The disordering of chromosomes in the course of reading and translating DNA during reproduction – during mitosis — is a critical factor in some blood diseases. (For example, translocation of genetic material on chromosomes is responsible for the creation of the BCR-ABL oncogene and the onset of chronic myeloid leukemia.)
Karyotyping is the analysis of chromosomes in the mitotic stage to determine deletions, insertions, and other disorders. While still not a routinely ordered test, this is a test that can uncover significant issues. Chromosomal anomalies occur in an estimated 17% of MF high risk patients. Their early discovery can help in determining the timing of stem cell transplant.
JAK2 and Other MPN Mutations
JAK2 and other mutations: The more familiar landscape of MPN mutations includes recognizable features like the JAK2 and CALR mutations. Mutations generally occur in the course of reproduction, arising within genes – sections of DNA residing within chromosomes. Genes are coded with the recipe to create proteins, like the JAK2 kinase. Mistakes in translating and combining the elements of that recipe are common. In the JAK2 mutation a simple transposition of two letters – two amino acids — creates the mutant JAK2 clone carried by about half of all MPN patients.
Recent advances in biotechnology have permitted the discovery of several MPN mutations, some relatively benign, some considered High Molecular Risk, such as ASXL1, EZH2, SRSF2, IDH1/2. This is an on-going search of a moving and expanding target whose precise role in driving myelofibrosis progression is not yet fully understood.
A relatively new MF prognostic scale, the MIPSS70 (Mutation-enhanced International Prognostic Scoring System) adds three new hazard factors to the DIPSS Plus scale : High Molecular Risk mutations, the absence of CALR Type 1 mutation, and the impact of bone marrow fibrosis levels. By incorporating genetic, cytogenetic and clinical information in a single scale MIPSS70 may improve the accuracy of stem cell transplant timing.
While the MIPSS70 scale is gaining increased acceptance, particularly in Europe, current expert opinion awaits further validation before the scale can be reliably used on its own to predict the timing of stem cell transplant.
NB: Expand: Fm JCO)
Current evidence supports prognostic distinction based on the presence or absence of type 1–like CALR mutations,whereas ASXL1, SRSF2, EZH2, and IDH1/IDH2 mutations are considered as high–molecular risk (HMR) mutations, the prognostic relevance of which is further amplified by the number of such mutations in an individual patient.
Treatment of PMF includes supportive care, use of JAK2 inhibitors and other drugs, surgical removal or involved-field irradiation of the spleen, and allogeneic stem-cell transplantation (alloSCT). These treatment measures, with the exception of alloSCT, are mostly palliative and unlikely to modify the natural history of the disease.18 Unfortunately, alloSCT carries a substantial risk of treatment-related mortality and morbidity, which underscores the need for reliable prognostic models that facilitate treatment decision making and justify the risk involved in alloSCT in otherwise transplantation-eligible patients.19 Accordingly, current treatment recommendations favor alloSCT for DIPSS/DIPSS-plus high- or intermediate-2–risk disease, whereas a more conservative treatment approach might be considered for lower-risk disease.2,20
In this multicenter study with training and validation cohorts of patients with PMF, we integrated clinical data with molecular and cytogenetic information and also accounted for bone marrow (BM) fibrosis grade. The main objective was to develop new prognostic models, specifically directed toward transplantation-age patients, operationally defined as age ≤ 70 years, in line with current practice guidelines.
MYSEC Prognostic Model Risk Calculator (MYSEC-PM)
MPN Personalized Risk Calculator
(This is the Nangalia-Grinfeld calculator, full description in development)
From the authors: “This web portal is for research purposes only. The algorithm has not been validated for clinical use.
“This web tool allows for the input of clinical and genomic information from individual patients with Myeloproliferative Neoplasms to provide personalised predictions on patient outcome and disease progression. It is based on data and prognostic models from Grinfeld and Nangalia et al. 2018. The original publication can be found at Grinfeld et al., N Engl J Med 2018 Oct 11;379(15):1416-30.”