Histiocytic disorders are characterized by abnormal accumulation of myeloid-derived histiocytes and a shared biology marked by RAS/MAPK/ERK pathway activation, yet the rarity and heterogeneity of these conditions have limited the availability of robust, well-controlled clinical trials to guide therapy. This review highlights Langerhans cell histiocytosis, the most common subtype, and Rosai-Dorfman disease, a less common non–Langerhans cell histiocytosis entity, using them as key examples to illustrate how advancements in molecular diagnostics and targeted MAPK inhibitors are reshaping clinical management in histiocytic disorders. In both disorders, treatment approaches range from active observation in mild cases to more aggressive interventions in high-risk or progressive disease, emphasizing the spectrum of clinical presentations and the need for individualized, biology-driven strategies.
Low- and intermediate-risk myelodysplastic syndromes (LR-MDS and Int-MDS, respectively) are characterized by ineffective hematopoiesis, along with the presence of at least 10% dysplasia in one cell line, accompanied by a low number and depth of peripheral blood cytopenias, a low bone marrow blast percentage, and a score of ≤0 on the Molecular International Prognostic Scoring System (IPSS-M). The information gleaned from mutational profiles at the time of myelodysplastic syndrome (MDS) diagnosis and over subsequent time points help with classification and prognosis, guiding therapeutic decisions. In LR-MDS, these decisions are initially focused on improving symptom control and optimizing hematologic parameters. New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits. Patients can derive years of benefit from these approaches in LR-MDS, but despite these therapies, ultimately MDS will evolve into higher-risk MDS (HR-MDS)/acute myeloid leukemia. Even though most LR-MDS patients present with anemia, patients can have isolated thrombocytopenia for which thrombopoietin receptor analogues can be used if blasts are low. Immunosuppressive therapy such as antithymocyte globulin is favored in the hypocellular MDS setting. Dose-modified hypomethylating agent use can be considered for LR-MDS, although neither overall survival (OS) nor progression-free survival (PFS) has been shown to improve with this approach. Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1
Arterial and venous thromboses differ in pathophysiology but share overlapping risk factors such as obesity, metabolic syndrome, and aging. Patients with established arterial disease, such as coronary artery disease, stroke, and peripheral artery disease, may develop venous thromboembolism (VTE) during the acute or chronic phase of their illness. This creates therapeutic tension when anticoagulation for VTE overlaps with antiplatelet therapy. We propose a stepwise clinical approach that first identifies precipitating factors for VTE, then modifies antiplatelet therapy according to the chronicity of the arterial condition and finally estimates thrombosis against bleeding risk aided by scoring systems, available evidence for combination treatment, and interdisciplinary collaboration. Two clinical cases exemplify this stepwise approach.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a complex paraneoplastic syndrome related to a lambda-restricted low–tumor burden neoplasm. The diagnosis must be considered in the context of what might otherwise be believed to be a “monoclonal gammopathy of undetermined significance,” with unusual features including, but not limited to, peripheral neuropathy, thrombocytosis, and extracellular volume overload. Once a diagnosis of POEMS syndrome is made, besides very specific supportive care, the treatments resemble those of multiple myeloma or solitary plasmacytoma of the bone. Based on case series, autologous stem cell transplant is still a favored therapy with durable remissions even without maintenance therapy. Even before the era of therapeutic monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor antibodies, 10-year overall survival approached 80%. Patients achieving a complete hematologic response have a progression-free survival of 88% even without maintenance therapy. Herein, a case of a patient with a less-than-average outcome is described to highlight some of the long-term challenges and complexities of managing patients with POEMS syndrome.
Allogeneic hematopoietic stem-cell transplantation is a curative modality for hematologic malignancies, bone marrow failure syndromes, hemoglobinopathies, and other nonmalignant disorders. Graft-versus-host disease (GVHD)—in its acute or chronic form—is an important transplant complication. The effective prevention of GVHD is crucial to the success of allotransplantation. Acute GVHD is mediated by the recognition of recipient antigens by donor T lymphocytes, with the subsequent activation and proliferation of T cells and establishment of an inflammatory cytokine cascade. Chronic GVHD is mediated by T-cell, B-cell, and macrophage activation with eventual inflammation and fibrosis. Standard approaches for GVHD prevention have been calcineurin-inhibitor (CNI) based, while newer approaches have focused on adding in-vivo T-cell modulation to a CNI backbone with antimetabolites such as posttransplant cyclophosphamide (PTCy), checkpoint blocking agents such as abatacept, or mammalian target of rapamycin (mTOR) inhibition with sirolimus. Still other approaches focus on blocking T-cell trafficking to target organs via integrin blockade (vedolizumab), cytokine blockade (JAK inhibitors), and B-cell blockade for chronic GVHD prevention. The use of PTCy and abatacept have improved allotransplantation safety and efficacy with human leukocyte antigen (HLA)-mismatched as well as HLA-matched donors, thus expanding the donor pool greatly for patients of all ancestries, and ushering in a new era in transplantation where donors are available for almost every patient.
