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INGRAIN-MF
Incorporating genetics, risk and associated burden into MF management

MODULE 1: The burden of myelofibrosis

Presentation and diagnosis of myelofibrosis

63-year-old Jane has been feeling more tired than usual and gets out of breath easily. She has had a loss of appetite and has unintentionally lost weight.

Fictional patient.

Signs and symptoms at diagnosis

Myelofibrosis (MF) is associated with a high symptom burden, with myeloproliferative neoplasm (MPN) symptoms common at diagnosis and increasing in incidence and severity as the disease progresses.1,2

In a real-world study of 200 patients with MF in the UK, the most common signs and symptoms that were documented at diagnosis were:2

Enlarged spleen: 47%
n=94/200

Anaemia 44%:
n=88/200

Constitutional symptoms 30%:
n=60/200

Unexplained tiredness: 27%

Unexplained weight loss: 21%

Excessive sweating: 16%

Shortness of breath: 9%

Bone and joint pain: 8%

Satiety, loss of appetite, indigestion: 7%

Abdominal discomfort or pain: 7%

  • The median age at diagnosis was 69.7 years (IQR: 63.5-75.7)
  • 71% of patients (n=141/200) were found to have a JAK2 mutation
  • Over half of the patients for whom an International Prognostic Scoring System risk score was available had been classified as intermediate-2 or high risk (98/171)

Diagnostic criteria for MF

Diagnosis of MF is based on results from:

  • clinical assessment
  • bone marrow biopsy
  • blood tests

WHO diagnostic criteria:* major3

  • Presence of megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grade 2 or 3
  • Presence of JAK2, CALR or MPL mutation OR presence of other clonal marker† OR absence of reactive MF‡
  • Does not meet criteria for other myeloid disorder

WHO diagnostic criteria:* minor3

At least one of the following, confirmed in two consecutive determinations:

  • Anaemia (not attributed to comorbid condition)
  • Leukocytosis (≥11 x 109/L)
  • Palpable splenomegaly
  • Increased serum lactate dehydrogenase (>ULN)
  • Leukoerythroblastosis
  • Diagnostically relevant:4,5 constitutional symptoms (night sweats, weight loss, unexplained fever, diffuse bone pains)
  • Prognostically relevant:6 cytogenetic aberrations

*WHO criteria for overt primary MF: diagnosis requires all three major criteria to be met, plus at least one minor criterion.3

†For example, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1.3

‡Bone marrow fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukaemia or other lymphoid neoplasm, metastatic malignancy or toxic (chronic) myelopathies.3

MF grading3,7

MF-0
Normal 		Scattered linear reticulin with no intersections (crossovers) - corresponding to normal bone marrow Pre-primary MF
MF-1
Reticulin 		Loose network of reticulin with many intersections, especially in perivascular areas
MF-2
Collagen fibrosis 		Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibres mostly consistent with collagen, and/or focal osteosclerosis Overt primary MF:
associated with a worse prognosis than MF-0 and MF-1
MF-3
Osteosclerosis		 Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibres consistent with collagen, usually associated with osteosclerosis

The proportion of consultant haematologists (out of 42 surveyed) using recommended diagnostic assessments:8

  • Blood counts: 100%
  • Blood film: 100%
  • Bone marrow biopsy: 100%
  • Cytogenetics: 93%
  • Molecular testing: 93%
  • Spleen size measurement: 80% (all by palpation, 48% additionally used ultrasound and 5% computed tomography)

Several prognostic scoring systems are available for predicting survival at the time of diagnosis with MF; three of the more commonly used are the International Prognostic Scoring System (IPSS), Dynamic IPSS (DIPSS) and DIPSS+.9-12

Risk factors Assigned risk score
IPSS9 DIPSS11
Hb <10 g/dL 1 2
WBC count >25,000/mm3 1 1
Constitutional symptoms§ 1 1
Age >65 years 1 1
Peripheral blood blasts ≥1% 1 1

§Constitutional symptoms defined as weight loss ≥10% and/or unexplained fever or excessive sweating persisting for ≥1 month.9,11

DIPSS+ assigns points according to DIPSS risk level: 1 point for intermediate-1, 2 points for intermediate-2 risk and 3 points for high risk. Then additionally, 1 point is added for:10

  • Red blood cell transfusion need
  • Platelet count <100 × 109L
  • Unfavourable karyotype
Risk group IPSS risk score9 DIPSS risk score11 DIPSS+ risk score10
Low 0 0 0
Intermediate-1 1 1 or 2 1
Intermediate-2 2 3 or 4 2 or 3
High ≥3 5 or 6 ≥4

Jane's spleen was enlarged on palpation. Biopsy revealed collagen fibrosis in the bone marrow and she was found to have a JAK2 mutation.

Jane was diagnosed with overt primary MF, with a risk level classified by IPSS as intermediate-2.

Fictional patient; image is of a model.

Hb: haemoglobin; IQR: interquartile range; ULN: upper limit of normal; WBC: white blood cell; WHO: World Health Organization

Continue to next section: Symptom burden and quality of life 
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References
  1. Harrison C N, Koschmieder S et al. The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey. Ann Hematol 2017;96(10):1653-1665
  2. Mead A, Somervaille T. A retrospective real-world study of the current treatment pathways for myelofibrosis in the UK (the REALISM UK Study). Presented at the 61st American Society of Hematology Meeting, Orlando, Florida, US, 7-10 December 2019; poster 1671
  3. Arber D A, Orazi A et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391-2405
  4. Barbui T, Barosi G et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29(6):761-770
  5. Reilly J T, McMullin M F et al. Use of JAK inhibitors in the management of myelofibrosis: a revision of the British Committee for Standards in Haematology guidelines for investigation and management of myelofibrosis 2012. Br J Haematol 2014;167(3):418-420
  6. Tefferi A, Nicolosi M et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia 2018;32(5):1189-1199
  7. Li B, Zhang P et al. Bone marrow fibrosis grade is an independent risk factor for overall survival in patients with primary myelofibrosis. Blood Cancer J 2016;6(12):e505
  8. Harrison C N, Mead A J et al. A physician survey on the application of the British Society for Haematology guidelines for the diagnosis and management of myelofibrosis in the UK. Br J Haematol 2020;188(6):e105-e109
  9. Cervantes F, Dupriez B et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113(13):2895-2901
  10. Gangat N, Caramazza D et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011;29(4):392-397
  11. Passamonti F, Cervantes F et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115(9):1703-1708
  12. Reilly J T, McMullin M F et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol 2012;158(4):453-471