Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population‐based setting: a report from the Swedish MDS register

The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population‐based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population‐based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS‐R) and the World Health Organization (WHO) Classification‐based Prognostic Scoring System (WPSS). We also present population‐based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy‐related MDS (t‐MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2·9 per 100 000 inhabitants. IPSS‐R had a significantly better prognostic power than IPSS (P < 0·001). There was a trend for better prognostic power of IPSS‐R compared to WPSS (P = 0·05) and for WPSS compared to IPSS (P = 0·07). IPSS‐R was superior to both IPSS and WPSS for patients aged ≤70 years. Patients with t‐MDS had a worse outcome compared to de novo MDS (d‐MDS), however, the validity of the prognostic scoring systems was comparable for d‐MDS and t‐MDS. In conclusion, population‐based studies are important to validate prognostic scores in a ‘real‐world’ setting. In our nationwide cohort, the IPSS‐R showed the best predictive power.     

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia,even in patients with early stage disease

Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high‐resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere ‘fusogenic’ range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P < 0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI] = 11·6–106·4) and this was preserved in early‐stage disease patients (P < 0·0001, HR=19·3, 95% CI = 17·8–802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high‐resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.     

Telomere length is a critical determinant for survival in multiple myeloma

The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high‐resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk‐stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS.     

Pre-transplant short telomeres are associated with high mortality risk after unrelated donor haematopoietic cell transplant for severe aplastic anaemia

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (<10th percentile-for-age) or very short (<5th or <1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL <10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL <10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18–2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P > 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P < 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL <1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P < 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.     

Identification of relapse-associated gene mutations by next-generation sequencing in low-risk acute myeloid leukaemia patients

Recommended genetic categorization of acute myeloid leukaemias (AML) includes a favourable-risk category, but not all these patients have good prognosis. Here, we used next-generation sequencing to evaluate the mutational profile of 166 low-risk AML patients: 30 core-binding factor (CBF)-AMLs, 33 nucleophosmin (NPM1)-AMLs, 4 biCEBPα-AMLs and 101 acute promyelocytic leukaemias (APLs). Functional categories of mutated genes differed among subgroups. NPM1-AMLs showed frequent variations in DNA-methylation genes (DNMT3A, TET2, IDH1/2) (79%), although without prognostic impact. Within this group, splicing-gene mutations were an independent factor for relapse-free (RFS) and overall survival (OS). In CBF-AML, poor independent factors for RFS and OS were mutations in RAS pathway and cohesin genes, respectively. In APL, the mutational profile differed according to the risk groups. High-risk APLs showed a high mutation rate in cell-signalling genes (P = 0·002), highlighting an increased incidence of FLT3 internal tandem duplication (ITD) (65%, P < 0·0001). Remarkably, in low-risk APLs (n = 28), NRAS mutations were strongly correlated with a shorter five-year RFS (25% vs. 100%, P < 0·0001). Overall, a high number of mutations (≥3) was the worst prognostic factor RFS (HR = 2·6, P = 0·003). These results suggest that gene mutations may identify conventional low-risk AML patients with poor prognosis and might be useful for better risk stratification and treatment decisions.     

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy,adjusting for patient‐related factors and measuring from time of first red blood cell transfusion dependence: an MDS‐CAN analysis

Analyses suggest iron overload in red blood cell (RBC) transfusion‐dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient‐related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient‐related factors. TD International Prognostic Scoring System (IPSS) low and intermediate‐1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease‐modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non‐ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non‐randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease‐modifying agents. This provides additional evidence that ICT may confer clinical benefit.     

Patient‐related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS‐CAN prospective study

Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi‐centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS‐related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS‐R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age‐adjusted IPSS‐R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7–4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1–2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS‐R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02537990.     

Graft-versus-host disease and graft-versus-leukaemia effects in secondary acute myeloid leukaemia: a retrospective,multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT

We assessed the susceptibility of secondary acute myeloid leukaemia (sAML) to graft-versus-leukaemia effects. Data from 2414 sAML patients in first (n = 2194) or second (n = 220) complete remission were included. They were given grafts from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD (P < 0·001). Limited (hazard ratio [HR] = 0·66, P < 0·001) and extensive (HR = 0·52, P < 0·001) chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute (HR = 7·04, P < 0·001) as well as limited (HR = 1·42, P = 0·03) and extensive (HR = 3·97, P < 0·001) chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS; HR = 0·61, P < 0·001) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS (HR = 3·16, P < 0·001 and HR = 1·21, P = 0·03, respectively). Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse (HR = 0·82, P = 0·03) but higher NRM (HR = 1·38, P = 0·004). In conclusion, these data demonstrate that sAML is susceptible to graft-versus-leukaemia effects.     

Mean corpuscular volume predicts prognosis in MDS patients with abnormal karyotypes

The prognostic value of karyotype in patients with myelodysplastic syndrome (MDS) is generally appreciated. However, the factors that are predictive of prognosis of patients with abnormal karyotypes are not known. In this study, we evaluated the prognostic value of International Prognostic Scoring System (IPSS) and World Health Organization classification-based prognostic scoring system (WPSS) in 164 adult MDS patients with abnormal karyotypes. We also analyzed the prognostic relevance of mean corpuscular volume (MCV) in these patients. We found that both IPSS and WPSS had strong prognostic value in patients with abnormal karyotypes (P < 0.001, P < 0.001). Furthermore, we observed the significant differences in the survival of patients with abnormal karyotypes based on MCV stratification: The median survival of patients with macrocytosis was 31.0 months, significantly longer than the 16.5-month median survival time of patients with MCVs of less than 100 fl (P = 0.001). Multivariate analysis revealed that lower level of hemoglobin (P = 0.012, HR = 6.83), higher level of marrow blasts (P < 0.001, HR = 1.93), complex karyotype (P = 0.001, HR = 3.32), and MCV of less than 100 fl (P = 0.026, HR = 1.75) were independent risk factors that affected the survival of patients with abnormal karyotypes.     

Combined somatic mutation and copy number analysis in the survival of familial CLL

Recurrent large‐scale somatic copy number alterations (SCNAs), and somatic point mutations can be analysed to stratify patients with chronic lymphocytic leukaemia (CLL) into distinct prognostic groups. To investigate the relationship between SCNAs and somatic mutations, we performed whole‐exome sequencing and single nucleotide polymorphism microarray analyses on 98 CLL patients from 40 families with a high burden of CLL. Overall, 69 somatic mutations in 29 CLL driver genes were detected among 45 subjects (46%), with the most frequently mutated genes being TP53 (8·2%), NOTCH1 (8·2%) and ATM (5·1%). Additionally, 142 SCNAs from 54 subjects (57%) were detected, including losses of chromosome 13q14 (28·9%), 11q (5·6%), 17p (2·1%), and gain of chromosome 12 (4·2%). We found that patients having both an adverse point mutation in a CLL driver gene and an unfavourable SCNA tended to have poorer survival (Hazard ratio [HR] = 3·17, 95% confidence interval [CI] = 0·97–10·35; P = 0·056) than patients having either a point mutation (HR = 1·34, 95%CI = 0·66–2·71; P = 0·42) or SCNAs (HR = 2·65, 95%CI = 0·77–9·13; P = 0·12). TP53 mutation carriers were associated with the poorest overall survival (HR = 4·39, 95%CI = 1·28–15·04; P = 0·018). Our study suggests that combining SCNA and mutational data could contribute to predicting outcome in familial CLL.     

Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5‐aza‐2′‐deoxycytidine (Decitabine)

Although azanucleoside DNA‐hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β‐like globin gene locus is tightly regulated by DNA methylation, is HMA‐sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre‐treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre‐treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74–42·49, P = 0·008, with similarly longer progression‐free and AML‐free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26–7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time‐dependent Cox models revealed that the prognostic value of treatment‐induced HbF induction was inferior to that of pre‐treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre‐treatment HbF, warranting prospective, randomized studies.     

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.     

TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis

Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS‐F). Expression of TP53 was evaluated in BM core biopsy specimens using dual‐colour CD34/TP53 immunohistochemistry with computer‐assisted image analysis. Mutation analysis was performed using next‐generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high‐ and very‐high risk IPSS‐R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34‐positive cells was associated with shorter OS and leukaemia‐free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS‐F.     

Smoking and alcohol and subsequent risk of myelodysplastic syndromes in Japan: the Japan Public Health Centre‐based Prospective Study

Smoking and alcohol are important modifiable risk factors for human cancers. However, few epidemiological studies have investigated their association with the risk of myelodysplastic syndromes (MDS). Here, we investigated the association of smoking and alcohol consumption and the risk of MDS in a large‐scale population‐based cohort study in Japan. We included 95 510 Japanese subjects (45 451 men and 50 059 women; age 40–69 years at baseline) and identified 70 MDS cases (50 men and 20 women) during 18·3 years of follow‐up. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox regression model adjusted for potential confounders. Smoking was marginally associated with an increased risk of MDS among men, with a HR for current smokers relative to never smokers of 2·11 (95% CI: 0·91–4·89). In contrast, alcohol consumption was associated with a dose‐dependent decrease in the risk of MDS among men (nondrinkers: reference, occasional drinkers: HR = 0·48, 0·16–1·41; 0–299 g/week: HR = 0·37, 0·19–0·73; ≥300 g/week: HR = 0·49, 0·22–1·08, P for trend = 0·010). This study showed that alcohol has a significant protective effect on the risk of MDS. In addition, this study might indicate that smoking increases the risk of MDS among Japanese population, as it does in Western populations.     

Anthropometric factors and risk of myeloid leukaemias and myelodysplastic syndromes: a prospective study and meta-analysis

There is insufficient evidence linking excess body weight to risk of myeloid malignancies. We investigated this association using data from the Cancer Prevention Study-II (CPS-II), and a meta-analysis of published cohort studies. Among 152 090 CPS-II participants, 387 acute myeloid leukaemias (AML), 100 chronic myeloid leukaemias (CML) and 170 MDS were identified over 21 years of follow-up. In CPS-II, body mass index (BMI) was weakly associated with risk of CML (hazard ratio [HR] = 1·04, 95% confidence interval [CI]: 0·99–1·09 per 1 unit increase in BMI), AML (HR = 1·01, 95% CI: 0·98–1·03) and MDS (HR = 1·03, 95% CI: 0·99–1·07). After controlling for other anthropometric factors, no clear association was observed for height, BMI at age 18 years or weight change. In the meta-analysis (n = 7117 myeloid leukaemias), BMI 25–29·9 kg/m² (HR_pooled = 1·36, 95% CI: 1·12–1·59) and BMI ≥30 kg/m² (HR_pooled = 1·43, 95% CI: 1·18–1·69) were associated with higher risk of myeloid leukaemia overall, compared to a BMI <25 kg/m². Likewise, BMI ≥25 kg/m² was positively associated with both AML and CML risk individually in the meta-analysis. These results underscore the need for large studies to detect associations with rare cancers, and show a modest, but positive association between excess body weight and myeloid malignancy risk.     

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta-analysis

Tumor protein p53 (TP53) is frequently expressed in patients with myelodysplastic syndromes (MDS). Studies have already reported the poor prognostic impact of TP53 gene mutations in MDS patients. However, parts of this subgroup of patients with low-risk MDS still have relatively better survival and longer remission times. Therefore, we performed a meta-analysis to evaluate the prognostic difference intra-gene of variant allele frequency (VAF). The primary endpoint was overall survival (OS), and event-free survival (EFS) was selected as the secondary endpoint. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for OS and EFS from univariate and multivariate Cox proportional hazard models. A total of 4003 MDS patients and 1278 TP53-mutated patients from 13 cohorts of 11 studies up to February 24, 2020, were included in our meta-analysis. Pooled HRs suggested that a high mutant VAF had an adverse impact on OS (HR = 2.11, 95% CI: 1.48-3.01, P < .0001) but no impact on EFS (HR = 15.57, 95% CI: 0.75-324.44, P = .003) in MDS patients. Twenty percent is a proper threshold to set (HR = 2.02, 95% CI: 1.31-3.13, P = .001) and is a rough line between high clone burden and low clone burden, while 40% is an exact cutoff point (HR = 2.11, 95% CI: 1.26-3.55, P < .0001) to guide diagnosis and treatment. Beyond the traditional binary classification of gene mutation, we aimed to find a way to divide mutant molecular markers more specifically by VAF to provide clinical therapeutic values. Our meta-analysis indicates that a high VAF is an independent, adverse prognostic factor for OS in TP53 mutant MDS patients. Patients with mediate/low-frequency parts who could be treated like wide-type patients have relatively better survival and may choose allogeneic hematopoietic stem cell transplantation as conditions permitting. Further prospective studies are needed in the future, and a large subgroup analysis of the same cutoff point subgroups is needed to obtain a more reliable basis for the impact of other mutant gene VAFs on the prognosis of MDS.     

Influence of patient and provider characteristics on quality of care for the myelodysplastic syndromes

Little is known about quality of care for patients with myelodysplastic syndromes (MDS), or patient and provider factors that influence quality. We identified Medicare enrollees diagnosed with MDS between 2006 and 2011, and analysed linked claims for performance on two widely‐accepted quality measures: diagnostic bone marrow cytogenetic testing (diagnostic quality) and pre‐treatment iron assessment for patients receiving an erythropoiesis‐stimulating agent (ESA; treatment quality). A total of 4575 patients met the criteria for diagnostic quality measurement, and 3379 for treatment quality measurement. In the diagnostic cohort, 74% had a claim for marrow cytogenetic testing 3 months before to 3 months after diagnosis. In multivariate models, younger age (P < 0·001), treatment at a higher‐volume MDS centre (P < 0·001), and claims for pancytopenia (P < 0·001) were all associated with higher levels of testing. A borderline result was observed for diagnostic year, with improvement over time (P = 0·06). In the treatment cohort, 56% had evidence of pre‐ESA iron assessment, with higher rates for later years of diagnosis (P < 0·001), higher household income (P = 0·03), and those treated at higher‐volume centres (P = 0·01). In this large cohort of patients with MDS, quality of care was suboptimal overall, but worse in several specific subgroups. These data suggest that targeted educational and/or process‐focused interventions are warranted.     

High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3‐ITD,KMT2A‐PTD,and NUP98‐NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML‐05 trial

Recent reports described the NUP98‐NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98‐NSD1 fusion. PRDM16 gene expression levels were measured via real‐time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥ 0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)‐ partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98‐NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event‐free survival (EFS) among PRDM16‐overexpressing patients were significantly worse than in patients with low PRDM16 expression (3‐year OS: 51% vs. 81%, P < 0·001, 3‐year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3‐internal tandem duplication‐positive AML patients (3‐year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate‐risk cytogenetic profiles and was independently associated with an adverse outcome.     

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia

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.     

Impact of socioeconomic status on disease phenotype,genomic landscape and outcomes in myelodysplastic syndromes

Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower‐risk MDS in 82% of patients, with higher‐risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub‐analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub‐types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease‐risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia‐free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease‐modifying therapies are influenced by SES.