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Treatment policy prepared by

Polycythemia Vera
Dr. Jeannie Callum
Updated May 2003
Introduction
PV is a chronic, clonal, myeloproliferative disorder, classically associated with an increase in red cellmass, leukocytosis, thrombocytosis, splenomegaly, thrombosis and bleeding.
2 in 100 000 incidence with peak age of 60.
20% of patients present with thrombosis and 30% develop in follow-up despite control of disease in along-term follow-up study of 1213 patients over a 20-year period, followed for a median of 6 years [1].
ƒ Thrombosis sites – stroke/TIA > AMI > DVT/PE > Peripheral arterial thrombosis > hepatic /portal vein - Patients < 60 years AND no history of prior thrombosis – 20%/15 years (1%/yr) - Patients > 60 years OR history of thrombosis – 40%/15 years (3%/yr) ƒ Cause of death: 50% related to PV (24% arterial thrombosis, 15% AML, 5% venous thrombosis, 3% major hemorrhage, 2% spent phase complications) ƒ Highest rates of thrombosis = age > 70, history of thrombosis, active disease (> 6
phlebotomies/yr) [2]
ƒ Hepatic and portal vein thrombosis can be the first manifestation of the disease before rise in red ƒ 5% of patients with ET eventually fulfill the criteria for PV [4] Symptoms
(a) Hyperviscosity – headache, dizziness, tinnitus, dyspnea, weakness, chest pain (b) Ruddy skin(c) Hemorrhage(d) Splenomegaly – 66%(e) Cyanotic extremities(f) Aquagenic pruritus(g) Erythromelalgia (esp. with extreme thrombocytosis)(h) Arterial & Venous thrombosis(i) Hypertension(j) Gastric and duodenal erosions and ulcers ƒ Median survival of untreated PV is 18 months ƒ 15% will progress to myelofibrosis at 10 years, with median life-expectancy after the diagnosis of the TSRCC Hematology Site Group Treatment Policies
Definitions [5]
The following criteria are used to make diagnosis of PV:
A Criteria
1. Raised RBC mass (male > 36 ml/kg: females > 32 ml/kg)2. Absence of any secondary cause of erythrocytosis3. Bone marrow biopsy – increased cellularity, enlarged megakaryocytes with hyperploid nuclei or clusters of megakaryocytes, increase reticulin (optional) B Criteria
1. Platelet count > 4002. Granulocytes > 103. Splenomegaly by palpation or ultrasound4. Spontaneous EEC in absence of epo A123 – early PV
A123 + any B – overt PV
A3 + B1 – Essential thrombocythemia

Baseline Investigations
ƒ CBC and blood film
ƒ Ferritin
ƒ Creatinine
ƒ Peripheral blood or BM for PCR for BCR-ABL to exclude CML
ƒ Oxygen saturation
ƒ RBC mass
ƒ Ultrasound abdomen – if spleen not palpable
ƒ BM – Confirmatory marrow histology should be established before embarking on
cytoreductive therapy.
- BM shows hyperplasia of the myeloid, erythroid and megakaryocyte lineages, enlarged megakaryocytes with hyperploid nuclei or clusters of megakaryocytes, increase reticulin - Cytogenetics – 30% have a detectable clonal abnormality; del 20q is the most common Management (Chemotherapy)
Treatment Objectives
1. Longest survival2. Fewest complications of disease – thrombosis, bleeding, and myelofibrosis (MF)3. Fewest complications of treatment – AML, MDS, NHL, other malignancies Goal – HCT > 0.45
Hazardous to aggressively phlebotomize at diagnosis – therefore isovolemic therapy for extreme
erythrocytosis (Hct > 0.60) at diagnosis
Important Studies
1. PVSG-01 RCT – phlebotomy vs. 32-P vs. chlorambucil [6]
ƒ Patients in the phlebotomy alone arm had an unacceptable risk of thrombosis vs. patients on 32-P or chlorambucil had higher rates of AML, NHL, and carcinomas of the GI tract & skin; no differences inthe myelofibrosis rates between the three arms.
ƒ 30% of all deaths were due to thrombosis;1/3 of all thrombotic events were fatal Polycythemia Vera
ƒ A subsequent publication regarding this cohort was published in 1994 [7] - Chlorambucil – 22/42 died due to malignancies - P32 – 60 patients; @ 15 years 78% alive @ 20 years 55% alive (risk of MF 19% at 15 yrs, 53% - Phlebotomy – 56 patients; only 37/56 still on phlebotomy alone at 3 yrs due to intolerance/thrombosis/thrombocytosis; at 9 yrs only 7/56 on phlebotomy alone (6 of 7 have MF) 2. PVSG-05 RCT – phlebotomy + 900 mg/d ASA + persantine 225 mg/d vs. 32-P – addition of
antithrombotic agents failed to protect patients from thrombosis and increased the rate of life-
threatening hemorrhage (20% vs. 5% at 2 yrs) [8]

3. PVSG-08 Cohort Study [9] – 51 patients with PV treated with hydroxyurea; in 80% Hct was
controlled by 12 weeks and 88% control of thrombocytosis by 12 weeks, followed for 12 years
(range 9-15 yrs), average dose 500-1000 mg/d

ƒ PVSG-08 compared to PVSG-01 (phlebotomy arm) – patients in the PVSG-08 cohort had a higher rate of previous thrombosis (35% vs. 14%); reduced thrombosis rate in HU group with 8 years of f/ufrom 38% to 13%; trend toward an increased AML/MDS rate in HU arm (5.9% vs.1.5%) 4. Interferon Studies (three published studies):
ƒ 54 patients treated with IFN mIU/d until response then 2.5 mIU/d – at 4 yrs, 72% maintained response even after drug stopped (median follow-up 39 weeks); 13 % had to stop due to adverseeffects [10] ƒ 38 patients with PV 9 mIU/wk – 30% CR; 25% flu like symptoms, 13% had to stop due to late ƒ 32 patients with PV – 12 mU/wk x 1 yr, 9 mU/wk x 1 yr, then 12 mU/wk thereafter – reduced thrombosis (1.8%/yr vs. 3.6% before treatment); reduced frequency of phlebotomy (0.49/month to0.19/month) [12] 5. Patients age > 65 [13] – study by the French PSG randomized patients to HU (10 mg/kg/d) or
no HU after clinical remission induced by P-32 in 461 patients
ƒ OAS – trend toward a reduction in those patients on HU (9.1 vs. 11.2 years) vs. 11.4 for age matched ƒ No difference in thrombosis rate (25% at 10 years)ƒ Greater risk of MDS/AML after 10 years in the HU arm (21% vs. 14%)ƒ No reduction in myelofibrosis – 30% at 15 years 6. Patients age < 65 [14] – n = 292 patients, randomized to HU (25 mg/kg then 10 mg/kg) vs.
pipobroman (1.2 mg/kg then 0.5 mg/kg)
ƒ No difference in thrombosis rate (15% at 10 yrs), AML rate 20% at 15 yrs, or survivalƒ Better hematologic control with pipobroman and less MF with pipobroman (40 vs. 17% at 15 years)ƒ Higher mortality than age matched controlsƒ Drug not available in Canada or USA 7. Anagrelide [15] – n = 113 patients with PV; 70% response rate (plt < 600); average dose 2.4
mg/d; time to response 20 days; adverse: headache 25%, palpitations 15%, diarrhea 25%, fluid
retention 15%, intolerance rate 13%; rate of bleeding/thrombocytopenia was 9/942 patients
(1%)

ƒ Insufficient data on the impact of anagrelide on thrombosis rate in PV TSRCC Hematology Site Group Treatment Policies
TSRCC Policy
< 70 YRS
> 70 yrs
1. Hydroxyurea 15 mg/kg starting dose; increase by 5 mg/kg q6 wks as needed to maintain hematocrit < 2. Interferon 3 mU sc qMWF; commence at 1 mU sc qMWF and titrate up to 3 mU sc qMWF over 1 month; increase dose if required q8wks; maximum dose 5 mU/M2/d 3. Phlebotomy – start qwk until Hct < 0.45; then as needed4. Anagrelide 0.5 mg po qid; can titrate up to a maximum of 1.0 mg po qid; (Patients with renal and hepatic dysfunction should be closely monitored during the start of therapy) Perioperative Management
ƒ Patients should have good hematologic control of disease, if possible, for 6 weeks preopƒ Bleeding time is not accurate in identifying patient at risk of perioperative bleeding [16]ƒ Preop ensure DIC work-up is negative (D-Dimers/Fibrinogen) – patients with evidence of DIC have a higher incidence of perioperative bleeding. If possible surgery should be delayed until evidence ofDIC resolves. DIC may be responsive to hydroxyurea.
Anticoagulants/Antiplatelet Agents
ƒ GISP Trial – Low dose ASA has been shown to be safe at 40 mg/d in safety trial of 112 patients compared to placebo; no difference in thrombosis rate at 1 year follow-up [17] ƒ Efficacy of low dose ASA un-proven – ongoing European ECLAP trial (dose 40 mg/d)ƒ High dose ASA – see PVSG-05 above, not useful Recommendation:
ƒ Venous thrombosis – warfarin for 3 months minimum, may consider stopping warfarin once Hct controlled; consider hypercoagulable assessment ƒ Arterial thrombosis or ischemic heart disease – ASA 40-80 mg/d; rule out other causes of stroke (perform dopplers or echocardiogram as needed) Management of the Spent Phase
ƒ TRANSFUSIONS – no manipulation of cellular products required (i.e. irradiation or CMV-negative
ƒ SPLENOMEGALY – therapeutic options include – IFN, Hydroxyurea; splenectomy may result in an
increased risk of AL transformation (Although not confirmed by all investigators); splenic irradiation(200-300 cGy in 10-15 daily fractions) usually results in only temporary benefit (3-6 months) and maypreclude future splenectomy due to scarring ƒ EXTRAMEDULLARY HEMATOPOEISIS (spinal cord, peritoneal or pleural cavities) – radiation
Polycythemia Vera
Outcome Data
(Managed with phlebotomy and/or hydrea; estimates based on all the reported studies referred below) 10 yrs (%)
15 yrs (%)
Thromboembolism
Myelofibrosis
Acute Leukemia
AML with HU tx
Monitoring
ƒ Hydroxyurea – q2wkly blood counts x 8 weeks then q8 weeksƒ Interferon –q2wkly blood counts x 8 weeks then q8 weeksƒ Anagrelide – q2wks blood counts x 6 weeks then q8 weeksƒ Phlebotomy alone – hematocrit q8 weeks References
Polycythemia vera: the natural history of 1213 patients followed for 20 years. Gruppo Italiano
Studio Policitemia.
Ann Intern Med, 1995. 123(9): p. 656-64.
Berk, P.D., et al., Therapeutic recommendations in polycythemia vera based on Polycythemia
Vera Study Group protocols.
Semin Hematol, 1986. 23(2): p. 132-43.
Valla, D., et al., Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective
study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome.
Ann Intern
Med, 1985. 103(3): p. 329-34.
Murphy, S., et al., Experience of the Polycythemia Vera Study Group with essential
thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by
treatment.
Semin Hematol, 1997. 34(1): p. 29-39.
Michiels, J.J. and E. Juvonen, Proposal for revised diagnostic criteria of essential
thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group.
Semin
Thromb Hemost, 1997. 23(4): p. 339-47.
Berk, P., et al., Treatment of polycythemia vera: a summary of clinical trials conducted by thePolycythemia Vera Study Group, in Wasserman LR, et al. (eds): Polycythemia vera and themyeloproliferative disorders. 1995, Saunders: Philadelphia, PA. p. 166-194.
Najean, Y. and J.D. Rain, The very long-term evolution of polycythemia vera: an analysis of 318
patients initially treated by phlebotomy or 32P between 1969 and 1981.
Semin Hematol, 1997.
34(1): p. 6-16.
Tartaglia, A., et al., Aspirin and persantine do not prevent thrombotic complications in patients
with polycythemia vera treated with phlebotomy.
Blood, 1981. 58(suppl 1, abstract 872): p. 240a.
Donovan, P.B., et al., Treatment of polycythemia vera with hydroxyurea. Am J Hematol, 1984.
17(4): p. 329-34.
Gilbert, H.S., Long term treatment of myeloproliferative disease with interferon-alpha- 2b:
feasibility and efficacy.
Cancer, 1998. 83(6): p. 1205-13.
Foa, P., et al., Long-term therapeutic efficacy and toxicity of recombinant interferon- alpha 2a in
polycythaemia vera.
Eur J Haematol, 1998. 60(5): p. 273-7.
Heis, N., et al., The effect of interferon alpha on myeloproliferation and vascular complications in
polycythemia vera.
Eur J Haematol, 1999. 62(1): p. 27-31.
Najean, Y. and J.D. Rain, Treatment of polycythemia vera: use of 32P alone or in combination
with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. The
French Polycythemia Study Group.
Blood, 1997. 89(7): p. 2319-27.
Najean, Y. and J.D. Rain, Treatment of polycythemia vera: the use of hydroxyurea and
pipobroman in 292 patients under the age of 65 years.
Blood, 1997. 90(9): p. 3370-7.
Petitt, R.M., M.N. Silverstein, and M.E. Petrone, Anagrelide for control of thrombocythemia in
polycythemia and other myeloproliferative disorders.
Semin Hematol, 1997. 34(1): p. 51-4.
Murphy, S., et al., Template bleeding time and clinical hemorrhage in myeloproliferative disease.
Arch Intern Med, 1978. 138(8): p. 1251-3.
Low-dose aspirin in polycythaemia vera: a pilot study. Gruppo Italiano Studio Policitemia (GISP).
Br J Haematol, 1997. 97(2): p. 453-6.
TSRCC Hematology Site Group Treatment Policies

Source: http://www.toledoxray.com/sec/Guides/Nuclear/Polycythemia%20Vera%20Tx.pdf

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