Interferons (IFNs) are pleiotropic cytokines involved in antiviral defense, immune regulation, and tumor suppression. In myeloproliferative neoplasms (MPNs) and related disorders—including classical BCR, ABL1-negative MPNs, chronic myeloid leukemia (CML), and rarer entities such as chronic neutrophilic leukemia and hypereosinophilic syndromes—disease pathogenesis arises from a spectrum of somatic and structural genetic abnormalities and chronic inflammation, in which IFNs play a paradoxical role. They contribute to disease pathogenesis by promoting abnormal hematopoiesis and immune dysregulation, while also representing a therapeutic option capable of inducing hematologic and molecular remissions. This review outlines the biology and classification of IFNs, focusing on their signaling pathways and downstream effects in both normal and malignant hematopoiesis. We discuss the dual impact of IFN signaling on hematopoietic stem cells, including induction of proliferation, senescence, apoptosis, and DNA damage, and how these mechanisms may both sustain clonal evolution and facilitate disease control. Clinical data supporting the efficacy and safety of IFN-α, particularly pegylated formulations, in polycythemia vera, essential thrombocythemia, myelofibrosis, and chronic myeloid leukemia are reviewed, along with insights into next-generation IFNs and combination therapies. Understanding the dichotomous effects of IFNs in MPNs not only clarifies their role in disease biology but also informs their optimal use in clinical practice. This duality highlights the need for personalized approaches to IFN-based therapies.

Background: Ibrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), has revolutionized the treatment of Chronic Lymphocytic Leukemia (CLL), yet hepatotoxicity remains a rare and poorly characterized adverse event. Case Presentation: We report the case of a 54-year-old man with progressive CLL and radiologically confirmed hepatic involvement who developed acute hepatocellular injury during ibrutinib monotherapy. Baseline liver tests showed mild abnormalities attributed to hepatic steatosis and leukemic infiltration. After approximately 10–12 weeks of ibrutinib (420 mg/day), transaminases markedly increased (ALT 660 U/L, AST 326 U/L), while bilirubin and synthetic function remained normal. Viral, autoimmune, and obstructive causes were excluded. Stepwise dose reductions to 140 mg/day provided limited benefit. The addition of prednisone (50 mg/day) led to rapid biochemical improvement. Ibrutinib was successfully re-escalated to 280 mg/day alongside venetoclax initiation, maintaining disease control without recurrence of liver injury. Discussion: The temporal relationship, exclusion of alternative causes, and corticosteroid responsiveness suggest an ibrutinib-induced liver injury, possibly exacerbated by pre-existing hepatic steatosis and leukemic infiltration. Conclusions: This case underscores the multifactorial pathogenesis of BTKi-related hepatotoxicity and highlights the potential role of corticosteroids in management. Prompt recognition, stepwise dose adjustment, and corticosteroid therapy may enable continued treatment and sustained disease control in selected patients.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm characterized by CSF3R mutations. Here, we report the first case of a CNL patient positive for a de-novo germline CSF3R T618I variant effectively treated with ruxolitinib and pegylated interferon (peg-IFN), obtaining normalization of blood counts and maintaining good disease control for over 8 years. In addition, the RUNX1 L56S variant was detected at diagnosis and confirmed in subsequent next-generation sequencing (variant allele frequency of 50.4%). Although this variant has been debated, it is now widely recognized as a benign polymorphism and current evidence shows it does not modify prognosis. Our report adds to the growing body of evidence confirming the importance of a good evaluation of the mutational status of driver mutations in the setting of germline variants.