How Advanced Prognostic Models are Shaping Personalized Myelofibrosis Treatment Strategies

Explore the latest advancements in prognostic models for patients with myelofibrosis (MF), revealing the impact of biological architecture and molecular landscape on overall survival, leading to improved treatment decisions and personalized care strategies.

MF is a rare neoplasm characterized by splenomegaly, constitutional symptoms, heterogeneous blood cell alterations, and bone marrow fibrosis. It can evolve into blast phase and includes primary MF (PMF) and secondary MF (SMF). The median age at MF onset is in the seventh decade, but younger patients may also be affected. Specific gene mutations characterize MF and can lead to poor outcomes without proper prognostic assessment and treatment.

The 2009 International Prognostic Scoring System (IPSS) is widely used for assessing prognosis during PMF diagnosis, based on factors such as age, hemoglobin levels, and leukocyte counts. The Dynamic IPSS (DIPSS), developed in 2011, evaluates patients at follow-up and assigns greater importance to anemia. The MIPSS-70 model incorporates mutations and histological features for patients under 70, while the MIPSS-70+ adds cytogenetic data to refine risk assessment further. Additionally, the Genetically Inspired Prognostic Scoring System (GIPSS) focuses solely on cytogenetic and molecular data, showing predictive power like MIPSS-70+. Recent advancements include the integration of artificial intelligence for better prognostic accuracy, alongside studies identifying specific gene expressions linked to outcomes in patients with PMF.

A recent meta-analysis of over 3000 patients with polycythemia vera (PV) treated with hydroxyurea found varying rates of transformation into SMF over time. Evolving into SMF was also observed in 9.5% of subjects with essential thrombocythemia (ET) after 15 years of follow-up. The timing of transformation to SMF appeared to be linked to the type of driver mutation, with patients with CALR-mutated having a longer time to progress. Predictive factors for PV and ET cases evolving into SMF include clinical features, cytogenetic alterations, bone marrow characteristics, driver mutations, and dysregulation of biological pathways. The MYelofibrosis SECondary to PV and ET (MYSEC) project aimed to create a prognostic model for SMF patients based on factors like anemia, blast count, and genetic mutations.

Allogeneic stem cell transplantation (allo-SCT) remains the only curative treatment for patients with MF, with age not being a strict limitation for candidates. Recent guidelines from the European Society for Blood and Marrow Transplantation emphasize evaluating patient outcomes based on MF biology and potential transplant complications, recommending allo-SCT for fit patients under 70 with an expected overall survival below five years. Two scoring systems, the Myelofibrosis Transplant Scoring System (MTSS) and a simpler model by Tamari, help assess risk and predict outcomes, highlighting the importance of personalized approaches that consider clinical and genomic factors in treatment decisions.

Data on the impact of JAKis on outcomes should be interpreted with caution due to limitations in study design and endpoints. Most evidence currently supports the use of RUX, with long-term analysis showing a reduction in risk of death and improved overall survival when treatment is started early. Predictors of survival in patients treated with RUX include baseline prognostic risk factors, spleen response, and RBC transfusions. A new prognostic model, RR6, has been developed to help identify patients who may benefit from alternative treatments or clinical trials based on changes in RUX dose and spleen length during the first 6 months of treatment.

Improved outcomes for patients with MF are attributed to early diagnosis and use of JAKis, but the disease is still severe and requires accurate prognostic definitions. The biological understanding of PMF has led to multiple survival models being used for personalized outcome assessment, particularly in younger patients.

“Majority of MF patients are not suitable for allo-SCT and mostly receive JAKis,” said researchers. “In RUX treated cases, the RR6 model is a useful tool to early identify subjects with reduced survival and that deserve a prompt treatment shift. There are some signs of survival benefit with RUX or innovative drugs in phase 2 studies, but we believe that more definitive evidence could be drawn only by designing trials with survival or its surrogate markers as primary endpoint.” 

Reference
Mora B, Bucelli C, Cattaneo D, et al. Prognostic and predictive models in myelofibrosis. Curr Hematol Malig Rep. 2024;19:223–235. doi:10.1007/s11899-024-00739-6