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Journal presentation

Dr. Samim Reza

Phase-B resident

Dept of haematology

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Blood Reviews

REVIEW ARTICLE

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Current and Future Therapies For Myelofibrosis

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Samir Asher, Donal P. McLornan, Claire N. Harrison*

Date of Publication: 24 July, 2020

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Introduction

  • Classified as ‘Philadelphia chromosome’ negative clonal myeloproliferative disorder
  • Characterized by variable cytopenias,marrow fibrosis,spleenomegaly,extramedulary haematopoesis and mutational landscape

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Broadly, the term myelofibrosis encompasses four distinct subtypes: primary myelofibrosis (PMF), prefibrotic MF (PF-MF) , post-polycythaemia vera myelofibrosis (post PV-MF) and post-essential thrombocythaemia myelofibrosis (post ET-MF)

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  • LEB with tear drop cells is an important clue

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Pathogenesis

MF is characterised by stem cell-derived clonal myeloproliferation, abnormal cytokine production and presence of so-called somatic ‘driver mutations’ functionally associated with JAK-STAT hyperactivation. (JAK2, MPL and CALR mutations) as well as

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Epigenetic dysregulation (e.g. TET2, ASXL1 or EZHZ)

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  • JAK 2 mutaion occur in 46-68%,CALR :25-35% and MPL 5-10%
  • CALR mutation occurs in younger pt, higher plt, less anaemic, improved OS
  • 9% MF has no mutation , poor OS ,more leukaemic transformation

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Diagnostic Criteria for PMF, Prefibrotic MF, PPV-MF and PET-MF

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Diagnostic Criteria for PMF, Prefibrotic MF, PPV-MF and PET-MF

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Pre treatment evaluation

  • goals of care: Relief of symp and improvement of QL
  • Symp are assessed through MPN-10 score
  • Medical fitness by performance status,co morbidities

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Risk stratification

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  • Higher Risk PMF include : intermediate -2 and high risk( GIPSS)
  • Lower risk PMF: low risk and int -1

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Higher risk PMF( Transplant eligible)

  • ASCT
  • Poor outcome ,more transplant related mortality

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Non transplant

  • JAK 1/2 inhibitor : Ruxolitinib
  • Reduce spleen size 35% by 24 wks of 41.9% pt and symptoms relived by 50% in 45.9% pt
  • No significant OS( 56 vs 44% after 4.3 yr follow up)

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Dose

  • 5 mg bd (50 × 109/L to < 100 × 109/L),
  • 15 mg bd (100 to 200 × 109/L),
  • 20 mg bd (> 200 × 109/L).
  • If no improvement after6 months then look for complaince,CYP3 inducer , herbal then slowly withdrwal

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  • Avoid in active infection, with cautious in thrombocytpenia ,hepatic and renal impairement, CYP3 inducer e.g. azole
  • Latent infection should be ruled out and active infection should be treated

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  • Adverse effect : Anaemia ,thrombocytopenia, infection reactivation, opportunistic infection, withdrawal symptoms
  • Withdrawal syndrome: fever ,hypoxia,hypotension,SIRS
  • Rx : prednisolone 20mg 7 days then tapering over 1 wk,vasopressor ,resumpsion of Rux

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Fedratinib

  • 400mg once daily
  • AE: anaemia serious infection and Wernicke encephalopathy ,incrsd LFT,creatinine,GI upset
  • Plt should be >50000
  • Reduction of spleen and sypm in 1/3 pt not respond to Rux and PPV and PET MF

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Hydroxyurea

  • Used who r not candidates for Rux and Fed
  • Lower dose than other MPN (500-1000) alternate day
  • Improves spleenomegaly,thrombocytosis ,leukocytosis ,bone pain ,itching,
  • AE:cytopenia, ulcers, diarrhea, PN,Skin cancer

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Management and Monitoring strategy for Myelofibrosis

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Other drugs

  • INF alpha in Pregnancy,Should not used who have plan for ASCT
  • Thalidomide or lenalidomide with steroid in anaemia ,Rux withdrawl synd ,also reduce spleen and other symp,
  • more effective in 5q –

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Androgens

  • Danazol in MF associated anaemia when EPO level is high, median response time 5 months
  • 600-800mg per day
  • AE: Cholestatic hepatitis, hirsitism, virilization ,prostate cancer,

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  • Recombinant human erythropoietin (rHuEPO) when EPO level low
  • Can be used with RUX
  • Thrombotic risk increase spleen

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Spleenectomy and irradiation

  • Usually not indicated as site of extramedullary haematopoesis
  • Indicated in refractory haemolysis ,infarction, severe portal HTN, troublesome spleenomegaly
  • Iradiation who are unfit for surgery

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Low risk group

  • asypmtomatic ; follow up 3 monthly
  • symptomatic: hydroxyurea ,INF alpha,EPO, Danazol, Linalidomide if 5q-

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Common clinical challenge

Symptoms : B symptoms ,itching, bone pain

Anaemia : Multifactorial; ineffective erythropoiesis,hyperspleenism, inflamtory cytokines ,haematinics deficiency

Thrombocytopenia ; 25-26% cases, poor prognosis , drug dose modification

Extreme age

Pregnancy

Iron chelation

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Evolving therapy and clinical trials

  • Other JAKi: Pacritinb Jak2 and FLT-3 inhibitor
  • Momelotinib: JAK 1/2 inhibitor ,withcytopenia
  • Itacitinib: MF and thrombocytopenia

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Non JAk inhibitors

PI3K/mToR inhibitor: Bupralisib

Ponabinostat

Azacitidine

Telomerse inhibitor(Imetektat)

Luspatercept( activin receptor antgonist)

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Reversing marrow fibrosis

  • Aurora kinase A inhibitor (alesertib)
  • Inhibition of IGF-B receptor (Galunosertib)
  • Activin receptor antgonist (Luspatercept)
  • rHu pentaxin 2 reduce myelofibroblast differentiation