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Keywords:

  • myelofibrosis;
  • treatment;
  • pegylated-interferon;
  • response criteria;
  • European Myelofibrosis Network

The moderate effect of most palliative treatments in primary and secondary myelofibrosis in addition to the restricted possibilities of allogeneic stem cell transplantation has encouraged physicians to look for alternative treatments (Kröger & Mesa, 2008; Hasselbalch, 2009). Since 1987, several studies have suggested that interferons (alpha or beta that are either pegylated or not) may be beneficial in the treatment of myelofibrosis (Parmeggiani et al, 1987; Kiladjian et al, 2008a). Given the efficacy of pegylated interferon α-2a (Peg-IFN α-2a) on biological and molecular parameters in polycythemia vera (PV) patients (Kiladjian et al, 2008b), we undertook a multicentre retrospective study in order to evaluate the impact of this treatment on the clinical and biological parameters inherent to myelofibrosis.

From December 2006 to July 2008, all of the patients who were treated with Peg-IFN α-2a for myelofibrosis (according to the World Health Organization 2007 classification) were analysed in seven French GEM (Groupe d’Etudes des Myélofibroses) and FIM (France Intergroupe des Syndromes Myéloprolifératifs) centres (Tefferi et al, 2007). All of the tests were performed during routine visits and informed oral consent was obtained from each patient. The clinical and biological records included a spleen palpation examination and a complete blood count (haemoglobin, leucocyte and platelet counts). In addition, every patient was locally assessed for the presence of the JAK2V617F mutation with each centre using its own method. Fourteen patients in this study were pre-treated prior to analysis, the majority of whom were pre-treated with hydroxycarbamide. We analysed the response according to the European Myelofibrosis Network (EUMNET) criteria for response in myelofibrosis patients (Barosi et al, 2005). Notably, all of the patients were at least 18 years old.

A total of 18 patients (10 females, eight males, aged 36–77 years) who were treated with Peg-IFN α-2a for myelofibrosis were identified. Nine of these patients were aged over 70 years. Fifteen patients had secondary myelofibrosis (10 post-PV and five post-essential thrombocythaemia), 14 patients carried the JAK2V617F mutation. All of these data are summarised in Table I.

Table I.   Characteristics of the myelofibrotic patients before treatment with Peg-IFN α-2a and evaluation of the response according to the EUMNET criteria.
PatientSexAge (years)MFJAK2 statusHb (g/l)WBC (×109/l)Plt (×109/l)Pre therapyResponse itemOverall response
AnaemiaLeucocytosisThrombocytosisSplenomegaly
  1. Each response item is expressed as the best response obtained and response duration (months).

  2. +, transfusion-dependent patients; HC, hydroxycarbamide; PIP, piprobroman; ANA, anagrelide; MP, mercaptopurine. Criteria of item response: CR, complete response; PR, partial response; –, no response or non-evaluable. Criteria of global response: CR, complete response; Maj, major response; Mod, moderate response; Min, minor response; no, no response. Myelofibrosis (MF): P, primary and S, secondary.

 1M72SPos 85+4·2577NoPR (3)CR (6)Mod
 2F72SPos938·4145NoCR (3)Min
 3M77SPos14837949NoPR (3)CR (3)Min
 4F74SPos956·1587HC/MPCR (6)CR (3)CR (3)CR
 5F73SPos9725·3214HC/PIPCR (9)CR (3)Maj
 6M64PPos11263·9708HC/ANAPR (3)CR (3)Min
 7M57PNeg9178·3548HC/PIPCR (9)CR (9)CR (3)CR
 8M65PPos1029·580HCNo
 9F36SPos1375535NoPR (9)No
10F71PNeg 80+2·9680HCCR (3)Min
11F74SPos1546·2518HC/PIPCR (3)CR (3)CR
12F52SPos1229·1433ANACR (3)CR
13F44SNeg1414·5589NoPR (3)CR (3)Maj
14F68SPos13817·1482HC/PIPCR (3)CR (3)_Min
15F66SPos11316·2398HC/ANACR (9)Min
16M60SPos12544·3686HCCR (9)CR (3)CR
17M74SPos 86+4292HC/MPCR (6)Mod
18M74SNeg946·9385HCCR (9)CR

The median leucocyte count was 22·7 × 109/l (range 2·9 × 109/l to 78·4 × 109/l). Nine patients had leucocytosis. Interestingly, five of these patients were characterised as achieving a ‘complete response’ and four of these patients were characterised as obtaining a ‘partial response’. A single patient with leucopenia normalised his leucocyte count. The median platelet count was 461 × 109/l (range 35 × 109/l to 949 × 109/l). Eleven patients were diagnosed with thrombocytosis; 10 of these 11 patients achieved a ‘complete response’ and one out of three thrombocytopenic patients normalised their platelet count. The median level of haemoglobin was determined to be 112 g/l (range 80–15 g/l). Among the three transfusion-dependent patients, two became transfusion-independent. In addition, four of the five other anaemic patients normalised their haemoglobin level (Hb > 100 g/l). Furthermore, splenomegaly was palpable in 12 patients with a median mass size of 11 cm below the left costal margin (range 2–22 cm). Complete disappearance of splenomegaly was observed in only two cases.

Since 1987, several reports have indicated significant heterogeneity in the response of myelofibrosis to treatment with recombinant IFN (α, β and γ) (Parmeggiani et al, 1987; Kiladjian et al, 2008a). The first available treatments required daily injections and were poorly tolerated, with only a few ‘major’ or ‘complete responses’ observed. More recent reports have indicated that IFN-α is most frequently used in myelofibrotic patients (Kiladjian et al, 2008a). However, the use of Peg-IFN (α-2b) was reported only once and was found to produce poor results, with only one patient out of 11 achieving a ‘complete response’ (Jabbour et al, 2007). In a recent report, Peg-IFN α-2a induced haematological and even molecular responses in polycythaemic patients (Kiladjian et al, 2008b).

Herein we report the results from what we believe to be the first study using the Peg-IFN α-2a in patients with primary and secondary myelofibrosis and our results favour a true efficacy, because all of the patients except two responded to achieve either ‘complete remission’ (six patients) or ‘major responses’ (two patients, 44% of patients). Only two patients stopped treatment because of the loss of efficacy or symptomatic phase of the disease. Peg-IFN acts more specifically and rapidly (3 months) on proliferative patterns (leucocytosis and thrombocytosis). Interestingly, anaemia improved in 80% of the patients after 6 months of treatment. Also, splenomegaly appeared insensitive to Peg-IFN α-2a treatment. We conclude that Peg-IFN is efficient and safe and should be considered when treating both young and old patients with myelofibrosis regardless of whether or not the JAK2V617F mutation is present. In order to ascertain these preliminary results, a randomised trial must be performed.

References

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