CRISPR-Cas9 in acute myeloid leukaemia: Current state-of-art and future perspectives.

Survival after acute paediatric (014 years), adolescent (15-19 years) and young adult (20-39 years) leukaemia has improved substantially over the last five decades, particularly for acute lymphoblastic leukaemia (ALL) and acute promyelocytic leukaemia, a subtype of acute myeloid leukaemia. This progress represents one of the most successful achievements in the history of medicine and has been attributed to the development of effective chemotherapy regimens, improvement in supportive care, better risk stratification, use of targeted therapies, and advances in haematopoietic stem cell transplantation. Currently, long-term survival for children diagnosed with acute lymphoblastic leukaemia is 80%-90% in developed countries. Strikingly, survival among adolescents and young adults with this disease is about 60% and 40% respectively. In addition, in these countries, 5-year survival for young patients with acute myeloid leukaemia (excluding acute promyelocytic leukaemia) remains approximately 60% in the modern era of treatment. This project aimed to evaluate how survival and, when appropriate, early death (death occurring within 30 days of diagnosis) after acute leukaemia varied during almost 25 years in California, the most populous and racially/ethnically diverse state in the United States (US). A second aim was to investigate the association between sociodemographic and selected clinical factors and outcomes. Using high-quality data from the California Cancer Registry, I evaluated survival trends from acute lymphoblastic leukaemia among patients aged 0-19 years, and survival and early death trends after acute myeloid leukaemia among patients aged 0-39 years. I also investigated whether early death has decreased among young patients after the approval by the US Food and Drug Administration of all-trans retinoic acid (ATRA) for the treatment of acute promyelocytic leukaemia. The overall results of this thesis showed improvement in survival over time for all age groups and subtypes of leukaemia. Early death after acute promyelocytic and myeloid leukaemias declined during the study period. However, these outcomes varied widely by age at diagnosis and were associated with sociodemographic and clinical factors. Racial/ethnical survival inequalities were identified and found to persist even after adjustment for other covariates. These inequalities were more marked among patients of Hispanic (acute lymphoblastic leukaemia) and black race/ethnicity (for acute lymphoblastic and myeloid leukaemias). Patients living in lower socioeconomic neighbourhoods had worse survival than those living in higher socioeconomic neighbourhoods (for acute lymphoblastic and myeloid leukaemias). Early death and worse survival were associated with initial care at hospitals not affiliated with National Cancer Institute-designated cancer centres (for acute myeloid leukaemia) and lack of health insurance (for acute myeloid and promyelocytic leukaemias). Intriguingly, over the 25-year study period, adolescents and young adults with acute leukaemia continued to have worse survival than children. These results suggest that lack of timely access to treatment and suboptimal care have influenced outcome among vulnerable patients. In conclusion, survival and early death after acute leukaemia has greatly improved among young patients in California. However, inequalities in outcomes remain and are likely a result of multiple factors. My studies highlight the importance of population-based data to reveal the actual burden of the disease in this population and help clinicians, policy makers, government, and researchers better understand the predictors of outcomes. I expect my work to contribute to the development of strategies aimed at improving survival from acute leukaemia, especially among

This Good Practice Paper was compiled according to the BSH process (https://b-s-h.org.uk/media/19922/bsh-guidance-development-process-july-2021.pdf). The British Society for Haematology (BSH) produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org.

NPM1 Mutated AML with Concurrent DNMT3A Mutation, and FLT3-Internal Tandem Duplication Has Outcomes Similar to European Leukemianet Adverse Risk Category

Integrin-Linked Kinase a Novel Therapeutic Target for Acute and Chronic Myeloid Leukemia

Acute myelogenous leukemia

Secondary-type mutations do not impact prognosis in acute myelogenous leukemia AML with mutated NPM1.

Venetoclax plus '2 + 5' modified intensive chemotherapy with daunorubicin and cytarabine in fit elderly patients with untreated de novo acute myeloid leukaemia: a single-centre retrospective analysis.

RUNX1 Mutation Does Not Significantly Impact the Outcome of Newly Diagnosedadult AML: A Retrospective Study of Chinese AML Patients

Detection of FLT3 Internal Tandem Duplication in Targeted, Short-Read-Length, Next-Generation Sequencing Data

The Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) and the electronic Physical Activity Readiness Medical Examination (ePARmed-X+) were created recently to reduce the barriers to physical activity participation for individuals with and without established chronic disease. Our primary purpose was to provide preliminary evidence on the effectiveness of these new forms for pre-participation screening and risk stratification. In particular, we sought to examine the new PAR-Q+ (and ePARmed-X+) risk stratification strategy in comparison to the previous PAR-Q. The new PAR-Q+ and ePARmed-X+ risk stratification and pre-participation strategy reduced significantly the number individuals that were sent for medical referral in comparison to the PAR-Q (i.e., 0.8% vs. 15%, respectively). The reliability of the PAR-Q+ over a three month period was high (r = 0.99). Moreover, the new strategy demonstrated high sensitivity (0.90 (95% CI = 0.77-0.96)) and specificity (1 (95% CI = 0.99-1)) for determining those with and without hypertension, respectively. In conclusion, our preliminary evaluation of the new PAR-Q+ and ePARmed-X+ risk stratification and pre-participation strategy in comparison to the PAR-Q reveals that the new process reduces greatly the barriers to physical activity participation, with a high reliability, sensitivity, and specificity of measurement.

Unraveling the Impact of 2022 Classifications on Secondary Acute Myeloid Leukemia: Assessing the True Qualification Power of Diagnostic Qualifiers

Prevalence & Prognosis Value of TET2 Gene Polymorphisms in Childhood Acute Myeloid Leukemia in Taiwan

Current and emerging therapies for acute myeloid leukemia

Myelodysplasia-Related Changes Have Adverse Prognostic Significance in Children with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

Integrating Genomics and Functional Phenotypes to Refine Risk Assessment in Acute Myeloid Leukemia across the Age Spectrum: Insights from Singapore