Personalized Transplant Decision Model for Myelofibrosis

Abstract

Background

Here, we aimed to develop a uniform decision model to define the optimal timing of treatment in MF patients based on clinical and genomic information in the modern era of JAK inhibition.

Patients and methods

We studied a retrospective, international cohort of 1913 patients with primary (PMF, 58%) or secondary MF (SMF, 42%), of whom 1010 patients underwent HCT. All patients who did not undergo HCT were treated with ruxolitinib.

First, we developed a multi-state model to estimate transition hazards between different disease-specific categories. Next, we simulated a randomized clinical trial where subjects are selected to receive HCT at different time points, stratified according to transplant-specific risk and response to ruxolitinib.

Results

Considering the scenario of PMF, a low/intermediate MTSS was associated with better outcomes for early transplantation in all DIPSS categories as well as MIPSS70 intermediate/high risk. Ideal timing of HCT was suggested within first 3 years from diagnosis for DIPSS low/intermediate-1, 2 years for MIPSS70 intermediate, and within 1 year from diagnosis for both DIPSS intermediate-2/high and MIPSS70 high. In contrast, considering a scenario of MTSS high/very high risk, prolonged life expectancy for transplantation was only found for MIPSS70 intermediate/high and DIPSS intermediate-2/high, suggesting delay HCT by an average of 0.5 years.

Considering SMF, a scenario of low/intermediate MTSS was associated with better outcomes for transplantation only for a MYSEC-PM intermediate-2/high risk constellation. Ideal timing of HCT for achieving prolonged life expectancy of patients was suggested within first 1.5 years from diagnosis.

In a next step considering response to ruxolitinib suggested earlier transplantation by an average of 0.5 years for RR6 high risk, while RR6 low risk suggested delayed transplantation by an average of 1 year. Importantly, high risk RR6 suggested earlier HCT for patients with intermediate DIPSS and MYSEC-PM.

Additional genomic constellations significantly affected decision modelling (P<0.001). First, present ASXL1 drove the decision towards delayed transplantation for patients with MYSEC-PM low/intermediate-1 and MTSS low/intermediate risk. Second, patients with TP53 mutation (irrespective of disease type and risk) benefitted from early transplantation within 1 year of diagnosis.

Finally, we developed a novel uniform decision and prognostic model for PMF and SMF and HCT outperforming all current prognostic systems (transplant and nontransplant) with a uniform website application (will be presented at the meeting).

Conclusion

We provided evidence for the relevance of combining all clinico-genomic and treatment-specific in the modern era of genomics and JAK inhibition, enabling personalized decision making in MF.