Cost-Effectiveness Analysis of a HMGA2 Prognostic Test for Acute Myeloid Leukemia in a Canadian Setting.

BACKGROUND: Current strategies for risk stratification of patients with acute myeloid leukemia assign approximately 40% of patients to the intermediate-risk group, where uncertainty about optimal therapy still persists. OBJECTIVE: The objective of this study was to assess the cost effectiveness of a HMGA2 prognostic test based on HMGA2+/HMGA2- expression, which improves genetic risk stratification in acute myeloid leukemia, and compare this test with the current standard of care in Canada. METHODS: A cost-effectiveness model was developed from the Canadian National Healthcare Service and societal perspective using data from the Quebec Leukemia Cell Bank, published literature, and physician surveys. The model includes a lifetime horizon assessing the HMGA2 test vs. standard of care. RESULTS: The HMGA2 test outperformed the standard of care at all time horizons culminating with estimated improvements of 1.92 and 3.12 months in leukemia-free survival and overall survival, respectively. Costs associated with the HMGA2 test were consistently lower, except diagnostic costs, routine medical costs, and costs related to infections and false positives. From a societal perspective, total lifetime costs were $161,358 CAD and $151,908 CAD with the standard of care and the HMGA2 test, respectively. The incremental quality-adjusted life-year gain was 0.138, which led to dominance over the standard of care. Deterministic sensitivity analyses confirmed the results of the base-case scenario. Probabilistic sensitivity analyses revealed that for a willingness-to-pay threshold of $100,000 CAD, the probability of cost effectiveness was 87.19%. CONCLUSIONS: The HMGA2 test is estimated to improve leukemia-free survival and overall survival outcomes, and yield costs savings from a healthcare system and societal perspective.

Correction: High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia.

Since the publication of the original article the authors noticed the the affiliation details for Paresh Vyas are incorrect. The correct affiliation details for this author are given below.

High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia.

In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.

Reliable assessment of the incidence of childhood autoimmune hemolytic anemia.

BACKGROUND: Childhood autoimmune hemolytic anemia (AIHA) is a rare and severe disease characterized by hemolysis and positive direct antiglobulin test (DAT). Few epidemiologic indicators are available for the pediatric population. The objective of our study was to reliably estimate the number of AIHA cases in the French Aquitaine region and the incidence of AIHA in patients under 18 years old. PROCEDURE: In this retrospective study, the capture-recapture method and log-linear model were used for the period 2000-2008 in the Aquitaine region from the following three data sources for the diagnosis of AIHA: the OBS'CEREVANCE database cohort, positive DAT collected from the regional blood bank database, and the French medico-economic information system. RESULTS: A list of 281 different patients was obtained after cross-matching the three databases; 44 AIHA cases were identified in the period 2000-2008; and the total number of cases was estimated to be 48 (95% confidence interval [CI]: 45-55). The calculated incidence of the disease was 0.81/100,000 children under 18 years old per year (95% CI 0.76-0.92). CONCLUSION: Accurate methods are required for estimating the incidence of AIHA in children. Capture-recapture analysis corrects underreporting and provides optimal completeness. This study highlights a possible under diagnosis of this potentially severe disease in various pediatric settings. AIHA incidence may now be compared with the incidences of other hematological diseases and used for clinical or research purposes.

ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia.

Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5 T1562C, tandem-repeat ASNS polymorphism, derived haplotype, and ASS1 G1343T and G34T substitutions (P ≤ .03). Associations were limited to patients who received Escherichia coli asparaginase. Variations that sustained correction for multiple testing (ATF5 T1562C, P = .005; ASNS tandem-repeat and related haplotype, P ≤ .01) were subsequently analyzed in the replication cohort. The E coli-dependent association of the ATF5 T1562 allele with reduced EFS was confirmed (P = .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P ≤ .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P ≤ .02) and were further corroborated by quantitative mRNA analysis in lymphoblastoid cell lines. The ATF5-regulated increase in ASNS expression in response to more efficacious E coli-induced asparagine depletion may explain our observed results.