Polycythemia Vera

OVERVIEW

Polycythemia vera (PV) is a trilineage, Philadelphia chromosome–negative myeloproliferative neoplasm (MPN) characterized by chronic, unregulated proliferation of erythrocytes along with leukocytes and/or platelets without significant bone marrow fibrosis.1,2

Erythrocytosis (elevated total red cell mass) is the most prominent clinical expression of PV, and it distinguishes PV from all other MPNs, including essential thrombocythemia (ET) and primary myelofibrosis (MF).1,3,4

PV affects all 3 hematopoietic cell lines4 PV is the most common phenotypic consequence of JAK2V617F mutation images of Cell lineages involved - MPNConnect.com

Overactive JAK signaling plays a key role in the pathophysiology of PV.5,6 The JAK2 mutation V617F (or JAK2V617F) is a diagnostic feature of PV and is present in >95% of cases.4

PV affects about 100,000 people in the United States and occurs mostly in older people, with a median age of diagnosis of approximately 60 years.7-9 PV may be slightly more prevalent in men.8

Maintaining hematocrit (Hct) levels of <45% and controlling the clinical signs and symptoms of PV, including splenomegaly, are important clinical considerations in PV management.7,10 Clinical studies have shown, however, that more than 1 in 4 patients with PV had Hct levels ≥45% even with standard treatment that includes phlebotomy and hydroxyurea.11-13 In these patients, and those who continued to experience clinical signs and symptoms such as fatigue, pruritus, night sweats or splenomegaly, PV remained uncontrolled.

Overactive JAK signaling plays a key role in the pathophysiology of PV.5,6 The JAK2 mutation V617F (or JAK2V617F) is a diagnostic feature of PV and is present in >95% of cases.4

PV affects about 100,000 people in the United States and occurs mostly in older people, with a median age of diagnosis of approximately 60 years.7-9 PV may be slightly more prevalent in men.8

Maintaining hematocrit (Hct) levels of <45% and controlling the clinical signs and symptoms of PV, including splenomegaly, are important clinical considerations in PV management.7,10 Clinical studies have shown, however, that more than 1 in 4 patients with PV had Hct levels ≥45% even with standard treatment that includes phlebotomy and hydroxyurea.11-13 In these patients, and those who continued to experience clinical signs and symptoms such as fatigue, pruritus, night sweats or splenomegaly, PV remained uncontrolled.

Diagnosis

The presence of the JAK2V617F mutation and increased hemoglobin (Hb) are major diagnostic criteria, according to World Health Organization (WHO) guidelines.14

Diagnosis of PV requires either both major criteria and 1 minor criterion or the first major criterion and 2 minor criteria14:

Signs and Symptoms

SYMPTOMS OF POLYCYTHEMIA VERA

Although patients with PV may be asymptomatic for many years, the disease is associated with substantial symptom burden. Patients have assessed the following symptoms to be most severe15:

  • Fatigue
  • Concentration problems
  • Early satiety
  • Pruritus
  • Night sweats

The signs and symptoms of PV may be similar to those of other myeloproliferative neoplasms. Consider the following tool to assess the symptoms your patients may be experiencing:

Fatigue, pruritus, and splenomegaly are among the most frequent signs and symptoms of PV at presentation

  • PV is associated with significant symptom burden
    • – Fatigue is the most common and intense symptom reported15-17
    • – Intractable pruritus can be debilitating7
  • Splenomegaly occurs in 30%-40% of patients7

The following graph shows the most common signs and symptoms of PV (self-reported results of an Internet-based survey of 405 patients with PV).7

Chart of symptoms of PV- Fatique,pruritus, and splenomegaly are frequent signs and symptoms of PV presentation- MPNConnect.com

Risk

TRADITIONAL CONSIDERATIONS WHEN ASSESSING RISK

Recommendations for the management of polycythemia vera are aimed at lowering the risk of thrombosis.18

Age at diagnosis (>60 years) and history of thrombosis are important, traditional prognostic risk factors when evaluating patient risk for thrombosis.18

Other risk factors include comorbid cardiovascular disease, including arterial hypertension, hypercholesterolemia, diabetes mellitus, and smoking.12,18,19

CLINICAL CONSIDERATIONS

CLINICAL NEED IN POLYCYTHEMIA VERA

Goals that drive clinical decision-making for PV include18,20,21:

  • Maintaining an Hct level of <45%
  • Managing the complications of thrombosis and hemorrhage
  • Controlling leukocyte and platelet counts
  • Managing disease-related symptoms and splenomegaly
  • Lowering the risk of thrombotic events without increasing the risk of leukemic transformation

Phlebotomy is usually the starting point of treatment in patients with PV, in addition to therapy with low-dose aspirin.11,18 Low-dose aspirin has been shown to prevent thrombotic complications in patients with PV.22

Cytoreductive therapy with hydroxyurea (HU) or interferon-alpha may also be helpful in patients who have difficulty with phlebotomy, who have symptomatic or progressive splenomegaly, or who experience severe disease-related symptoms.18

MORE THAN 1 IN 4 POLYCYTHEMIA VERA PATIENTS HAS UNCONTROLLED DISEASE (HCT ≥45%) WITH TREATMENT11-13

In two prospective clinical studies totaling more than 2,000 patients with PV, hematocrit levels remained elevated in more than 25% despite treatment with standard therapies such as phlebotomy and HU.11-13

In these patients, and those who continued to experience clinical signs and symptoms such as fatigue, pruritus, night sweats or splenomegaly, PV remained uncontrolled.

Although HU may be tolerated by most patients in clinical studies, approximately 25% of patients with PV developed HU resistance or intolerance.20

  • Baseline characteristics were balanced between both groups
  • ≈50% had received an initial diagnosis of PV within 2 years before randomization
  • 67.1% were at high risk because of advanced age or previous thrombosis
  • The composite primary end point was the time until cardiovascular death or major thrombotic events
  • Therapy options for maintaining Hct levels were phlebotomy, cytoreductive drugs, or both

The study revealed that maintenance of Hct level <45% was associated with a significantly lower rate of cardiovascular death or major thrombotic events.11

PROGNOSIS AND SURVIVAL

Rate of cardiovascular death or major thrombotic events was 4-fold higher with Hct level of 45% to 50% compared with Hct level <45%11

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HYDROXYUREA RESISTANCE

In two prospective clinical studies totaling more than 2,000 patients with PV, hematocrit levels remained elevated in more than 25% despite treatment with standard therapies such as phlebotomy and hydroxyurea (HU).11-13

In these patients, and those who continued to experience clinical signs and symptoms such as fatigue, pruritus, night sweats or splenomegaly, PV remained uncontrolled.

EVALUATING THE IMPACT OF HU RESISTANCE

HU resistance has emerged as an adverse prognostic factor for survival and disease progression in PV.

In a retrospective chart review of 261 patients with PV, at a median follow-up of 7.2 years, 13% developed intolerance and 11% developed resistance to HU.20

Resistance to HU was associated with a 5.6 fold increase in the risk for death and a 6.8-fold increase in the risk for hematologic transformation.20

PATIENT ASSESSMENT

When assessing patients, consider the ELN response criteria21:

Questions to keep in mind when assessing response to therapy in PV:

Other considerations when treating with HU include18,23:

Questions to keep in mind when assessing tolerance to therapy in PV:

PATIENT ASSESSMENT

When assessing patients, consider the ELN response criteria21:

Questions to keep in mind when assessing response to therapy in PV:

Other considerations when treating with HU include18,23:

Questions to keep in mind when assessing tolerance to therapy in PV:

References

  1. Spivak JL. Blood. 2002;100:4272-4290.
  2. Spivak JL, et al. Hematology Am Soc Hematol Educ Program. 2003:200-204.
  3. Tefferi A. Am J Hematol. 2013;88:507-516.
  4. Spivak JL. Ann Intern Med. 2010;152:300-306.
  5. Rampal R, Al-Shahrour F, Abdel-Wahab O. Blood. 2014;123(22):e123-133.
  6. Keohane C, Radia D, Harrison C. Biologics. 2013;7:189-198.
  7. Passamonti F. Blood. 2012;120:275-284.
  8. Stuart BJ, Viera AJ. Am Fam Physician. 2004;69:2139-2144.
  9. Data on file. Incyte Corporation. Wilmington, DE.
  10. Finazzi G, Barbui T. Blood. 2007;109:5104-5111.
  11. Marchioli R, Finazzi G, Specchia G, et al; for the CYTO-PV Collaborative Group. N Engl J Med. 2013;368:22-33.
  12. Marchioli R, Finazzi G, Landolfi R, et al. J Clin Oncol. 2005;23:2224-2232.
  13. Di Nisio M, Barbui T, Di Gennaro LD, et al. Br J Haematol. 2006;136:249-259.
  14. Tefferi A, et al. Leukemia. 2008;22(1):14-22.
  15. Emanuel RM, Dueck AC, Geyer HL, et al. J Clin Oncol. 2012;30:4098-4103.
  16. Mesa RA, Niblack J, Wadleigh M, et al. Cancer. 2007;109:68-76.
  17. Johansson P, Mesa R, Scherber R, et al. Leuk Lymphoma. 2012;53:441-444.
  18. Barbui T, Barosi G, Birgegard G, et al. J Clin Oncol. 2011;29:761-770.
  19. Falanga A, Marchetti M. Hematology Am Soc Hematol Educ Program. 2012;2012:571-581.
  20. Alvarez-Larrán A, Pereira A, Cervantes F, et al. Blood. 2012;119:1363-1369.
  1. Barosi G, Mesa R, Finazzi G, et al. Blood. 2013;121:4778-4781.
  2. Landolfi R, Marchioli R, Kutti J, et al; for the European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. N Engl J Med. 2004;350:114-124.
  3. Barosi G, et al. Br J Haematol. 2009;148(6):961-963.