Steroid-refractory graft-versus-host disease (SR-GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Ruxolitinib is food and drug administration (FDA) approved for patients ≥12 years, but data remain limited in other pediatric cohorts. This single-center retrospective study evaluated 77 acute (51% grades III–IV) and 45 chronic (82% severe) SR-GVHD patients under 18 years of age (range 0–17). The overall response rate (ORR) was 83% and 87% in patients with acute and chronic SR-GVHD, respectively. The organ-specific ORRs in chronic SR-GVHD for the skin, gastrointestinal (GI) tract, liver, oral mucosa, eyes, lungs, joints, and genitalia were 71%, 83%, 88%, 56%, 52%, 37%, 42%, and 40%, respectively. Three-year overall survival was 70% (acute) and 85% (chronic). By 3 years, 43% of chronic and 60% of acute patients discontinued all immunosuppression. Age < 12 years did not affect outcomes (acute ORR: 78% vs. 76%, P = 0.96; chronic ORR: 89% vs. 79%, P = 0.14). Hematological toxicity was the main adverse event. The initial ruxolitinib dose correlated with hematologic toxicity and liver function test elevations in chronic GVHD. These results support the efficacy and safety of ruxolitinib across pediatric age groups, though further prospective studies are needed to optimize dosing and long-term monitoring.
T-cell receptor alpha/beta+ T-cell/CD19+ B-cell (TCRαβ+/CD19+) depletion of allografts is increasingly used as a graft manipulation strategy for allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. While outcomes using this approach are encouraging, limited data exist on associated costs and healthcare resource utilization (HRU). We conducted a single-center analysis comparing costs and HRU through HSCT day +100 in patients who received a TCRαβ+/CD19+-depleted (TCD) HSCT ( n = 20) to a contemporary cohort of patients who received a non-TCD HSCT ( n = 22). Median total inpatient costs through day +100 were $623,085 (interquartile range (IQR): $356,466–1,081,013] for TCD HSCTs and $451,876 (IQR: $313,601–787,351) for non-TCD HSCTs ( P = 0.234). Engraftment was rapid, with a median time to neutrophil engraftment of 10.0 versus 21.0 days ( P < 0.001) and platelet engraftment of 11.0 versus 22.0 days ( P < 0.001) for TCD and non-TCD HSCTs, respectively. Length of stay for the initial admission was shorter for patients who received a TCD HSCT (28.5 vs. 34.0 days, P < 0.001). Readmission through day +100 was required for 12 (60.0%) TCD patients and 6 (27.3%) non-TCD ( P = 0.060). In summary, while clinical outcomes were comparable, costs and HRU were not decreased after TCRαβ+/CD19+ depletion.
Inherited bone marrow failure syndromes (IBMFSs) are rare, genetically heterogeneous disorders characterized by BMF with possible increased risk of myeloid malignancies. Recent advances in genomic diagnostic techniques have identified a new IBMFS, including Oncostatin M ( OSM ) deficiency, which is an autosomal recessive condition linked to early-onset BMF with possible predisposition to myelodysplastic syndrome (MDS). OSM is a cytokine in the interleukin-6 family and regulates hematopoiesis through the OSM receptor and leukemia inhibitory factor receptor-mediated signaling, activating pathways essential for hematopoietic stem cell progenitor proliferation and differentiation. The reported cases from consanguineous families presented with early-onset cytopenias of variable severity, and some patients developed MDS. In patients with biallelic variants in OSM , hematologic improvement was observed following eltrombopag in two reported patients, while transfusion dependency and high-risk cytogenetics required hematopoietic stem cell transplantation. OSM deficiency is rare; its mechanistic and clinical parallels with other IBMFS underscore its importance. This review outlines the emerging evidence on OSM’s function in hematopoiesis and its deficiency as a newly recognized IBMFS with a potential predisposition to MDS, highlighting the need for early genetic diagnosis and tailored treatment strategies.
Background: Acute leukemias with KMT2A rearrangements (KMT2Ar) or mutant NPM1 (NPM1m) have historically poor outcomes despite intensive therapy. Menin, a scaffold protein encoded by MEN1, is a critical cofactor for the leukemic transcriptional program in these subsets. Targeting the menin-KMT2A interaction emerged as an effective strategy, leading to the first approvals of menin inhibitors (revumenib and ziftomenib) for relapsed/refractory disease. This review assesses the current evidence and future directions for menin inhibition in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Methods: We systematically searched PubMed, clinical trial registries, and conference proceedings (2015–2025) for studies on menin inhibitors in AML/ALL. Both peer-reviewed articles and pivotal trial data, including FDA labels and regulatory documents, were included. Key trials were appraised for bias using the Cochrane criteria, which indicated a high risk of bias due to single-arm designs and short follow-up. Findings: Menin inhibitors achieve CR or CRh in ∼20%–25% of heavily pretreated KMT2Ar or NPM1m leukemia patients. Median remission duration is ∼5–6 months, with over half of responders attaining minimal residual disease (MRD) negativity. Differentiation syndrome (DS) occurs in ∼15% of patients and is generally reversible with corticosteroids. Menin inhibitors’ class-specific toxicities include QTc prolongation (notable with revumenib) and require careful electrocardiographic monitoring. Acquired resistance arises in ∼40% of relapsed cases via MEN1 point mutations (especially M327I and T349M) that interfere with drug binding. Next-generation menin inhibitors (e.g., bleximenib) retain activity against some resistant variants. In newly diagnosed older adults with NPM1m or KMT2Ar AML, triplet therapy with revumenib, venetoclax, and azacitidine yielded composite CR rates >80% and MRD-negative remissions in nearly all responders. Early integration of menin inhibitors into frontline regimens and maintenance therapy is feasible, including use in pediatric patients ≥1 year old. Emerging AI-driven models (e.g., multimodal drug response predictors and optimal-transport embedding of flow cytometry data) show promise in guiding combination strategies and MRD assessment. Interpretation: Menin inhibitors represent a significant advance for genetically defined acute leukemias, safely delivering clinically meaningful responses in KMT2Ar and NPM1m cases. Ongoing phase 3 studies will clarify if there is a survival benefit and the optimal use. Integrating menin inhibitors with existing therapies, from low-intensity combinations in older adults to intensive chemotherapy backbones in fit patients, is driving unprecedented response rates. Continued research into resistance mechanisms and innovative AI-guided treatment personalization will be essential to extend remission durability. As menin inhibitors move into frontline and pediatric settings, and as maintenance therapy posttransplant, they are positioned to become a new pillar of precision hematology, potentially improving cure rates for high-risk acute leukemia subgroups.
