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In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal post-remission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint. [ABSTRACT FROM AUTHOR]

Background: Colonization by multidrug-resistant organisms (MDRO) is a frequent complication in hematologic departments, which puts patients at risk of life-threatening bacterial sepsis. Fever of unknown origin (FUO) is a condition related to the delivery of chemotherapy in hematologic malignancies, in which the use of antibiotics is debated. The incidence, risk factors, and influence on the outcome of these conditions in patients with acute myeloid leukemia (AML) are not clearly defined. Methods: We retrospectively analyzed 132 consecutive admissions of non-promyelocytic AML patients at the Hematology Unit of the University Tor Vergata in Rome between June 2019 and February 2022. MDRO swab-based screening was performed in all patients on the day of admission and once weekly after that. FUO was defined as fever with no evidence of infection. Results: Of 132 consecutive hospitalizations (69 AML patients), MDRO colonization was observed in 35 cases (26%) and resulted independently related to a previous MDRO colonization (p=0.001) and length of hospitalization (p=0.03). The colonization persistence rate in subsequent admissions was 64%. MDRO-related bloodstream infection was observed in 8 patients (23%) and correlated with grade III/IV mucositis (p=0.008) and length of hospitalization (p=0.02). FUO occurred in 68 cases (51%) and correlated with an absolute neutrophilic count <500µ/L at admission (0.04). Conclusion: In our experience, MDRO colonization is a frequent and difficult-to-eradicate condition that can arise at all stages of treatment. Prompt discharge of patients as soon as clinical conditions allow could limit the spread of MDRO. In addition, the appropriate use of antibiotics, especially in the case of FUO, and the contraction of hospitalization length, when feasible, are measures to tackle the further spread of MDRO. [ABSTRACT FROM AUTHOR]

Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic workup and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio. [ABSTRACT FROM AUTHOR]

Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), including reduced proliferative and clonogenic capacity, altered morphology, impaired immunoregulatory properties and capacity to support hematopoiesis. Here, we investigated expression of the FOXM1 gene, a transcription factor driving G2/M gene expression, in BM-MSCs isolated from patients with MDS and AML, de novo and therapy-related, compared to BM-MSCs isolated from healthy donors (HD). We observed a statistically significant downregulation of FOXM1 expression in BM-MSCs isolated from MDS and AML patients, as compared to controls. In parallel, expression of FOXM1 mitotic targets (CCNB1, CDC20, PLK1 and NDC80) was suppressed in patients' BM-MSCs, as compared to HD. No differences in the expression of FOXM1 and its mitotic targets were observed in BM-mononuclear cells from the different sources. From a functional standpoint, silencing of FOXM1 mRNA in healthy MSC induced a significant decrease in the expression of its targets. In this line, healthy MSC silenced for FOXM1 showed an impaired ability to support hematopoiesis in vitro. These findings suggest that deregulation of FOXM1 may be involved in the senescent phenotype observed in MSC derived from myeloid neoplasms. [ABSTRACT FROM AUTHOR]

Simple Summary: The reported incidence of thrombotic events (TE) in non-promyelocytic acute myeloid leukemia (AML) patients varies in the literature from 2% to 13%. The aim of our retrospective study was to assess the incidence of TE in a real-word population of AML patients to determine the impact of TE on survival and to recognize risk factors for early venous thromboembolism (VTE). We observed a TE incidence of 14.6% among 300 patients with newly diagnosed AML. Arterial TE but not VTE was associated with a poorer OS. Furthermore, we observed a higher relapse rate among patients experiencing a VTE. We recognized platelets count >50 × 109/L, presence of comorbidities and a previous history of TE as risk factors for early VTE development. Accordingly, we proposed a score combining these factors that may help in implementing strategies to manage patients at higher risk of early thrombotic complications. Information regarding the incidence and the prognostic impact of thrombotic events (TE) in non-promyelocytic acute myeloid leukemia (AML) is sparse. Although several risk factors associated with an increased risk of TE development have been recognized, we still lack universally approved guidelines for identification and management of these complications. We retrospectively analyzed 300 consecutive patients with newly diagnosed AML. Reporting the incidence of venous TE (VTE) and arterial TE (ATE) was the primary endpoint. Secondarily, we evaluated baseline patient- and disease-related characteristics with a possible influence of VTE-occurrence probability. Finally, we evaluated the impact of TE on survival. Overall, the VTE incidence was 12.3% and ATE incidence was 2.3%. We identified three independent predictors associated with early-VTE: comorbidities (p = 0.006), platelets count >50 × 109/L (p = 0.006), and a previous history of VTE (p = 0.003). Assigning 1 point to each variable, we observed an overall cumulative incidence of VTE of 18.4% in the high-risk group (≥2 points) versus 6.4% in the low-risk group (0–1 point), log-rank = 0.002. Overall, ATE, but not VTE, was associated with poor prognosis (p < 0.001). In conclusion, TE incidence in AML patients is not negligible. We proposed an early-VTE risk score that could be useful for a proper management of VTE prophylaxis. [ABSTRACT FROM AUTHOR]

Simple Summary: Intensive induction strategies are rarely used for older patients in community on-cology practice, with comorbidities being the major cause of contraindication. 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. 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. Furthermore, 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. 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. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma is a hematologic malignancy consisting of extramedullary tissue involvement by myeloid blasts, usually considered as acute myeloid leukemia and treated accordingly. The disease itself, together with chemotherapy and disease-associated factors, may have an impact in increasing the risk of developing severe and frequently life-threatening infections. Herein, we describe the case of a patient with a right breast skin lesion, histologically diagnosed myeloid sarcoma, who developed a severe disseminated fungal infection by Saprochaete clavata (Magnusiomyces clavatus), during the first consolidation course of chemotherapy. Despite maximum antifungal therapy, the infection progressed and the fungus continued to be isolated until granulocyte transfusion therapy was initiated. Our experience suggests that patients with profound and long-lasting neutropenia could benefit from granulocyte transfusions as additional therapy in severe fungal infections resistant to broad-spectrum antimicrobial therapy. [ABSTRACT FROM AUTHOR]

The absence of measurable residual disease (MRD) in morphologic complete remission (CR) represents a favorable prognosticator in acute myeloid leukemia (AML) [[1]]. At the diagnostic evaluation, patients were defined as LSCs negative (LSC-0) in case of undetectable LSCs count, LSC SP low sp and LSC SP high sp when LSCs were detected below or above a threshold of 0.03%, respectively [[4]]. Indeed, patients with a high LSC burden at diagnosis have an unfavorable outcome unless LSCs are cleared by chemotherapy. [Extracted from the article]

Background: Several studies in immunocompromised patients, such as those with HIV infection, undergoing cancer chemotherapy or organ transplant, have led to the development of guidelines on the use of prophylaxis to prevent Pneumocystis jirovecii pneumonia (PJP), in these specific conditions. Instead, since the association between PJP and acute myeloid leukaemia (AML) is not clearly defined, the role of prophylaxis in patients with AML is not yet established. Methods: We retrospectively analysed 251 consecutive patients with newly diagnosed non‐M3‐AML, admitted at the Hematology Unit of University Tor Vergata in Rome, during the period 2010–2020. The aim of the study was to evaluate the incidence of PJP among AML patients during their first hospital admission, and to identify subjects at a high risk to develop PJP. Results: Among 251 consecutive patients with non‐M3‐AML, 67 bronchoalveolar lavages (BAL) were performed. PJP was proven in 11/67 (16.7%) subjects undergoing BAL (11 males, median age 71 years), with an incidence of 4.3%. The most common reason for BAL execution were radiological findings such as ground‐glass opacities (6/11, 55%) and atypical patterns like consolidations and nodules (5/11, 45%). One patient died because of PJP after 11 days of trimethoprim/sulfamethoxazole therapy. In multivariate analysis older age and smoking habit were independent factors significantly associated with PJP (p =.021 and 0.017 respectively). Conclusion: We conclude that PJP infection is not uncommon among patients with AML. If intensive chemotherapy is planned, physicians should be aware of this risk and prophylaxis should be considered, particularly in older patients. [ABSTRACT FROM AUTHOR]

The addition of Venetoclax (VEN) to Hypomethylating agents (HMAs) significantly improves the probability of complete remission and prolongs survival in patients with Acute Myeloid Leukemia (AML) when compared to HMA alone. However, the mutated clone composition may impact the probability of response and its duration. Here, we describe the molecular profile of a patient with AML rapidly evolved from a previous therapy-related-Chronic MyeloMonocytic Leukemia, who achieved safely complete remission after treatment with the VEN/Azacitidine combination, even in the presence of SARS-COVID-2 infection. The targeted NGS analysis showed that the VEN/AZA combination led to the eradication of the FLT3-ITD and RUNX1 mutated clone/s primarily associated with AML evolution, and subsequently, the SRSF2, NRAS, and ASXL1 mutated clone/s. This case also underlines the importance of the sequential use of targeted NGS for disease monitoring: the deep molecular remission achieved by this patient allowed to safely guide adjustments of drug dosage and treatment intervals in the presence of neutropenia, helping to rule out disease progression. [ABSTRACT FROM AUTHOR]

In the context of precision medicine, assessment of minimal residual disease (MRD) has been used in acute myeloid leukemia (AML) to direct individual treatment programs, including allogeneic stem cell transplantation in patients at high-risk of relapse. One of the limits of this approach has been in the past the paucity of AML markers suitable for MRD assessment. Recently, the number of biomarkers has increased, due to the identification of highly specific leukemia-associated immunophenotypes by multicolor flow-cytometry, and of rare mutated gene sequences by digital droplet PCR, or next-generation sequencing (NGS). In addition, NGS allowed unraveling of clonal heterogeneity, present in AML at initial diagnosis or developing during treatment, which influences reliability of specific biomarkers, that may be unstable during the disease course. The technological advances have increased the application of MRD-based strategies to a significantly higher number of AML patients, and the information deriving from MRD assessment has been used to design individual post-remission protocols and pre-emptive treatments in patients with sub-clinical relapse. This led to the definition of MRD-negative complete remission as outcome definition in the recently published European Leukemianet MRD guidelines. In this review, we summarized the principles of modern technologies and their clinical applications for MRD detection in AML patients, according to the specific leukemic markers. [ABSTRACT FROM AUTHOR]

Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell-based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37°C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy of AML with haploidentical NK cells.

The transition of patients with ≥ 20% < 30% bone marrow (BM) blast from the FAB category of myelodysplasia to the family of acute myeloid leukemia (AML) according to the recent WHO classification has not resolved the argument as to whether the natural history and responsiveness to therapy of these diseases is comparable to that of AML with > 30% BM blast. These controversies are even more manifest when it comes to elderly patients in whom concern for intensive chemotherapy (IC) related toxicity is the critical determinant for the therapeutic choice. In fact, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients ≥ 65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to alternative agents such as hypomethylators (azacitidine and decitabine). Actually, these agents have shown efficacy with reduced toxicity when administered to elderly patients with 20-30% BM blasts and not eligible for IC. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%-30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, our survey of the literature suggests that only controlled, randomized, clinical trials will answer the question as to whether hypomethylating agents has the potential to substitute for IC even in elderly patients with an optimal functional status. [ABSTRACT FROM AUTHOR]

BACKGROUND: The efficacy of azacitidine for the treatment of high-risk myelodysplastic syndromes has prompted the issue of its potential role even in the treatment of acute myeloid leukemia (AML). METHODS: The authors analyzed 82 patients with AML who were diagnosed according to World Health Organization criteria. The median patient age was 72 years (range, 29-87 years), and 27 patients (33%) had secondary AML. Of 62 patients with evaluable cytogenetics, 18 patients (29%) had a poor-risk karyotype, and 44 patients (71%) had an intermediate karyotype. Thirty-five patients (43%) received azacitidine as front-line treatment, and 47 patients (57%) had previously received 1 or more line of chemotherapy. RESULTS: The overall response rate was 32% (26 of 82 patients) and included 12 (15%) complete remissions (CRs), 4 (5%) CRs with incomplete blood count recovery (CRi), and 10 (12%) partial responses (PRs). Responses were observed more frequently among untreated patients compared with pretreated patients; in fact, 17 of 35 untreated patients (48%) responded, including 11 responses (31%) classified as CR/CRi. Conversely, only 9 of 47 pretreated patients (19%) responded, including 5 responses (11%) that were classified as CR/Cri. The response rate was significantly higher for untreated patients ( P = .006) and those who had white blood cell counts <10 × 109/L ( P = .006). For untreated patients who achieved a response, the median overall response duration was 13 months, and the 1-year and 2-years overall survival rates were 58% and 24%, respectively. CONCLUSIONS: The current results indicated that azacitidine promises to be an effective therapy for elderly patients with untreated AML and with white blood cell counts <10 × 109/L. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

The choice of either induction or post-remission therapy for adults with acute myeloid leukemia is still largely based on the "one size fits all" principle. Moreover, pre-treatment prognostic parameters, especially chromosome and gene abnormalities, may fail in predicting individual patient outcome. Measurement of minimal residual disease (MRD) is nowadays recognized as a potential critical tool to assess the quality of response after chemotherapy and to plan post-remission strategies that are, therefore, driven by the individual risk of relapse. Polymerase chain reaction and multiparametric flow cytometry have become the most popular methods to investigate MRD since they have been established as sensitive and specific enough to allow MRD to be studied serially. In the present review, we will examine the evidence supporting the appropriateness of incorporating MRD detection into the AML risk assessment process. A comprehensive prognostic algorithm, generated by combining pre-treatment cytogenetics/genetics and post-treatment MRD determination, should promote advances in development of personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

The primary cause of treatment failures in acute myeloid leukemia (AML) is the emergence of both resistant disease and early relapse. Among the most frequent agents of these phenomena are defects in the mitochondrial-mediated apoptotic pathway. This pathway is regulated by bcl-2 family of anti-apoptotic (bcl-2, bcl-xl, mcl-1) and pro-apoptotic proteins (bax, bad, bak). In particular, bcl-2 dimerizes with several members of bcl-2 family of proteins, altering the threshold of cell death. The flow cytometric quantitative measurement of bcl-2 and bax expression for the determination of bax/bcl-2 ratio provided crucial clinical information in AML: in our hands, lower bax/bcl-2 ratio conferred a very poor prognosis with decreased rates of complete remission (CR) and overall survival (OS). Moreover, striking correlations were found between lower bax/bcl-2 ratio and higher progenitor marker expression, such as CD34, CD117 and CD133 antigens, confirming the link between this apoptotic index and the maturation pathways. However, the capacity of bax/bcl-2 ratio to clearly identify patients with different prognosis with regard to CR and OS within the CD34+, CD117+ and CD133+ subgroups implies that other mechanisms, such as proliferation and/or cell cycle dysregulation may be involved to explain its clinical significance. Finally, small molecules that target both the receptor- and mitochondrial-mediated pathway of apoptosis are providing encouraging results in patients with relapsed and/or refractory disease (i.e. CDDOMe, bcl-2 antisense oligonucleotides, CEP-701, etc), confirming the key role of apoptotic mechanisms on the outcome of AML patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Upfront genetics/cytogenetics and minimal measurable disease (MRD) are becoming relevant biomarkers in the process of post-remission transplant allocation in AML. However, until recently the transplantation choice relied on the availability of a fully matched familiar donor, whereas individual patient- and disease-related characteristics played a secondary role in transplant allocation. In this paper we analyzed the evolution of the transplantation policy at our center in a 20-year time interval. At the beginning of our observation patients were submitted to allogeneic transplant, per protocol, mostly if a fully matched family donor was available or to autologous transplant if no fully matched family donor was identified ("donor vs. no donor" strategy) regardless of upfront genetics/cytogenetics or MRD status. Thereafter, persistence of MRD after consolidation cycle was included in the decision-making process for transplant selection. Patients with favorable and intermediate-risk cytogenetic risk were to receive allogeneic or autologous stem cell transplantation if MRD positive or negative, respectively, ("transplant vs. no transplant" strategy). In this cohort, patients with FLT3-ITD or adverse risk karyotype were submitted to allogeneic transplant as well. Measurable residual disease (MRD) is increasingly employed as a biomarker of quality of complete remission (CR) in intensively treated acute myeloid leukemia (AML) patients. We evaluated if a MRD-driven transplant policy improved outcome as compared to a policy solely relying on a familiar donor availability. High-risk patients (adverse karyotype, FLT3-ITD) received allogeneic hematopoietic cell transplant (alloHCT) whereas for intermediate and low risk ones (CBF-AML and NPM1-mutated), alloHCT or autologous SCT was delivered depending on the post-consolidation measurable residual disease (MRD) status, as assessed by flow cytometry. For comparison, we analyzed a matched historical cohort of patients in whom alloHCT was delivered based on the sole availability of a matched sibling donor. Ten-years overall and disease-free survival were longer in the MRD-driven cohort as compared to the historical cohort (47.7% vs. 28.7%, p = 0.012 and 42.0% vs. 19.5%, p = 0.0003). The favorable impact of this MRD-driven strategy was evident for the intermediate-risk category, particularly for MRD positive patients. In the low-risk category, the significantly lower CIR of the MRD-driven cohort did not translate into a survival advantage. In conclusion, a MRD-driven transplant allocation may play a better role than the one based on the simple donor availability. This approach determines a superior outcome of intermediate-risk patients whereat in low-risk ones a careful evaluation is needed for transplant allocation. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML), with an incidence increasing with age, is the most common acute leukemia in adults. Concurrent comorbidities, mild to severe organ dysfunctions, and low performance status (PS) are frequently found in older patients at the onset, conditioning treatment choice and crucially influencing the outcome. Although anthracyclines plus cytarabine-based chemotherapy, also called "7 + 3" regimen, remains the standard of care in young adults, its use in patients older than 65 years should be reserved to selected cases because of higher incidence of toxicity. These adverse features of AML in the elderly underline the importance of a careful patient assessment at diagnosis as a critical tool in the decision-making process of treatment choice. In this review, we will describe selected recently approved drugs as well as examine prognostic algorithms that may be helpful to assign treatment in elderly patients properly. [ABSTRACT FROM AUTHOR]

In the acute myeloid leukemia (AML) setting, research has extensively investigated the existence and relevance of molecular biomarkers, in order to better tailor therapy with newly developed agents and hence improve outcomes and/or save the patient from poorly effective therapies. In particular, in patients with AML, residual disease after therapy does reflect the sum of the contributions of all factors associated with diagnosis and post-diagnosis resistance. The evaluation of minimal/measurable residual disease (MRD) can be considered as a key tool to guide patient's management and a promising endpoint for clinical trials. In this narrative review, we discuss MRD evaluation as biomarker for tailored therapy in AML patients; we briefly report current evidence on the use of MRD in clinical practice, and comment on the potential ability of MRD in the assessment of the efficacy of new molecules. [ABSTRACT FROM AUTHOR]

Coagulation disorders frequently complicate the clinical course of acute myeloid leukemia (AML) patients. This study examined the frequency and prognostic significance, with regards of early mortality, of the presence of overt disseminated intravascular coagulation (DIC) at AML diagnosis and its correlation with clinical and biological characteristics. A retrospective analysis of 351 newly diagnosed non-promyelocytic AML patients was conducted, utilizing the 2018 ISTH DIC-Score criteria to evaluate the presence of overt DIC at AML onset. The study cohort had a median age of 65 years with a predominance of male gender (59 %). Overt DIC was present in 21 % of cases and was associated with advanced age, comorbidities, poor performance status, hyperleukocytosis, LDH levels, NPM1 mutations, expression of CD33 and CD4, and lack of expression of CD34. With a median follow-up of 72 months (3–147 months), the 6-year overall survival (OS) was 17.4 %, with patients having overt DIC showing significantly poorer outcomes (7.2 % compared to 20.3 % of those without DIC, p < 0.001). Patients with overt DIC showed markedly high early mortality rates at 30 (42.5 % vs 8 %), 60 (49.3 % vs 16.9 %), and 120 days (64.4 % vs 25.6 %) from disease onset. In multivariate analysis overt DIC retained its independent prognostic value for early mortality. In conclusion, the prevalence and clinical relevance of DIC in non-promyelocytic AML is not negligible, underlining its potential as an unfavorable prognostic marker. In newly diagnosed patients with AML, early recognition and measure to counteract coagulation disturbances might help mitigate the elevated mortality risk associated with DIC. • Disseminated intravascular coagulation frequently complicates acute leukemias. • The 2018 ISTH DIC-Score criteria serve as a simple tool to diagnose disseminated intravascular coagulation in acute myeloid leukemia patients. • Acute myeloid leukemia patients with disseminated intravascular coagulation at presentation have a 14-fold increased risk of major bleeding. • Disseminated intravascular coagulation has independent prognostic value for early death. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting. • Mutation profile showed a higher VAF in the R/REF group as compared to CR AML. • RNA-Seq revealed OXPHOS as one of the most downregulated pathways at relapse. • Ven/Met combination showed synergistic effect in inv(16) ME-1 cell line. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Central venous catheters (CVC) related thrombosis (CRT) represents a well known complication in patients with acute myeloid leukemia (AML) receiving intensive chemotherapy but the efficacy of antithrombotic prophylaxis still remains controversial. Patients and Methods: We analyzed 71 consecutive AML patients whose CVC was inserted before each chemotherapy cycle for an overall number of 106 CVC placements. In 47/106 insertions, a prophylaxis with 100 IU /kg/day low molecular weight heparin (LMWH) was administered for 7days after CVC insertion and additional 7 after CVC removal. This unconventional dose of LMWH, although higher than usual, appeared adequate for a short-course approach. LMWH was delivered regardless of the platelet (PLT) count once provided that it should have been maintained above 20x109/L by transfusions. Results: Of 106 insertions, we observed 19 (18%) episodes of CRT, 58 (54%) of sepsis and 50 (47%) infections of CVC-exit site with no difference between LMWH and no-LMWH group. Occurrence of CRT was significantly associated with CVC-exit site infections (14/19, p=0.01) and sepsis (16/19, p=0.005) with no difference between LMWH and no-LMWH group. In multivariate analysis, both CVC-exit site infections and sepsis were confirmed to be independent risk factors for CRT development. Conclusion: Our retrospective study, although based on a small sample size, suggests that the occurrence of CVC-exit site infections and neutropenic sepsis following chemotherapy significantly increases the risk of CRT in AML, independently from the use of LMWH prophylaxis. [Copyright &y& Elsevier]

Measurable residual disease (MRD; previously termed minimal residual disease) is an independent, postdiagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be evaluated using a variety of multiparameter flow cytometry and molecular protocols, but, to date, these approaches have not been qualitatively or quantitatively standardized, making their use in clinical practice challenging. The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRD in clinical practice. The work was accomplished over 2 years, during 4 meetings by a specially designated MRD Working Party of the European LeukemiaNet. The group included 24 faculty with expertise in AML hematopathology, molecular diagnostics, clinical trials, and clinical medicine, from 19 institutions in Europe and the United States. [ABSTRACT FROM AUTHOR]

Fluorescence in situ hybridization (FISH) is becoming popular in the diagnosis of clonal chromosomal abnormalities. We set up a fast FISH procedure using an extensive set of specific probes. Conventional banding analysis (CBA) and FISH were compared in 260 newly diagnosed acute myeloid leukemia (AML) patients. For FISH the following probes were used: MLL, CBF-?/MYH11, ETV-6/AML1; AML1/ETO, BCR/ABL, PML/RAR, c-MYC, TP53, RB1, 5q31/5p15.2, 5q33-34, 7q31/CEP7 , 20q13; CEP 4, X, Y. Result time was 96?h for CBA versus 5?h for FISH from direct harvest. CBA showed clonal abnormalities in 41% (n=105/260), normal karyotype in 39% (n=102/260) and failed in 20% (n=53/260). FISH screened all patients and detected abnormalities in 39% (n=102/260); CBA and FISH together identified abnormalities in 49% (n=128/260). In six patients with normal CBA and in eight patients with clonal karyotype, it detected further cryptic abnormalities. CBA showed clonal abnormalities in 13% of patients negative at FISH (n=21/158). FISH screening does not add relevant information to CBA, but is the quickest method for detecting major genetic abnormalities in AML. The speed of FISH is very valuable in AML-M3/M3v because PML/RAR+ patients require specific therapy. Furthermore, we suggest FISH screening in failed, complex or suboptimal quality chromosome and specific FISH analysis for 5q, 7q, 12p, 17p, inv(16), t(11q23) in order to implement CBA accuracy.The Hematology Journal (2003) 4, 263-270. doi:10.1038/sj.thj.6200262 [ABSTRACT FROM AUTHOR]

• The TdT enzyme may be involved in the generation of FLT3 -ITD and NPM1 mutations in AML • Median TdT expression assessed by flow cytometry on blasts is significantly higher in FLT3-ITD mutated AMLs • TdT expression levels are predictive of FLT3 -ITD mutations (C-index = 0.69) • TdT + patients had poorer OS as compared to TdT- patients in univariate analysis The terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in acute myeloid leukemias (AMLs), where it may be involved in the generation of NPM1 and FLT3 -ITD mutations. We studied the correlations between TdT expression and FLT3 -ITD or NPM1 mutations in primary AML samples, and the impact on patients' survival. TdT expression was analyzed in 143 adult AML patients by flow cytometry as percentage of positivity and mean fluorescence intensity (MFI) on blasts. TdT was positive in 49 samples (34.2%), with a median of 48% TdT-positivity (range 7-98) and a median MFI of 2.70 (range 1.23-30.54). FLT3 -ITD and NPM1 mutations were present in 24 (16.7%) and 34 (23.7%) cases, respectively. Median TdT expression on blasts was significantly higher in FLT3 -ITD+, as compared with FLT3 -ITD- AMLs (median 8% vs 0% respectively, p = 0.035). NPM1 mutational status, FLT3 -ITD allelic ratio, karyotype, and ELN risk groups, did not correlate with TdT expression or MFI on blasts. TdT + patients had poorer survival as compared to TdT-, but this result was not confirmed by the multivariable analysis, where ELN risk stratification as well as age and type of treatment remained independent prognostic factors for OS. In summary, our results support the possible implication of TdT enzyme in the generation of FLT3 -ITD mutations in AML. [ABSTRACT FROM AUTHOR]