Hydrea - still useful

[Guest guest]

Hydrea Trumps Agrylin as Therapy for High Risk Thrombocythemia

By Peggy Peck, Senior Editor, MedPage Today

Reviewed by Zalman <http://www.medpagetoday.com/reviewer.cfm?reviewerid=30>

S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of

Medicine.

July 06, 2005

Review

LONDON, July 6-Hydrea (hydroxyurea) plus aspirin should remain the first

line of treatment for patients with high-risk thrombocythemia, researchers

here reported today.

In the results of an 809-patient comparison trial, published in the July 7

issue of the New England Journal of Medicine, Hydrea plus aspirin emerged as

a clear winner over Agrylin (anagrelide) plus aspirin.

Patients randomized to the newer, more expensive drug Agrylin plus aspirin

had significantly increased rates of arterial thrombosis (P = 0.004),

serious hemorrhage (P = 0.008), and transformation to myelofibrosis (P =

0.006) than patients randomized to Hydrea plus aspirin, according to

N. on, M.D., and colleagues for the United Kingdom Medical Research

Council Primary Thrombocythemia 1 Study.

Moreover, patients randomized to Agrylin were more likely to withdraw from

their assigned group (P <0.001).

However, Agrylin-treated patients had a significantly lower rate of venous

thromboembolism (P = 0.006).

The authors pointed out that Agrylin, which blocks megakaryocyte

differentiation and proliferation and inhibits the action of cyclic AMP

phosphodiesterase, is commonly used as first line therapy for patients with

high risk thrombocythemia, even though there is no evidence to support this

use.

Hydrea is widely used as first-line therapy for high-risk patients, often in

combination with low-dose aspirin, but Agrylin, an imidazoquinazoline

derivative that reduces the platelet count and selectively inhibits

maturation of megakaryocytes, is also extensively used as well.

Nevertheless, clinical studies of Agrylin to treat essential thrombocythemia

have not been randomized and lacked control groups.

Essential thrombocythemia, one of the chronic myeloproliferative disorders,

is a clonal hematologic stem-cell disorder. Patients with this disease have

a life span that nearly rivals that of a healthy population. The principal

causes of death in patients with essential thrombocythemia are thrombosis,

hemorrhage, and progression to myelofibrosis or acute myelogenous leukemia.

Arterial events are more common than venous events. Factors that increase

the risk of thrombosis are an age of more than 60 years, prior thrombosis,

and, to a lesser extent, cardiovascular risk factors.

In an editorial that accompanied the paper, Tiziano Barbui, M.D., and Guido

Finassi, M.D., of Osperdali Riuniti in Bergamo, Italy, wrote that the

British investigators provided ample evidence that Agrylin is not an

appropriate therapeutic choice.

The British team also confirmed that control of platelet count alone is not

a good surrogate to measure the clinical efficacy of a treatment for

thrombocythemia, said the editorialists, because " there was an excess of

vascular events in the [Agrylin] group despite a platelet count that was

similar to the reduction in the [Hydrea] group. "

The study randomized 404 patients at high risk for vascular events to Hydrea

0.5 to 1 g daily or 0.5 mg Agrylin twice daily. Patients were classified as

high risk if they met one or more of the following criteria: age of at least

60 years; platelet counts of 1 million per cubic millimeter; a history of

ischemia, thrombosis, or embolism; hemorrhage caused by essential

thrombocythemia; hypertension requiring therapy; and diabetes requiring the

administration of a hypoglycemic agent. Doses were adjusted to maintain

platelet count at less than 400,000 per cubic millimeter. Patients in

Britain and Ireland also received 75 mg of aspirin daily, while patients in

Australia were given 100 mg aspirin daily.

The primary end point was a composite of arterial or venous thrombosis,

serious hemorrhage, or death from vascular causes.

Among the findings:

* The estimated risk of primary end point at five years was 16% in the

Agrylin arm versus 11% in the Hydrea arm, with an average of 39 months

follow-up.

* Compared with Hydrea treated patients, twice as many Agrylin treated

patients developed arterial thrombosis (OR 2.16; 95% CI 1.27 to 3.69; P =

0.004).

* There were 14 transient ischemic attacks (TIA) in the Agrylin arm

versus one in the Hydrea arm (P <0.001).

* Hemorrhage, especially GI bleeding events, were significantly more

common in the Agrylin arm (OR for hemorrhage 2.61, 95% CI 1.27 to 5.33, P =

0.008).

* The rate of venous thromboembolism was significantly lower in the

Agrylin arm (OR: 0.27, 95% CI 0.11 to 0.71 P = 0.006).

* Compared with Hydrea, patients treated with Agrylin were about three

times more likely to transform to myelofibrosis (OR 2.92), The estimated

five-year risk of myelofibrosis was 2% in the Hydrea group versus 7% in the

Agrylin arm.

* Four patients in the Agrylin group and six in the Hydrea group

developed myelodysplasia or acute myeloid leukemia.

The researchers speculated that the increased hemorrhage rate in the Agrylin

arm may " reflect interference of [Agrylin] with platelet function in a way

that synergizes with low-dose aspirin. "

Recently, an acquired mutation of the JAK2 gene (which activates Janus

kinase 2) was identified in about one half the patients with essential

thrombocythemia. New tyrosine kinase inhibitors are being developed and may

represent therapeutic agents of the future for patients with this condition.