Search Results (37)

After many years of stagnation in the treatment of acute myeloid leukemia (AML), there is currently a rapid move towards personalized medicine. Improvements in molecular diagnostics, risk assessment tools, targeted therapies, overall patient fitness assessments, and quality-of-life assessments have significantly changed how patients are treated. Genetic and molecular analyses, risk and health assessments, and measurable residual disease (MRD) monitoring are now integral to the treatment plan for evaluating patient responses and recurrence. In this regard, lower-intensity treatments are provided to older or unfit individuals. On the other hand, younger patients are usually subjected to curative therapies such as intensive chemotherapy to induce remission. Depending on their fitness and disease risk, they can be considered for hematopoietic cell transplantation, which is done after close observation for MRD. In addition, newer therapeutic drugs and immunotherapy techniques are being applied for patient management. Tremendous strides have been made in improving the efficiency of treatment programs in the relatively new area of personalized AML therapy, with a focus on functionality. Full article

Background: Chromosomal rearrangements involving lysine methyltransferase 2A (KMT2A) define a genetically distinct subset of acute myeloid leukemia (AML) in 10% of cases in adult patients; the frequency of KMT2A-r is higher in pediatric AML. Translocations involving the KMT2A locus at chromosome 11q23 result in the formation of a chimeric oncogene partner, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The leukemogenic activity of KMT2A-fusion partners is related to their capacity to hyperactivate the expression of HOX-A and MEIS1 target genes, which stimulate the proliferation of hematopoietic stem cells. The oncogenic activity of KMT2A fusion proteins requires the binding with Menin, and this interaction can be targeted pharmacologically by small molecules acting as potent and selective Menin inhibitors. Methods: A search of the literature showed a marked development of experimental studies exploring the molecular pathogenesis of AML with KMT2A-r and of clinical studies evaluating new induction intensive treatments and the development of a targeted therapy based on Menin inhibitors. Results and Conclusions: In the present review article, we summarize our current understanding of the biology of KMT2A-r in AML development and the recent consistent progress made in the treatment of KMT2A-r AML through new chemotherapy regimens and targeted therapy using Menin inhibitors. However, the prognosis of older KMT2A-r AML patients remains poor and could be improved by drug combination studies including Menin inhibitors. Many encouraging observations derived from ongoing clinical trials with Menin inhibitors need to be confirmed through randomized clinical trials. Full article

For decades, induction treatment of acute myeloid leukemia consisted of intensive chemotherapy for induction. High relapse rates and severe toxicity resulted in a five-year overall survival of ~30%. In patients ineligible for intensive treatment, hypomethylating agents (HMA) could be administered but generally failed to induce durable remissions. These limitations have driven the development of targeted drugs and less toxic therapeutic regimens. In the past decade, fourteen new agents have gained FDA and/or EMA approval, including small-molecule inhibitors targeting FLT3, IDH1, IDH2, BCL-2, menin, and the hedgehog pathway, as well as a CD33-directed antibody-drug conjugate. The combination of targeted drugs with intensive chemotherapy or HMA has resulted in improved remission rates and prolonged survival in certain patient subpopulations. However, many promising combinations are currently being evaluated in randomized trials and are not yet available in clinical routine. A combination that has become standard of care is HMA plus venetoclax for patients unfit for intensive chemotherapy, achieving high remission rates with relatively manageable toxicity. Moreover, targeted drugs directed against FLT3 and IDH1 have been approved in combination with intensive chemotherapy and HMA, respectively. Clinical decision-making requires rapid molecular diagnostic testing, assessment of a patient’s fitness for intensive chemotherapy, and management of toxicities and drug interactions. This narrative review, illustrated with patient vignettes, summarizes currently available therapies, guides through the latest trials on frontline combinations in AML, and provides a preview of how the therapeutic landscape may evolve in the near future. Full article

The development of targeted treatments, including inhibitors of BCL-2, FLT3, IDH1/2, and menin, has significantly expanded the therapeutic landscape of acute myeloid leukemia (AML), offering more personalized and molecularly driven treatment approaches. Despite these advances, achieving durable responses represents a major challenge, limited by the emergence of intrinsic and acquired resistance to targeted agents. This review summarizes the current understanding of the cellular and molecular mechanisms underlying resistance to targeted therapies in AML. Key mechanisms include acquired mutations that alter the drug target, other co-occurring genetic and epigenetic alterations, activation of bypass signaling pathways, and metabolic reprogramming. Furthermore, the role of clonal heterogeneity and the bone marrow microenvironment in the development of resistance is increasingly recognized. In addition, we discuss emerging strategies aiming at overcoming resistance, such as combination treatments and novel inhibitors designed to target resistant clones. Finally, this review highlights the critical need for mechanism-driven therapeutic design in order to achieve sustained responses and improve long-term outcomes in patients with AML. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with historically poor outcomes, particularly among older adults and patients harboring high-risk molecular features. Advances in genomic profiling have enabled the development of targeted therapies, reshaping treatment algorithms beyond conventional cytarabine-anthracycline induction and hypomethylating agent-based regimens. This review summarizes current evidence and emerging therapeutic strategies across four evolving areas: menin inhibition, FLT3 inhibition, IDH inhibition and treatment approaches for TP53-mutated AML. Methods: We reviewed published clinical trials, preclinical studies, and ongoing clinical trials evaluating targeted therapies in AML. Emphasis was placed on agents with regulatory approval or substantial clinical development, including menin inhibitors, FLT3 inhibitors, IDH inhibitors and novel therapies directed at TP53-mutated disease. Mechanistic data, response rates, survival outcomes, and resistance patterns were analyzed to provide an updated overview of therapeutic progress. Results: Menin inhibitors have demonstrated significant activity in NPM1-mutated and KMT2A-rearranged AML, with agents such as revumenib and ziftomenib producing meaningful remission rates and ongoing studies exploring combination strategies to mitigate resistance. FLT3 inhibitors, including midostaurin, gilteritinib, and quizartinib, have improved survival in FLT3-mutated AML, while emerging evidence supports potential benefit in selected FLT3–wild-type disease based on FLT3-like gene expression signatures. IDH inhibitors, namely ivosidenib and enasidenib, have provided increased efficacy in AML patients carrying these mutations. Questions still remain regarding their efficacy in contrast to venetoclax which has been shown to be particularly effective against this population. In contrast, TP53-mutated AML remains a therapeutic challenge: although hypomethylating-agent/venetoclax-based regimens yield improved initial responses, remissions are generally short-lived and overall survival remains poor. Early-phase therapies, including p53 reactivators and multi-kinase inhibitors, show preclinical promise but lack definitive clinical efficacy to date. Conclusions: Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets. Full article

Menin inhibitors are the first targeted therapies for KMT2A-rearranged and NPM1-mutated acute leukemias, addressing a significant unmet need in these high-risk subtypes. Revumenib received approval in 2024–2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML. The AUG-MENT-101 trial reported a 23% composite complete remission rate in heavily pretreated patients, with 61% of responders achieving MRD negativity. Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development. They demonstrate similar efficacy, but their safety profiles differ, especially regarding QTc prolongation and coverage of resistance mutations. Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment. Acquired resistance, often due to MEN1 mutations at the drug-binding interface, occurs in about 40% of cases. Distinct resistance patterns among menin inhibitors suggest the possibility of sequential therapy. Approximately 30–40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination. Full article

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. Full article

Acute myeloid leukemia (AML) is a highly aggressive malignancy defined by significant biological diversity and variable patient outcomes. A key subset of AML is driven by abnormalities that lead to the overexpression of the oncogenic transcription factors HOXA9 and MEIS1. These abnormalities include KMT2A (formerly MLL) rearrangements and NPM1 mutations, as well as other rare lesions such as NUP98 rearrangements. This review focuses on the biology of the KMT2A, NPM1, and HOX/MEIS1 pathways, dissecting their molecular mechanisms of leukemogenesis. A central theme is the role of the scaffolding protein menin in the epigenetic regulation of this pathway, which ultimately drives malignant transformation. Currently, the clinical landscape is being transformed by the emergence of menin inhibitors as promising therapeutic agents for AML harboring these specific genetic anomalies. We evaluate the latest data on various menin inhibitors—both as monotherapy and in combinations—emphasizing their efficacy and safety profiles. As new evidence continues to accumulate with recent drug approvals and ongoing randomized, phase 3 studies, menin inhibitors are rapidly becoming a component of the AML treatment paradigm for relapsed/refractory and likely newly diagnosed disease. Full article

KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL), particularly in infants, represents one of the most aggressive pediatric hematological malignancies with a historically dismal prognosis. While KMT2A-AFF1 (t(4;11)) is the most prevalent fusion, a diverse array of partner genes exists, each conferring distinct biological and clinical features. This review focuses on the rare but clinically significant KMT2A-AFF3 subtype, which arises from the t(2;11)(q11.2;q23) chromosomal translocation. This review summarizes the molecular pathogenesis driven by the KMT2A-AFF3 fusion oncoprotein, which functions as an aberrant transcriptional complex. This complex hijacks essential epigenetic machinery, including the recruitment of DOT1L and interaction with Menin, leading to pathogenic histone modifications (e.g., H3K79 hypermethylation) and the subsequent upregulation of critical target genes, notably the HOXA cluster and MEIS1, thereby enforcing a B-lymphoid differentiation arrest at the pro-B/pre-B stage. Clinically, KMT2A-AFF3 ALL is characterized by high-risk features, including infant onset, hyperleukocytosis, central nervous system (CNS) involvement, and a distinct CD10-negative immunophenotype. This review highlights the evidence defining its poor prognosis, which is primarily driven by profound chemoresistance to conventional therapies, including glucocorticoids. Finally, we discuss the rapidly evolving therapeutic landscape, detailing the limitations of standard intensive chemotherapy and the immense promise of novel targeted strategies, such as Menin inhibitors (e.g., Revumenib), DOT1L inhibitors, and immunotherapies (e.g., CAR-T cells, Blinatumomab), which hold the potential to revolutionize outcomes for this high-risk leukemia subtype. Full article

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the clonal proliferation of myeloid precursors and rapid progression. Historically consisting of intensive chemotherapy, AML management has evolved significantly due to advances in molecular diagnostics and risk stratification. This review discusses current therapeutic paradigms in AML, emphasizing the growing role of personalized medicine across age and risk groups. For younger, fit patients, intensive regimens such as the “7 + 3” protocol remain the standard, often enhanced by targeted agents like FMS-like tyrosine kinase 3 (FLT3) and IDH inhibitors. Older or unfit individuals benefit from low-intensity treatments such as hypomethylating agents combined with venetoclax, now considered a frontline standard of care. The use of liposomal chemotherapy (CPX-351), measurable residual disease (MRD) monitoring, and maintenance therapy further refine post-remission strategies. Emerging therapies, including menin inhibitors, antibody–drug conjugates, and immunotherapies like CAR-T cells and vaccines, offer additional options, especially in relapsed/refractory settings. This comprehensive review outlines the current landscape and future directions in AML therapy, emphasizing the transition toward individualized, mutation-driven treatment strategies. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare malignancies, accounting for 1–2% of pancreatic cancers, with an incidence of ≤1 case per 100,000 individuals annually. Originating from pancreatic endocrine cells, pNETs display significant clinical and biological heterogeneity. Traditional classification based on proliferative grading does not fully capture the complex mechanisms involved, such as oxidative stress, mitochondrial dysfunction, and tumor-associated macrophage infiltration. Recent advances in molecular profiling have revealed key oncogenic drivers, including MEN1 (menin 1), DAXX (death domain–associated protein), ATRX (alpha thalassemia/mental retardation syndrome X-linked), CDKN1B (cyclin-dependent kinase inhibitor 1B) mutations, chromatin remodeling defects, and dysregulation of the mTOR pathway. Somatostatin receptors, particularly SSTR2, play a central role in tumor biology and serve as important prognostic markers, enabling the use of advanced diagnostic imaging (e.g., Gallium-68 DOTATATE PET/CT) and targeted therapies like somatostatin analogs and peptide receptor radionuclide therapy (PRRT). Established biomarkers such as Chromogranin A and the Ki-67 proliferation index remain vital for diagnosis and prognosis, while emerging markers, like circulating tumor DNA and microRNAs, show promise for enhancing disease monitoring and diagnostic accuracy. This review summarizes the molecular landscape of pNETs and highlights genomic, transcriptomic, proteomic, and epigenomic factors that support the identification of novel diagnostic, prognostic, and therapeutic biomarkers, ultimately advancing personalized treatment strategies. Full article

Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements (KMT2Ar) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with NPM1m—which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with KMT2Ar—and is present in 5–10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the MEIS1–HOXA axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For KMT2Ar AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In NPM1m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed NPM1m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by HOX and MEIS1, disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options. Full article

The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML); the gene, located in the nucleolus, codes for a protein that normally shuttles between the nucleus and the cytoplasm of the normal hematopoietic cells. Patients harboring NPM1 mutations are diagnosed as having NPM1-mutated AMLs, which are types of leukemia with distinct clinical and laboratory characteristics. The essential diagnostics for investigating NPM1-mutated AMLs, the interactions with concomitant mutations affecting prognosis and the therapeutic interventions that the treatment of such patients requires are discussed in this review. Novel investigational agents in current clinical trials are also highlighted, along with the roles of exportin 1 (XPO1), menin-KMT2A inhibitors and immunotherapy in NPM1-mutated AMLs. This review focuses on critically evaluating the available data and aims to reveal the secrets of NPM1-mutated AMLs. Full article

Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody–drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies. Full article

Acute myeloid leukemia (AML) is characterized by the clonal expansion of myeloid progenitors blocked at various stages of their differentiation process, and drugs that bypass this differentiation block are therapeutically efficient, as shown by retinoic acid and arsenic trioxide in acute promyelocytic leukemia. However, the successful application of differentiation therapy in APL has not translated into clinical benefit for other non-APL subtypes of AML, in which intensive chemotherapy regimens represent the standard of care. However, the development of molecular studies has led to the identification of therapeutic targets (such as mutated proteins and deregulated pathways) and has led to the generation of a new category of specific pharmacologic agents. Some of these agents, such as inhibitors of mutant isocitrate dehydrogenase (IDH1 and IDH2), lysine-specific demethylase-1 (LSD1), and Menin, have shown the capacity to induce leukemic cell differentiation and with significant therapeutic efficacy. Full article