Case 89 – summary

 

Thank you for all of the contributions with Case 89 where we encountered a fit 64 year old who presented with progressive anaemia and leucocytosis over the past 6 months. He also had associated weight loss of 0.5 stones and generalised bone pains.

 

This man had a leucoerythroblastic blood film (with no circulating blasts) with atypical megakaryocytes and marked fibrosis on trephine consistent with myelofibrosis. JAK2 positive and no reactive causes of fibrosis identified. A diagnosis of Primary Myelofibrosis was established.

 

His DIPPS-plus score was 3 (Hb 95g/l, Plts 90, adverse cytogenetics – monosomy 7). Given that he was previously very fit we aimed to offer him an allogenic stem cell transplant given that his prognosis is limited otherwise. We also discussed the role of other treatments to control in his symptoms if an allogenic HSCT was not an option.

 

Primary Myelofibrosis

Myelofibrosis is a heterogenous disease characterised by clonal haemopoietic proliferation associated with increased marrow fibrosis, and commonly with splenomegaly and a leucoerythroblastic film.

WHO 2016 Diagnostic Criteria:

Major Criteria
Megakaryocytic hyperplasia with atypia + increased bone marrow reticulin /collagen (grade 2-3)
Not meeting WHO criteria for other myeloid neoplasms (e.g PV, ET, CML, MDS)
Presence of a pathogonomic mutation (JAK2, CALR, MPL) or in the absence of these another clonal mutation (e.g TET2, EZH2, SF3B1) or absence of a reactive myelofibrosis*
Minor criteria
Presence of at least 1 of the following:
Unexplained anaemia
Leucocytosis >11
Leucoerythroblastic film
LDH >ULN
Palpable splenomegaly

*BM fibrosis secondary to infection, autoimmune disorders, hairy cell leukaemia, other malignancies.

 

Clinical features

Myelofibrosis is a heterogenous disorder with a marked spectrum of clinical features:

  • Anaemia
  • Bleeding / bruising associated with thrombocytopenia
  • Infection associated with leucopenia
  • Symptomatic splenomegaly (e.g pain, early satiety) and less commonly symptomatic hepatomegaly
  • Constitutional symptoms
  • Extramedullary haematopoiesis

 

Prognosis

DIPPS-Plus score
Age >65 yrs
Constitutional symptoms
Haemoglobin <100
Platelets <100
WCC >25
Circulating blasts >1%
Adverse cytogenetics (e.g 7-,7+, 5-, 11q23, +8)
RBC transfusion need

 

Risk Group Predictors (n) Median survival (yrs)
Low 0 15.4
Intermediate 1 1 6.5
Intermediate 2 2 2.9
High ≥3 1.3

 

Treatment

The therapeutic decisions should initially be based on upon what is the aim of treatment is:

  • Cure
  • Quality of life

This decision will be based upon the prognosis and if the patient would be a candidate for an allogeneic HSCT. Allogenic HSCT is the only potential curative approach.

 

Treatment for disease specific symptoms are documented below:

Treatment of anaemia

  • Blood transfusion (NB iron chelation not routinely recommended but to be considered depending on prognosis / aim for HSCT)
  • rErythropoietin if EPO level <125U/l. Double dose after 2 months if no reponse. If still no reponse after 3-4 months – stop.
  • Androgens – response rates vary but between 30-60%. Failure of one androgen does not predict response to another
    • Danazol is first line. Need to be treated for a minimum of 6 months
    • Strict LFT monitoring and 6-12 monthly liver USS due to risk of hepatic cancer. Screen male patients for prostate cancer.

Treatment of constitutional symptoms

  • Ruxolitinib (JAK2 inhibitor, Comfort 2 trial). May worsen anaemia. No prognostic benefit

Treatment of Splenomegaly and extramedullary haemopoiesis

Medical management

  • Ruxolitinib (JAK2 inhibitor. Comfort 2 trial)
  • Hydroxycarbamide
    • Often need doses between 1.5g/d can cause significant cytopenias
    • Benefit usually noticeable within 8-10wks.
  • Immunomodulatory
    • Low dose thalidomide (e.g 50mg / day) combined with tapering steroids. ORR 20-30%
    • ORR ~30%

Surgical Management

Indication: symptomatic splenomegaly, significant splenic infarction, severe portal HTN, severe hypercatabolic symptoms, refractory haemolysis.

Perioperative management:

  • Cardiac, hepatic, renal and metabolic status
  • Meticulous control of platelet count pre- and post-splenectomy
  • Appropriate vaccination and long term penicillin

Post splenectomy myeloproliferation

  • Cytoreductive therapy (Hydroxycarbamide)
  • Cladribine

Requires pre-op evaluation

  • Mortality ~10%, morbidity 31%
  • Requires dynamic circulatory studies throughout surgery as portal HTN is ameliorated with splenectomy.
  • Can develop hepatic extramedullary haematopoiesis
  • Post operative thrombocytosis ~20% (associated thrombotic risk)

Radiotherapy:

  • Symptomatic splenomegaly but requires adequate plt count >50 who are not deemed candidates for surgical intervention. May develop worseding cytopenias post RT. Can consider low-dose intermittent radiation .
  • Extramedullary disease in vital organs
  • Severe bone pains

Treatment of hyperproliferation

  • Hydroxycarbamide
  • Alpha-interferon – use with early phase disease
  • Use anagrelide with caution due to risk of cauding progressive fibrosis

 

 References:

  • Reilly J,T et al on behalf of British Committee for Standards in Haematology Guideline for the diagnosis and management of myelofibrosis. British Journal of Haematology. 158 (4). 453-471. 2012.
  • Reilly J,T et al. Use of JAK2 inhibitors in the management of myelofibrosis: a revision of the British Committee for Standards in Haematology Guidelines for Investigation and Management of Myelofibrosis 2012. 167 (3): 418-420. 2014.

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