Acute myeloid leukemia (AML) is characterized by differentiation arrest, driving blast proliferation, and abnormal blood formation. While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents. This narrative review synthesizes preclinical and clinical evidence into differentiation-inducing therapy, with a focus on IDH1/2, FLT3 and menin inhibitors. Following SANRA guidelines, we searched PubMed (2010–September 2025) for clinical trials and key preclinical studies, with particular attention to the molecular mechanism of differentiation induction, clinical efficacy, and the management of differentiation syndrome (DS). IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30–94% in AML with DS in 10–19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33–88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10–25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1–5%. Resistance mutations limit durability and combinations enhance efficacy. Differentiation therapy represents a paradigm shift towards non-cytotoxic AML management. Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL.

Primary Mediastinal Large B Cell Lymphoma (PMLBCL) is a rare but aggressive B-cell lymphoma. This study compares the outcomes and toxicities of DA-EPOCH-R (Dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin in combination with rituximab) and RCHOP-21 (rituximab, cyclophosphamide, doxorubicin, and vincristine, every 21 days) in the treatment of newly diagnosed PMLBCL. We retrospectively reviewed the medical records of adults (>18 years) diagnosed with PMLBCL and treated at our center from 2010 to 2023. Baseline characteristics were compared using chi-square and Mann Whitney U-tests. Survival outcomes were analysed using Kaplan Meier and log-rank tests. Eighty-seven patients were included, with a median age of 30 years (range: 18-55), 48 patients (55.2%) received RCHOP-21, and 39 patients (44.8%) received DA-EPOCH-R. Radiotherapy was more frequent in the RCHOP-21 group (66.6% vs 15%, p < 0.001). DA-EPOCH-R achieved a higher complete metabolic response (CMR) (92% vs 69%, p = 0.007). After a median follow-up of 47.4 months, patients treated with DA-EPOCH-R had superior overall survival (OS) and progression free survival (PFS); 3-year OS rates were 94.4% vs 69.8% (p = 0.01) and the 3-year PFS rates were 86.7% vs 62.2% (p = 0.016), particularly in patients with aa-IPI >1. Post-chemotherapy delta SUV max <0.75, and <0.7 correlated with relapse and mortality, respectively. Grade III-IV anemia and non-hematological toxicities were more frequent in the DA-EPOCH-R, but no therapy-related deaths occurred. DA-EPOCH-R improves CMR, PFS, and OS compared to R-CHOP-21 with radiotherapy in PMLBCL, particularly in high-risk patients. Longer follow-up is needed to assess long-term toxicities.

Measurable residual disease (MRD) is the most powerful predictor of relapse and long-term survival in adult acute lymphoblastic leukemia (ALL), consistently outperforming traditional clinical and cytogenetic risk factors. The advent of high-sensitivity next-generation sequencing (NGS) capable of detecting MRD at 10⁻⁶ has transformed monitoring, reclassifying a substantial proportion of patients previously deemed negative by multiparameter flow cytometry (MFC) or quantitative PCR (qPCR), and revealing clinically relevant disease persistence at ultra-low levels. This review synthesizes current MRD detection platforms and their clinical applications across frontline therapy, allogeneic hematopoietic cell transplantation, and relapsed/refractory disease with specific focus on B-ALL. We integrate the 2024 European LeukemiaNet (ELN) and the 2025 US expert panel recommendations, highlighting important differences in preferred methodologies and decision thresholds. Particular attention is given to the emerging role of early deep NGS negativity in guiding transplant deferral among selected standard-risk patients, including some with Ph+ ALL treated with chemotherapy-free regimens, and to the challenges of interpreting persistent low-level positivity (10⁻⁴–10⁻⁶). Despite technological advances, key questions remain: when should deeper detection trigger therapeutic escalation, and how should discordance between modalities, peripheral blood monitoring, and subtype-specific variability be interpreted? Addressing these issues through prospective validation, platform harmonization, and broader global access will be essential to ensure that increasing sensitivity translates into evidence-based, equitable clinical benefit.

Acute Myeloid leukemia (AML) is characterized by differentiation arrest, driving blast proliferation and abnormal blood formation. While differentiation therapy revolu-tionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents. This narrative review synthesizes preclinical and clinical evidence in-to differentiation-inducing therapy, with a focus on IDH1/2, FLT3 and menin inhibi-tors. Following SANRA guidelines, we searched pubmed (2010-sep,2025) for clinical trials and key preclinical studies, with particular attention to the molecular mecha-nism of differentiation induction, clinical efficacy and management of differentiation syndrome (DS). IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rate (ORR) of 30-94% in AML with DS in 10-19%. Menin inhibitors (re-vumenib, ziftomenib, enzomenib, bleximenib) achieve an ORR of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3-inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%. Resistance mutations limit durability and com-binations enhance efficacy. Differentiation therapy represents a paradigm shift to-wards non-cytotoxic AML management. Improved recognition of DS and rational combination approaches will be essential to maximize therapeutic benefit. Future re-search should address mechanisms of resistance and biomarkers to achieve cure be-yond APL.