12 research outputs found
Methodological approaches to measuring mental health in a cost-of-living crisis: a rapid review
Background
Cost-of-living crises are damaging to population mental health and require a public health response. It is important to assess whether public health interventions are effective. We aimed to identify population-level methods and measures and the appropriateness of the measures for vulnerable populations.
Methods
A rapid evidence review was undertaken. Nineteen databases, including grey literature, were searched for evidence published between 1970 and April 2023.
Results
Seven reviews, nine primary studies and two reports from grey literature were identified. Methods consisted of analyses of existing data from national or regional cohort studies, household panel surveys, repeated cross-sectional surveys, routine medical data, or data on suicide death rates. Twelve brief validated mental health measurement tools, embedded in population-level surveys, were identified. Two quasi-experimental studies used data from a UK household panel survey to examine the impact of the introduction of specific welfare policies on mental health. Studies identified socio-economic vulnerabilities, but it was not possible to determine whether data were effectively captured from people from minority ethnic groups.
Conclusion
Population-level surveys can be used in quasi-experimental studies to measure the effects of a public health initiative with specific roll out dates to tackle cost-of-living impacts. It is unclear as to whether the identified methods and tools are suitable for use with people from minority ethnic groups
P484: Gemtuzumab-based induction chemotherapy combined with midostaurin for FLT3 mutated AML. Updated toxicity and interim survival analysis from the NCRI AML19v2 "Midotarg" Pilot Trial
A randomised comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial
Liposomal daunorubicin and cytarabine (CPX-351) improves overall survival (OS) compared to 7+3 chemotherapy in older patients with secondary acute myeloid leukaemia (AML); to date there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly-diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). 189 patients were randomized (median age 56y). By clinical criteria 49% had de novo AML, 20% secondary AML and 30% high risk MDS. MDS-related cytogenetics were present in 73% of patients, with complex karyotype in 49%. TP53 was the most commonly mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 patients (44%). The overall response rate (CR + CRi) after course two was 64% and 76% for CPX-351 and FLAG-Ida (OR:0.54, 95%CI 0.28-1.04, p=0.06). There was no difference in OS (13.3 months vs 11.4 months, HR:0.78, 95%CI 0.55-1.12, p=0.17) or event-free survival (HR:0.90, 95%CI 0.64-1.27, p=0.55) in multivariable analyses. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months, HR:0.58, 95% CI 0.36-0.95, p=0.03). There was no difference between the treatment arms in patients with clinically defined secondary AML (HR:1.1, 95%CI 0.52-2.30) or those with MDS-related cytogenetic abnormalities (HR:0.94, 95%CI 0.63-1.40), however an exploratory sub-group of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months, HR:0.42, 95%CI 0.21-0.84, heterogeneity p=0.05). In conclusion, OS in younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida
Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations
Purpose
To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics.
Patients and Methods
One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS).
Results
There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO.
Conclusion
Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit
Methodological approaches to measuring mental health in a cost-of-living crisis: A rapid review
BackgroundCost-of-living crises are damaging to population mental health and require a public health response. It is important to assess whether public health interventions are effective. We aimed to identify population-level methods and measures and the appropriateness of the measures for vulnerable populations.MethodsA rapid evidence review was undertaken. Nineteen databases, including grey literature, were searched for evidence published between 1970 and April 2023.ResultsSeven reviews, nine primary studies and two reports from grey literature were identified. Methods consisted of analyses of existing data from national or regional cohort studies, household panel surveys, repeated cross-sectional surveys, routine medical data, or data on suicide death rates. Twelve brief validated mental health measurement tools, embedded in population-level surveys, were identified. Two quasi-experimental studies used data from a UK household panel survey to examine the impact of the introduction of specific welfare policies on mental health. Studies identified socio-economic vulnerabilities, but it was not possible to determine whether data were effectively captured from people from minority ethnic groups.ConclusionPopulation-level surveys can be used in quasi-experimental studies to measure the effects of a public health initiative with specific roll out dates to tackle cost-of-living impacts. It is unclear as to whether the identified methods and tools are suitable for use with people from minority ethnic groups.<br/
Design considerations when transitioning from paper case report forms (CRFS) to electronic data capture (EDC)
P484: GEMTUZUMAB-BASED INDUCTION CHEMOTHERAPY COMBINED WITH MIDOSTAURIN FOR FLT3 MUTATED AML. UPDATED TOXICITY AND INTERIM SURVIVAL ANALYSIS FROM THE NCRI AML19V2 “MIDOTARG” PILOT TRIAL
S134: FLAG-IDA COMBINED WITH GEMTUZUMAB OZOGAMICIN (GO) REDUCED MRD LEVELS AND IMPROVED OVERALL SURVIVAL IN NPM1MUT AML INDEPENDENT OF FLT3 AND MRD STATUS, RESULTS FROM THE AML19 TRIAL
Genomic correlates of outcome in a randomised comparison of CPX-351 and FLAG-Ida in high-risk acute myeloid leukaemia and myelodysplastic syndrome: results from the UK NCRI AML19 Trial
Background Liposomal daunorubicin and cytarabine (CPX-351) improves survival compared to 3+7 chemotherapy in patients aged 60 years with secondary AML defined by clinical or cytogenetic criteria (Lancet JE, JCO 2018). It is increasingly recognised that secondary AML may be better defined by mutational profile than clinical history (Döhner, Blood 2022; Khoury, Leukemia 2022), however patients with molecularly defined secondary AML were not specifically included in previous studies. Moreover, no randomised data for CPX-351 in patients aged <60y were available prior to this study.
Previous UK NCRI trials established the FLAG-Ida regimen as a preferred regimen in patients aged <60y with high-risk and secondary AML (Burnett AK, Leukemia 2018). The UK NCRI AML19 trial randomised patients with AML or high grade MDS between induction therapy with CPX-351 and FLAG-Ida. Initial results reporting similar event-free and overall survival (OS) have been previously presented (Russell NH, HemaSphere 2022). Here we present an exploratory analysis of outcomes stratified by genomic, cytogenetic and clinical definitions of secondary AML.
Methods AML19 (ISRCTN78449203) enrolled patients with previously untreated AML, MDS-EB2, or MDS-EB1 with IPSS score >3.5, predominantly aged <60 years. Patients known to have an adverse karyotype at diagnosis according to MRC criteria were randomised between CPX-351 and FLAG-Ida. Treatment consisted of up to 4 courses of CPX-351 or 2 courses of FLAG-Ida followed by MACE/MidAC consolidation with allogeneic transplant recommended after 2 cycles if feasible. Of note, patients could also enter the FLAG-IDA vs CPX randomisation if they became high risk at other defined points after induction, the results of which will be reported separately.
Cytogenetic testing was performed in local laboratories with results reviewed and coded centrally. Complex karyotype was defined as ≥4 unrelated abnormalities. Following the completion of the trial, banked diagnostic DNA was analysed for variants in 41 recurrently mutated myeloid genes, including the entire coding regions of all myelodysplasia-related genes according to 2022 WHO and ELN criteria (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) (Döhner, Blood 2022; Khoury, Leukemia 2022). Libraries were prepared using the Agilent SureSelect XT HS2 platform and sequenced on an Illumina NextSeq2000 to a depth of >1000x.
Results In total, 195 patients entered were randomised at trial entry, and NGS was performed on 173. Of the whole cohort, 49% were classified by clinical features as de novo AML, 20% as secondary AML and 31% as high-risk MDS. Myelodysplasia-related cytogenetic abnormalities were present in 70% of patients, with a complex karyotype in 51%. TP53 was the most commonly mutated gene in 43% of patients, followed by DNMT3A in 19% and ASXL1 in 18% (Figure A). A mutation in at least one myelodysplasia-related gene was present in 75 (43%) patients, of whom 60 (35%) were categorised as secondary AML by mutational status, which by ELN 2022 criteria requires the absence of TP53 variants.
As previously reported, OS did not differ between the two randomisation arms (Hazard Ratio [HR] for CPX-351 0.84, 95% confidence interval [95CI] 0.59 - 1.20). In patients with clinically defined secondary AML, there was no OS benefit for CPX-351 (HR 1.1, 95CI 0.53 - 2.30), while high-risk MDS had a trend to benefit (HR 0.54, 95CI 0.28 - 1.00) (Figure B). When secondary disease was defined by the presence of myelodysplasia-related cytogenetic abnormalities, CPX-351 did not provide benefit (HR 1.04, 95CI 0.77 - 1.55). However, in patients with mutationally defined secondary AML, there was an OS benefit from CPX-351 (HR 0.42, 95CI 0.21 - 0.84, p value for heterogeneity 0.05) (Figure B).
Patients with TP53 mutations had an adverse prognosis, with median OS of 7 months compared to 28 months in those with wild-type TP53. CPX-351 did not provide benefit compared to FLAG-Ida in this group (HR 0.92, 95CI 0.57 - 1.49).
Conclusion In this exploratory subgroup analysis, CPX-351 had a significant survival benefit over FLAG-Ida in young high-risk patients with secondary AML/MDS as defined by the presence of myelodysplasia-related gene mutations, but not by clinical criteria. We observed no significant difference in patients with TP53 mutations
FLAG-Ida combined with Gemtuzumab Ozogamicin (GO) improves event free survival in younger patients with newly diagnosed Acute Myeloid Leukaemia (AML) and shows an overall survival benefit in NPM1 and FLT3 mutated subgroups. Results from the UK NCRI AML19 trial
Background The optimal induction regimen for younger patients with newly diagnosed AML is uncertain. The MRC AML15 trial suggested a higher response rate and reduced relapse risk with FLAG-Ida compared to a Daunorubicin-araC (DA) +etoposide but did not show an overall survival (OS) benefit (Burnett, JCO,2013,31,3360). GO has been shown to improve survival in patients with favourable and intermediate risk cytogenetics, although it is unclear whether a single or fractionated dose is optimal. (Hills, Lancet Oncology,2014, 15,986)
Methods The NCRI AML19 trial (ISRCTN78449203) randomised 1475 patients with newly diagnosed AML or MDS-EB2, not known to have adverse cytogenetics, between FLAG-Ida ( n=738) and DA (Daunorubicin, AraC, n=737). Of these, 1031 were also randomised to receive a single dose of GO (GO1, 3mg/m2 on D1, n=513) or a fractionated schedule (GO2, max 5mg on D1+4 , n=518). Post-remission therapy consisted a second course of DA or FLAG-Ida without GO followed by up to 2 courses of HDAC . No FLT3 inhibition was used.
Patients were designated as high risk after course 1 based on a validated risk score, or if they had the genotype FLT3-ITD+, NPM1-. After course 2, patients could be designated high risk based on measurable residual disease (MRD) positivity (i.e. detectable NPM1 mutated transcripts in the peripheral blood (PB) or following protocol amendment, flow cytometric MRD >0.1% in the bone marrow). High-risk patients were recommended for transplant and could enter a separate randomisation, but are included in this analysis.
The primary endpoint was OS. Secondary endpoints included event free survival (EFS), relapse free survival (RFS), response defined according to ELN criteria and MRD. Patients aged 18-60 years were eligible but older patients could be enrolled at the investigators discretion. Here we report the outcomes of the patients randomised between FLAG-Ida-GO and DA-GO.
Results The median age was 51.5 yrs. 88% had de novo AML, 7% secondary AML and 5% MDS-EB2. MRC defined cytogenetic risk was favourable in 12%, intermediate in 75% and adverse in 9%, the remaining had missing data. Of major molecular subgroups, 30% had NPM1 and 26% FLT3 ITD or TKD mutations. Median follow-up was 32 months. Complete remission (CR/CRi) was 91% for DA-GO and 93% for FLAG-Ida-GO and did not differ by GO dose (92.3% for GO1 and 91.2% for GO2). Day 30 and 60 mortality were not different between DA and FLAG-Ida (D30, 2.9% vs 3.1%, p=0.37; D60 4.6% vs 4.3%, p=0.27) or between GO1 and GO2 (D30, 2.15% vs 3.3%, p=0.1; D60 3.3% vs 5.6%, p=0.07).
There was no difference in OS or EFS by GO dose so further outcome analyses were undertaken combined. EFS was significantly better with FLAG-Ida-GO compared to DA-GO (HR 0.73, CI 0.61-0.87, p<0.001) but there was no difference in OS (HR 0.92, CI 0.75-1.13, p=0.41) (Figure 1a and 1b). RFS also favoured FLAG-Ida-GO.
In subgroup analysis OS benefit was observed for FLAG-Ida-GO in patients with NPM1 mutation (OS 82% vs 64% at 3 yrs, HR 0.5, CI 0.31-0.81, p=0.005). Furthermore NPM1 MRD positivity by RT-qPCR in the PB after 2 courses of induction was 23% (30/130) with DA-GO compared to 12% (16/130) (p=0.03) with FLAG-Ida-GO. The survival benefit for FLAG-Ida-GO was also seen in FLT3+ve AML (OS of 64% vs 54% at 3 yrs, HR 0.67, CI 0.45 -0.99, p=0.047) with the greatest benefit seen in NPM1 co-mutated patients (HR 0.32 CI 0.16 -0.61). In patients with favourable risk cytogenetics, there was no EFS or OS benefit for FLAG-Ida-GO over DA-GO.
Fewer transplants were performed in the FLAG-Ida-GO arm overall, 237 (46%) compared to 278 (54%) with DA-GO including fewer in CR1 (177 compared to 194) reflecting the application of MRD negativity to guide transplant decisions and the reduced relapse risk with FLAG-Ida.
Conclusion In this large, randomized comparison we observed no benefit for a fractionated GO schedule but FLAG-Ida-GO significantly improved EFS compared to DA-GO. Although there was no overall survival benefit for FLAG-Ida-GO, there was evidence of an OS benefit in major sub-groups, including patients with NPM1 and FLT3 mutations. This finding was supported by MRD analysis that showed a reduction in NPM1 MRD positivity after two courses of FLAG-Ida-GO. Furthermore this survival benefit was associated with a reduction in the requirements for transplant in CR1 and overall. Given the benefit observed in FLT3 mutated AML in the absence of a FLT3 inhibitor, studies combining FLAG-Ida-GO with Midostaurin are warranted