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Baseline cytogenetic/genetic features have been widely recognized to play a critical prognostic role in acute myeloid leukemia (AML) and have proven useful in designing risk-adapted treatment strategies. Nevertheless, to improve further the outcome of AML patients we are still in need of accurate methods to explore the quality of response and to adequately discriminate patients who are likely to relapse over time from those who are in deep and stable remission. In this view, is it well established that measurement of leukemic cells surviving chemotherapy (called measurable residual disease, MRD) during the course of treatment may be a reliable biomarker in predicting relapse. Detection of MRD relies on highly sensitive techniques, such as quantitative polymerase chain reaction and multiparametric flow cytometry, which, due to their levels of specificity and sensitivity, are increasingly included in the decision-making process of AML treatment. In the present manuscript, we will review the current techniques of MRD investigation and their clinical contribution to AML management.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy, characterized by poor prognosis if treated with conventional therapy. Allogenic hematologic stem cell transplant can improve survival and can be curative, but it is available in a small percentage of patients given that the median age at diagnosis is 70 years. In this scenario it is assumed that only the development of precision medicine-driven therapy will change BPDCN patient prognosis. CD123 (the α-subunit of interleukin (IL)-3 receptor) is over-expressed on BPDCN cells surface and seems to be the ideal marker to develop antibody-based therapies. Tagraxofusp (Elzonris ® ), a recombinant immunotoxin consisting of human interleukin-3 fused to a truncated diphtheria toxin, has been approved by FDA in December 2018 for the treatment of BPDCN in adult and pediatric patients. tagraxofusp has shown promising clinical activity, with a high overall response rate and quite manageable safety profile even in elderly patients. It seems to improve overall survival too, but comparative trials are necessary to confirm this. Adverse events are commonly reported and the most important are transaminitis, thrombocytopenia and capillary leak syndrome (CLS). Therefore, to prevent the onset of severe CLS is recommended to reserve tagraxofusp for patients with preserved hepatic and cardiac functions, and to strictly observe serum albumin level. Further studies are required to resolve many several unanswered questions about tagraxofusp. In this review, we will resume and discuss pharmacological characteristic of tagraxofusp, results of clinical trials leading to its approval by FDA in 2018 and future perspectives about its use in BPDCN and other hematological malignancies.

The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.

Patients with acute lymphoblastic leukemia (ALL) are characterized by an unfavorable outcome in the majority of adult cases. Several clinical trials have confirmed the usefulness of a pediatric-type therapy applied to adult patients. Adults present with higher risk features at diagnosis that predispose them to chemotherapy resistance and disease relapse after an initial achievement of complete remission. The recent introduction of novel immune-targeted therapies, including monoclonal antibodies (MoAbs) targeting B cell-associated antigens such as CD19 (blinatumumab) and CD22 (inotuzumab), tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, bispecific antibodies and chimeric antigen receptor T- cell therapy (CAR-T), circumvent B-ALL cell chemo-refractoriness through novel mechanisms of action, potentially eradicating minimal residual disease (MRD) and enabling more patients to receive allogeneic hematopoietic stem cell transplantation and to achieve a better clinical outcome.

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33 + acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.

Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for adult patients over 60 years old. Not surprisingly several cases of therapy-related AML (tAML) and secondary AML, both characterized by poorer prognosis, are more common in older population. For several decades initial therapy for AML remained unchanged and typically treatment consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the so-called "7+3" standard regimen. The efforts made by the researchers to improve this standard schedule, have led to only modest improvement in the response rate (RR) but no change in overall survival (OS), until the recent evolution seen with new target specific mutation therapies. In 2017, a new liposomal-encapsulated formulation with daunorubicin and cytarabine (CPX-351) was approved by the US Food and Drug Administration for the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). Based on the findings that ratiometric delivery may be more effective than administration of either drug at their maximum tolerated dose (MTD), CPX-351 was designed to deliver a fixed 5:1 molar ratio of the two molecules historically used in the standard "7+3" regimen, cytarabine and daunorubicin respectively. CPX-351 did show improvements of overall survival compared to traditional "7+3" in newly diagnosed secondary and therapy-related AML in adult patients. However, questions remain regarding how to select across AML patient subgroups to maximize the clinical benefit. Possible future directions include evaluating CPX-351 dose intensification, combining this liposomal formulation with targeted therapies and not least important a better understanding about the mechanism of improved responses in tAML and AML-MRC, two entities recognized to be less chemo-sensitive than other hematologic malignancies. In summary, CPX-351 offers finally something new in the landscape of AML therapy. Herein we will review the rationale behind this new drug product development, the main pharmacological characteristics, and discuss the results of clinical trials that led to its FDA approval at first and by EMA in 2018.