A novel algorithmic approach to generate consensus treatment guidelines in adult acute myeloid leukaemia.

Induction therapy for acute myeloid leukaemia (AML) has changed with the approval of a number of new agents. Clinical guidelines can struggle to keep pace with an evolving treatment and evidence landscape and therefore identifying the most appropriate front-line treatment is challenging for clinicians. Here, we combined drug eligibility criteria and genetic risk stratification into a digital format, allowing the full range of possible treatment eligibility scenarios to be defined. Using exemplar cases representing each of the 22 identified scenarios, we sought to generate consensus on treatment choice from a panel of nine aUK AML experts. We then analysed >2500 real-world cases using the same algorithm, confirming the existence of 21/22 of these scenarios and demonstrating that our novel approach could generate a consensus AML induction treatment in 98% of cases. Our approach, driven by the use of decision trees, is an efficient way to develop consensus guidance rapidly and could be applied to other disease areas. It has the potential to be updated frequently to capture changes in eligibility criteria, novel therapies and emerging trial data. An interactive digital version of the consensus guideline is available.

A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML.

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3-tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively.

A no-prophylaxis platelet-transfusion strategy for hematologic cancers.

BACKGROUND: The effectiveness of platelet transfusions to prevent bleeding in patients with hematologic cancers remains unclear. This trial assessed whether a policy of not giving prophylactic platelet transfusions was as effective and safe as a policy of providing prophylaxis. METHODS: We conducted this randomized, open-label, noninferiority trial at 14 centers in the United Kingdom and Australia. Patients were randomly assigned to receive, or not to receive, prophylactic platelet transfusions when morning platelet counts were less than 10×10(9) per liter. Eligible patients were persons 16 years of age or older who were receiving chemotherapy or undergoing stem-cell transplantation and who had or were expected to have thrombocytopenia. The primary end point was bleeding of World Health Organization (WHO) grade 2, 3, or 4 up to 30 days after randomization. RESULTS: A total of 600 patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) underwent randomization between 2006 and 2011. Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients (50%) in the no-prophylaxis group, as compared with 128 of 298 (43%) in the prophylaxis group (adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 to 15.2; P=0.06 for noninferiority). Patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode than did patients in the prophylaxis group. Platelet use was markedly reduced in the no-prophylaxis group. A prespecified subgroup analysis identified similar rates of bleeding in the two study groups among patients undergoing autologous stem-cell transplantation. CONCLUSIONS: The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.).

Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial.

Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1.46 (1.04-2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m(2) treatment (10% vs 7%) resulting in similar overall response rate [89% vs 86%; hazard ratio 1.34 (0.88-2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs 54%; hazard ratio 1.17 (0.94-1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90-1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m(2) recipients: 7% versus 3%; hazard ratio 2.07 (1.11-3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m(2) of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m(2) dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535).

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial.

BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia. METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535. FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group. INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy.

Pregnant women should be managed by a multidisciplinary team that includes haematologists, obstetricians, neonatologists and anaesthetists (Grade 1C) As for non-pregnant patients, acute myeloid leukaemia (AML) should be diagnosed using the World Health Organization (WHO) classification (Grade 1A) Women diagnosed with AML in pregnancy should be treated without delay (Grade 1B) When the diagnosis of AML is made in the first trimester, a successful pregnancy outcome is unlikely and spontaneous pregnancy loss in this situation carries considerable risks for the mother. The reasons for and against elective termination should be discussed with the patient (Grade 2C) In the case of presentation beyond 32 weeks gestation, it may be reasonable to deliver the foetus prior to commencement of chemotherapy (Grade 2C) Between 24 and 32 weeks, risks of foetal chemotherapy exposure must be balanced against risks of prematurity following elective delivery at that stage of gestation (Grade 1C) The risk-benefit ratio must be carefully considered before using any drugs in pregnancy (Grade 1C) Where AML induction chemotherapy is delivered, a standard daunorubicin, cytarabine 3 + 10 schedule should be used (Grade 1B) Chemotherapy should be dosed according to actual body weight and adjustments made for weight changes during treatment (Grade 1C) Quinolones, tetracyclines and sulphonamide use should be avoided in pregnancy (Grade 1B) Amphotericin B or lipid derivatives are the antifungal of choice in pregnancy (Grade 2C) Cytomegalovirus (CMV)-negative blood products should be administered during pregnancy regardless of CMV serostatus (Grade 1B) A course of corticosteroids should be considered if delivery is anticipated between 24 and 35 weeks gestation, given over a 48-h period during the week prior to delivery (Grade 1A) Use of magnesium sulphate should be considered in the 24 h prior to delivery if this is before 30 weeks gestation (Grade 1A) Where possible, delivery should be planned for a time when the woman is at least 3 weeks post-chemotherapy to minimize risk of neonatal myelosuppression (Grade 1C) Planned delivery is easier to manage than spontaneous labour; induction of labour is usually advised (Grade 2C) Epidural analgesia should be avoided in a woman who is significantly thrombocytopenic (platelet count <80 × 10(9) /l) and/or neutropenic (white blood cell count <1 × 10(9) /l): (Grade 1C) Elective caesarean section should only be recommended for obstetric indications (Grade 2C) Antibiotics should be administered during and after premature rupture of membranes and delivery (Grade 1C).

A functional variant in the core promoter of the CD95 cell death receptor gene predicts prognosis in acute promyelocytic leukemia.

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.

Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study.

The SHIELD program for Hodgkin lymphoma in patients 60 years of age or older, prospectively evaluated clinical features and outcome in a large patient cohort (n = 175). The central element was a phase 2 study of VEPEMB chemotherapy (n = 103, median age 73 years) incorporating comorbidity assessment. A total of 72 other patients were treated off-study but registered prospectively and treated concurrently with: ABVD (n = 35); CLVPP (n = 19), or other (n = 18). Of VEPEMB patients, 31 had early-stage disease (stage 1A/2A) and received VEPEMB 3 times plus radiotherapy. Median follow-up was 36 months. Complete remission (CR) rate (intention-to-treat) was 74% and 3-year overall survival (OS) and progression-free survival (PFS) were 81% and 74%, respectively. A total of 72 patients had advanced-stage disease (stage 1B/2B/3 or 4) and received VEPEMB 6 times. CR rate was 61% with 3-year OS and PFS of 66% and 58%, respectively. Of patients achieving CR, 13% with early-stage and 5% with advanced-stage disease progressed. Overall treatment-related mortality was 7%. In patients treated with curative intent with VEPEMB, ABVD, and CLVPP (n = 157), CR linked to several factors in univariate analysis. In a Cox regression model only, obtaining CR remained significant for OS and CR plus comorbidity and age for PFS. RS-EBV status had no significant effect on outcome.

Video analysis tool system: implementation and evaluation of use with clinical nursing assessments of older adults.

The purpose of this project was to implement and evaluate the Video Analysis Tool (VAT) system, a tool for capturing and analyzing video evidence of students' clinical performance. Through the VAT system, nursing student dyads from 4 universities used a video camera, a computer, and a tripod in the residences of older adults to record interactions and psychosocial assessments of older adult clients. Using their recordings to compare their clinical activities with predefined clinical objectives derived from gerontological nursing standards, they made video clips of their assessments to demonstrate the required outcomes. Use of the VAT system received positive evaluations from students, faculty, and residents in multiple clinical sites. The process has significant implications for assessing clients and health care providers in their interactions in a variety of settings, including on home visits. It has additional applications for documenting performance measures of nurses and team members as they provide client care.

Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant*.

The British Committee for Standards in Haematology first produced guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant in 2000. This revision updates those guidelines and covers the areas of diagnosis, treatment and assessment of response to therapy.

Object relations and emotional processing deficits among psychiatric outpatients.

The aim of this study was to investigate the association between object relations and emotional processing deficits among a general sample of psychiatric outpatients. The sample consisted of 104 patients consecutively referred to 2 outpatient clinics. Participants completed measures of object relations, emotional processing deficits, and general psychiatric distress. After controlling for the effect of current symptom distress, we found that object relations impairment was significantly associated with emotional processing deficits relating to unregulated emotions, signs of unprocessed emotions, and emotion suppression. These findings support the notion that patients with impoverished mental structures possess maladaptive strategies for modulating intense affects.

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

The effect of voice disorders on lexical tone variation: Exploratory study in an African language.

Purpose: The aim was to determine if the presence of a voice disorder in speakers of Setswana, an African tone language, will negatively impact the accuracy of identification by typical first language judges of words belonging to tonal minimal pairs.Method: A quasi-experimental between-group comparison and individual case studies were conducted. Five participants with different types and degrees of voice disorders and nine control participants produced 10 tonal minimal word pairs. Five judges had to identify which of a pair was produced.Result: The mean scores of the control and experimental speakers as groups differed, but the difference was not statistically significant. Control participants scored between 19.6/20 and 14.2/20 words correctly identified. Individual data revealed that four of the nine control participants attained at least one perfect score across judges and six had mean scores of 18.0/20 and higher. The highest scoring experimental participant, presenting with a mild voice disorder, attained a mean of 18.0/20. The lowest scoring participant, presenting with the most severe dysphonia, had a mean of 12.2/20 words correctly identified.Conclusion: These preliminary results appear to suggest that a severe voice disorder could compromise lexical tone variation and by implication the intelligibility of a message.

Author Correction: High-dose chemotherapy and autologous stem cell transplantation in enteropathy-associated and other aggressive T-cell lymphomas: a UK NCRI/Cancer Research UK Phase II Study.

In the original version of this article, the mention of 'ifosfamide 1500 mg/m2 days 1-3' should, in fact, read 'ifosfamide 1500 mg/m2 bd days 1-3'. This has now been updated in the original version of the article.