been
followed for 20
years.
Measurement of
Variables
All causes of
mortality. Incidence
of venous and
arterial thrombosis,
hematologic and
nonhematologic
Key Findings
Comments/
Analysis
acute leukemia in
both the
hydroxyurea treated
patients and
phlebotomy treated
patients was very
similar and not
statistically
significant.
*There was not a
statistically
significant
difference in overall
survival between
the two groups.
a criticism of the
study. There also
maybe inherent
differences in the
two groups that
cannot be
accounted for.
*There are newer
agents used to treat
PV such as
interferon that
should be tested
against hydroxyurea
in a randomized
prospective
controlled clinical
trial.
*PV is more
common m men
than women 1.2: 1.
*PV is most
commonly
diagnosed between
The objective of the
study was to
reassess the natural
history ofPV,
gather reliable
estimates of
•
•
•
•
46
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
neoplastic disease
the ages of 50-75.
*14% of patients
had a thrombotic
event before dx and
20% had a
thrombotic event as
the presenting
complaint.
*After diagnosis of
PV, MJ and TIA's
were the most
frequent nonfatal
arterial
complications.
*MJ's accounted for
1/2 of all fatal
thrombotic events.
*The rate of
thrombotic events
increased with age:
for those <40 the
rate was 1.8/ 100
pts/yr; for those
>70 the rate was
incidence of
thrombosis and
survival data to be
used to develop
future clinical trials.
This study provided
data that supports
treating patients
with different
approaches
depending on age
and risk profile. It
re-evaluated current
therapeutic
strategies and
tested new
therapeutic
approaches. This
study provided
concrete
complication and
survival data which
is important in
planning future
•
•
•
•
47
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
5.1/100 pts/yr.
*The cumulative
median survival was
more that 15 years;
this decreased with
increasing age.
*The most frequent
fatal complications
were thrombosis
and cancer.
*Those treated with
myelosuppressive
therapy died of
cancer four times as
often as those
treated with
phlebotomy or
other
pharmacological
treatment.
*The overall risk of
mortality and
nonfatal thrombotic
events was greater
clinical trials to
evaluate therapeutic
approaches to PV.
•
•
&
&
48
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
in those receiving
more aggressive
therapy.
Kaplan, et aI.
(1986)
Update ofPVSG
08
51 patients who
were enrolled in
PVSG 08 who had
not received prior
myelosuppressive
therapy prior to
being enrolled into
the trial. They had
received
hydroxyurea for a
median period of
245 weeks on
PVSG08.
These patients were
compared with 134
patients who were
assigned to the
phlebotomy arm of
PVSGOI
Phase III nonrandomized
controlled after
only efficacy
clinical trial with
results compared to
a historical control
group on PVSG 01.
Patients were
started on
hydroxyurea
30mg/kg/day x 1
week as a loading
dose. It was then
reduced to
15mg/kg/day.
Long-term disease
control as
previously
described in PVSG
08, thrombotic
events, drug
intolerance and
occurrence of acute
leukemia.
Comments/
Analysis
-
*Long-term therapy *The 51 patients
with hydroxyurea
treated with
hydroxyurea and
effectively
controlled the
the 134 patients
hemoglobin and
treated with
platelet count in
phlebotomy alone
patients with PV.
in the historical
*During the first
control group were
389 weeks,
not identically
matched. This is a
thrombotic events
were less in the
big criticism of the
hydroxyurea treated study. There were
group than those
younger females in
managed with
the hydroxyurea
group, the
phlebotomy alone
from PVSG 01
hydroxyurea group
(13.7% vs 38. 1%).
had a stronger
*During the first
history of previous
378 weeks of the
thrombotic events,
there was a
studies, acute
difference in mean
leukemia occurred
•
•
•
6
49
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
in 2 hydroxyurea
patients and in 2
phlebotomized
patients.
lab values in both
groups and the
hydroxyurea group
initially presented
with a higher
platelet count.
Using a historical
control carries the
risk of some
outside influence
affecting the data
which cannot be
accounted for.
However, patients
were diagnosed in
the same way, they
were referred by
and cared for by the
same group of
physicians (PVSG
members) and the
administration of
the studies were
similar.
•
•
•
~
50
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
Landolfi &
Marchioli (1997)
3500 patients with
PV. In these
patients the
risklbenefit ratio of
aspirin therapy was
not clear.
Prospective
Placebo controlled
double blind
randomized clinical
trial to assess the
risklbenefit ratio of
low dose aspirin in
patients with PY.
Patients are
randomized to
either 100mg of
aspirin daily or
placebo. The
endpoints of the
study are all fatal
and nonfatal arterial
and venous
thrombotic events.
Information will be
gathered at baseline
and every 12
months until the
end of the study.
*Pilot study is
completed showing
that low dose
aspirin is well
tolerated and that a
large-scale efficacy
trial is feasible with
this patient
population.
Results of interim
analysis after the
first 2 years of
follow-up have not
been reported as of
yet.
Messinezy,
Westwood,
Woodcock, Strong
& Pearson (1995)
42 adult patients
with PY.
Correlational
Research
Blood was drawn
for serum Epo
estimation.
*A single Serum
Epo estimation
provides a reading
that is below the
lower limit in 64%
of patients with PV.
*If two serum Epo
estimations are
taken on two
Sample size is small
but demonstrated
high specificity and
moderate sensitivity
of this test.
,
•
•
•
6
51
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
different occasions,
72% of the patients
have at least one
result below the
lower limit.
*Comparison
patients with either
secondary polycythemia or idiopathic
erythrocytosis had
serum Epo
estimations and
only 2 patients out
of88 had Epo
levels below the
reference range.
Petitt, Silverstein &
Petrone (1997)
942 patients with
myeloproliferative
thrombocythemia:
546 with essential
thrombocythemia,
113 with PV, 179
with chronic
Prospective,
nonrandomized,
non controlled,
after only clinical
trial evaluating the
effectiveness of
Anagrelide in
Complete response
(CR), reduction in
platelet count to
less than
600,000/~L or to
50% or less of
pretreatment level
*Overall response
rate was 79%.
*Responses varied
according to the
underlying
myeloproliferative
disorder: In PV
Comments/
Analysis
.
Study primarily
summarized the
experience with
Anagrelide in 942
patients with
myeloproliferative
thrombocytopenia.
•
•
•
•
52
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
myelocytic
leukemia, and 108
with other or
undifferentiated
myeloproliferative
disease.
reducing platelet
counts in patients
with
myeloproliferative
thrombocythemia.
for at least 4 weeks~
Partial response
(PR), 20% to 50%
reduction in platelet
count from
pretreatment level
for at least 4 weeks~
or failure to
respond, less than
20% reduction in
platelet count.
there was a 66%
CR, in essential
thrombocythemia
there was a 73%
CR, in chronic
myelocytic
leukemia there was
a 63% CR, other
myeloproliferative
diseases showed a
73%CR
*Adverse events
included headache,
palpitations,
diarrhea and fluid
retention.
Patients were
accrued from a
variety of settings
and the patient's
physicians had
varied experience
with Anagrelide.
Patients whose
physicians had a
great deal of
experience with the
drug did better than
those whose
physicians had little
expenence.
The dose varied
from patient to
patient and
physician to
physician.
However, this is
often what occurs
in the community.
This study
.'
•
•
•
53
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Commentsl
Analysis
provides
information on use
in a variety of
settings with
physicians with a
variety of
experience with
Anagrelide.
Silver (1997)
28 patients with PV
with a median age
of 51 years. There
were 12 men and
16 women. The
median disease
duration for the
group was 36
months before the
start of
interferon. 10 of the
28 patients had
received
hydroxyurea before
the start of
interferon and the
Prospective
nonrandomized,
nonplacebo
controlled, after
only, clinical trial
evaluating the
effects ofrIFN-a in
the treatment of
PV.
*The number of
supplemental
phlebotomies
needed to maintain
the HCT :5 45% in
all patients on
rIFN-a
*The dose and %
dose change needed
at 1 and 2 years.
(All patients
received interferon
therapy and after
reaching a target
dose of 3 MU of
interferon 3x week,
*Striking decrease
in the need for
phlebotomy in both
patient groups
(prior phlebotomy
treatment group
and prior
hydroxyurea
group).
*Doses of
interferon varied for
all patients at the
end of the second
year from 2.4
MU/wk to 31.5
MU/wk with
This study had no
control arm due to
the fact that it
would not be ethical to not treat
patients with PY.
However this study
does not directly
compare treatment
with interferon to
treatment with
hydroxyurea. This
maybe due to the
fact that other
studies have already
demonstrated
•
•
54
Polycythemia Vera
Author & Year
Sample & Size
remaining 18 had
received prior
treatment with
phlebotomy alone.
These groups were
evaluated
separately.
Design
Measurement of
Variables
Key Findings
Commentsl
Allalysis
the doses needed
to control HCT~
45% varied from
patient to patient.)
* Change in platelet
counts at year 1 and
year 2.
*Change in spleen
size at year 1 and
year 2
*Types of toxicity
seen in patients
receiving interferon
was noted.
*Development of
malignancy or
thrombohemorrhagic events.
a median of7.5
MU/wk.
*Platelet counts
decreased in all
patients.
*Spleen size
diminished in all 13
patients who had
initial enlargement.
* No patient
developed any
malignancy or
thrombohemorrhagic event.
*Most toxicities
were influenza type
symptoms. Only 2
patients
discontinued
interferon therapy
due to side effects.
beneficial results
with interferon and
the purpose of this
study is to
demonstrate long
term response to
interferon alone.
This study
evaluates a small
number of patients
and but represents a
study with long
term follow-up of
patients treated
with interferon and
replicates previous
work.
•
•
•
•
55
Polycythemia Vera
Author & Year
Sample & Size
Design.
Measurement of
Variables
Key Findings
Comments/
Analysis
Stasi, et al. (1997)
18 PV patients who
ha a median age of
47 years. There
were 11 men and 7
women. The
median disease
duration before
interferon therapy
was 7.5 months. All
patients had active
disease and
required treatment
with phlebotomy,
cytoreductive
therapy or both.
cytoreductive
treatment had been
discontinued for 2
months and patients
had their HCT
brought to"near
normal" range by
phlebotomy prior to
the start of
Prospective
nonrandomized,
nonplacebo
controlled, after
only, drug
evaluation clinical
trial.
Comparison of
clinical and
hematologic
parameters: HCT
(%), Spleen size
(cm), platelet count
(103/ml),
Leukocytes
(103/ml), Ferritin
(mg/L), MCV (fl)
and Pruritus score.
The number of
phlebotomies
required to maintain
HCT .s45%.
*Although malaise
and flu-like
syndrome was seen
during the early
phase of therapy,
symptoms
responded to
acetaminophen and
these symptoms did
not require
discontinuation or
dose reduction.
*The total response
rate (CR and PR)
was 94.4% (17 out
of 18 patients).
*Phlebotomy
requirement was
reduced from 5.2
during 6 months
prior to interferon
to 1.6 during the
first 6 months of
treatment with
Results of this
study confirm that
interferon is an
effective agent for
controlling
myeloproliferation
in PV. The sample
size is small. Larger
studies with longer
follow-up are
necessary to
determine the
natural history of
patients with PV
who are treated
with interferon
therapy and
whether or not the
incidence of
myelofibrosis or
leukemic
transformation is
altered. Since
placebo control
.
•
•
•
~
56
Polycythemia Vera
Author & Year
Sample & Size
interferon therapy.
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
interferon therapy.
*Splenomegaly
resolved in 6 out of
the 10 patients with
splenomegaly,
57.1% of the
patients achieved a
normal platelet
count and 62.5% of
the patients
achieved a normal
leukocyte count.
*Serum iron and
ferritin
concentrations
increased, MVC
and pruritus
complaints
decreased.
*Two patients
continued their
response after
discontinuation of
treatment. 5
would be unethical, .
a long term study of
patients receiving
interferon cold be
controlled with a
retrospective
matched control
arm of patients who
were treated with
hydroxyurea.
•
•
•
•
57
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
patients could not
tolerate having their
dose reduced.
*During the study
period, no
thrombohemorrahgic
complications or
occurrence of
malignancy was
seen.
Tararsky & Sharon
(1997) Site specific
data on PV 08 from
Rambam Medical
Center in Israel
71 patients who
were treated with
hydroxyurea from
May 1980 to
December 1995.
Some of these
patients began the
hydroxyurea
treatment after the
PVSG closed
accrual to the study
in 1984.
Phase III nonrandomized
controlled, after
only efficacy trial.
The control group
was made up of the
patients who
received
phlebotomy alone
from PVSG 01.
The occurrence of
complications,
thrombotic events,
acute leukemia,
malignant tumors
and incidence of
myelofibrosis.
Survival was not a
measured outcome.
*6 out of71
patients
experienced late
complications
which included leg
ulcers, elevated
creatinine, jaundice,
hypothyroidism and
impotence which
resulted in
discontinuation of
treatment.
*Most patients
were of Ashkenazi
Jewish origin so the
population was
homogeneous for
this ethnic
background. There
may have been
agenetic
predisposition for
PY.
*Myelofibrosis is
•
•
•
•
58
Polycythemia Vera
Author & Year
Sample & Size
They were treated
off study but data
collection occurred
in the same manner
as the study
patients. 33 patients
had received prior
treatment with
phlebotomy. 38
patients were only
treated with
hydroxyurea and
supplemental
phlebotomy.
Design
Measurement of
Variables
Key Findings
Comments/
Analysis
*5 patients
expenence a
thrombotic event
after 6-10 years of
therapy. This was
much less than any
of the arms in
PVSG 01 as well as
patients in PVSG
08.
*4 patients (5.6%)
developed acute
leukemia which was
much less than all
arms ofPVSG 01
as well as patients
in PVSG 08.
*7 patients
developed a
malignant tumor.
*2 patients (2.8%)
progressed to
myelofibrosis after
9 and 13 years of
a late complication
ofPVand i~
expected. A
randomized clinical
trial is needed to
evaluate the
prevention of this
complication.
*The two solid
malignancies
occurred soon after
treatment so it is
unlikely that they
are connected with
the use of
hydroxyurea.
*This study
confirms that
hydroxyurea is an
effective agent in
controlling
complications
associated with PY.
*Long term
,
•
•
~
59
Polycythemia Vera
Author & Year
Sample & Size
Design
Measurement of
Variables
Key Findings
Comments!
Analysis
treatment. When
compared to data in
PVSG 01, the
incidence overall
was much lower in
patients receiving
hydroxyurea.
survival however
was not a variable
that was measured.