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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]

Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal plasma cell proliferation in the bone marrow. Recent advancements in anti-CD38 monoclonal antibody therapies, such as daratumumab and isatuximab, have significantly improved MM patient survival. However, the lack of predictive factors of response to these therapies remains a challenge. Notably, anti-CD38 antibodies can interfere with laboratory tests, complicating response assessment. We conducted a retrospective study to evaluate the association between the appearance of positive IgGk (therapeutic antibody) on immunofixation/immunosubtraction (IF) and clinical parameters in 87 non-IgGk MM patients treated with anti-CD38 therapy. Positive IgGk IF was observed in 42 patients after a median of three treatment courses. Patients with positive IgGk IF had higher rates of complete/very good partial responses (p = 0.03) and improved progression-free survival (median not reached vs. 21.83 months, p < 0.01). High BMI (p = 0.03), higher hemoglobin (p = 0.02), lower CRP (p = 0.04), and lower monoclonal protein levels (p = 0.03) were associated with positive IgGk IF. Our findings suggest that monitoring therapeutic antibody appearance on IF may predict and optimize anti-CD38 therapy in MM. Potential explanations include the impact of patient factors (e.g. BMI) on drug pharmacokinetics, the relationship between antibody levels and immune response, and the influence of tumor biology. Further research is needed to elucidate the underlying mechanisms and clinical utility of this biomarker. Nonetheless, our results highlight the importance of considering therapeutic antibody detection when interpreting laboratory tests and managing MM patients receiving anti-CD38 therapies. [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]

Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as "myelodysplastic neoplasm with low blast and isolated del(5q)" identified by the sole presence of 5q deletion or in combination with one other abnormality excluding −7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Light-chain amyloidosis (AL) is a rare multisystem disorder. One of the most common organs involved in AL is the heart. We conducted a multi-center, retrospective analysis of 67 patients with the European 2012 modification of Mayo 2004 stage III cardiac AL. The prognosis of patients with advanced cardiac amyloidosis is poor. The median OS for the entire group was 35 months (95% CI: 7–67). The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment. Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light chains in various organs. One of the most common organs involved in AL is the heart, with 50–70% of patients clinically symptomatic at diagnosis. We conducted a multi-center, retrospective analysis of 67 patients diagnosed between July 2012 and August 2022 with the European 2012 modification of Mayo 2004 stage III cardiac AL. The most important factors identified in the univariate Cox analysis contributing to a longer OS included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1, New York Heart Association functional classification (NYHA FC) ≤ 2, the use of autologous stem cell transplantation (ASCT) after induction treatment, achieving a hematological response (≥very good partial response) and cardiac (≥partial response) response after first-line treatment. The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment. [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]

Human papillomaviruses (HPVs) commonly infect the anogenital mucosa; most infections are transient, but a fraction of those caused by high-risk (HR) types persist and may lead to anogenital cancer. The epidemiology of HPV genotypes in anal infections in groups at different risk for anal cancer has not been well described in Italy. This retrospective study reports the results of HPV DNA testing and complete genotyping performed on anal swabs from 691 female and male patients attending proctology clinics in Rome during 2012–2021; one-third had repeated testing. Cumulative HPV positivity in 1212 anal swabs was approximately 60%, was not age related, and showed an increasing trend over the study period. HPV rates differed significantly by sex and HIV status: HIV-negative women had the lowest (43.6%) and HIV-positive men the highest (83.5%) HPV prevalence. HIV-positive men had more oncogenic HPV genotypes detected, more multiple infections, and the highest frequency of persistent infections. Two-thirds of all infections were vaccine-preventable. This study found that anal HPV infection rates are still elevated and even increasing in groups at low and high risk of developing anal cancer. Prevention programs need to be improved to reduce rates of anal infection in young women and men. [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]

ABSTRACT 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]

ABSTRACT 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]

Competing Interests: The authors declare no conflict of interest.

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., (© 2024 John Wiley & Sons Ltd.)

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.