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Summary: European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo‐HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia‐free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse‐plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2‐year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo‐HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group. [ABSTRACT FROM AUTHOR]

Summary: Despite advancements in utilizing genetic markers to enhance acute myeloid leukaemia (AML) outcome prediction, significant disease heterogeneity persists, hindering clinical management. To refine survival predictions, we assessed the transcriptome of non‐acute promyelocytic leukaemia chemotherapy‐treated AML patients from five cohorts (n = 975). This led to the identification of a 4‐gene prognostic index (4‐PI) comprising CYP2E1, DHCR7, IL2RA and SQLE. The 4‐PI effectively stratified patients into risk categories, with the high 4‐PI group exhibiting TP53 mutations and cholesterol biosynthesis signatures. Single‐cell RNA sequencing revealed enrichment for leukaemia stem cell signatures in high 4‐PI cells. Validation across three cohorts (n = 671), including one with childhood AML, demonstrated the reproducibility and clinical utility of the 4‐PI, even using cost‐effective techniques like real‐time quantitative polymerase chain reaction. Comparative analysis with 56 established prognostic indexes revealed the superior performance of the 4‐PI, highlighting its potential to enhance AML risk stratification. Finally, the 4‐PI demonstrated to be potential marker to reclassified patients from the intermediate ELN2017 category to the adverse category. In conclusion, the 4‐PI emerges as a robust and straightforward prognostic tool to improve survival prediction in AML patients. [ABSTRACT FROM AUTHOR]

Summary: We have conducted a retrospective, single‐centre analysis of 20 patients with relapsed or refractory FLT3‐mutated acute myeloid leukaemia (FLT3m AML) who received a salvage quadruplet regimen consisting of gilteritinib, venetoclax, low‐dose cytarabine and actinomycin D (G‐ACTIVE). G‐ACTIVE resulted in a 95% (19/20) overall response rate and 75% (15/20) complete remission and complete remission with an incomplete platelet recovery (CR + CRp) rate. Out of 13 transplant‐eligible patients, 11 (86%) proceeded to an allogeneic stem cell transplantation. The median overall survival and relapse‐free survival after G‐ACTIVE were 32 and 12.9 months respectively. The Day 60 mortality rate was 15%. [ABSTRACT FROM AUTHOR]

Summary: HAX1‐related congenital neutropenia (HAX1‐CN) is a rare autosomal recessive disorder caused by pathogenic variants in the HAX1 gene. HAX1‐CN patients suffer from bone marrow failure as assessed by a maturation arrest of the myelopoiesis revealing persistent severe neutropenia from birth. The disorder is strongly associated with severe bacterial infections and a high risk of developing myelodysplastic syndrome or acute myeloid leukaemia. This study aimed to describe the long‐term course of the disease, the treatment, outcome and quality of life in patients with homozygous HAX1 mutations reported to the European branch of the Severe Chronic Neutropenia International Registry. We have analysed a total of 72 patients with different types of homozygous (n = 68), compound heterozygous (n = 3), and digenic (n = 1) HAX1 mutations. The cohort includes 56 paediatric (<18 years) and 16 adult patients. All patients were initially treated with G‐CSF with a sufficient increase in absolute neutrophil counts. Twelve patients required haematopoietic stem cell transplantation for leukaemia (n = 8) and non‐leukaemic indications (n = 4). While previous genotype–phenotype reports documented a striking correlation between two main transcript variants and clinical neurological phenotypes, our current analysis reveals novel mutation subtypes and clinical overlaps between all genotypes including severe secondary manifestations, e.g., high incidence of secondary ovarian insufficiency. [ABSTRACT FROM AUTHOR]

Summary: Oral azacitidine (Oral‐AZA) maintenance therapy improved relapse‐free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML‐001 study. Immune profiling was performed on the bone marrow (BM) at remission and on‐treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on‐treatment immune effects by Oral‐AZA with clinical outcomes. Post‐IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T‐cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD‐L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD‐L2+. High co‐expression of T‐cell exhaustion markers PD‐1 and TIM‐3 was associated with inferior outcomes. Oral‐AZA augmented T‐cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T‐cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T‐cell content and expression of T‐cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral‐AZA modulates T‐cell activity in the maintenance setting of AML, and these immune‐mediated responses are associated with clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: To reduce the risk of invasive aspergillosis (IA), air purification by high‐efficiency particulate air filtration and laminar air flow (HEPA/LAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non‐transplant haematological patients is inconsistent. Objectives: We sought to assess the incidence and outcome of pulmonary IA in non‐transplant patients with life‐threatening neutropenia by comparing an ambient air hospitalisation period (2008–2011) with a subsequent HEPA/LAF hospitalisation period (2012–2014). Patients and Methods: We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia‐related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia‐related hospitalisations under HEPA/LAF conditions. IA was defined using the 2008 EORTC/MSG criteria. Results: Within a 7‐year study period, we observed one 'proven', three 'probable' and 73 'possible' IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life‐threatening neutropenia (1–10 days, 1.8%; >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2%; >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPA/LAF conditions (odds ratio [OR], 0.368 [95% confidence interval, 0.207–0.654]; p <.001) and duration of neutropenia (OR, 1.043 [1.023–1.062] per day; p <.001) and anaemia (OR, 1.044 [1.008–1.081] per day; p =.016). IA‐associated fatal outcomes were non‐significantly reduced under HEPA/LAF (OR, 0.077 [0.005–1.151]; p =.063). The protective effect of HEPA/LAF was not seen under posaconazole prophylaxis (OR, 0.856 [0.376–1.950]; p =.711). Conclusions: Implementation of HEPA/LAF was associated with a significant reduction in neutropenia‐related IA in non‐transplant haematological patients. [ABSTRACT FROM AUTHOR]

Summary: Since the early 1970s, the treatment of acute myeloid leukaemia (AML) has undergone a major transformation. Initially based on only two drugs, an anthracycline and cytosine arabinoside, the aim of therapy was to achieve a haematological response allowing patients to recover and go home. Back in those early days, cure was not a realistic expectation. Treatment was analogous to a heart attack; upon recovery and a short respite, recurrence and death inevitably followed. Over the subsequent decades, slow but remarkable progress was made such that a subgroup of young adults could become long‐term survivors. This astonishing feat was achieved initially without the use of new drugs. Supportive care played a major role with the widespread availability of platelet transfusions and improved antimicrobial therapy, particularly antifungal. No less important was the better use of existing drugs and the development of allogeneic haematopoietic cell transplantation. While initially the focus was on maximal tolerated therapy, an understanding of the immunologic role of allogeneic transplantation, better genetic characterization of the biology of the disease, advanced tools for detection of minimal disease as well as the recent development of new drugs changed the focus to a more refined approach targeting patients who are more likely to respond. Clearly, the historical paradigm where the term AML was generic and applicable to all patients requires a rethinking from the traditional therapeutic demarcations of therapy into phases of induction, consolidation and maintenance. These evolving new concepts and paradigm will be herein considered. [ABSTRACT FROM AUTHOR]

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic neoplasm and classified under acute myeloid leukemia. Here, we describe the clinicopathological features of three cases of BPDCN: two with classical and one uncommon immunophenotype. A-35-year-old female (case 1) presented with complaint of nasal mass and generalized lymphadenopathy. Biopsy from axillary lymph node showed infiltration by cells with scant cytoplasm which were immunopositive for LCA, CD4, CD43, and ALK1. Flowcytometry showed positivity for CD45, CD4, CD33, and CD123 while negative for rest all markers. The other two cases have classical immunophenotype. In clinical practice, nasal mass with lymphadenopathy suggests natural killer T-cell/peripheral T-cell lymphoma. Again immunohistochemical positivity for CD4, CD43, and ALK while negativity for CD3 suggests anaplastic large cell lymphoma. In this case, morphology and extensive bone marrow involvement raise the suspicion. Fowcytometry positivity for HLADR, CD123, and CD33 helps in making diagnosis. [ABSTRACT FROM AUTHOR]

Summary: Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)‐based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy‐related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30‐ and 90‐day mortality between DR and non‐DR patients. Furthermore, DR did not affect median relapse‐free survival (RFS) [DR, 14.5 (95% confidence interval, 9.0–41.7) months; non‐DR, 15.0 (12.3–19.3)] with an adjusted difference in five‐year restricted mean survival time (Δ5y‐RMST) of 0.2 (−8.4 to 8.8) months nor median OS (DR, 17.0 [11.9 to 45.5] months; non‐DR, 17.5 [14.8 to 20.5]) with an adjusted Δ5y‐RMST of 0.8 (−5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is the commonest chromosomal disorder and is considered to be the most common syndrome associated with acute leukaemia. The objective of this study was to determine the characteristics of acute leukaemia in children with DS in Pakistan. It was a retrospective, cohort study conducted over a 2-year period, and the data was analysed in SPSS 20.0 in terms of descriptive statistics. Nineteen DS patients with acute leukaemia were enrolled. The proportion of DS-acute leukaemia was found to be 1.84% among all cases of paediatric acute leukaemia. The mean age of presentation was 5.5 years ± 4.3 SD with a male to female ratio of 1.1:1. The precursor B-cell ALL was found in 13 (68.4%) and acute myeloid leukaemia was found in 6 (31.6%) patients of DS. Thirteen patients (68.4%) completed treatment, while 6 (31.6%) expired due to treatment-related toxicity. Mean overall survival was 38 months ± 5.34 SD. The status of diagnosis of DS before presentation with acute leukaemia was the only statistically significant factor associated with the outcome. Few distinct characteristics of DS-acute leukaemia have been found in our population. Treatment toxicity was the sole cause of treatment failure. [ABSTRACT FROM AUTHOR]

Summary: To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database as a training set and included 189 patients from our centre as a validation set. In the training set, age at diagnosis, ‐7/del(7q) or ‐5/del(5q), core binding factor fusion genes, FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)/nucleophosmin 1 (NPM1) status, Wilms tumour 1 (WT1) mutation, biallelic CCAAT enhancer binding protein alpha (CEBPA) mutation were strongly correlated with overall survival and included to construct the model. The prognostic model demonstrated excellent discriminative ability with the Harrell's concordance index of 0.68, 3‐ and 5‐year area under the receiver operating characteristic curve of 0.71 and 0.72 respectively. The model was validated in the validation set and outperformed existing prognostic systems. Additionally, patients were stratified into three risk groups (low, intermediate and high risk) with significantly distinct prognosis, and the model successfully identified candidates for haematopoietic stem cell transplantation. The newly developed prognostic model showed robust ability and utility in survival prediction and risk stratification, which could be helpful in modifying treatment selection in clinical routine. [ABSTRACT FROM AUTHOR]

Canine acute leukaemia is a heterogeneous neoplasm with multiple phenotypes. Criteria to subtype acute leukaemia by flow cytometry have not been validated. The goal of this study was to develop a panel of antibodies and objective antigen expression criteria for the assignment of lymphoid or myeloid lineage by flow cytometry. We isolated mRNA from the blood of 45 CD34+ acute leukaemia cases and measured expression of 43 genes that represent lymphoid and myeloid lineages using NanoString technology. We determined differentially expressed genes between major groups identified by unsupervised hierarchical clustering. We then evaluated the expression of antigens by flow cytometry to determine if cases could be assigned to a lineage. Two groups were identified by gene expression. Group 1/LYMPH overexpressed lymphoid‐associated genes (ex. DNTT) and had a higher percentage of CD5 + CD3‐ cells by flow cytometry. Group 2/MYELO overexpressed myeloid‐associated genes (ex. ANPEP/CD13) and had a higher percentage of class II major histocompatibility complex (MHCII)‐ CD14+ and/or CD18 + CD4‐ cells. We proposed that >12.5% CD5 + CD3‐ cells in the blood was indicative of lymphoid lineage, and > 3.0% CD14 + MHCII‐ cells or > 18% CD18 + MHCII‐CD4‐ cells was indicative of myeloid lineage. 15/15 cases that met the proposed criteria for acute lymphocytic leukaemia were in LYMPH group and 12/15 cases that met the proposed criteria for acute myeloid leukaemia were in MYELO group. The majority of CD34+ cases that did not meet either immunophenotyping lineage criterion (12/13) clustered within the LYMPH group. In conclusion, currently available antibodies can be useful for determining canine acute leukaemia subtypes. [ABSTRACT FROM AUTHOR]

It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform approaches to diagnosis and management of immature leukaemias, with a specific focus on T‐lymphoid and myeloid cases. In particular, we consider whether next‐generation analytical tools could provide new perspectives that could improve our understanding of immature blood cancer biology. [ABSTRACT FROM AUTHOR]

Patient reported outcomes (PROs) are a pillar of modern-day patient-centered care and clinical trials. PROs complement clinical information with the patient's own report about their experiences of health, without influence or interpretation by other people. However, choosing an appropriate PRO measure from the many available remains challenging for clinicians and researchers. One of the common pitfalls in instrument selection is that the instrument is often developed with a different patient population than the group being cared for or researched. This difference can result in salient items of importance to the patients, being under-reported or missed altogether. We highlight, through the reporting of some of our own data, that PRO instrument development does not stop with a validation study and we provide suggestions for future research for further improvement in this space. [ABSTRACT FROM AUTHOR]

We included RCTs of supportive-care interventions delivered to adults (>18 years) with an AML diagnosis undergoing treatment (induction or consolidation chemotherapy, and/or allo-SCT), with studies of pharmacological, surgical or treatment-specific interventions (e.g. chemotherapy dose adjustment, blood transfusion strategies etc.) excluded. Non-pharmacological supportive-care interventions in acute myeloid leukaemia: a review of randomised controlled trials. [Extracted from the article]

Summary: Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low‐dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC‐T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick‐a‐Winner' LI‐1 trial. There was a statistically non‐significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC‐T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30–1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37–1·27; P = 0·22). However, overall survival (OS) showed no difference (2‐year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73–1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre‐clinical, early non‐randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019 [ABSTRACT FROM AUTHOR]

Summary: Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR‐Ts), opened up new horizons for the treatment of B‐cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR‐T therapies. Although non‐engineered T cells targeting multiple leukaemia‐associated antigens [i.e. leukaemia‐specific T cells (Leuk‐STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large‐scale Leuk‐ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent‐Leuk‐STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non‐transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell‐derived myeloid DCs and subsequently polyclonal bivalent‐Leuk‐STs. Those bivalent‐Leuk‐STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk‐STs, as a 'third‐party', 'off‐the‐shelf' T‐cell product for the treatment of acute leukaemias. [ABSTRACT FROM AUTHOR]

Summary: Following the 2017 European LeukemiaNet (ELN) guidelines, we changed our practice from using high‐dose cytarabine (HIDAC‐3 g/m2 q12h‐D1,3,5) to intermediate‐dose cytarabine (IDAC‐1·5 g/m2 q12h‐D1,3,5/D1–3) for consolidation in young(<60 years) favourable‐risk acute myeloid leukaemia (AML) patients. We assessed the clinical impact of this practice change. Of 80 patients, 51 received HIDAC prior to the protocol change, and subsequently, 29 received IDAC. The three‐year risk of relapse was significantly higher with IDAC [61%; 95% confidence interval (CI) 40–82] compared with HIDAC (22%; 10–34), P < 0·01. Our findings suggest HIDAC, rather than IDAC, is the preferred dose for single‐agent cytarabine consolidation in young, favourable‐risk AML following 7+3 induction. [ABSTRACT FROM AUTHOR]

Introduction: Acute leukemia (AL) occurring in pregnancy is extremely rare, and its treatment is a clinical dilemma. Methods: We retrospectively reviewed the medical records of our hospital from 2010 to 2019. Results: Twenty-one patients were diagnosed with AL during pregnancy. Of whom, eighteen had acute myeloid leukemia, and 3 had acute lymphoblastic leukemia. Six, eight and seven patients were diagnosed during the first, second, and third trimester, respectively. Six of the 21 patients experienced therapeutic abortion and 1 had spontaneous abortion, whereas 9 gave birth to healthy babies (4 through vaginal deliveries and 5 with Caesarean sections). Four babies had been exposed to chemotherapeutic agents, but no congenital malformations were observed. Sixteen patients received chemotherapy, while 4 patients died before chemotherapy and one was discharged after refusing chemotherapy. The complete remission rate of the 10 patients who began chemotherapy immediately after diagnosis was 80%, compared with 66.7% in the 6 patients who started chemotherapy after abortion or delivery. Three remain alive. Conclusions: In general, initiation of chemotherapy as early as possible may increase the CR rate. Combined with literature data, we proposed that, for patients diagnosed in early and late stages of pregnancy (>30 weeks), elective termination or induced delivery before chemotherapy may be a good choice for better maternal (and fetal) outcome. [ABSTRACT FROM AUTHOR]

Keywords: acute leukaemia; AML; cytogenetics of leukaemia; cytogenetics; FISH; MDS EN acute leukaemia AML cytogenetics of leukaemia cytogenetics FISH MDS 935 938 4 12/07/20 20201201 NES 201201 Recent approvals of multiple new agents for the treatment of acute myeloid leukaemia (AML) have highlighted the need for rapid and precise diagnostic laboratory studies.1,2 Although the same cytarabine and anthracycline-based (typically daunorubicin) induction chemotherapy regimen (7 + 3) was the mainstay of therapy for fit patients for decades,3,4 there is no longer a one-size-fits-all approach to induction chemotherapy. MDS FISH testing is not necessary for those patients with a known history of prior MDS or cytotoxic and/or radiotherapy as these patients are potential candidates for liposomal daunorubicin/cytarabine based on history alone. In our cohort, there was a median time from admission to beginning induction chemotherapy of 2-5 days for patients with positive CBF FISH (range 1-7 days), four days for patients with positive MDS FISH (range 2-7 days) and 3-5 days for the remaining patients (range 0-9 days). [Extracted from the article]

Objective: The study explores how newly diagnosed patients with acute leukaemia and their patient ambassadors experience the mentorship during the patient ambassador support programme. Methods: Explorative semi‐structured individual interviews (n = 28) were carried out in patients with acute leukaemia (n = 15) and their patient ambassadors (n = 13). Interpretive description was the methodological framework used for the thematic analysis of the qualitative interview data. Results: Identified themes were as follows: (a) exchanging life experiences (subthemes: individualised support and a meaningful return); (b) existential cohesion; (c) interreflection; and (d) terms and conditions (subtheme: break in journey). Patients experienced a feeling of being understood, the cohesion leading to hope and a feeling of being able to cope with their situation. Patient ambassadors experienced a sense of meaningfulness and gratitude for life. Conclusions: Patients and patient ambassadors experienced benefits from the individualised support. Their shared experiences created a connection and mutual mirroring, which led to a sense of hope and gratitude for life. Initiatives that introduce peer‐to‐peer support in newly diagnosed patients with acute leukaemia as part of treatment and in daily clinical practice are crucial. Future studies should further examine the feasibility of peer‐to‐peer support interventions along the trajectory of acute leukaemia. [ABSTRACT FROM AUTHOR]

Interleukin-1 blockade with anakinra in acute leukaemia patients with severe COVID-19 pneumonia appears safe and may result in clinical improvement Keywords: haemophagocytic syndrome; acute leukaemia; infection; immunotherapy EN haemophagocytic syndrome acute leukaemia infection immunotherapy e80 e83 4 07/20/20 20200715 NES 200715 As of 17 May 2020 the number of patients infected by coronavirus disease 2019 (COVID-19) worldwide has exceeded 4-5 million.1 A subgroup of patients with COVID-19 pneumonia develop a hyperinflammatory syndrome which has a similar cytokine release profile to secondary haemophagocytic lymphohistiocytosis (HLH).2 Immunomodulatory drugs are hypothesised to abrogate the dysfunctional immune response in hyperinflammatory COVID-19 and are currently being investigated in clinical trials. In this report we demonstrate that anakinra is safe in haematology patients and resulted in a clinical improvement in three patients with acute leukaemia and confirmed or suspected COVID-19 pneumonia with a life-threatening hyper-inflammatory syndrome. [Extracted from the article]

Background and Objectives: Haematological malignancies account for approximately 40% of all cancers by the age of 15 years. Acute leukaemia (AL) account for one-third of childhood cancer cases; consisting of Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML). The aim of this work is to describe the epidemiological, clinical, biological and evolutionary characteristics of children with acute leukaemia in the western and south-western region of Algeria. Patients and Methods: A three-year retrospective study was undergone from January 2016 to December 2018 on children with acute leukaemia. The study was conducted at the paediatric oncology department of the anti-cancer -Emir AEK- of Missreghine in Oran. Results: During this period, we identified 135 cases of diagnosed AL. The sex ratio M/F was 1.1. The "two to five -year" age group was the most affected. The prevalence of ALL, AML, and biphenotypic acute leukaemia (BAL) was 60.45%, 23.88%, and 15.57%, respectively. The clinical signs were mainly presented by the tumour syndrome dominated by the presence of lymphadenopathy (63%) and splenomegaly (56.3%). The most frequent abnormal blood abnormalities were anaemia (66.66% in ALL and 28.14% in AML), thrombocytopenia (75.9% in ALL and 24.4% in AML) and leukocytosis (76.3% ALL and 23.7% AML). Conclusion: Paediatric acute leukaemia is a real public health problem that requires special care and attention. This management must involve all epidemiological, clinical and biological aspects for this highly sensitive age group. [ABSTRACT FROM AUTHOR]

Summary: The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB‐RC) was calculated for treatment‐naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB‐RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB‐RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24–2·64, P < 0·005). PBB‐RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27–3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52–0·87]. African American patients had poorer OS adjusted for PBB‐RC (HR = 2·18; 95% CI: 1·13–4·23), while race was not associated with D14BM or CR rate. PBB‐RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML. [ABSTRACT FROM AUTHOR]

Venetoclax can lead to rapid tumour lysis syndrome (TLS) in CLL patients and is therefore administered in a weekly dose ramp-up to minimize toxicity (Roberts I et al i , [9]). A modified dose ramp-up of venetoclax over 3-4 days in combination with HMAs has been investigated in AML trials without any reported cases of TLS (DiNardo I et al i , [4]). Once venetoclax dose ramp-up is complete, azole prophylaxis can be added, if necessary, with appropriate venetoclax dose reduction in order to reduce potential TLS complications. As venetoclax becomes standard management for newly diagnosed older and unfit AML patients, vigilant monitoring is required to mitigate the possible TLS complications and ensure the safety of patients on these therapeutic agents. [Extracted from the article]

Tetrasomy 8, a rare genetic abnormality in haematological disorders is associated with Acute Myeloid Leukaemia (AML), Myelodysplastic Syndrome, Myeloproliferative Neoplasms and Acute Non Lymphocytic Leukaemia. It may be found as a sole chromosomal abnormality or co-exist with Trisomy 8. Tetrasomy 8 has shown to have proliferative advantage and aggressive clinical course with lower survival rates. Four cases of Tetrasomy 8 were reported in present series, of which one case showed Tetrasomy 8 as a sole chromosomal abnormality, two cases with it's co-existence with Trisomy 8 and one case with complex rearrangement of chromosome 8. Trisomy 8 as a sole abnormality is associated with intermediate prognosis; hence the aggressive behaviour of the disease with Tetrasomy 8 can be attributed to increase in gene dosage of extra chromosome 8. The fourth case of AML with monocytic differentiation showed complex karyotype with presence of two isochromosomes 8, resulting in five copies for long arm of chromosome 8. This demonstrates presence of crucial genes for leukemogenesis in 8q region. From various studies, it is evident that the role of Tetrasomy 8 in poor prognosis and role of associated genes in leukemogenesis needs further investigation on molecular deregulation mechanisms with biologic and clinical consequences. Building up on rare abnormalities by this study would help in a better understanding of the disease with appropriate classification and ultimately can lead to an effective clinical management. [ABSTRACT FROM AUTHOR]

The article offers information on the role of nucleated bone marrow (BM) cells for acute myeloid leukaemia (AML) patient. It discussed the increasingly standard to perform morphological tests and multiparameter flow cytometry (MFC) in parallel to assess remission; and also examine the data for discrepant response assessment by standard criteria.

The article focuses on the impact of the multikinase inhibitor Midostaurin in children experiencing relapsed acute leukaemia despite past tretaments. It talks about the relapse of acute leukaemia being common in children along with diseases like myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL).

Summary: Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case‐control study that included 3053 AML patients, diagnosed in Denmark between 2000 and 2013, and 30 530 sex‐ and age‐matched population controls. We retrieved information on autoimmune disease, infections, and use of antibiotics and computed odds ratios for AML (conditional logistic regression). Results were stratified by AML type, sex, and age. Autoimmune diseases were associated with an overall increased risk of AML {odds ratio [OR] 1·3 [95% confidence interval (CI) = 1·1–1·5]}. However, the risk was confined to patients with previous haematological disease or cytotoxic therapy exposure [secondary/therapy‐related AML (sAML/tAML0) OR 2·0 (95% CI = 1·6–2·6)] and not de novo AML [OR 1·1 (95% CI = 0·9–1·3)]. Similarly, any prior infection requiring hospitalization was associated with a higher risk of AML [OR 1·3 (95% CI = 1·1–1·4)]. Again, this association was evident for sAML/tAML [OR 1·8 (95% CI = 1·5–2·2)], and not de novo AML [OR 1·1 (95% CI = 1·0–1·2)]. In conclusion, autoimmune diseases and infections were associated with an increased AML risk only in subjects with prior haematological disease and/or cytotoxic treatment. These observations suggest, that inflammation plays – if any – a minor role for the development of de novo AML. [ABSTRACT FROM AUTHOR]

Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches. [ABSTRACT FROM AUTHOR]

Acute leukaemia (AL) is a critical neoplasm of white blood cells. Diagnosing AL requires bone marrow puncture procedure, which many patients do not consent to for it is invasive. Hence sensitive and specific early diagnostic biomarkers are essential for non-invasive diagnosis, new therapeutics and improving the disease prognosis. To differentiate the metabolic alterations associated with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), we investigated serum of ALL and AML patients in comparison with two controls using gas chromatography coupled with triple quadrupole tandem mass spectrometry and multivariate statistical analysis. Twenty seven out of 1425 metabolites were found differentiative among ALL, AML, aplastic anaemia (APA) patients and healthy control using p-value ≤ 0.001. ALL is the most dissimilar group from other three groups as in hierarchical clustering showed 72.1% dissimilarity. Model generation using PLSDA gave an overall accuracy of 91.9%. This study helps in metabolic fingerprinting of control and disease serum at high significance levels and could be used for early diagnosing of AL. Based on pathways analysis, fatty acid metabolism is deregulated in patients with AL and may represent an underlying metabolic pathway associated with disease progression. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Few studies have evaluated the impact of complications, sociodemographic and clinical factors on early mortality (death ≤60 days from diagnosis) in acute myeloid leukaemia (AML) patients. Using data from the California Cancer Registry linked to hospital discharge records from 1999 to 2012, we identified patients aged ≥15 years with AML who received inpatient treatment ( N = 6359). Multivariate logistic regression analyses were used to assess the association of complications with early mortality, adjusting for sociodemographic factors, comorbidities and hospital type. Early mortality decreased over time (25·3%, 1999-2000; 16·8%, 2011-2012) across all age groups, but was higher in older patients (6·9%, 15-39, 11·4%, 40-54, 18·6% 55-65, and 35·8%, >65 years). Major bleeding [Odds ratio ( OR) 1·5, 95% confidence interval ( CI) 1·3-1·9], liver failure ( OR 1·9, 95% CI 1·1-3·1), renal failure ( OR 2·4, 95% CI 2·0-2·9), respiratory failure ( OR 7·6, 95% CI 6·2-9·3) and cardiac arrest ( OR 15·8, 95% CI 8·7-28·6) were associated with early mortality. Higher early mortality was also associated with single marital status, low neighbourhood socioeconomic status, lack of health insurance and comorbidities. Treatment at National Cancer Institute-designated cancer centres was associated with lower early mortality ( OR 0·5, 95% CI 0·4-0·6). In conclusion, organ dysfunction, hospital type and sociodemographic factors impact early mortality. Further studies should investigate how differences in healthcare delivery affect early mortality. [ABSTRACT FROM AUTHOR]

Multiresistant bacterial infections are a potentially life-threatening condition in acute leukaemia (AL) patients. We aimed to better define the very recent epidemiology and outcome of bloodstream infections (BSIs) in a real-life setting. We prospectively collected all consecutive febrile/infectious episodes occurring in AL patients admitted to 9 haematology units. In 293 AL patients, 433 BSIs were diagnosed. Gram-positive (GP) bacteria were isolated in 44.8 % BSI and Gram-negative (GN) in 38.3 %, while polymicrobial aetiology- or fungi-related events were identified in 15.7 and 1.1 % of the cases, respectively. GP was observed more frequently in patients not in complete remission (p = 0.04), while GN during consolidation cycles (p = 0.003). Extended spectrum β-lactamase-producing strains accounted for 23.2 % of enterobacteria. They were associated with previous antibiotic exposure, including fluoroquinolones prophylaxis (p = 0.01). Carbapenem-resistant (CR) strains occurred in 9 % of enterobacteria. Among Pseudomonas aeruginosa strains, 21.6 % were multiresistant. Overall 30-day mortality was 8.5 %. CR GN and multiresistant P. aeruginosa BSIs were independent predictors of death (p = 0.002), as well as relapsed/resistant AL (18.3 %; p = 0.0002) and the presence of pulmonary infiltrates (26.6 %; p < 0.001). Although GP still predominate over GN BSI, the percentage of antibiotic resistant GN strains is considerable in AL patients and it is associated with poor prognosis. [ABSTRACT FROM AUTHOR]

Longitudinal minimal residual disease (MRD) evaluation in acute myeloid leukaemia with NPM1 mutation: from definition of molecular relapse to MRD-driven salvage approach Patients with Mol-relapse defined according to the aforementioned criteria progressed to overt Haem-relapse within 3 months from the third BM sample (range 0-5-3); no patient experienced haematological relapse before fulfilling Mol-relapse criteria. GLO:1XW/15sep19:bjh16116-fig-0001.jpg PHOTO (COLOR): Pre- and post-therapy disease burden in patient treated for MRD relapse compared to patients treated for haematological relapse. [Extracted from the article]

A letter to the editor is presented on examining the effectiveness of the second-generation irreversible proteasome inhibitors carfilzomib and oprozomib compared to bortezomib on acute myeloid leukaemia stem cell survival.

Introduction Automated haematology analysers may inaccurately determine platelet counts in several circumstances. Spuriously elevated automated platelet counts have been reported in some acute leukaemia ( AL) cases because of fragmentation of circulating blast cells (pseudoplatelets). Haemorrhagic diathesis is a common manifestation of AL, which is often caused by severe thrombocytopenia. Therefore, overestimation of the actual platelet count in patients with AL can affect its clinical management. We aimed to detect the frequency of pseudoplatelets in patients with AL. Methods Complete blood cell counts were performed on 86 AL patients with three automated analysers ( ADVIA 2120, Coulter LH 750 and Sysmex XE-2100D). Platelet counts were also performed by quantitative flow cytometry ( QFC). The platelet counts of the automatic analysers were compared to the platelet counts by QFC. Blood smears were checked for the presence of pseudoplatelets. Results The automated analysers overestimated the platelet count due to the presence of pseudoplatelets in patients with AL. Pseudoplatelets were observed in the blood smears of 11 patients (13%). Three of these patients were near the prophylactic platelet transfusion threshold. Conclusion Spurious increases in automated platelet counts by blast cell fragments are little known but frequent artefacts that should be ruled out by careful examination of peripheral blood smears. [ABSTRACT FROM AUTHOR]

Hospital environment is considered the main source of invasive aspergillosis (IA) in leukemic patients. This study aimed to describe Aspergillus colonisation in leukemic patients and their hospital environment and to test whether Aspergillus environmental contamination was associated with IA. For a 2-year period including 14-month renovation work, 91 acute leukaemia inpatients at the hematology department of University hospital in Sousse (Tunisia) were prospectively included. The incidence of probable IA (EORTC/MSG criteria) was 9.9%. Fifty-six Aspergillus were isolated from 53 (6.5%) of 811 sputa collected from 35 (38.5%) patients. Aspergillus spp. were isolated in 59.7% of 494 air samples and in 52.8% of 1579 surface samples taken in the patients' room. Aspergillus section Nigri (72.7%) was the most frequent. Aspergillus contamination peaked in autumn and winter on surface and in summer and autumn in air samples and was higher ( P = 0.03) during the renovation work period. Multivariate analysis showed that for each Aspergillus section Nigri CFU airborne contamination IA risk increased by 1.05 ( P = 0.04). In Tunisia, Aspergillus section Nigri and Flavi, but not Fumigati, are chiefly involved in IA. Our findings support swift implementation of airborne fungal contamination control measures in areas where immunocompromised patient are hospitalised. [ABSTRACT FROM AUTHOR]

The usefulness of posaconazole therapeutic drug monitoring ( TDM) is still a matter of debate. A correlation between posaconazole serum levels and breakthrough invasive fungal infections ( IFI) has not been clearly demonstrated so far. We analysed posaconazole serum levels in patients with acute myeloid leukaemia ( AML) during induction therapy and correlated them with the incidence of breakthrough IFI and the need of systemic antifungal therapy. Overall, 77 AML patients receiving posaconazole were evaluated for serum levels; breakthrough IFI were observed in five with at least one posaconazole TDM (6.5%). Median serum level was 534 ng ml−1 ( IQ range: 298.5-750.5 ng ml−1) and did not change significantly over time. Four of the 40 patients with median posaconazole levels <500 ng ml−1 developed IFI, as compared with only 1 of the 37 patients with median levels ≥500 (10% vs. 2.7%, P = 0.19). Median posaconazole levels on day 7 were 384.5 ng ml−1 ( IQ range: 207-659 ng ml−1) and 560.5 ng ml−1 ( IQ range: 395-756 ng ml−1) in patients requiring or not systemic antifungal treatment respectively ( P = 0.067). These results seem to confirm that higher median serum levels of posaconazole correlate with higher prophylactic efficacy against proven/probable IFI and with lesser need of systemic antifungal therapy. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia ( AML) is a heterogenous disease. Prognosis of AML is influenced both by patient-specific as well as disease-specific factors. Age is the most prominent patient-specific risk factor, while chromosomal aberrations are the strongest disease-specific risk factors. For patients with cytogenetically normal AML, prognosis can be specified by mutational status of the genes NPM1, FLT3 and CEBPA. A growing number of recurrent mutations in additional genes have recently been identified, for which the prognostic effect yet has to be determined. Performance status, geriatric assessment, secondary leukaemia following myelodysplastic syndrome or cytotoxic treatment, common laboratory parameters, leukaemic stem cell frequency, bone marrow microenvironment, gene expression levels, epigenetic changes, micro- RNA's as well as kinetics and depth of response to treatment influence prognosis of AML patients. Despite the high number of established risk factors, only few predictive markers exist which can truly aid therapy decisions in patients with AML. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase 1 (IDO1) metabolizes L-tryptophan to kynurenines (KYN), inducing T-cell suppression either directly or by altering antigen-presenting-cell function. Cyclooxygenase (COX)-2, the rate-limiting enzyme in the synthesis of prostaglandins, is over-expressed by several tumours. We aimed at determining whether COX-2 inhibitors down-regulate the IFN-g-induced expression of IDO1 in acute myeloid leukaemia (AML) cells. IFN-γ at 100 ng/mL up-regulated COX-2 and IDO1 in HL-60 AML cells, both at mRNA and protein level. The increased COX-2 and IDO1 expression correlated with heightened production of prostaglandin (PG)E2 and kynurenines, respectively. Nimesulide, a preferential COX-2 inhibitor, down-regulated IDO1 mRNA/protein and attenuated kynurenine synthesis, suggesting that overall IDO inhibition resulted both from reduced IDO1 gene transcription and from inhibited IDO1 catalytic activity. From a functional standpoint, IFN-g-challenged HL-60 cells promoted the in vitro conversion of allogeneic CD4+CD25- T cells into bona fide CD4+CD25+FoxP3+ regulatory T cells, an effect that was significantly reduced by treatment of IFN-γ-activated HL-60 cells with nimesulide. Overall, these data point to COX-2 inhibition as a potential strategy to be pursued with the aim at circumventing leukaemia-induced, IDO-mediated immune dysfunction. [ABSTRACT FROM AUTHOR]

This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 ( CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia ( T- ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T- ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2 A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T- ALL and acute myeloid leukaemia ( AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T- ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T- ALL and AML. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) is defined as a clinically silent, symptom-free state that does not meet the diagnostic criteria of multiple myeloma (MM), Waldenstrom macroglobulinemia, AL-amyloidosis or any other malignant lymphoproliferative disease. Long-term follow-up has demonstrated that this may be a pre-cancerous state with transformation into a malignant monoclonal gammopathy in approximately 1% of cases annually. Probably all cases of MM arise as a transformation of MGUS. In this overview, the author attempts to answer the key question, namely whether it is currently possible in some way to prevent the transformation of MGUS into MM or to at least to slow this down. The answer in MGUS patients is currently unequivocally NO. In view of the significantly higher risk of transformation in patients with asymptomatic multiple myeloma than in patients with MGUS, further analysis by the CMG will focus on this group of patients with the goal of selecting the group at highest risk and to subject this group to early and if possible nontoxictreatment. [ABSTRACT FROM AUTHOR]

The article presents information on high frequency of copy number alterations in myeloid leukaemia of down syndrome (ML-DS). The genetic aberrations which are found in non-DS paediatric acute myeloid leukaemia (AML) do not occur in ML-DS. A table representing clinical and genetic characteristics of the ML-DS patients including disease, sex, age and Karyotype is also shown.

Immunotherapy is currently under active investigation as an adjuvant therapy to improve the overall survival of patients with acute myeloid leukaemia (AML) by eliminating residual leukaemic cells following standard therapy. The graft-versus-leukaemia effect observed following allogeneic haematopoietic stem cell transplantation has already demonstrated the significant role of immune cells in controlling AML, paving the way to further exploitation of this effect in optimized immunotherapy protocols. In this review, we discuss the current state of cellular immunotherapy as adjuvant therapy for AML, with a particular focus on new strategies and recently published results of preclinical and clinical studies. Therapeutic vaccines that are being tested in AML include whole tumour cells as an autologous source of multiple leukaemia-associated antigens (LAA) and autologous dendritic cells loaded with LAA as effective antigen-presenting cells. Furthermore, adoptive transfer of cytotoxic T cells or natural killer cells is under active investigation. Results from phase I and II trials are promising and support further investigation into the potential of cellular immunotherapeutic strategies to prevent or fight relapse in AML patients. [ABSTRACT FROM AUTHOR]