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Stefano Molica1, Rosanna Mirabelli1, Matteo Molica1, Luciano Levato1, Francesca R Mauro2, Robin Foà21Department of Hematology and Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro; 2Department of Cellular Biotechnologies and Hematology, Division of Hematology, Sapienza University, Rome, ItalyAbstract: Anemia has an unfavorable impact on quality of life in chronic lymphocytic leukemia (CLL), increases the likelihood of receiving blood transfusions, and eventually has a negative impact on overall survival. Although discrepancies in perception of health-related quality of life between doctors and patients lead to the undertreatment of anemia, CLL patients undergoing chemotherapy who have a hemoglobin level

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Assessing the suitability of older adults with acute myeloid leukemia (AML) for intensive chemotherapy or stem cell transplantation remains a long-standing challenge. Geriatric assessment, which involves the evaluation of multiple dimensions of health, may influence a patient's ability to tolerate intensive or mild-intensity approaches, including treatment-related mortality. Prospective studies are required to validate different fitness criteria, in addition to making it possible to compare the effectiveness of geriatric assessment-based fitness against other criteria, in order to identify which aspects of geriatric assessment are linked to treatment tolerance. It is hoped that validation studies will include different groups of patients receiving either intensive or lower-intensity chemotherapy. At a minimum, geriatric assessment should involve the measurement of the comorbidity burden, cognition, physical function, and emotional health-factors previously associated with mortality in AML. These assessments should be conducted before starting chemotherapy in order to minimize the treatment's impact on the results. While treatment tolerance has traditionally been evaluated through toxicity rates in solid tumor patients, AML treatment often results in high toxicity rates regardless of the intensity. Therefore, early mortality should be the primary endpoint for assessing treatment tolerance, given its significant and clear implications. Other important endpoints might include declines in functional status and quality of life and treatment adjustments or discontinuation due to toxicity. Validating these fitness criteria is essential for guiding treatment choices, improving supportive care, determining trial eligibility, interpreting study outcomes, and informing drug labeling.

High-risk acute myeloid leukemia has been associated with a poor outcome. Hematopoietic stem cell transplantation (HSCT) represents the only curative option for eligible patients. Relapse after HSCT is a dramatic event with poor chances of survival. With the aim of reducing the rate of post-HSCT relapse, maintenance treatment has been investigated in this setting. Results from clinical trials suggest an advantage in the use of a maintenance strategy; however, standardized guidelines are not yet available due to the lack of prospective clinical trials. In this review, we have reported the most important strategies adopted as post-HSCT maintenance, highlighting their efficacy, but the current research also opens questions.

Background: α-dystroglycanopathies are congenital muscular dystrophies in which genetic mutations cause the decrease or absence of a unique and complex O-linked glycan called matriglycan. This hypoglycosylation of O-linked matriglycan on the α-dystroglycan (α-DG) protein subunit abolishes or reduces the protein binding to extracellular ligands such as laminins in skeletal muscles, leading to compromised survival of muscle cells after contraction. Methods: Surrogate molecular linkers reconnecting laminin-211 and the dystroglycan β-subunit through bispecific antibodies can be engineered to improve muscle function in the α-dystroglycanopathies. This study reports the metabolic engineering of a novel glycofusion bispecific (GBi) antibody that fuses the mucin-like domain of the α-DG to the light chain of an anti-β-DG subunit antibody. Results: Transient HEK production with the co-transfection of LARGE1, the glycoenzyme responsible for the matriglycan modification, produced the GBi antibody only with a light matriglycan modification and a weak laminin-211 binding activity. However, when a sugar feed mixture of uridine, galactose, and manganese ion (Mn 2+ ) was added to the culture medium, the GBi antibody produced exhibited a dramatically enhanced matriglycan modification and a much stronger laminin-binding activity. Conclusions: Further investigation has revealed that Mn 2+ in the sugar feeds played a critical role in increasing the matriglycan modification of the GBi antibody, key for the function of the resulting bispecific antibody.

FLT3 inhibitors combined with chemotherapy are the standard of care for newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, no head-to-head studies have established the superiority of one FLT3 inhibitor over another. We conducted a network meta-analysis (NMA) to evaluate overall survival (OS) among different FLT3 inhibitors. Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. The hazard ratios (HRs) revealed no significant differences in OS between midostaurin and quizartinib (HR, 1.00; 95 % CI, 0.73-1.36), midostaurin and sorafenib (HR, 0.97; 95 % CI, 0.52-1.84), or quizartinib and sorafenib (HR, 0.97; 95 % CI, 0.51-1.85). This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making., Competing Interests: Declaration of Competing Interest Authors declare no competing financial interests, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Introduction: In patients with myelodysplastic syndromes (MDS), anemia is prevalent affecting 80%-85% of low-risk (LR-MDS) patients, with 40% eventually requiring red blood cell (RBC) transfusions. Except forlenalidomide, exclusively approved for those with deletion of chromosome 5q,erythropoiesis-stimulating agents (ESAs) are the primary treatment choice for low-risk patients. Those unresponsive to ESAs face limited alternatives, eventually necessitating long-term RBC transfusions, leading to secondary iron overload and adversely affecting quality of life (QoL)., Area Covered: Luspatercept is a pioneering erythroid maturation agent. It received approval by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for treating adults experiencing transfusion-dependent anemia associated with LR-MDS or β-thalassemia. Recently, the FDA approved luspatercept as first- line therapy in patients with very low- to intermediate-risk MDS who require RBC transfusions and have not previously received ESAs. This review summarizes the historical impact of luspatercept intreating LR-MDS unresponsive to ESAs and illustrates its potential benefit asfrontline therapy in MDS and its employment in patients with myelofibrosis-induced anemia., Expert Opinion: Luspatercept has revolutionized the therapeutic paradigm of LR-MDS, for which there was a limited therapeutic arsenal, especially in the setting of patients who did not respond or fail after ESA treatment.

The combination approach based on venetoclax (VEN) with azacytidine (AZA) has significantly improved outcomes for elderly patients with acute myeloid leukemia (AML). This innovative approach has led to higher rates of overall response, measurable residual disease (MRD)-negative remissions, and overall survival compared with AZA monotherapy. As a result, this combination has emerged as the gold-standard treatment for elderly or unfit patients with AML who are not eligible for intensive therapy. In younger, fit patients with AML, intensive induction and consolidation chemotherapy is commonly used as a first-line approach; however, relapse continues to be the main reason for treatment failure in approximately 30-40% of patients. Efforts to improve MRD-negative response rates and to facilitate the transition to allogeneic hematopoietic stem cell transplantation, particularly in high-risk AML, have inspired trials exploring the combination of intensive chemotherapy with targeted agents. VEN, a first-in-class anti-BCL2 agent, combined with intensive chemotherapy regimens has shown deep MRD-negative remissions, producing prolonged event-free survival and enhancing the transition to allogeneic transplant in first-complete-remission patients. These benefits support the incremental advantages of adding VEN to intensive chemotherapy approaches across ELN risk subcategories, and provides a robust benchmark to design future trials. In this review, we will discuss current studies assessing the efficacy of frontline regimens integrating VEN into intensive chemotherapy in younger patients with AML and specific molecularly defined subgroups.

Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias-in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives.

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival., (© 2023 Wiley Periodicals LLC.)

Gilteritinib is currently approved for patients with relapsed/refractory AML with FLT3 mutations, based on the positive results of the pivotal ADMIRAL study. In ADMIRAL trial, no increased risk of bleeding was reported, but in the previous dose finding study, a single event of intracranial hemorrhage (ICH) was registered after exposure to subtherapeutic doses of gilteritinib. Here, we report the first case series on five ICHs diagnosed in patients with FLT3-mutated AML, occurred within the first month of exposure to gilteritinib. Our cohort included 24 patients treated in three Italian centers. Most of these ICH cases were non-severe and self-limiting, while one was fatal. This link with ICHs remains in any case uncertain for the presence of active AML. We further reported that an analysis of the post-marketing surveillance data (EudraVigilance) retrieved other 11 cases of ICHs present in the database after gilteritinib treatment. A causality assessment was performed according to the Dx3 method to evaluate the possibility that ICHs might be an actual side effect of gilteritinib. In conclusion, further research is needed to elucidate the potential role of gilteritinib in the pathogenesis of ICHs., (© 2023. The Author(s).)

In the last few years, molecularly targeted agents and immune-based treatments (ITs) have significantly changed the landscape of anti-cancer therapy. Indeed, ITs have been proven to be very effective when used against metastatic solid tumors, for which outcomes are extremely poor when using standard approaches. Such a scenario has only been partially reproduced in hematologic malignancies. In the context of acute myeloid leukemia (AML), as innovative drugs are eagerly awaited in the relapsed/refractory setting, different ITs have been explored, but the results are still unsatisfactory. In this work, we will discuss the most important clinical studies to date that adopt ITs in AML, providing the basis to understand how this approach, although still in its infancy, may represent a promising therapeutic tool for the future treatment of AML patients.

The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 ( FLT3 ) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both FLT3-ITD and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3 -mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review.

FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1 st and 2 nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib)., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2023.)

This study has employed mammalian transient expression systems to generate afucosylated antibodies and antibody Fc mutants for rapid candidate screening in discovery and early development. While chemical treatment with the fucose analogue 2-fluoro-peracetyl-fucose during transient expression only partially produced antibodies with afucosylated N-glycans, the genetic inactivation of the FUT8 gene in ExpiCHO-S™ by CRISPR/Cas9 enabled the transient production of fully afucosylated antibodies. Human IgG 1 and murine IgG 2a generated by the ExpiCHOfut8KO cell line possessed a 8-to-11-fold enhanced FcγRIIIa binding activity in comparison with those produced by ExpiCHO-S™. The Fc mutant S239D/S298A/I332E produced by ExpiCHO-S™ had an approximate 2-fold higher FcγRIIIa affinity than that of the afucosylated wildtype molecule, although it displayed significantly lower thermal-stability. When the Fc mutant was produced in the ExpiCHOfut8KO cell line, the resulting afucosylated Fc mutant antibody had an additional approximate 6-fold increase in FcγRIIIa binding affinity. This synergistic effect between afucosylation and the Fc mutations was further verified by a natural killer (NK) cell activation assay. Together, these results have not only established an efficient large-scale transient CHO system for rapid production of afucosylated antibodies, but also confirmed a cooperative impact between afucosylation and Fc mutations on FcγRIIIa binding and NK cell activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflicts of interest The authors declare no financial or commercial conflict of interest., (Copyright © 2022 Pfizer Inc. Published by Elsevier B.V. All rights reserved.)

Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous disease for which the treatment armamentarium has been historically restricted to chemotherapy. However, genomic and epigenomic alterations that contribute to AML initiation, maintenance, and relapse have disclosed new insights to the 5th update in WHO Classification of Haematolymphoid Tumours., Areas Covered: After four decades of intensive chemotherapy as a 'one-size-fits-all' concept, several targeted agents have been approved for the treatment of AML. Several compounds, directed against regulators of apoptotic, epigenetic, or micro-environmental pathways, and immune-system modulators, are currently in development and investigation in clinical trials. We review advances in target-based therapy for AML focusing on their mechanism of action, examining the intracellular events and pathways, and the results from published clinical trials., Expert Opinion: To improve patient clinical outcomes, find new biomarkers for therapeutic response, and pinpoint patients who might benefit from novel targeted medicines, next-generation sequencing is being used to evaluate AML-associated mutations. In fact, the new 5th edition of WHO classification has reaffirmed the importance of genetically defined entities that have a prognostic impact, but not all have a specific treatment available. New class of target drugs are in clinical development and could be beneficial to improve the therapeutic armamentarium available.

Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes ( TP53 ) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9-10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7-46) and 17.4% (95% CI 11.7-23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.

Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the "3+7" regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment's half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60-75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML.

Introduction: Until the late 1980s, acute promyelocytic leukemia (APL) was the most rapidly fatal leukemia; however, nowadays, it is a curable disease with survival rates exceeding 90-95%. The improvement of APL outcome is mainly due to two agents, which target the typical translocation t(15;17) and its fusion transcript PML-RAR α responsible for initiating and maintaining the disease: all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The story of APL represents a pioneering model for the development of precision medicine and curative chemotherapy-free approaches for acute leukemia., Area Covered: The authors examine the major advances in the treatment of patients with APL focusing on three different eras: 1) the pre-ATRA era; 2) the ATRA era; 3) the ATO era., Expert Opinion: The combination of ATRA and ATO is effective and curative for the majority of APL patients. It has been approved for low/intermediate risk cases while an experimental trial with a minimal addition of chemotherapy for high-risk ones is ongoing. Disease relapse is infrequent and can be cured with ATRA-ATO rechallenging, with or without subsequent transplantation depending on the interval between complete remission and relapse. New therapeutic landscapes contemplate the use of an oral chemo-free ATRA-ATO combination, implementing treatment as outpatient care, thus increasing quality of life and decreasing medical costs.

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first "target therapy" to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a 'repurposed drug' that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing.

Background: According to 2008/2016 classification of the World Health Organization (WHO), a platelet (PLT) count ≥ 450 × 10 9 /L, reduced from the previously published WHO 2001 indicated level ≥ 600 × 10 9 /L, was considered the new PLT threshold for the diagnosis of essential thrombocythemia (ET)., Patients and Methods: To validate this important diagnostic change in a setting of current clinical practice, we retrospectively analyzed clinical and hematologic features at diagnosis and during follow-up of 162 patients with ET, diagnosed in our center from January 2008 to December 2017. We subdivided patients according to PLT value at baseline into Group A (PLT ≥ 600 × 10 9 /L) (124 patients; 76.5%) and Group B (PLT ≥ 450 × 10 9 /L < 600 × 10 9 /L) (38 patients; 23.5%)., Results: Among clinical features, only the median value of leukocytes (P < .001) was significantly higher in Group A. Cytostatic treatment was administered in 103 patients, with a significantly higher rate in patients of group A (P < .001). After a median follow-up of 42.4 months (interquartile range, 22.1-70.6 months), 8 thrombotic events were recorded in the entire cohort, without differences between the 2 groups (P = .336). The 5-year overall survival (OS) of the entire cohort was 96.9% (95% confidence interval, 92.6%-100%), without differences between the 2 groups (P = .255)., Conclusions: Our data indicate a substantial homogeneity among patients with ET regardless of the PLT count at diagnosis, thus confirming the usefulness of the 2008/2016 WHO diagnostic criteria., (Copyright © 2020 Elsevier Inc. All rights reserved.)

TP53 is a key tumor suppressor gene with protean functions associated with preservation of genomic balance, including regulation of cellular senescence, apoptotic pathways, metabolism functions, and DNA repair. The vast majority of de novo acute myeloid leukemia (AML) present unaltered TP53 alleles. However, TP53 mutations are frequently detected in AML related to an increased genomic instability, such as therapy-related (t-AML) or AML with myelodysplasia-related changes. Of note, TP53 mutations are associated with complex cytogenetic abnormalities, advanced age, chemoresistance, and poor outcomes. Recent breakthroughs in AML research and the development of targeted drugs directed at specific mutations have led to an explosion of novel treatments with different mechanisms. However, optimal treatment strategy for patients harboring TP53 mutations remains a critical area of unmet need. In this review, we focus on the incidence and clinical significance of TP53 mutations in de novo and t-AML. The influence of these alterations on response and clinical outcomes as well as the current and future therapeutic perspectives for this hardly treatable setting are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Molica, Mazzone, Niscola and de Fabritiis.)

Prognostic role of chromosomal translocations (CT) in myelodysplasia (MDS) was retrospectively analyzed in 77 patients from GROM-L registry. Forty (51.9%) balanced, 28 (36.4%) unbalanced and 9 (11.7%) concomitant balanced and unbalanced CT were identified. Five-year overall survival (OS) of the entire cohort was 34.5% (CI 95% 22.5-46.5). Five-year OS of patients with unbalanced CT was significantly shorter than that of patients carrying balanced CT [22.3% (CI 95% 4.0-40.6) vs 44.0% (CI 95% 26.7-61.3) ( p  = 0.042)]. Five-year OS of patients with CT included in complex karyotype (CK) was significantly shorter than that of patients with isolated CT or CT with another abnormality [5.5% (CI 95% 0-15.7) vs 42.9% (CI 95% 21.3-64.5) and vs 4% (CI 95% 31.6-79.2) ( p  < 0.001)]. Presence of CT in MDS characterizes a more aggressive outcome only when associated with CK.

In addition to the best possible overall survival, discontinuation of the tyrosine kinase-inhibitor (TKI) treatment [treatment free remission (TFR)] without observing a recurrence of the disease has become a standard part of chronic myeloid leukemia (CML) care. Worldwide, more than 2000 patients with CML have attempted TFR, and very rare instances of disease transformation have been reported. Several studies in the last decade have demonstrated the feasibility and safety of TKI discontinuation in selected patients with CML who achieve deep and sustained molecular response with TKI. This has moved prime-time into clinical practice although open questions remain in terms of understanding the disease biology that leads to successful TKI cessation in some patients while not in others. Despite the remaining questions regarding which factors may be considered predictive for TFR, treatment interruption is a safe option provided that adequate molecular monitoring is available, with prompt re-initiation of TKIs as soon as major molecular response has been lost. Data from ongoing trials should help refine decisions as to which patients are the best candidates to attempt TKI discontinuation, frequency of a safe monitoring, optimal strategies to sustain ongoing TFR and increase the number of patients who can access to discontinuation programs., (©Copyright: the Author(s).)

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene. In more than 95% of CML patients, the typical BCR-ABL1 transcript subtypes are e13a2 (b2a2), e14a2 (b3a2), or the simultaneous expression of both. Other less frequent transcript subtypes, such as e1a2, e2a2, e6a2, e19a2, e1a3, e13a3, and e14a3, have been sporadically reported. The main purpose of this review is to assess the possible impact of different transcripts on the response rate to tyrosine kinase inhibitors (TKIs), the achievement of stable deep molecular responses (s-DMR), the potential maintenance of treatment-free remission (TFR), and long-term outcome of CML patients treated with TKIs. According to the majority of published studies, patients with e13a2 transcript treated with imatinib have lower and slower cytogenetic and molecular responses than those with e14a2 transcript. They should be considered a high-risk group that would most benefit from frontline treatment with second-generation TKIs (2GTIKIs). Although few studies have been published, similar significant differences in response rates to 2GTKIs have been not reported. The e14a2 transcript seems to be a favorable prognostic factor for obtaining s-DMR, irrespective of the TKI received, and is also associated with a very high rate of TFR maintenance. Indeed, patients with e13a2 transcript achieve a lower rate of s-DMR and experience a higher probability of TFR failure. According to most reported data in the literature, the type of transcript does not seem to affect long-term outcomes of CML patients treated with TKIs. In TFR, the e14a2 transcript appears to be related to favorable responses. 2GTKIs as frontline therapy might be a convenient approach in patients with e13a2 transcript to achieve optimal long-term outcomes., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Introduction: Acute lymphoblastic leukemia is the most frequent hematologic malignancy in children. Almost 95% of children potentially achieve a complete remission after the induction treatment, but over the last years, new insights in the genomic disease profile and in minimal residual disease detection techniques have led to an improvement in the prognostic stratification, identifying selected patients' subgroups with peculiar therapeutic needs., Areas Covered: According to a comprehensive search of peer-review literature performed in Pubmed, in this review we summarize the recent evidences on the induction treatment strategies comprised in the children acute lymphoblastic leukemia scenario, focusing on the role of key drugs such as corticosteroids and asparaginase and discussing the crucial significance of the genomic characterization at baseline which may drive the proper induction treatment choice., Expert Opinion: Current induction strategies already produce durable remissions in a significant proportion of standard-risk children with acute lymphoblastic leukemia. A broader knowledge of the biologic features related to acute lymphoblastic leukemia subtypes with worse prognosis, and an optimization of targeted drugs now available, might lead to the achievement of long-term molecular remissions in this setting.

Despite advances in understanding the pathogenesis of acute myeloid leukemia (AML), the standard therapy remained nearly unchanged for several decades. There have been many efforts to improve the response and survival by either increasing the cytarabine (ARA-C) dose or adding a third agent to the standard chemotherapy regimen. Several studies have evaluated the addition of cladribine (CdA) to standard induction, exploiting its property to potentiate ARA-C uptake. Response rates for combination regimens including CdA in relapsed/refractory (R/R) adults are approximately 50% and approximately 70% in de novo AML. Recently, a low intensity combination of CdA and ARA-C alternating with decitabine has shown promising results in older patients with AML. In this review, we will discuss the role of CdA in the treatment of AML, summarizing the recent clinical data regarding its incorporation into the induction therapy for adult AML.

Background: Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2 ndG /3 rdG TKIs) in the real-life practice., Methods: We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib., Results: The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control., Conclusion: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tyrosine kinase inhibitors (TKIs) represent a major breakthrough in the treatment of chronic myeloid leukemia (CML). Thanks to these agents, CML has been transformed from a disease with limited treatment options and a dismal prognosis into a more indolent disease with survival comparable to that of the general population. The need for ongoing TKI therapy remains controversial for several reasons, including cost and toxicity. Studies in CML patients with a sustained deep molecular response have demonstrated that stopping TKI therapy is feasible and safe. Given the heterogeneity of results reported in clinical trials, practice guidelines for optimal patient selection and proper monitoring after discontinuation of TKIs are proposed outside of clinical trials. Current data available show that 40% to 60% of patients who stop therapy relapse; molecular relapses typically occur within 6 months, but nearly all relapsing patients regain response upon reinitiation of the TKI. Several factors that predict for relapse have been investigated. Duration of prior TKI therapy, achievement of deep molecular response, depth of molecular response, prior interferon treatment, and Sokal risk score have been shown to be potential predictors for relapse. Leukemia stem cells that are resistant to TKIs, and that persist despite undetectable BCR/ABL1 transcript levels, likely are responsible for disease relapse after discontinuation. Efforts geared toward better identification of low levels of BCR/ABL1 transcript using new techniques such as digital polymerase chain reaction, along with eradicating CML clones using combination therapies with agents such as pegylated interferon or venetoclax with TKIs, will hopefully lead to a functional cure of this disease.

Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post-remission therapy to prevent relapse. High relapse rates after consolidation therapy and after allogeneic stem cell transplant contribute to suboptimal outcomes in AML patients, and continue to represent a difficult challenge. Effective maintenance therapy could play an important role in prolonging the remission interval in the post-consolidation setting, especially in high risk AML patients. Maintenance treatment approaches based on conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have been explored in this setting, but no data so far have been convincing enough to establish this approach as the standard of care. However, ongoing and future studies including novel targeted therapies may demonstrate promising efficacy that could facilitate incorporation of maintenance therapy into clinical practice. In this review we summarize previous and ongoing approaches of maintenance therapy in AML and discuss the most promising strategies., (© 2019 Wiley Periodicals, Inc.)

The outcome of high-risk myelodysplastic syndrome (MDS) patients treated with 5-azacitidine (5-AZA) in the real-life setting remains largely unknown. We evaluated 110 MDS patients (IPSS intermediate 2/high) treated outside of clinical trials at a single institution between September 2003 and January 2017. Median duration of therapy was 9.5 cycles. The overall survival (OS) of the whole cohort was 66.1% at 1 year and 38.3% at 2 years. No differences in terms of OS were observed with regard to gender (p = 0.622) and age at baseline (< 65 years, 65-75, and > 75 years, p = 0.075). According to the IPSS-R, the very high-risk group had an inferior 2-year OS (17%) compared with intermediate-group patients (64%, p < 0.001). Transfusion independency at baseline was identified as a favorable prognostic factor on 1-year (66.8%) and 2-year OS (43.4%) (p < 0.001). After four cycles, the persistence of bone marrow blasts > 10% identified patients with a worse outcome, with a 2-year OS of 9.4% (p = 0.002). The occurrence of an infection during the first four cycles impacted on the 2-year OS (31.6% vs 58.3% in patients without infections, p = 0.032). Patients receiving at least 24 cycles of the drug have a 5-year OS of 38.2%. This analysis allowed to identify features at baseline or during treatment with 5-AZA associated with a different 2-year OS.

Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

There is little information about cardiovascular adverse event (CV-AE) incidence in chronic myeloid leukemia (CML) patients treated with bosutinib in the real-life practice. We identified 54 consecutive CML patients treated with bosutinib, stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 40-month cumulative incidence of CV-AEs was 25.2 ± 8.1%. Patients with the SCORE of high-very high showed a significantly higher incidence of CV-AEs (55 ± 12.9% vs 9 ± 9.5%; p = 0.002). Overall, 9 CV-AEs were reported, with 2 deaths attributed to CV-AE. In conclusion, the SCORE assessment before starting treatment is helpful in identifying CV-AE high-risk patients during bosutinib treatment.