Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone. Large chromosomal translocations as well as mutations in the genes involved in hematopoietic proliferation and differentiation result in the accumulation of poorly differentiated myeloid cells. AML is a highly heterogeneous disease; although cases can be stratified into favorable, intermediate and adverse-risk groups based on their cytogenetic profile, prognosis within these categories varies widely. The identification of recurrent genetic mutations, such as FLT3-ITD, NMP1 and CEBPA, has helped refine individual prognosis and guide management. Despite advances in supportive care, the backbone of therapy remains a combination of cytarabine- and anthracycline-based regimens with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens, and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of AML.

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‘Acute myeloid leukemia: a comprehensive review and 2016 update’

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

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Acute myeloid leukemia, version 3.2017: Clinical practice guidelines in oncology

Summary Background Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia. Methods We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of gemtuzumab ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from gemtuzumab ozogamicin. Findings We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of gemtuzumab ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77–1·07; p=0·3). However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73–0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82–0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31–0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75–0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83–1·18; p=0·9). Doses of 3 mg/m 2 were associated with fewer early deaths than doses of 6 mg/m 2 , with equal efficacy. Interpretation Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of gemtuzumab ozogamicin should be reassessed and its licence status might need to be reviewed. Funding None.

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Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials

Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1.

Nature Reviews Molecular Cell Biology 12, 427–438 (2011) On page 435 of this article, there was a mistake in the personal communication. The scientists the author received the information from are R. Wolthuis and W. van Zon. This has been corrected online.

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Erratum: Cubism and the cell cycle: the many faces of the APC/C

Resveratrol: Review on its discovery, anti-leukemia effects and pharmacokinetics

Background
Anthracycline combined with cytarabine has been the standard for induction therapy of newly diagnosed acute myeloid leukaemia (AML) for several decades. Due to theoretical advantages, idarubicin (IDA) might be the most effective and tolerable anthracycline. However, there is no evidence that would definitively prove the superiority of IDA over other anthracyclines.

Objectives
To assess the efficacy and safety of IDA versus other anthracyclines in induction therapy of newly diagnosed AML.

Search methods
We identified relevant randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 8), MEDLINE (from 1946 to 3 August 2014), EMBASE (from 1974 to 3 August 2014), Chinese BioMedical Literature Database (1978 to 3 August 2014), relevant conference proceedings and databases of ongoing trials.

Selection criteria
RCTs that compared IDA with other anthracyclines in induction therapy of newly diagnosed AML.

Data collection and analysis
Two review authors independently extracted data and assessed the quality of studies according to methodological standards of the Cochrane Collaboration. We estimated hazard ratios (HRs) for time-to-event data outcomes using the inverse variance method, and risk ratios (RRs) for dichotomous data outcomes using the Mantel-Haenszel method. We adopted a fixed-effect model and repeated the main meta-analysis by a random-effects model in a sensitivity analysis.

Main results
We identified 2017 references. Ultimately, 27 RCTs (including 22 two-armed RCTs and five three-armed RCTs) involving 9549 patients were eligible. The consolidation treatments adopted in the studies were comparable and had no impact on the results. Overall, the risk of bias of the studies was unclear to high.

Eighteen RCTs (N = 6755) assessed IDA versus daunorubicin (DNR). The main meta-analyses showed that IDA compared with DNR prolonged overall survival (OS) (12 studies, 5976 patients; HR 0.90, 95% confidence interval (CI) 0.84 to 0.96, P = 0.0008; high quality of evidence) and disease-free survival (DFS) (eight studies, 3070 patients; HR 0.88, 95% CI 0.81 to 0.96, P = 0.004; moderate quality of evidence), increased complete remission (CR) rate (18 studies, 6692 patients; RR 1.04, 95% CI 1.01 to 1.07, P = 0.009; moderate quality of evidence), and reduced relapse rate (four studies, 1091 patients; RR 0.88, 95% CI 0.80 to 0.98, P = 0.02; moderate quality of evidence), although increased the risks of death on induction therapy (14 studies, 6349 patients; RR 1.18, 95% CI 1.01 to 1.36, P = 0.03; moderate quality of evidence) and grade 3/4 mucositis (five studies, 2000 patients; RR 1.22, 95% CI 1.04 to 1.44, P = 0.02; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (six studies, 2795 patients; RR 0.98, 95% CI 0.70 to 1.37, P = 0.91; moderate quality of evidence) and other grade 3/4 adverse events (AEs). None of the studies reported on quality of life (QoL).

Eight RCTs (N = 2419) evaluated IDA versus mitoxantrone (MIT). The main meta-analyses showed that there was no evidence for difference between arms in OS (six studies, 2171 patients; HR 0.98, 95% CI 0.89 to 1.08, P = 0.69; high quality of evidence), DFS (four studies, 249 patients; HR 0.88, 95% CI 0.70 to 1.10, P = 0.26; low quality of evidence), CR rate (eight studies, 2411 patients; RR 0.97, 95% CI 0.92 to 1.03, P = 0.32;moderate quality of evidence), the risks of death on induction therapy (five studies, 2055 patients; RR 1.10, 95% CI 0.88 to 1.38, P = 0.39; moderate quality of evidence) and relapse (three studies, 328 patients; RR 0.99, 95% CI 0.80 to 1.22, P = 0.89; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (one study, 160 patients; RR 0.67, 95% CI 0.11 to 3.88, P = 0.65; low quality of evidence) and other grade 3/4 AEs. None of the studies reported on QoL.

Two RCTs (N = 211) compared IDA with doxorubicin (DOX). Neither study assessed OS. One study showed that there was no evidence for difference in DFS (63 patients; HR 0.62, 95% CI 0.34 to 1.14, P = 0.12; low quality of evidence). The main meta-analysis for CR rate showed an improved CR rate with IDA (two studies, 187 patients; RR 1.28, 95% CI 1.03 to 1.59, P = 0.02; low quality of evidence). Neither study provided data for the risks of death on induction therapy and relapse. One trial showed that there was no evidence for difference in the risk of grade 3/4 cardiac toxicity (one study, 100 patients; RR 0.31, 95% CI 0.01 to 7.39, P = 0.47; very low quality of evidence). Neither study reported on QoL.

Two RCTs (N = 1037) evaluated IDA versus zorubicin (ZRB). Neither study assessed OS. One trial showed that there was no evidence for difference in DFS (one study, 155 patients; HR 1.25, 95% CI 0.83 to 1.88, P = 0.29; low quality of evidence). The main meta-analyses for CR and death on induction therapy both showed that there was no evidence for difference (CR rate: two studies, 964 patients; RR 1.04, 95% CI 0.96 to 1.13, P = 0.31; low quality of evidence. risk of death on induction therapy: two studies, 964 patients; RR 0.75, 95% CI 0.50 to 1.13, P = 0.17; moderate quality of evidence). Neither study reported the risks of relapse and grade 3/4 cardiotoxicity. One trial showed that IDA reduced the risk of grade 3/4 mucositis. Neither study reported on QoL.

Authors' conclusions
Compared with DNR in induction therapy of newly diagnosed AML, IDA prolongs OS and DFS, increases CR rate and reduces relapse rate, although increases the risks of death on induction therapy and grade 3/4 mucositis. The currently available evidence does not show any difference between IDA and MIT used in induction therapy of newly diagnosed AML. There is insufficient evidence regarding IDA versus DOX and IDA versus ZRB to make final conclusions. Additionally, there is no evidence for difference on the effect of IDA compared with DNR, MIT, DOX or ZRB on QoL.

The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia.

Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials

Extensive studies have investigated the prognostic value of CD56 for patients with acute myeloid leukemia (AML), but the results remained inconclusive. The aim of this meta-analysis is to resolve this controversial issue. A systematic search of PubMed, Embase, Cochrane Library, and CBM was performed to identify studies that assessed the prognostic value of CD56 in AML patients. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) for overall survival (OS) and disease-free survival (DFS) and pooled odds ratio (OR) with 95 % CIs for complete remission rate (CRR) and relapse rate (RR) were calculated. Totally, 32 studies with 4074 patients were included. For AML with t(8;21) translocation, CD56 overexpression was associated with shorter OS (HR 2.22; 95 % CI 1.30–3.78) and DFS (HR 2.63; 95 % CI 1.10–6.29) and increased RR (OR 3.29; 95 % CI 1.67–6.48), but did not affect CRR (OR 0.94; 95 % CI 0.49–1.80). For AML with t(15;17) translocation, CD56 overexpression was associated with shorter OS (HR 2.43; 95 % CI 1.66–3.57) and DFS (HR 4.27; 95 % CI 1.15–15.78), increased RR (OR 3.11; 95 % CI 2.01–4.81), and decreased CRR (OR 0.42; 95 % CI 0.25–0.72). For AML as a whole, CD56 overexpression was associated with shorter OS (HR 1.74; 95 % CI 1.38–2.19) and DFS (HR 2.38; 95 % CI 1.87–3.02), increased RR (OR 5.19; 95 % CI 2.84–9.48), and decreased CRR (OR 0.62; 95 % CI 0.41–0.96). This meta-analysis indicated that CD56 overexpression may be an adverse prognostic factor for AML.

https://link.springer.com/content/pdf/10.1007%2Fs00432-015-1977-3.pdf

Prognostic value of CD56 in patients with acute myeloid leukemia: a meta-analysis

Single-cell RNA sequencing (scRNA-seq) has been tremendously developed in the past decade owing to overcoming challenges associated with isolation of massive quantities of single cells. Previously, cell heterogeneity and low quantities of available biological material posed significant difficulties to scRNA-seq. Cell-to-cell variation and heterogeneity are fundamental and intrinsic characteristics of normal and malignant hematopoietic cells; this heterogeneity has often been ignored in omics studies. The application of scRNA-seq has profoundly changed our comprehension of many biological phenomena, including organ development and carcinogenesis. Hematopoiesis, is actually a maturation process for more than ten distinct blood and immune cells, and is thought to be critically involved in hematological homeostasis and in sustaining the physiological functions. However, aberrant hematopoiesis directly leads to hematological malignancy, and a deeper understanding of malignant hematopoiesis will provide deeper insights into diagnosis and prognosis for patients with hematological malignancies. Here, we aim to review the recent technical progress and future prospects for scRNA-seq, as applied in physiological and malignant hematopoiesis, in efforts to further understand the hematopoietic hierarchy and to illuminate personalized therapy and precision medicine approaches used in the clinical treatment of hematological malignancies.

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Xi Li

Papers

Resveratrol: Review on its discovery, anti-leukemia effects and pharmacokinetics

The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia.

Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials

Prognostic value of CD56 in patients with acute myeloid leukemia: a meta-analysis

Technical Advances in Single-Cell RNA Sequencing and Applications in Normal and Malignant Hematopoiesis.