The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) encompasses a heterogeneous group of aggressive myeloid malignancies, where FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent, accounting for approximately 25-30% of adult patients. The presence of this mutation is related to a dismal prognosis and high relapse rates. In the lasts years many FLT3 inhibitors have been developed. AREAS COVERED: This review provides a comprehensive overview of FLT3mut AML, summarizing the state of art of current treatment and available data about combination strategies including an FLT3 inhibitor. EXPERT OPINION: In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.

Momelotinib in myelofibrosis.

INTRODUCTION: Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation. AREAS COVERED: This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients. EXPERT OPINION: Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.

Selinexor in multiple myeloma.

INTRODUCTION: Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). AREAS COVERED: This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. EXPERT OPINION: The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations.

Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience.

BACKGROUND: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. METHODS: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. RESULTS: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. CONCLUSION: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

The impact of PARP inhibitors in the whole scenario of ovarian cancer management: A systematic review and network meta-analysis.

BACKGROUND: Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived agents remains the major predictor of long-term outcomes. PATIENT AND METHODS: We aimed to identify the best treatment of the aEOC in terms of efficacy and safety, considering all treatment phases. A systematic literature search has been done to compare all treatments in aEOC population. Randomized trials with available survival and safety data published in the 2011-2022 timeframe were enclosed. Only trials reporting the BRCA or HRD (Homologous Recombination Deficiency) status were considered. DATA EXTRACTION AND SYNTHESIS: A ranking of treatment schedules on the progression-free survival (PFS) endpoint was performed. The random-effect model was used to elaborate and extract data. The Network Meta-Analysis (NMA) by Bayesian model was performed by STATA v17. Data on PFS were extracted in terms of Hazard ratio with relative confidence intervals. RESULTS: This NMA involved 18 trials for a total of 9105 patients. Within 12 treatment groups, we performed 3 different sensitivity analyses including "all comers" Intention to Treat (ITT) population, BRCA-mutated (BRCAm), and HRD subgroups, respectively. Considering the SUCRA-reported cumulative PFS probabilities, we showed that in the ITT population, the inferred best treatment was niraparib plus bevacizumab with a SUCRA of 96.7. In the BRCAm subgroup, the best SUCRA was for olaparib plus chemotherapy (96,9). The HRD population showed an inferred best treatment for niraparib plus bevacizumab (SUCRA 98,4). Moreover, we reported a cumulative summary of PARPi toxicity, in which different 3-4 grade toxicity profiles were observed, despite the PARPi "class effect" in terms of efficacy. CONCLUSIONS: Considering all aEOC subgroups, the best therapeutical option was identified as PARPi plus chemotherapy and/or antiangiogenetic agents, suggesting the relevance of combinatory approaches based on molecular profile. This work underlines the potential value of "chemo-free" regimens to prolong the platinum-free interval (PFI).

Teclistamab-cqyv in multiple myeloma.

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.

Tagraxofusp in myeloid malignancies.

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.

Ivosidenib in acute myeloid leukemia.

INTRODUCTION: Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML therapy has evolved substantially in recent years, mainly due to the introduction of hypomethylating agents and small molecules.Bcl2 inhibitor venetoclax, Fms-like tyrosine kinase 3 (FLT3) inhibitors such as midostaurin and gilteritinib, and isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) inhibitors ivosidenib and enasidenib, as well as hedgehog (HH) pathway inhibitor glasdegib represented a significant step forward in AML therapeutic armamentarium. Smoothened (SMO) inhibitor in combination with low-dose cytarabine marks a recent milestone. AREAS COVERED: Ivosidenib, the first-in-class, selective, allosteric IDH1R132 inhibitor, showed the capability to induce in vitro differentiation of primary mIDH1 AML blasts. Clinical data highlighted its exceptional safety profile, as a standalone therapy and in combination strategy. Additionally, comprehensive studies consistently demonstrated its effectiveness, both in monotherapy and in association with chemotherapy. EXPERT OPINION: The identified ivosidenib's strengths, including its remarkable safety record and ability to yield positive therapeutic outcomes, position it as an ideal partner for both classic chemotherapy and biological treatments, i.e. hypometilant agents and/or venetoclax. Further studies are warranted to explore strategies for overcoming the occurrence of ivosidenib resistance.

Glasdegib for the treatment of acute myeloid leukemia.

INTRODUCTION: Over the last few years, substantial progress has been made in the management of acute myeloid leukemia (AML). The first changes in the management of AML date back to last 2000s with the advent of hypometilant agents, later with Bcl2 inhibitor venetoclax, and Fms-like tyrosine kinase 3 (FLT3) inhibitors (midostaurin and gilteritinib), and more recently with IDH1/2 inhibitors (ivosidenib and enasidenib) and the hedgehog (HH) pathway inhibitor glasdegib. AREAS COVERED: Glasdegid, formerly PF-04449913 or PF-913, acts as a smoothened (SMO) inhibitor and has been recently approved in combination with low-dose cytarabine (LDAC) by FDA and EMA for the treatment of naïve AML patients unfit for intensive chemotherapy.Several studies have explored the efficacy and safety of glasdegib, as a single agent or in combination with other drugs, in both the setting of relapsed/refractory and naïve AML patients, confirming its efficacy in controlling disease and safety profile. EXPERT OPINION: All these trials suggest that glasdegib seems to be an ideal partner for both classic chemotherapy and biological treatments (such as therapy with FLT3 inhibitors). Further studies are needed to better understand which patients are more likely to respond to glasdegib.

Safe and Effective Administration of Caplacizumab in COVID-19-Associated Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening, rare acute thrombotic microangiopathy (TMA), caused by a severe ADAMTS13 deficiency. As the COVID-19 pandemic rapidly spread around the globe, much data about the pathogenicity of this virus were published. Soon after the detection of the first cases of COVID-19, it was clear that there was a wide range of COVID coagulopathy manifestations, such as deep venous thrombosis, pulmonary thromboembolism, and thrombotic microangiopathies. In the literature, little data have been reported about the association between TTP and COVID-19, and the treatment of COVID-19-associated TTP is still under debate. Here we present the case of a 46-year-old woman who developed a COVID-associated TTP, successfully treated with plasma exchange (PEX), steroids, and caplacizumab.

A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics.

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (p = 0.01) and as prognostic of survival (p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an "inflammatory-score" and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease.

miR-221/222 as biomarkers and targets for therapeutic intervention on cancer and other diseases: A systematic review.

Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords "miR-221" and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view.