A phase II trial of pirfenidone (5-methyl-1-phenyl-2-(ih)-pyridone), a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia

R. A. Mesa, A. Tefferi, M. A. Elliott, H. C. Hoagland, T. Call, G. S. Schroeder

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1 Scopus citations


Background: Myelofibrosis with myeloid metaplasia (MMM) is a clonal myeloid stem cell disorder with no effective standard therapy. Polyclonal fibroblast proliferation and intramedullary stromal reaction is felt to arise from aberrant cytokine (Transforming Growth Factor-Beta (TGF-β), basic Fibroblast Growth Factor (bFGF), Vascular Endothelial Growth Factor (VEGF)) expression of the underlying clone. Pirfenidone (Marnac Inc. Dallas,TX,USA) is a novel antifibrosis agent whose mechanism of action is through antagonizing the effects of the same pro-fibrotic cytokines implicated in the pathogenesis of MMM. Given the mechanism of action of Pirfenidone, and its relative lack of significant toxicity from Phase 1 studies, we conducted a Phase II trial of this agent in MMM. Patients and Methods: 28 patients (pts) ( 12 females, median age 59.6 years (range 36-71)) meeting standard diagnostic criteria for MMM were enrolled in the study. Median interval from diagnosis of MMM to enrollment was 37.4 months (range 1-232). Treatment with pirfenidone was given for 1 year at a dose of 2400 mg/day orally. The primary endpoint of response was improvement in either anemia or organomegaly. In addition, treatment effects on constitutional symptoms and bone marrow histology were monitored. Results: A total of 12 pts completed the full 1 year of treatment with pirfenidone. The remaining 16 received a median of 4.5 months of treatment (range 1.5-9 months). Thirteen pts were withdrawn secondary to disease progression, while three withdrew secondary to drug intolerance. No significant improvement was observed in either marrow cellularity, reticulin fibrosis, megakaryocyte clumping, or osteosclerosis over the course of pirfenidone therapy as evaluated by serial marrow examinations. In addition, serial assessments of marrow angiogenesis, through CD 34 immunohistochemistry, showed no treatment effect on microvessel density. The lack of treatment effect on histologie markers correlated with the overall lack of clinical benefit observed. Only 1 pt experienced a clinically relevant benefit with a >2g/dL improvement in anemia with corresponding improvement in organomegaly after 1 year of therapy. In general the agent was well tolerated: 8 pts experienced minor dyspepsia and three patients experienced diarrhea. Conclusions: In the current pilot study we did not document sufficient evidence of biologic or clinical activity to warrant further trials with Pirfenidone as monotherapy in MMM.

Original languageEnglish (US)
Pages (from-to)268b
Issue number11 PART II
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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