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myelofibrosis

myelofibrosis

introduction

  • a myeloproliferative disorder in which the proliferation of an abnormal type of bone marrow stem cell results in the replacement of the marrow with collagenous connective tissue fibers and thus fibrosis
  • mainly in those over 50 years age
  • associated with activation of the Janus kinase pathway resulting in increased signalling in some cytokines and growth factors involved in haematopoiesis and immune functions
  • overall survival from diagnosis without stem cell transplant is usually 2 - 11 years
  • survival of patients with primary myelofibrosis is dependent on the underlying mutually exclusive mutation1):
    • MPL exon 10 mutation ⇒ 60% 5yr survival, 30% 10 yr survival (median survival 8 yrs, 25% die in 1st 2 yrs )
    • JAK2-V617F mutation ⇒ 80% 5yr survival, 50% 10 yr survival (median survival 11 yrs)
    • CALR exon 9 mutation ⇒ 95% 5yr survival, ~88% 10 yr survival (median survival 21 yrs), lower risk of thrombosis

aetiology

  • primary
    • 50-60% due to acquired Janus kinase 2 gene JAK2 (V617F) mutation
    • 20-30% due to somatically acquired calreticulin gene CALR exon 9 mutation 2)
    • 5-10% due to acquired thrombopoietin receptor gene MPL exon 10 mutation
    • ~10% have none of the above mutations
  • secondary to:

clinical features

  • progressive pancytopenia
  • patients often have hepatosplenomegaly due to liver and spleen becoming haematopoietic tissues (splenomegaly may result in the spleen weighing > 4kg!) and poikilocytosis
    • risk of splenic infarction, splenic trauma, perisplenitis
  • occasionally, extramedullary haematopoiesis in the lungs may result in pulmonary hypertension (PAH)
  • night sweats
  • abdominal discomfort
  • anorexia
  • weight loss
  • susceptibility to infections and reactivation of herpes zoster
  • gouty arthritis that is secondary to hyperuricaemia
  • priapism, tinnitus, or stupor from leukostasis
  • occasionally acute febrile neutrophilic dermatosis (Sweet syndrome):
    • fever accompanied by painful, maculopapular, violaceous lesions on the trunk, arms, legs, and face

treatment options

  • supportive:
    • folic acid
    • allopurinol
    • blood transfusions
  • possible adjuncts:
    • alpha-interferon
    • hydroxyurea - useful to suppress the number of circulating cells
    • thalidomide
    • lenalidomide
      • ruxolitinib
        • marketed in Aust from 2013 as Jakavi
        • selective inhibitor of Janus kinase I and II
        • appears to reduce spleen size or prevent it enlarging further
        • 50% reduction in disease associated symptoms compared with 5% for placebo, but these return to baseline within 1 week of stopping Rx, and serious withdrawl symptoms make gradual dose reduction a recommendation.
        • BUT 82% developed anaemia, 67% thrombocytopenia and 15% neutropenia hence need to monitor FBE
        • dose 15-25mg bd
    • radiotherapy to spleen
    • splenectomy
  • allogeneic stem cell transplantation
1) , 2)
NEJM Dec 2013
myelofibrosis.txt · Last modified: 2014/11/24 10:12 by 127.0.0.1

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