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27-09-2011 | Immunology | Article

Myelofibrosis detected in most treated ITP patients


Free abstract

MedWire News: The majority of patients with long-standing immune thrombocytopenia (ITP) treated with thrombopoietin receptor agonists (Tpo-RA) will develop myelofibrosis (MF), research shows.

But the team says there was "no clear evidence of continued progression with sustained exposure," and raise the possibility that Tpo-RA agents may actually "halt the progression of BM fibrosis" in some patients.

Waleed Ghanima (Weill Cornell Medical College, New York) and co-investigators write in the British Journal of Haematology: "BM fibrosis has only been reported in a small number of patients treated with Tpo-RA, but its frequency, the extent of BM fibrosis, its clinical significance, and its reversibility is unknown at this time."

To investigate further, the team analyzed BM biopsies from 25 ITP patients treated with Tpo-RA for reticulin using a standard grading system. Reticulin is a scleroprotein fibril consisting mostly of type III collagen that has a role in maintaining the structural integrity of organs.

Comparison of eight BM biopsies taken before initiation of Tpo-RA treatment and during treatment revealed statistically significant increases in the level of reticulin following Tpo-RA treatment.

After a median 1.4 years of Tpo-RA treatment, the team graded reticulin levels as MF-O (normal BM) in 12% of patients and MF-1 (loose reticulin network with many intersections especially in perivascular areas) in 76%.

Eight percent of samples were graded as MF-2 (diffuse, dense increase in reticulin with extensive intersections, may have only focal bundles of collagen and/or focal osteosclerosis), while 4% were graded as MF-3 (diffuse, dense reticulin with extensive intersections, coarse bundles of collagen, often showing significant osteosclerosis).

There was no evidence of cytogenetic or flow-cytometric abnormalities in any patient.

Of note, the presence of procollagen III N-propeptide (PIIINP) - a marker for collagen fibril formation - was significantly reduced after initiation of Tpo-RA treatment.

Specifically, median pre-treatment levels were significantly higher than those detected during treatment, at 6.6 versus 5.6 µg/l. Levels of PIIINP in ITP patients both before and during Tpo-RA treatment were significantly higher those detected in controls (3.4 µg/l).

Assessment of changes in growth factors during Tpo-RA treatment showed that levels of transforming growth factor (GF)-beta and basic-fibroblast GF were similar in patients and controls, while levels of hepatocyte growth factor (HGF) increased.

Ghanima et al suggest: "The apparent deceleration of reticulin production with Tpo-RA treatment may partially be related to HGF, a cytokine with well-documented anti-fibrotic properties."

They conclude: "Although these data seem reassuring, longer-term studies are needed to elucidate the risk of late progression of BM fibrosis and malignant transformation.

"Such studies are currently under way."

By Josephine McCoan

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