• pirfenidone;
  • myelofibrosis with myeloid metaplasia;
  • stem cells;
  • erythropoiesis;
  • cytokines


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results and discussion
  5. References

The anti-fibrotic and cytokine modulatory properties of pirfenidone suggest its usefulness in the treatment of myelofibrosis with myeloid metaplasia (MMM). In a prospective study, 28 patients with MMM were treated with oral pirfenidone. Twelve patients completed 1 year of therapy; 13 were withdrawn because of disease progression and three because of drug intolerance. Only one patient experienced a clinically relevant benefit with respect to anaemia and splenomegaly. The overall lack of clinical benefit correlated with no significant improvement in the bone marrow morphological features of the disease. We conclude that pirfenidone has no significant clinical or biological activity in MMM.

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloid stem cell disorder characterized by a marked stromal proliferation that results in deposition of extracellular matrix proteins, osteosclerosis and increases in marrow vascularity (Mesa et al, 2000). Clinically, patients with MMM suffer from ineffective erythropoiesis, significant extramedullary haematopoiesis, splenomegaly and premature death (Tefferi, 2000). Currently, there is no widely applicable therapy shown to improve survival in MMM.

The prominent marrow stromal reaction and ineffective erythropoiesis seen in MMM have been associated with increased marrow expression of profibrogenic and proangiogenic cytokines, including transforming growth factor beta (TGF-β) (Martyre et al, 1994), platelet-derived growth factor (PDGF) (Martyre et al, 1991), and tumour necrosis factor alpha (TNF-α) (Kanfer et al, 1993). Therapy targeted at implicated pathogenetic pathways is a rational basis for therapeutic trials in MMM. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) (Marnac, Dallas, TX, USA) is a novel anti-fibrosing drug shown to inhibit the very same cytokines implicated in the pathogenesis of MMM: PDGF (Gurujeyalakshmi et al, 1999), TNF-α (Cain et al, 1998) and TGF-β (Iyer et al, 1999). In addition, in vitro investigation suggests that pirfenidone also inhibits the fibrotic process through inhibition of fibroblast proliferation and deposition of extracellular matrix proteins (Kaneko et al, 1998). Clinically, in humans, pirfenidone has been demonstrated to be well tolerated and to have activity in idiopathic pulmonary fibrosis (Raghu et al, 1999). The mechanism of action of pirfenidone strongly suggested the potential for biological activity of this drug in MMM.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results and discussion
  5. References

We initiated a phase II study of oral pirfenidone therapy in patients with MMM after approval of the protocol by the Mayo Clinic Institutional Review Board. Persons enrolled were required to meet standard diagnostic criteria for MMM (Barosi et al, 1999). Patients with all subtypes of MMM (agnogenic, post-polycythaemic and post-thrombocythaemic forms of myeloid metaplasia) were eligible. In addition, patients were required to have either anaemia (haemoglobin < 10 g/dl) or palpable splenomegaly as a manifestation of their disease. Prior therapy of another kind was not a reason for ineligibility as long as it was discontinued at least 4 weeks before enrolment. Pirfenidone was administered at a dose of 2400 mg/d orally (one 800 mg tablet three times/d) for a goal duration of 1 year. Laboratory and physical examinations were performed in a frequent and structured manner to assess response and toxicity. Serial bone marrow morphological examinations were performed at registration and at 6 month intervals by two of the authors to assess any changes in cellularity, reticulin fibrosis (grades 1–4) and osteosclerosis (grades 0–2). Treatment effect on marrow microvessel density was assessed according to previously described methods (Mesa et al, 2000). Primary end-points of response were improvements in anaemia and organomegaly (spleen or liver); secondary end-points were improvements in the bone marrow morphological manifestations of the disease.

Results and discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results and discussion
  5. References

Patient characteristics at registration are summarized in Table I. Twenty-eight patients with MMM were enrolled in the study. Overall, 18 patients (64·3%) and 12 patients (42·9%) could be evaluated after 6 and 12 months of pirfenidone therapy respectively. The 16 who were withdrawn prematurely from the study had received a median of 4·5 months of treatment (range 1·5–9 months). Thirteen patients were withdrawn because of disease progression: progressive anaemia in seven cases, progressive organomegaly in four patients, congestive heart failure in one case and progressive constitutional symptoms in one patient. Three patients withdrew as a result of drug intolerance: gastrointestinal distress, neuropathy and rash in one patient each. However, overall the drug was well tolerated, with eight patients experiencing mild nausea (ameliorated by taking the drug with food) and three having mild diarrhoea. No significant differences were seen in disease characteristics at registration between patients who completed the trial and those who were withdrawn.

Table I.   Characteristics of 28 patients with myelofibrosis with myeloid metaplasia at registration.
  1. *Dupriez prognostic score (Dupriez et al, 1996).

Age at registration (years)59·6 (range 36–71)
Interval diagnosis of MMM to registration (months)37·4 (range 0–232)
MMM prognostic score (%)*
 017 (60·7)
 17 (25·0)
 24 (14·3)
Haemoglobin (g/dl)10·7 (7·3–13·9)
Leucocyte count (× 109/l)6·6 (2·8–62·2)
Platelet count (× 109/l)235 (35–970)
Spleen size (cm below left costal margin)7·5 (0–20)
Liver size (cm below right costal margin)0 (0–9)
Bone marrow findings at registration
 Cellularity (median) (%)85 (range 5–95)
 Abnormal karyotype (%)9 (32·1)
 Reticulin fibrosis grade (%)
   212 (42·9)
   313 (46·4)
   43 (10·7)
 Microvessel grade (%)
   26 (21·4)
   318 (64·3)
   44 (14·3)

In two patients who experienced progression of anaemia while receiving pirfenidone, their disease subsequently became transformed into acute myeloid leukaemia. These patients had received 2·5 and 4·9 months of pirfenidone treatment respectively. Although transformation of the disease process occurred after pirfenidone therapy, one of these patients had been heavily pretreated (including radioactive phosphorus) and both had characteristics of advanced disease at registration. We saw no evidence that pirfenidone contributed to the subsequent disease transformation. In addition, the blastic transformation rate, 2 out of 28 (7·2%), is consistent with the natural history of MMM (Tefferi, 2000).

Clinical response to therapy in the evaluated patients after both 6 and 12 months of therapy is summarized in Table II. Overall response (intention-to-treat) was 17·9% at 6 months and 10·7% after 12 months of pirfenidone treatment. One patient experienced an increase in haemoglobin concentration of 2·7 g/dl, with corresponding improvement in splenomegaly, only after 12 months of treatment with pirfenidone. However, no other patients had a clinically relevant improvement in anaemia. Mild improvement in splenomegaly was transiently observed in five patients, although only two of these had sustained improvement, from a barely palpable to an impalpable spleen. No patient had complete resolution of pathological splenomegaly, even after 12 months of pirfenidone.

Table II.   Response to pirfenidone therapy in evaluated patients with MMM.
Change in parameter6 months12 months
  • *

    Anaemia response – CR, complete response : normalization of anaemia; PR, partial response : > 2 g/dl improvement in haemoglobin; SD, stable disease : < 2 g/dl increase or decrease in haemoglobin; PD, progressive disease : > 2 g/dl decrease in haemoglobin.

  • Splenomegaly response – CR, complete response : normalization of splenomegaly; PR, partial response : > 50% decrease in splenomegaly; SD, stable disease : < 50% increase or decrease in splenomegaly; PD, progressive disease : > 50% increase in splenomegaly.

  • MMM, myelofibrosis with myeloid metaplasia.

Patients (number)1812
Response (%)*
   PR01 (8·3)
   SD16 (88·9)10 (83·4)
   PD2 (1·1)1 (8·3)
   CR3 (16·7)2 (16·7)
   PR2 (11·1)1 (8·3)
   SD13 (72·2)8 (66·7)
   PD01 (8·3)
Response of any type5/28 (17·9%)3/28 (10·7%)
Bone marrow response
 Cellularity2 (11·1)4 (33·3)
 Reticulin fibrosis (%)5 (27·8)1 (8·3)
 Microvessel grade (%)00

The overall lack of significant clinical activity was reflected in the results of serial bone marrow evaluation (Table II). There was no sustained improvement in bone marrow cellularity, fibrosis or osteosclerosis. In addition, serial estimations of marrow microvessel density showed no improvement in angiogenesis. In fact, after 12 months, 7 out of 12 patients (58·3%) had a clear increase in angiogenesis. The patient who had experienced improvement in anaemia and splenomegaly had no improvement in marrow cellularity, reticulin fibrosis, osteosclerosis or microvessel density. Thus, we saw no significant biological activity or clinical efficacy of oral pirfenidone therapy in MMM. In this group of 28 patients, we observed clear progression of the disease in 14 cases (50·0%) and stable disease in 10 patients (35·7%). The lack of corresponding improvement in the bone marrow morphological features of MMM in the only patient who had a response makes us skeptical that his improvement was as a result of the pirfenidone therapy. In addition, this patient continues to have an improved and stable haemoglobin concentration 4 months after use of the drug was discontinued, which further suggests that the improvement was not related to pirfenidone. Accordingly, we believe there is not sufficient evidence from this trial to warrant further investigation of pirfenidone as monotherapy for MMM. Various reasons may exist for the lack of response to pirfenidone observed in this trial. First, the limitations of a prospective trial in a rare disorder do not allow dose escalation. The doses chosen for this trial were extrapolated from clinical trials in pulmonary fibrosis and may potentially be too low for myelofibrosis. Second, the evidence of the clinical utility of pirfenidone outside the lung has not yet been shown and this agent may simply not be effective in the bone marrow. Third, the elevation of the cytokine levels in MMM (which are inhibited by pirfenidone) may be an epiphenomenon and not truly causal in the pathogenesis of the disease. Therefore, the inhibition of these cytokines may not have therapeutic benefit. Nevertheless, therapy targeting implicated pathogenetic pathways is intriguing and worthy of further investigation.


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results and discussion
  5. References
  • Barosi, G., Ambrosetti, A., Finelli, C., Grossi, A., Leoni, P., Liberato, N.L., Petti, M.C., Pogliani, E., Ricetti, M., Rupoli, S., Visani, G., Tura, S. (1999) The Italian consensus conference on diagnostic criteria for myelofibrosis with myeloid metaplasia. British Journal of Haematology, 104, 730737.
  • Cain, W.C., Stuart, R.W., Lefkowitz, D.L., Starnes, J.D., Margolin, S., Lefkowitz, S.S. (1998) Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone. International Journal of Immunopharmacology, 20, 685695.DOI: 10.1016/s0192-0561(98)00042-3
  • Dupriez, B., Morel, P., Demory, J.L., Lai, J.L., Simon, M., Plantier, I., Bauters, F. (1996) Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood, 88, 10131018.
  • Gurujeyalakshmi, G., Hollinger, M.A., Giri, S.N. (1999) Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. American Journal of Physiology, 276, L311L318.
  • Iyer, S.N., Gurujeyalakshmi, G., Giri, S.N. (1999) Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. Journal of Pharmacology and Experimental Therapeutics, 291, 367373.
  • Kaneko, M., Inoue, H., Nakazawa, R., Azuma, N., Suzuki, M., Yamauchi, S., Margolin, S.B., Tsubota, K., Saito, I. (1998) Pirfenidone induces intercellular adhesion molecule-1 (ICAM-1) down-regulation on cultured human synovial fibroblasts. Clinical and Experimental Immunology, 113, 7276.
  • Kanfer, E.J., Price, C.M., Gordon, A.A., Barrett, A.J. (1993) The in vitro effects of interferon-gamma, interferon-alpha, and tumour-necrosis factor-alpha on erythroid burst-forming unit growth in patients with non-leukaemic myeloproliferative disorders. European Journal of Haematology, 50, 250254.
  • Martyre, M.C., Magdelenat, H., Bryckaert, M.C., Laine-Bidron, C., Calvo, F. (1991) Increased intraplatelet levels of platelet-derived growth factor and transforming growth factor beta in patients with myelofibrosis with myeloid metaplasia. British Journal of Haematology, 77, 8086.
  • Martyre, M.C., Romquin, N., Le Bousse-Kerdiles, M.C., Chevillard, S., Benyahia, B., Dupriez, B., Demory, J.L., Bauters, F. (1994) Transforming growth factor beta and megakaryocytes in the pathogenesis of idiopathic myelofibrosis. British Journal of Haematology, 88, 916.
  • Mesa, R.A., Hanson, C.A., Rajkumar, S.V., Schroeder, G., Tefferi, A. (2000) Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia. Blood, 96, 33743380.
  • Raghu, G., Johnson, W.C., Lockhart, D., Mageto, Y. (1999) Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. American Journal of Respiratory and Critical Care Medicine, 159, 10611069.
  • Tefferi, A. (2000) Myelofibrosis with myeloid metaplasia. New England Journal of Medicine, 342, 12551265.
  1. All authors certify they have reviewed the manuscript and agree with its contents.