Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/10⁵ peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.

(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. (2) Methods: In this retrospective, single-center study, we compared allo-HSCT outcomes in 36 adult patients with MF transplanted at two-time intervals (2001–2015 versus 2016–2021). (3) Results: The estimated median overall survival was 48.9 months (95%CI 0.00–98.2) in the cohort transplanted before 2016 and not reached in the more recent years (p = 0.04) due to markedly lower non-relapse mortality (p = 0.02). The 3-year relapse incidence was low in both cohorts (11.1% and 12.5%, p > 0.99). When comparing only subgroups within the more recent cohort based on the presence or absence of total body irradiation (TBI) or the use of sequential regimens, OS and PFS were comparable. (4) Conclusion: Pretreatment with ruxolitinib, intensified conditioning, and the preferential use of haploidentical related instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allo-HCT in MF in recent years.

Background: Pre-fibrotic myelofibrosis (pre-PMF) is a rare subentity of myeloproliferative neoplasm (MPN) with limited overall survival and the potential for progression toward overt, symptomatic myelofibrosis or blastic transformation. To date, a consensus on the treatment of pre-PMF, especially in asymptomatic cases, has yet to be reached. Interferon therapy has been employed as an effective treatment for MPN for many decades, due to its immunomodulatory properties and disease-modifying effects. Methods: The objective of this monocentric study was to evaluate hematological, molecular, and clinical responses, as well as the overall outcome, to pegylated interferon (peginterferon) in pre-PMF cases harboring a JAK2 or CALR mutation. Results: In a cohort of 55 consecutive patients with a median follow-up period of 3.89 (1.63; 6.10) years, a high rate of complete hematological response (81%) was documented after 24 months. Deep molecular responses with a >50% reduction in allele burden were documented in 54.6% of the JAK2-mutated and 7.7% of CALR-mutated patients, respectively (p = 0.023). Concerning fibrosis, at least the stabilization of disease was achieved in 73% of evaluable patients. Furthermore, only one case of blastic transformation was observed, along with three cases of thromboembolic events in the JAK2-mutated cohort. Conclusions: The study confirms the substantial efficacy of interferon in pre-PMF patients with rapid hematological normalization in most patients. Molecular responses were striking, but largely confined to JAK2-mutated patients. To our knowledge, this is the largest retrospective cohort of strictly WHO-defined pre-PMF patients treated with interferon and observed for a reasonable duration of time.