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Simple Summary: To assess the prognosis of myelofibrosis (MF), one takes into account age and the degree of anemia and leukocytosis together with the presence of very immature cells ("blasts") in the peripheral blood and constitutional symptoms (fever, night sweats and weight loss). Since both disease- and patient-related factors determine the course of disease, we investigated the influence of comorbidities on the prognosis of MF. For this purpose, we applied the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI), which offers a comprehensive tool to assess the extent of comorbidities in a structured way. Cardiac diseases and solid tumors were the comorbidities most often observed in our cohort and overall survival showed significant differences between the single risk groups of the MDS-CI. In addition, we found that the MDS-CI provided prognostic information independently from the standard tool of prognostication, the Dynamic International Prognostic Scoring System (DIPSS), and a related score, which additionally takes the mutational profile of the disease into account (Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70). Taken together, our study suggests that the MDS-CI represents a valuable tool to identify MF patients with an increased vulnerability due to comorbidities. In myelofibrosis, comorbidities (CMs) add prognostic information independently from the Dynamic International Prognostic Scoring System (DIPSS). The Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) offers a simple tool for CM assessment as it is calculable after having performed a careful history and physical examination, a small routine chemistry panel (including creatinine and liver enzymes) and a limited set of functional diagnostics. To assess the prognostic impact of the MDS-CI in addition to the DIPSS and the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70, we performed a retrospective chart review of 70 MF patients who had not received allogeneic stem cell transplantation (primary MF, n = 51; secondary MF, n = 19; median follow-up, 40 months) diagnosed at our institution between 2000 and 2020. Cardiac diseases (23/70) and solid tumors (12/70) were the most common CMs observed at MF diagnosis. Overall survival (OS) was significantly influenced by the MDS-CI (median OS MDS-CI low (n = 38): 101 months; MDS-CI intermediate (n = 25): 50 months; and high (n = 7): 8 months; p < 0.001). The MDS-CI added prognostic information after inclusion as a categorical variable in a multivariate model together with the dichotomized DIPSS or the dichotomized MIPSS70: MDS-CI high HR 14.64 (95% CI 4.42; 48.48), p = 0.0002, and MDS-CI intermediate HR 1.97 (95% CI 0.96; 4.03), p = 0.065, and MDS-CI high HR 19.65 (95% CI 4.71; 81.95), p < 0.001, and MDS-CI intermediate HR 1.063 (95% CI 0.65; 4.06), p = 0.2961, respectively. The analysis of our small and retrospective MF cohort suggests that the MDS-CI represents a useful tool to identify MF patients with an increased vulnerability due to comorbidities. However, analyses of larger cohorts are necessary to define the value of the MDS-CI as a prognostic tool in comparison with other comorbidity indices. [ABSTRACT FROM AUTHOR]

Simple Summary: To assess prognosis in myelofibrosis (MF), age and degree of anemia and leukocytosis are taken into account together with the presence of blasts in the peripheral blood and constitutional symptoms (fever, night sweats, weight loss). The latter are signs of systemic inflammation, which plays a pivotal role in MF pathophysiology. Considering information about genetic changes can refine prognostication. The goal of our retrospective study was to assess the prognostic impact of two laboratory markers of inflammation that are readily available in clinical routine at low costs: C-reactive protein (CRP) and albumin. We found a significant prognostic impact of both parameters either alone or combined within the CRP/albumin ratio or the Glasgow Prognostic Score, which was independent of the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70. Therefore, assessing CRP and albumin helps to identify a vulnerable population of MF patients, which eludes current prognostic models, even if the presence of high-risk mutations is considered. In myelofibrosis, the C-reactive protein (CRP)/albumin ratio (CAR) and the Glasgow Prognostic Score (GPS) add prognostic information independently of the Dynamic International Prognostic Scoring System (DIPSS). Their prognostic impact, if molecular aberrations are considered, is currently unknown. We performed a retrospective chart review of 108 MF patients (prefibrotic MF n = 30; primary MF n = 56; secondary MF n = 22; median follow-up 42 months). In MF, both a CAR > 0.347 and a GPS > 0 were associated with a shorter median overall survival (21 [95% CI 0–62] vs. 80 months [95% CI 57–103], p < 0.001 and 32 [95% CI 1–63] vs. 89 months [95% CI 65–113], p < 0.001). Both parameters retained their prognostic value after inclusion into a bivariate Cox regression model together with the dichotomized Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70: CAR > 0.374 HR 3.53 [95% CI 1.36–9.17], p = 0.0095 and GPS > 0 HR 4.63 [95% CI 1.76–12.1], p = 0.0019. An analysis of serum samples from an independent cohort revealed a correlation of CRP with levels of interleukin-1β and albumin with TNF-α, and demonstrated that CRP was correlated to the variant allele frequency of the driver mutation, but not albumin. Albumin and CRP as parameters readily available in clinical routine at low costs deserve further evaluation as prognostic markers in MF, ideally by analyzing data from prospective and multi-institutional registries. Since both albumin and CRP levels reflect different aspects of MF-associated inflammation and metabolic changes, our study further highlights that combining both parameters seems potentially useful to improve prognostication in MF. [ABSTRACT FROM AUTHOR]

Simple Summary: With demographic ageing, improved cancer survivorship and increased diagnostic sensitivity, incident cases of patients with Myelodysplastic Syndromes (MDS) are continuously rising, leading to a relevant impact on health care resources. Disease heterogeneity and various comorbidities are challenges for the management of the generally elderly patients. Therefore, experienced physicians and multidisciplinary teams should be involved in the establishment of the correct diagnosis, risk-assessment and personalized treatment plan. Next-generation sequencing allows for early detection of clonal hematopoiesis and monitoring of clonal evolution, but also poses new challenges for its appropriate use. At present, allogeneic hematopoietic stem cell transplantation remains the only curative treatment option for a minority of fit MDS patients. All others receive palliative treatment and will eventually progress, having an unmet need for novel therapies. Targeting compounds are in prospect for precision medicine, however, abrogation of clonal evolution to acute myeloid leukemia remains actually out of reach. Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine. [ABSTRACT FROM AUTHOR]