Explore the vast range of titles available.

With rapid advances in sequencing technologies, tremendous progress has been made in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), thus revealing enormous genetic and clonal heterogeneity, and paving the way for precision medicine approaches. The successful development of precision medicine for patients with AML has been exemplified by the introduction of targeted FLT3, IDH1/IDH2 and BCL-2 inhibitors. When used as single agents, these inhibitors display moderate antileukaemic activity. However, augmented clinical activity has been demonstrated when they are administered in combination with drugs with broader mechanisms of action targeting epigenetic and/or other oncogenic signalling pathways or with conventional cytotoxic agents. The development of immunotherapies has been hampered by the expression of antigens that are expressed by both leukaemic and non-malignant haematopoietic progenitor cells; nonetheless, a diverse range of immunotherapies are now entering clinical development. This myriad of emerging agents also creates challenges, such as how to safely combine agents with different mechanisms of action, the need to circumvent primary and secondary resistance, and new challenges in future clinical trial design. In this Review, we discuss the current state of precision medicine for AML, including both the potential to improve patient outcomes and the related challenges.Advances in sequencing technology have rapidly improved our understanding of the biology of acute myeloid leukaemia and led to the development of several novel targeted therapies. In this Review, the authors summarize the landscape of novel targeted therapies for patients with acute myeloid leukaemia and provide guidance on future research directions.

The affordability of newly approved anticancer agents is a challenge to many national health services and reimbursement systems. Therefore, we have developed an approach based upon the adoption of a novel model of price setting and herein provide examples of how it might be implemented. This model is intended to alter the balance between social and economic entrepreneurship.

Treatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses. For identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2Rγ-/- mice. At diagnosis (n=88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n=91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n=91), which reflect the total neoplastic burden, revealed four patient groups with different survival. Discrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies.

Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38− fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38−LSC levels at diagnosis ( n  = 594), and, to identify LSC low /LSC high ( n  = 302) and MRD low /MRD high patients ( n  = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34 + CD38 − LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRD high /LSC high patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRD low /LSC high , MRD high /LSC low , and especially MRD low /LSC low patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.

Allogeneic haematopoietic stem-cell transplantation (HSCT) is frequently applied as part of treatment in patients with acute myeloid leukaemia in their first or subsequent remission. In this Review, the authors propose risk assessment as a dynamic process during treatment, incorporating both disease-related and transplant-related factors for the decision to proceed either to allogeneic HSCT or to apply a nontransplant strategy. Allogeneic haematopoietic stem-cell transplantation (HSCT) is frequently applied as part of the treatment in patients with acute myeloid leukaemia (AML) in their first or subsequent remission. Allogeneic HSCT reduces relapse, but nonrelapse mortality and morbidity might counterbalance this beneficial effect. Here, we review recent studies reporting new disease-specific prognostic markers, in addition to allogeneic-HSCT-related risk factors, which can be assessed at specific time points during treatment. We propose risk assessment as a dynamic process during treatment, incorporating both disease-related and transplant-related factors for the decision to proceed either to allogeneic HSCT or to apply a nontransplant strategy. We suggest that allogeneic HSCT might be favoured if the projected disease-free survival is expected to improve by at least 10% based on an individual's risk assessment. The approach requires initial disease risk assessment, identifying a sibling or unrelated donor soon after diagnosis and the incorporation of time-dependent risk factors, all within the context of an integrated therapeutic management approach.

High-dose cytarabine is up to 30 times the standard dose of this drug. Although more effective, the higher dose is more toxic. In this study, an intermediate dose was equally effective but considerably less toxic than a high dose. Cytarabine has been one of the cornerstone drugs in the treatment of acute myeloid leukemia (AML) for more than three decades. 1 It was initially used in remission-induction therapy at a dose of 100 to 200 mg per square meter of body-surface area. From about 1975 to 1985, investigators began evaluating the use of high-dose cytarabine therapy, given in a dose of 3000 mg per square meter twice daily for 6 days. 2 , 3 In single-group studies, high response rates were noted among patients with relapse and promising results were reported for those with a new diagnosis of AML. 2 – 4 Subsequently, a . . .

Patients with acute myeloid leukemia (AML) who were more than 60 years of age received treatment to induce a complete remission that consisted of cytarabine and daunorubicin; the latter was given at a dose of either 45 mg per square meter of body-surface area (the conventional dose of the drug) or 90 mg per square meter. As compared with patients who received the conventional dose of daunorubicin, those who received the high dose had a significantly higher rate of complete remission without an increase in toxic effects. Patients with acute myeloid leukemia who were more than 60 years of age received treatment to induce a complete remission that consisted of cytarabine and daunorubicin. As compared with patients who received the conventional dose of daunorubicin, those who received the high dose had a significantly higher rate of complete remission without an increase in toxic effects. Most patients with acute myeloid leukemia (AML) are 60 years of age or older, and in this age group, the outcome of treatment is unfavorable. Among these older patients, a combination of daunorubicin plus cytarabine induces a complete remission in 40 to 50% of cases. It is standard practice to treat patients with daunorubicin at doses of 45 to 50 mg per square meter of body-surface area for 3 days, plus cytarabine at a dose of 100 to 200 mg per square meter for 7 to 10 days. 1 – 11 However, the optimal dose of daunorubicin is unknown. Maximizing the rate . . .