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

MODULE 2: Molecular profiling and NGS

Which mutations?

Given the diagnostic relevance of JAK2, CALR and MPL mutations in myelofibrosis (MF),1 it is important to screen for these mutations as a minimum.2 These analyses are frequently carried out with PCR methods, such as allele-specific quantitative PCR; Sanger sequencing may also be used, especially for CALR mutations, due to the heterogeneity of insertions and deletions detected.3

Identification of additional mutants, for example by next-generation sequencing (NGS), may be advantageous for prognostication (and thus influence choice of therapy), as well as for identifying clonal evolution during the course of the disease.2,3

Which patients?

In a survey of 42 consultant haematologists from the UK, published in 2020, 39 (93%) used molecular testing and cytogenetics to aid diagnosis of MF.4

37/42 (88%) had access to an NGS myeloid panel or equivalent. Most commonly NGS testing was performed in patients:4

  • who were transplant candidates (50% of survey respondents)
  • who were triple negative (50%)
  • whose disease status had changed (24%)

Six haematologists screened all their patients. Less than 20% of those surveyed used a prognostic scoring system that includes genetic information.4

Treatment options for MF depend on the risk category of the individual.6

In England, ruxolitinib is only reimbursed by NICE in patients with MF defined as having intermediate-2 or high-risk disease, whereas in Scotland it is available irrespective of risk stratification.5,6

It is recommended that allogeneic stem cell transplantation is considered for patients with:

  • intermediate-2 or high-risk MF (IPSS/ DIPSS/ DIPSS+) and age <70 years
  • intermediate-1 risk MF and age <65 years, only if they present with refractory, transfusion-dependent anaemia, percentage of blasts in peripheral blood >2%, or adverse cytogenetics, or are triple negative, ASXL1 positive, or both7

The presence of unfavourable mutations, revealed by NGS results, may appreciably change the risk classification of a patient, and potentially alter eligibility for different treatments. Thus, NGS could be considered for those at low or intermediate risk (IPSS/ DIPSS/ DIPSS+).5,7-10

The non-driver mutations reported in MF are not exclusive; they are also known to be associated with other myeloid malignancies, including acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). The frequency with which they are identified is higher in blast phase, ie after leukaemic transformation, than in primary MF.11 More detailed molecular information, for example from NGS, may allow for differentiation from other conditions, or for diagnosis to be refined. This could be particularly relevant for triple negative patients in whom no driver mutation is found.11

Potential benefits of NGS3

  • high throughput: parallel sequencing
  • low sample requirements
  • high sensitivity (1%)
  • detection of known and unknown mutations
  • discriminates genomic aberrations, eg single/ multiple nucleotide variants, insertions and deletions, copy-number variations
Retest your knowledge 

DIPSS: Dynamic International Prognostic Scoring System; IPSS: International Prognostic Scoring System; PCR: polymerase chain reaction

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References
  1. 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
  2. Mesa R A, Passamonti F. Individualizing care for patients with myeloproliferative neoplasms: integrating genetics, evolving therapies, and patient-specific disease burden. Am Soc Clin Oncol Educ Book 2016;35:e324-335
  3. Palumbo G A, Stella S et al. The role of new technologies in myeloproliferative neoplasms. Front Oncol 2019;9:321
  4. 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
  5. National Institute for Health and Care Excellence (NICE). Technology appraisal guidance 386. Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis, March 2016 (last reviewed July 2019). Available at: nice.org.uk. Accessed March 2025
  6. Scottish Medicines Consortium (SMC). SMC No 867/13. Ruxolitinib (as phosphate), 5 mg, 10 mg, & 20 mg tablets (JAKAVI®), March 2015. Available at: scottishmedicines.org.uk. Accessed March 2025
  7. Kroger N M, Deeg J H et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia 2015;29(11):2126-2133
  8. Guglielmelli P, Lasho T L et al. MIPSS70: Mutation-enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol 2018;36(4):310-318
  9. Tefferi A, Guglielmelli P et al. MIPSS70+ Version 2.0: Mutation and karyotype-enhanced International Prognostic Scoring System for primary myelofibrosis. J Clin Oncol 2018;36(17):1769-1770
  10. Tefferi A, Guglielmelli P et al. GIPSS: Genetically Inspired Prognostic Scoring System for primary myelofibrosis. Leukemia 2018;32(7):1631-1642
  11. Loscocco G G, Guglielmelli P, Vannucchi A M. Impact of mutational profile on the management of myeloproliferative neoplasms: a short review of the emerging data. Onco Targets Ther 2020;13:12367-12382

© NICE 2016 Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. Available from nice.org.uk/guidance/ta386. All rights reserved. Subject to Notice of rights.

NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/ publication.