High Risk Essential Thrombocythemia Clinical Trial
Official title:
Single Arm Salvage Therapy With Pegylated Interferon Alfa-2a for Patients With High Risk Polycythemia Vera or High Risk Essential Thrombocythemia Who Are Either Hydroxyurea Resistant or Intolerant or Have Had Abdominal Vein Thrombosis
The aim of this research is to look at two conditions, Essential Thrombocythemia (ET) and
Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets
and PV causes too many platelets and red blood cells to be made. Platelets are particles
which circulate in the blood stream and normally prevent bleeding and bruising. Having too
many platelets in the blood increases the risk of developing blood clots, which can result
in life threatening events like heart attacks and strokes. When the number of red blood
cells is increased in PV this will slow the speed of blood flow in the body and increases
the risk of developing blood clots.
It is important for patients with ET or PV who are at risk of blood clots to receive drugs
which will minimize the risks of developing these blood clots but at the moment the
investigators are not sure which drugs will best control the disorder.
The purpose of this study is to look at the effectiveness of giving patients who have been
diagnosed with ET and PV a study drug regimen using Aspirin and PEGASYS (also known as
Pegylated interferon alfa-2a, instead of the standard treatment drug called Hydroxyurea (or
hydroxycarbamide or Hydroxyurea), for whom this drug may not be suitable. The drug may not
be suitable either because it is not adequately controlling the number of blood cells or
some specific side effects occur.
Myeloproliferative disorders (MPDs) are clonal hematologic diseases characterized by the
excess production of one or more lineages of mature blood cells, a predisposition to
bleeding and thrombotic complications, extramedullary hematopoiesis, and a variable
progression to acute leukemia. The classical Philadelphia chromosome-negative MPDs are
polycythemia vera (PV), characterized by an expansion in red blood cell production;
essential thrombocythemia (ET), characterized by an isolated elevation in the platelet
count; and myelofibrosis, distinguished by a fibrotic bone marrow and peripheral blood
cytopenias, and accompanied by the highest risk of leukemic transformation. Myelofibrosis
can arise de novo, as primary myelofibrosis (PMF), or can evolve out of PV or ET as those
diseases progress (so called post-PV MF and post-ET MF). Amongst the MPDs, those
characterized by myelofibrosis (PMF together with post-PV and post-ET MF) carry the worst
prognosis, with a median survival on the order of 3 to 5 years. Patients typically present
with anemia, often requiring transfusions, symptomatic splenomegaly and severe
constitutional symptoms. Donor stem cell transplantation is the only potentially curative
therapy. To date there is no therapy for myelofibrosis that has been shown to offer a
survival benefit, and all other therapies for myelofibrosis are palliative.
In 2005, a major breakthrough in understanding the pathophysiology of MPDs came when 4
groups described a recurrent somatic mutation in Janus kinase 2 (JAK2) in the majority of
patients with MPDs. The point mutation in JAK2 encodes a valine to phenylalanine change at
position 617 (JAK2 V617F), and confers constitutive tyrosine kinase activity. Introducing
the mutation into the bone marrow of mouse models recapitulates the PV phenotype (complete
with evolution to bone marrow fibrosis) and inhibitors of JAK2 attenuate the growth of cell
lines bearing the mutation in vitro and in vivo, suggesting that JAK2 V617F is a
pathophysiologically relevant therapeutic target. It is estimated that 95% of PV cases carry
JAK2 V617F, while 50 to 60% of ET and PMF cases are JAK2 V617F+. The discovery of the
JAK2V617F mutation in nearly all patients with PV and half those with ET and PMF have
redefined the classification and possibly the management of MPNs.
Despite the discovery of the JAK2V617F mutation, many of the clinical questions in the
management of MPNs remain unanswered. In PV, for example, cardiovascular mortality remains
1.4 to 1.6 times that of the reference normal population with leukemia and myelofibrosis
rates many times increased over baseline. Debate continues over the role of venesection
versus cytoreduction as first-line therapy, and whether hydroxycarbamide (Hydroxyurea) is
associated with better thrombotic prophylaxis and/or a higher rate of leukemic
transformation. Interferons may produce molecular responses in PV patients. In high-risk ET,
while Hydroxyurea and aspirin appear to be more optimal than anagrelide and aspirin,
vascular complications remain the most significant cause of mortality and morbidity,
suggesting that targeting vascular risk factors may be worthwhile.
Furthermore while Hydroxyurea is regarded as the first-choice therapy in most of high risk
patients with ET and PV; up to 10% of the patients do not attain the desired reduction of
platelet number or hematocrit with the recommended dose of the drug, exhibiting clinical
resistance, whereas some will develop unacceptable side effects, demonstrating clinical
intolerance.
Quantitation of the JAK2V617F allele burden provides for the first time the opportunity to
monitor the effect of potential therapeutic agents on the malignant clone in patients with
PV. Great enthusiasm has been expressed for the use of small molecule inhibitors of JAK2 for
the treatment of patients with MPN. Phase 1/2 trials have indicated greater than expected
toxicity, non specificity of action and an inability of these compounds to dramatically
alter the JAK2V617F allele burden. Interferon (rIFN -2b), is a drug that appears to be
non-leukemogenic (contrary to 32P, alkylating agents, and possibly Hydroxyurea), and may
have a preferential activity on the malignant clone in PV, as suggested by cytogenetic
remissions obtained in patients treated with rIFN -2b.
This trial was designed as open-label phase 2 study conducted in two strata of patients with
high risk PV or ET who were intolerant of hydroxyurea. Patients with ET or PV with
Splanchnic Vein Thrombosis (regardless of prior hydroxyurea) are enrolled in separate
strata.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01259856 -
Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)
|
Phase 3 |