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D.P. McLornan et al.
The transplant decision: how to decide who should be considered for allogeneic stem cell transplantation
Utilization of established and novel prognostic scoring systems in myelofibrosis
Clinical prognostic scoring systems play a pivotal role in decisions regarding allogeneic SCT. Until recently, the most commonly applied was the International Prognostic Scoring System (IPSS) which estimates survival from time of diag- nosis.8 The score is based upon five factors: age >65 years, hemoglobin <100 g/L, leukocyte count >25x109/L, circulat- ing blasts ≥1% and constitutional symptoms, permitting stratification into four groups: low risk (0 risk factors; esti- mated median survival, 135 months), intermediate risk-1 (1 risk factor; median survival, 95 months), intermediate risk- 2 (2 risk factors, median survival, 48 months) and high risk (3+ risk factors; median survival, 27 months). The Dynamic IPSS (DIPSS), utilizing the same five factors, permits appli- cation of the scoring system at any stage in the disease course.9 Finally, the DIPSS-plus incorporates three addition- al adverse factors – transfusion dependency; platelet count <100x109/L and unfavorable cytogenetics.10,11 We follow current European LeukemiaNet/EBMT expert consensus whereby “Patients with intermediate-2- or high-risk disease according to the IPSS, DIPSS or DIPSS-plus and age <70 years should be considered potential candidates for allo- geneic SCT”.12 Patients with “intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood >2%, or adverse (as defined by the DIPSS-plus classification) cytogenetics”. Decisions regarding transplantation for inter- mediate-1-risk disease remain complex and are discussed below.
A retrospective, comparative multicenter outcome analy- sis of 438 patients with primary myelofibrosis aged <65 years at diagnosis who underwent allogeneic SCT (n=190) or conventional therapy in the era before JAK inhibitors (n=248), utilizing DIPSS scoring, demonstrated that allo- geneic SCT clearly benefited intermediate-2 or high-risk patients whereas for low-risk disease, transplantation is not immediately indicated and is held in reserve for progressive disease.13 For intermediate-1 disease, individual counseling was recommended. Despite evident utility, marked hetero- geneity may be observed within each allocated IPSS/DIPSS subgroup. Grinfeld et al. performed genomic and clinical phenotype analyses of 2,041 patients with myeloprolifera- tive neoplasms, including 311 with myelofibrosis, and com- bined the findings into a unifying patient-specific predictive model.14 For myelofibrosis, this model predicted event-free survival better than did either the DIPSS or IPSS (81% versus 69% versus 77% concordance) and an online calculator is being developed for predicting patient-specific outcomes (https://jg738.shinyapps.io/mpn_app/). It will be of interest to apply this model to a population of myelofibrosis patients undergoing allogeneic SCT.
A collaborative group recently studied 685 molecularly- annotated patients with secondary myelofibrosis to assess whether an independent prognostic scoring system could be derived.15 The so-called MYelofibrosis SECondary to PV and ET-Prognostic Model (MYSEC-PM) allocated individu- als into four prognostic categories based on negative predic- tors of survival whereby two points were attributed to hemoglobin <110 g/dL, a CALR-unmutated phenotype and circulating blasts ≥3%, one point to thrombocytopenia
<150x109/L and constitutional symptoms and 0.15 points to any year of age. Median survival estimates for each group ranged from not reached in the low-risk cohort to 2 years in high-risk cohorts. Akin to IPSS/DIPSS, recent analyses sug- gested that transplant-specific age-adjustment of the MYSEC-PM provided prognostic predictive power as regards overall survival following allogeneic SCT.16-18
The role of mutational profiling in allogeneic stem cell transplant decisions
Comprehensive mutational profiling has helped identify heterogeneous somatic mutations in patients with myelofi- brosis. Delineation of this mutational landscape confers prognostic significance as regards overall survival and risk of disease progression/transformation and increasingly influences therapeutic decisions (Table 1).19-22 In the non- transplant setting, it is well established that myelofibrosis patients with CALR type-1/like mutations survive longer than patients with CALR type-2/like and MPL or JAK2 mutations.21 ‘Triple negativity’, i.e. lacking a detectable JAK2, MPL or CALR mutation, is associated with more adverse outcomes. Previous analyses of 617 myelofibrosis patients revealed that the median survival was only 3.2 years for those who were ‘triple negative’.19 Conventionally, high molecular risk myelofibrosis is defined by the presence of at least one of EZH2, ASXL1, IDH1/2 and SRSF2 muta- tions and is associated with worse overall and leukemia- free survival.22
These data raise the question of whether earlier trans- plantation should be considered for those who have ‘triple negative’ disease, particularly with high molecular risk mutations, and need to be taken into consideration when counseling patients, particularly transplant-eligible individ- uals with intermediate-1-risk disease and 'good' donors. Recently, Guglielmelli and colleagues described the utility of both the mutation-enhanced IPSS ‘MIPSS70’ and ‘MIPSS70-plus’ (including cytogenetic evaluation) scoring systems for ‘transplant-age’ patients ≤70 years old with either pre-fibrotic or overt, primary myelofibrosis who were considered candidates for transplantation.23 Significant risk factors for overall survival were leukocyte count >25x109/L, platelet count <100x109/L, presence of >2 high molecular risk mutations, hemoglobin <100 g/L, peripheral blood blasts ≥2%, constitutional symptoms, high molecular risk category, fibrosis grade >2 and absence of CALR type- 1/like mutations. These scoring systems enabled three dis- crete prognostic risk categories to be delineated: low-risk, intermediate-risk and high-risk with 5-year survival rates of 95%; 70% and 29%, respectively. The MIPSS70-plus included cytogenetics in the multivariable analysis. Recent updates to ‘MIPSS70-plus version 2’ occurred with recogni- tion of U2AF1Q157 as a high molecular risk mutation and the scoring system uses new sex- and severity-adjusted hemo- globin thresholds.24 Importantly these scores incorporate current molecular data and up-to-date WHO 2016 disease classification and will aid decisions regarding allogeneic SCT.
It can be difficult when a clinician is managing a young, fit patient with myelofibrosis who has intermediate risk-1 disease and a fully matched donor. Should we transplant upfront when the patient is fit, and the donor is available or should we wait for further disease upstaging before consid- ering allogeneic SCT? Collectively, we feel that this is a very individualized choice, and has many strata including the patient’s wishes and donor type, disease-associated
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haematologica | 2019; 104(4)