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ABSTRACT FLT3 mutations are among the most common genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Significant advancements have been made in developing FLT3 inhibitors (FLT3Is), such as quizartinib, which have improved treatment outcomes in both newly diagnosed and relapsed/refractory AML. Resistance to FLT3Is remains a major clinical challenge, driven by diverse mechanisms including FLT3 point mutations, cellular escape pathways, and the influence of the bone marrow microenvironment. Sustained STAT5 phosphorylation, AXL upregulation, and CXCR4 signaling have been identified as key factors in FLT3I resistance. Additionally, metabolic adaptations have been shown to support the survival of FLT3I‐resistant cells. Ongoing clinical trials are investigating various combination regimens, including quizartinib with chemotherapy, Bcl‐2 inhibitors, hypomethylating agents, and immune‐modulatory drugs, with promising preliminary results. The European LeukemiaNet 2022 guidelines recommend incorporating FLT3Is into treatment regimens; however, questions remain regarding the best timing for the administration of each FLT3I. Additional studies are required to determine the optimal FLT3I‐based combinations, reduce resistance emergence, and improve outcomes. This review highlights the current state of FLT3I therapy, ongoing challenges with resistance, and future directions in optimizing treatment for FLT3‐mutated AML, focusing on quizartinib. [ABSTRACT FROM AUTHOR]

The treatment landscape for relapsed/refractory follicular lymphoma (RR‐FL) is marked by a pivotal debate between chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific antibodies (BsAbs). While both CAR‐T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA‐5 study, underscore axicabtagene ciloleucel (axi‐cel)'s efficacy in treating RR‐FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso‐cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR‐FL patients. Thus, CAR‐T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost‐effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost‐effectiveness considerations are essential; while CAR‐T therapies incur higher initial costs, their potential for long‐term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR‐FL management strategies. [ABSTRACT FROM AUTHOR]

Therapy‐related acute promyelocytic leukemia (t‐APL) is rare and often linked to previous treatment with alkylating agents or topoisomerase II inhibitors. This report describes three cases of t‐APL treated at the Haematology Department of Cosenza Hospital between 2022 and 2024, which occurred after alkylating agents and exemestane, alkylating agents and radiation therapy, alkylating agents, taxane, and checkpoint inhibitor, respectively. Each case was managed with a different therapeutic approach. The first case involved a 71‐year‐old man with colorectal and breast cancer, who developed low‐risk t‐APL and achieved complete remission (CR) with ATRA alone. A second 71‐year‐old man case with colorectal cancer developed high‐risk t‐APL with PML/RARA and FLT3‐ITD fusion transcripts; he achieved CR with idarubicin and ATRA despite severe sepsis and acute heart failure. The third case involved a 74‐year‐old man with lung squamous cell carcinoma who developed intermediate‐risk t‐APL following chemoimmunotherapy but unfortunately succumbed to pseudotumor cerebri complications during induction therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Relapsed and refractory multiple myeloma (RRMM) remains a challenging condition despite advances in immunotherapies. Novel bispecific antibodies (BsAbs), including talquetamab, have shown promising efficacy in heavily pretreated patients, even those with triple‐ and penta‐refractory disease. Talquetamab, recently approved by the FDA and EMA, is indicated for patients who have progressed after at least three or four prior lines of therapy (LOTs). Administered following a step‐up dosing phase to manage cytokine release syndrome (CRS), talquetamab demonstrated a high overall response rate (ORR) of approximately 70%, including in patients previously treated with T‐cell redirecting therapies. Its safety profile is consistent with other BsAbs, with hematologic adverse events such as anemia and neutropenia commonly reported, alongside unique on‐target off‐tumor toxicities like dysgeusia and skin‐related events. Infections were less frequent compared to other BsAbs. The optimal sequencing of talquetamab and other therapies, including CAR‐T cell treatments, remains an area of active research, as resistance to anti‐BCMA therapies presents ongoing clinical challenges. Current trials are exploring the use of talquetamab in combination therapies, as well as therapeutic strategies post‐treating progression. The real‐world data further support talquetamab's efficacy, making it a valuable addition to the RRMM treatment landscape. [ABSTRACT FROM AUTHOR]

Introduction: Myelofibrosis (MF) is a clonal hematological disorder characterized by bone marrow fibrosis, splenomegaly, and inflammatory cytokine dysregulation. While the role of steroids in MF is not fully defined, their anti-inflammatory properties may offer therapeutic benefits, particularly in managing anemia and other cytopenias. Steroids exert their effects by suppressing pro-inflammatory cytokines such as IL1, IL6, and TNF, and by enhancing anti-inflammatory cytokines like IL4 and IL10. Elevated levels of IL6 and other cytokines in MF are associated with anemia and poor prognosis, suggesting that steroid therapy could mitigate these effects. Areas covered: In this manuscript, we review clinical studies which evaluated the safety and efficacy of steroids in MF patients. Moreover, we examine clinical data of the combination of steroids with immunomodulatory agents and JAK inhibitors. Our literature search consisted of an extensive review of PubMed and clinicaltrials.gov. Expert opinion: The role of steroids in the management of MF remains poorly defined, though emerging evidence suggests a potential therapeutic benefit, particularly in managing anemia and other cytopenias. The combination with IMIDs has also yielded positive outcomes as demonstrated in several studies. Steroids may also play a crucial role in managing cytopenias in MF patients receiving JAKi. [ABSTRACT FROM AUTHOR]

A "watch and wait" strategy, delaying treatment until active disease manifests, is adopted for most CLL cases; however, prognostic models incorporating biomarkers have shown to be useful to predict treatment requirement. In our prospective O-CLL1 study including 224 patients, we investigated the predictive role of 513 microRNAs (miRNAs) on time to first treatment (TTFT). In the context of this study, six well-established variables (i.e., Rai stage, beta-2-microglobulin levels, IGVH mutational status, del11q, del17p, and NOTCH1 mutations) maintained significant associations with TTFT in a basic multivariable model, collectively yielding a Harrell's C-index of 75% and explaining 45.4% of the variance in the prediction of TTFT. Concerning miRNAs, 73 out of 513 were significantly associated with TTFT in a univariable model; of these, 16 retained an independent relationship with the outcome in a multivariable analysis. For 8 of these (i.e., miR-582-3p, miR-33a-3p, miR-516a-5p, miR-99a-5p, and miR-296-3p, miR-502-5p, miR-625-5p, and miR-29c-3p), a lower expression correlated with a shorter TTFT, whereas in the remaining eight (i.e., miR-150-5p, miR-148a-3p, miR-28-5p, miR-144-5p, miR-671-5p, miR-1-3p, miR-193a-3p, and miR-124-3p), the higher expression was associated with shorter TTFT. Integrating these miRNAs into the basic model significantly enhanced predictive accuracy, raising the Harrell's C-index to 81.1% and the explained variation in TTFT to 63.3%. Moreover, the inclusion of the miRNA scores enhanced the integrated discrimination improvement (IDI) and the net reclassification index (NRI), underscoring the potential of miRNAs to refine CLL prognostic models and providing insights for clinical decision-making. In silico analyses on the differently expressed miRNAs revealed their potential regulatory functions of several pathways, including those involved in the therapeutic responses. To add a biological context to the clinical evidence, an miRNA–mRNA correlation analysis revealed at least one significant negative correlation between 15 of the identified miRNAs and a set of 50 artificial intelligence (AI)-selected genes, previously identified by us as relevant for TTFT prediction in the same cohort of CLL patients. In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of chronic lymphocytic leukemia (CLL) has dramatically changed following the availability of new drugs with targeted mechanisms of action. Traditional and new prognostic factors are being investigated to individualize and guide these new treatments. In this review, we discuss the clinical relevance of genomic factors including immunoglobulin heavy chain variable (IGHV) mutational status, TP53 abnormalities, complex karyotype, and prognostic scores in relation to new targeted agents. Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are the immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities, and the complex karyotype. In this review, we discuss the prognostic role of these genomic markers in relation to novel treatments. Moreover, we present and discuss new scoring systems that were elaborated and validated in the era of new drugs. In routine clinical practice, the application of an extensive genomic work-up with validated prognostic markers could improve the identification of "very high-risk" CLL patients who could benefit from novel, more effective targeted treatments. [ABSTRACT FROM AUTHOR]

The ELOQUENT‐3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18‐month follow‐up update of a previously published Italian real‐life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow‐up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression‐free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three‐fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow‐up. In conclusion, our real‐world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable neoplasm characterized by significant morbidity and mortality. Despite advances in treatment, MM patients eventually experienced a relapse of the disease. Penta‐drug refractory patients continue to be the hard core of relapsed/refractory (RR) settings. Teclistamab‐cqyv is a humanized IgG4 antibody and a bispecific BCMA‐director CD3 T‐cell engager. It recruits endogenous T cells, by targeting CD3 receptors expressed on their surface, resulting in their activation against BCMA, an antigen expressed by plasma cells. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Teclistamab‐cqyv in monotherapy for the treatment of RRMM patients who have received at least three prior therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti‐CD38 monoclonal antibodies (MoAbs) and have demonstrated disease progression during the last therapy. Its effectiveness was demonstrated in a pivotal clinical trial where the overall response rate (ORR) reached 60%. Other clinical studies are currently ongoing to investigate the association of the bispecific antibody with novel drugs with encouraging preliminary results, especially in the setting of heavily pretreated patients. In this review, the authors will provide a comprehensive overview of the drug, including its mechanism of action, major clinical trials, and future perspectives. [ABSTRACT FROM AUTHOR]

Tagraxofusp (or SL‐401) is a recombinant molecule composed of human interleukin‐3 that binds CD123 on neoplastic cells fused to a truncated diphtheria toxin (DT). Tagraxofusp's most significant success has come from studies involving patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive disease that is usually refractory to conventional chemotherapy. Tagraxofusp had an acceptable safety profile and high efficacy in early phase I/II studies on patients with BPDCN. Another phase II study confirmed the good response rates, resulting in Food and Drugs Administration and European Medicine Agency approval of tagraxofusp for the treatment of BPDCN. Considering its high efficacy and its manageable safety profile, tagraxofusp has been suddenly explored in other myeloid malignancies with high expression of cell surface CD123, both in monotherapy or combination strategies. The triplet tagraxofusp‐azacytidine‐venetoclax appears to be of particular interest among these combinations. Furthermore, combination strategies may be used to overcome tagraxofusp resistance. The downregulation of DPH1 (diphthamide biosynthesis 1), the enzyme responsible for the conversion of histidine 715 on eEF2 to diphthamide, which is then the direct target of ADP ribosylation DT, is typically associated with this resistance phenomenon. It has been discovered that azacitidine can reverse DHP1 expression and restore sensitivity to tagraxofusp. In conclusion, the success of tagraxofusp in BPDCN paved the way for its application even in other CD123‐positive malignancies. Nowadays, several ongoing trials are exploring the use of tagraxofusp in different myeloid neoplasms. This review aims to summarize the actual role of tagraxofusp in BPDCN and other CD123‐positive myeloid malignancies. [ABSTRACT FROM AUTHOR]