Which MPN patients do I need to really watch? Molecular variables in prognostic models for patients with myeloproliferative neoplasms (MPNs).
“...particularly in patients with low-risk scores, that you might be comfortable just ‘watching and waiting’, you really should be delving a bit deeper and looking for these mutations, which might influence your approach.”
Dr Mark Drummond
In the third webinar of this series, Dr Mark Drummond, Beatson Cancer Centre, Glasgow, discusses the impact of genetic mutations in the classification, diagnosis and prognosis of MPNs.
Mutations to the JAK2, CALR and MPL genes are associated with pathogenesis of MPNs.1
|Myeloﬁbrosis (MF)||JAK2 V617F
CALR (predominantly type 1 variant)
|Polycythaemia vera (PV)||JAK2 V617F
JAK2 exon 12
|Essential thrombocythaemia (ET)||JAK2 V617F
CALR (predominantly type 2 variant)
- JAK2 is a tyrosine kinase associated with cytokine receptors2
- MPL is a thrombopoietin receptor2
- The variant forms of CALR, a Ca2+ binding protein, act as activators of MPL2
10–15% of patients are triple-negative for these mutations, but may harbour new somatic JAK2 or MPL variants.3 Information on the presence or absence of these mutations from molecular profiling can aid in the diagnosis of MPNs, and in some cases also the prognosis.4
Here, Dr Mark Drummond discusses the driver mutations associated with MF, ET and PV
Overall survival can differ according to mutational status of patients with MF5,6
The pathogenesis of MF can involve mutations in the JAK2, MPL and CALR genes.7 It has also been shown that patients with different mutational profiles experience different overall survival rates:
- Triple-negative patients experience shorter survival compared with patients with JAK2, MPL or CALR mutations5
- Patients with type 1 CALR mutations experience longer survival compared with patients with type 2 CALR or JAK2 mutations6,8
- Patients with type 2 CALR mutations experience similar survival to patients with JAK2 mutations6,8
Here, Dr Mark Drummond explains the prognosis of triple-negative patients and those with other mutational profiles in MF
The three main driver mutations do not explain the entire heterogeneity of MF, ET and PV.2 Generally, only 1 mutation in an MPN driver gene is found in ET and PV, but in MF, 3 or more somatic mutations are often found.2 Most of the non-driver mutations in MPNs are involved in phenotypic changes and disease progression, for example:2
- Signalling: LNK
- Histone modification: ASXL1, EZH2
- RNA splicing: SRSF2
- DNA methylations: TET2, DNMTA3
Non-driver mutations do not hold a diagnostic value, but do influence prognosis in MF, affecting both survival rates and transformation to leukaemia.9,10 Three prognostic scoring systems for primary MF that take into account genetic profiles are MIPSS70, MIPSS70-plus 2.0 and GIPSS.9,11,12
In this clip, Dr Mark Drummond discusses high and low molecular risk in MF according to the specific non-driver mutations a patient carries
ET, essential thrombocythaemia; GIPSS, genetically inspired prognostic scoring system; MF, myelofibrosis; MIPSS, mutation-enhanced international prognostic scoring system; PV, polycythaemia vera.
Risk stratification can impact treatment decisions in MF13
Risk stratification impacts prognosis, with patients in higher risk categories having a poorer prognosis, and this can affect treatment choices.13
Ruxolitinib: According to NICE, ruxolitinib can be used for adults with MF-related splenomegaly or symptoms, classified as having intermediate-2 or high-risk disease.14 The SMC does not specify a patient risk group and accepts the use of ruxolitinib for any adult patient with disease-related splenomegaly or MF symptoms.15
Allogeneic stem cell transplant (allo-SCT): Allo-SCT should be considered for intermediate-2 or high-risk patients and selected intermediate-1 risk patients, depending on age and fitness.16
Here, Dr Mark Drummond talks about some of the treatment options available for patients with MF
MF, myelofibrosis; NICE, National Institute for Health and Care Excellence; SMC, Scottish Medicines Consortium.
One study of 95 patients with MF showed that, when being treated with ruxolitinib, having three or more mutations* significantly reduced:17
- the chance of spleen response
- the time to treatment discontinuation
- overall survival
*compared with two mutations or fewer
In this clip, Dr Mark Drummond describes a phase I/II study investigating the effect of multiple mutations on ruxolitinib response
- Barbui T, Thiele J et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J 2018;8(2):15.
- Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 2017;129(6):667–679.
- Langabeer S E. Chasing down the triple-negative myeloproliferative neoplasms: implications for molecular diagnostics. JAKSTAT 2016;5(2–4):e1248011.
- Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017;92(1):94–108.
- Rumi E, Pietra D et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 2014;124(7):1062–1069.
- Klampfl T, Gisslinger H et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379–2390.
- Tefferi A, Pardanani M. Myeloproliferative neoplasms: a contemporary review. JAMA Oncol 2015;1(1):97–105.
- Guglielmelli P, Rotunno G et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J 2015;5:e360.
- 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.
- Vannucchi A M, Lasho T L et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013;27(9):1861–1869.
- 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.
- Tefferi A, Guglielmelli P et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia 2018;32(7):1631–1642.
- 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.
- National Institute for Health and Care Excellence (NICE). TA386. Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. 2016. Available at www.nice.org.uk. Accessed May 2020.
- Scottish Medicines Consortium (SMC) 867/13. Ruxolitinib (Jakavi®). March 2015. Available at: www.scottishmedicines.org.uk. Accessed May 2020.
- Salit R B, Deeg H J. Transplant decisions in patients with myelofibrosis: should mutations be the judge? Biol Blood Marrow Transplant 2018;24(4):649–658.
- Patel K P, Newberry K J et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood 2015;126:790–797.