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A Large-scale Trial Testing the Intensity of CYTOreductive Therapy to Prevent Cardiovascular Events In Patients With Polycythemia Vera (PV)

Phase 3
18 Years
Not Enrolling
Polycythemia Vera

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Trial Information

A Large-scale Trial Testing the Intensity of CYTOreductive Therapy to Prevent Cardiovascular Events In Patients With Polycythemia Vera (PV)

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by clonal
proliferation of hematopoietic progenitors resulting in expansion of the erythrocyte mass,
and its clinical course is affected by cardiovascular events, the main cause of morbidity
and mortality. Arterial thrombotic events are predominant, particularly large vessel
arterial events including cerebrovascular accidents, myocardial infarction, and peripheral
arterial occlusion. Based on the complex relationship between thrombosis, hematocrit, and
parameters of tissue perfusion and blood viscosity, the latter has been proved to be an
exponential function of the hematocrit. Red cell aggregation increases at high hematocrit
(HCT) levels, creating the potential for vascular stasis. As a result, enhanced interplay
between platelet, leukocytes and vessel wall increases the risk of thrombosis.

Considering the lack of effective therapeutic strategy targeted at the mutated allele
JAK2V617F, there is no known treatment that eradicates the abnormal clone, apart from
anecdotal cases of bone marrow transplantation. Cytoreductive treatment by phlebotomy or
chemotherapy, however, has dramatically reduced the number of thrombotic complications and
substantially improved survival and today there is agreement that the goal of cytoreductive
treatment should be to keep the HCT value below 0.45 in all PV patients.

This was suggested on the basis of a small, retrospective study of PV that more than 30
years ago showed a progressive increase in the incidence of vascular occlusive episodes at
HCT levels higher than 44% and in patients treated according to the drugs and the
therapeutic tenets of the time. However no clinical trial has confirmed such findings. The
results of the two largest prospective studies currently available (namely PVSG-1 and ECLAP)
suggest no difference in the risk of thrombosis among patients kept at HCT below 50%.

An association between relevant outcome events (namely. thrombotic events, mortality, and
haematological progression) and HCT in the evaluable range of 40-55% was found in the ECLAP
population neither in the multivariate analysis at baseline nor in the time-dependent
multivariate analysis. The ECLAP trial demonstrated the antithrombotic efficacy of low-dose
aspirin in this setting and the use of this therapy in clinical practice is likely to
decrease meaningfully, though not eliminate, the high risk of thrombosis of PV patients.

In conclusion, the high incidence of thrombotic events irrespective of low-dose aspirin
administration as well as of haematological transformation in the long term which have been
shown in PV patients study suggest the need to investigate in depth the benefit/risk profile
of current therapeutic options for cytoreductive therapy. CYTO-PV is aimed at assessing the
benefit risk profile of cytoreductive therapy with phlebotomy and/or HU aimed at maintaining
HCT < 45% Vs. maintaining HCT in the range 45-50%. It is an independent,
investigator-generated pragmatic trial with broad selection criteria to mimic clinical
practice in order to strengthen the transferability of its results to the population of PV
patients; it has been designed to be conducted, without need of special facilities, in the
framework of the Italian Group of hematologic Adult diseases ("GIMEMA"). The optimization of
therapeutic management of PV patients will allow to improve the prognosis of PV patients,
the allocation of the resources the Italian National Health Service (IHS), and the knowledge
about the benefit/risk profile of pharmacological cytoreduction in PV

Inclusion Criteria:

Males and females aged 18 years or more are eligible for the study if they meet all the
following inclusion criteria:

- New diagnosis of PV according to WHO 2007 diagnostic criteria including Jak 2 V617F
mutation status;

- Old diagnosis of PV confirmed with JAK-2 positivity and clinical course of the

- Ability and willingness to comply with all study requirements;

- Written informed consent (obtained before any study specific procedure).

Exclusion Criteria:

- Pregnant or lactating women or women of childbearing potential who are not protected
from pregnancy by an accepted method of contraception;

- Known hypersensitivity or contraindication to study treatments;

- Significant liver (AST or ALT > 2.5 times ULN) or renal disease (creatinine > 2

- Presence of any life-threatening condition or of any disease (e.g. cancer) that is
likely to significantly shorten life expectancy;

- History of active substance or alcohol abuse within the last year;

- Any condition that in the opinion of the investigator would jeopardize the evaluation
of efficacy or safety or be associated with poor adherence to the protocol - Baseline
and FUP visits schedule and assessments

- Logistic problem related to the patient.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Reduction of PEP (Primary End Point)defined as CV deaths plus thrombotic events

Outcome Description:

To demonstrate that in patients with PV treatment with aggressive cytoreductive therapy aimed at maintaining HCT < 45% is more effective than cytoreductive therapy aimed at maintaining HCT between 45 and 50% in the reduction CV deaths plus thrombotic events (PEP: stroke, acute coronary syndrome [ACS], transient ischemic attack [TIA], pulmonary embolism [PE], abdominal thrombosis, deep vein thrombosis [DVT], and peripheral arterial thrombosis). The minimum clinically relevant beneficial effect is set at a 30% reduction of risk of the PEP.

Outcome Time Frame:

Expected average of 5 years

Safety Issue:


Principal Investigator

Tiziano Barbui, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Ospedali Riuniti di Bergamo


Italy: The Italian Medicines Agency

Study ID:




Start Date:

May 2008

Completion Date:

July 2012

Related Keywords:

  • Polycythemia Vera
  • Polycythemia
  • Hematocrit
  • Thrombosis
  • Polycythemia
  • Polycythemia Vera