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There has been remarkable progress in the treatment of acute myeloid leukemia (AML) which has spanned 5 decades. The changing trends have led to new approaches and significant improvement in outcomes. This review has summarized the historical insights that have shaped the current treatment paradigms of AML., (Copyright © 2021. Published by Elsevier Ltd.)

The past three years have witnessed remarkable progress in acute myeloid leukemia (AML). The approval and development of targeted therapies and novel agents has improved outcomes for patients with traditionally poor survival rates. This review has summarized the survival impact of chemotherapy-based regimens in AML and described recent advances that will be of significance in the near future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In recent years, several drugs-including midostaurin, gilteritinib, and gemtuzumab ozogamicin, to name a few-have been approved or reapproved in the United States to treat patients with acute myeloid leukemia (AML). Yet survival rates for younger patients had improved with chemotherapy alone even before the approvals of these new agents. This begs the question whether the new therapies will actually have a positive impact on survival. The 5-year survival rate for older patients has also risen, again without the addition of these new agents. The challenge will be to incorporate new therapies and use them where they will have the greatest impact-major work for clinicians and researchers alike., (Copyright © 2019. Published by Elsevier Ltd.)

The FLT3 inhibitor midostaurin, the antibody-drug conjugate gemtuzumab ozogamicin, CPX-351 (liposomal daunorubicin and cytarabine), and the IDH2 inhibitor enasidenib are among the novel agents approved for use in the clinic this past year. This year, 2018, already has seen the regulatory approval of the BCL2 inhibitor venetoclax in the form of breakthrough designation and the IDH1 inhibitor ivosidenib received full FDA approval. Much remains to be learned about how best to use these drugs to improve patient outcomes and how best to employ and interpret next-generation sequencing to determine measurable residual disease (MRD) levels that can more accurately predict risk of relapse., (Copyright © 2018. Published by Elsevier Ltd.)

Numerous advances have been made in the biology and treatment of acute myeloid leukemia (AML) in 2017. These include the integration of the assessment of minimal residual disease (MRD) into clinical practice, the approval and near approval of new agents, improvement in therapy for older patients, and the development of a number of promising new agents, including IDH inhibitors, a Hedgehog signaling pathway inhibitor, and a histone deacetylase inhibitor. In addition, the concept of chemotherapy manipulation is still valid and can increase efficacy in some AML populations, and transplant patterns have shifted, enabling more patients to receive a hematopoietic stem cell transplant. These and other advances are critical to improve the outcome for patients with AML., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia (ALL) offers curative therapy for patients who are in complete remission. Historically, there was great hesitation to offer this modality to patients with ALL due to the high attendant morbidity and mortality. Furthermore, the outstanding results in childhood ALL led many to believe that significant long-term survival could be achieved using chemotherapy-based regimens alone. The International ALL Study jointly conducted by ECOG and MRC completely changed perceptions indicating, surprisingly to many, that transplantation - particularly for patients at standard risk - offered a significant survival advantage. There followed trials of more intensive chemotherapy demonstrating improved results that may obviate the need for allogeneic transplantation. While a certain controversy reigns, there are unequivocal high-risk scenarios where allogeneic transplantation still forms the core of curative therapy. Such transplants should be performed as early as possible in the course of the disease once remission has been obtained., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A high relapse rate for patients with acute myeloid leukemia (AML) is still a major barrier to the long-term survival of these patients. Nevertheless, considerable progress has been made both in the biology and therapy of the disease. Specifically, progress has been made in the areas of integrated genomic analysis for prognosis, the widening application of minimal residual disease (MRD) monitoring in clinical practice, the development of new agents, and the increasing use of drugs, such as IDH and FLT3 inhibitors, as a bridge to transplant. Continued progress and inquiry into these and other areas are essential to improve the survival outcome for adult patients with AML., (Copyright © 2016. Published by Elsevier Ltd.)

Distinct progress has been made in recent years in the therapy of acute leukemia. For acute myeloid leukemia (AML), this progress has been anchored in the increased understanding of genomic complexity. Multiple targets and the relationships among them pose new challenges along with new possibilities for the development of targeted therapies. A number of new drugs are in early clinical development for AML, one of which centers on the role of isocitrate dehydrogenase (IDH) in malignancy. Epigenetic modulation, intracellular pathways, and the microenvironment are all being explored for possible therapies to treat AML. Dramatic clinical progress has also been made in therapy of acute lymphoblastic leukemia (ALL) with the rapid approval of blinatumomab, a bispecific T-cell engager antibody. Yet caution must also be exercised-not every mutation is an epigenetic target and early publication of clinical data is often misleading. Until the survival outcome for adult patients with acute leukemia improves, further inquiry into the biology of the disease and progress in the development of new therapies are needed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Therapy of acute myeloid leukemia (AML) is impacted by the increasing genomic complexity of the disease. Multiple targets as expressed by genetics and mutations and the relationships between them add another layer of intricacy to the prognosis and treatment of the disease. It is becoming increasingly apparent that the interactions between mutations are of utmost importance, particularly from a prognostic standpoint. For example, inv(16) or 6(16; 16) AML frequently involves a second genetic lesion that significantly impacts prognosis. In addition, epigenetic changes, including DNA methylation, are becoming increasingly integrated into the genetic landscape and may also have prognostic impact. Despite increased understanding of the genetic and epigenetic aspects of AML, the outcome for AML patients has not changed significantly. Until it does, further inquiry into the genomic complexity of the disease and advances in drug development are needed., (Copyright © 2014. Published by Elsevier Ltd.)

This year marked the occurrence of several important milestones in the treatment of acute leukemias. First, the standard 7 + 3 protocol for acute myeloid leukemia (AML) was developed 40 years ago, and with some adaptations, has stood the test of time. Second, the 1 millionth hematopoietic cell transplant was recorded this year. Stem cell transplant, the first reported by Dr E. Donnall Thomas in 1957, had been considered a rare procedure until about a decade ago. Today, it has become a proven and often life-saving therapy for patients with acute leukemia. Advances in the treatment of patients with AML continue to take place, many of which relate to an increased understanding of the clinical heterogeneity of known subtypes. Forty years ago, the regimen that has come to be known as 7+3 for acute myeloid leukemia (AML) was born [1,2]. Cytosine arabinoside, or arabinosylcytosine as it was then called, was given as a continuous intravenous infusion of 100 mg/m(2) for 7 days, and the anthracycline, daunorubicin, was administered at 45 mg/m(2) intravenously for 3 days. Sixteen patients were originally treated on this protocol, and 5 of 8 previously untreated and 2 of 8 previously treated patients achieved a complete response (CR). This regimen has withstood the test of time. Attempts to add or substitute other agents have not yielded superior results. The only major contemporary change is that a higher dose of daunorubicin is safe and has become the standard of care [3]., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Intensifying induction is not a new concept, but some recent and emerging information suggests that intensifying induction may be a relevant strategy for both young and older patients with acute myeloid leukaemia (AML). There are several potential strategies for intensifying induction therapy, including modulation of anthracyclines; modulation of ara-C; addition of other agents, including high-dose ara-C (HiDAC); addition of targeted or immunomodulatory agents, including gemtuzumab ozogamicin; or using timed-sequential therapy or very early intensification. It is clear that daunorubicin at a 45mgm(-2) dose is no longer acceptable as the standard for induction therapy in AML, but the optimal dose is unknown. No anthracycline dose attenuation should be made for older, fit adults, and modulation of induction can lead to significant survival benefit even without improving the initial response rate.

The graft-versus-leukaemia effect is one of the most important biological effects to influence outcome in patients with acute leukaemia. The recognition of this modality over the past three decades has led to far-reaching changes in the concept and conduct of allogeneic transplantation in acute myeloid leukaemia, and in the infusion of donor lymphocytes as a therapeutic modality. Despite these conceptual advances, there is a considerable need for more structured prospective studies to optimally define the role of reduced-intensity transplantation in both acute myeloid and acute lymphoblastic leukaemia.

Adults 18-60 years old with acute myelogenous leukemia (AML) should undergo some form of postremission therapy, however, how much and what kinds of postremission chemotherapy remain unclear. In contrast, for older patients more than one cycle of chemotherapy postremission does not appear justified except perhaps in those rare patients with favorable cytogenetics who are young enough to tolerate standard therapy and in whom there is still an option for cure. Routine postremission therapy is not justifiable for those with unfavorable cytogenetics. However, the median age of AML patients approaches 70 years; this is a group of patients who often reach minimal disease, but with a median disease-free survival of only 4 to 5 months, regardless of their cytogenetics, and are therefore an ideal patient group for clinical studies. Older patients have limited tolerance for intensive regimens, although relatively nontoxic agents exist that can be explored. The issue of maintenance remains open.

There is much confusion and uncertainty regarding the need for consolidation therapy before bone marrow transplantation. There are no prospective studies that have established clear guidelines and much of the information has been based on retrospective analyses of data obtained from the international bone marrow transplant registries. These data suggest that there may not be a role for consolidation therapy before an allogeneic transplantation. However, this may not be applicable to transplants performed following reduced intensity conditioning or to transplants performed beyond first remission. The data for autologous transplantation are substantially more confused. Common practice includes the administration of consolidation therapy prior to transplantation, although there is enormous variability in the amount of cycles and in the doses that are given before transplantation.

Stem cell transplantation preceded by reduced-intensity conditioning (RIC) is based on the use of immunosuppressive agents as the sine qua non to ensure donor cell engraftment. It is a curative option for select patients suffering from haematological and non-haematological malignancies. The most beneficial results are observed when a full donor engraftment is achieved with 'tolerable' graft-vs-host disease (GVHD). To date, a vast amount of clinical data has been published, but in an uncontrolled manner. This review summarizes the currently known outcome of allogeneic transplants with RIC, with every disease category analysed separately. Unresolved problems include the optimal combination of immunosuppressive agents, the degree of infectious complications, and GVHD that may appear in some patients. Directions to overcome these complications are discussed. Despite the paucity of controlled clinical data, the current indications for RIC allogeneic transplantation are summarized based on the best-available phase II data.

Acute promyelocytic leukaemia (APL) may be characterized simultaneously as the most potentially rapidly fatal human acute leukaemia if untreated, yet the most frequently cured acute leukaemia if promptly diagnosed and treated without delay. Co-operative group and single-institution studies which include large numbers of patients with relatively long follow-up demonstrate that, with all-trans retinoic acid (ATRA) plus anthracycline-based chemotherapy, the majority of newly-diagnosed patients appear cured of their disease. The 5-year disease-free survival rates range from 75 to 85%. Early death is still observed in approximately 10% of patients and remains a difficult obstacle to increasing the cure rate. Prognostic factors which identify patients at high risk for recurrence are becoming increasingly recognized. Older age (over age 55-60 years), elevated white blood cell count at presentation (higher than 5,000-10,000/microl), and expression of CD56 unfavourably influence outcome. The treatment of such patients remains a challenge, although it is important to note that APL is the only type of AML in which a significant proportion of older patients may be cured. Because more patients are cured of their disease, potential long-term consequences may become increasingly recognized. These include the emergence of extramedullary disease, the development of secondary myelodysplasia or acute myeloid leukaemia and the potential for late-onset cardiac toxicity.

Less than 40% of adult acute lymphocytic leukaemia (ALL) patients will still be alive at 5 years post-diagnosis. Ways to improve patients' outcome, using high-dose therapy followed by autologous/allogeneic stem cell transplantation (SCT) in first complete remission (CR1) rather than consolidation/maintenance chemotherapy, have been investigated. However, prospective studies are small and results are inconclusive. The largest prospective trial ever being performed in adult ALL patients, the ongoing UKALL 12/ECOG 2993 trial, is assigning all patients who have a sibling donor to receive allogeneic SCT (alloSCT) in CR1, whereas all other patients are randomized to continue chemotherapy versus autologous SCT. An interim analysis of this trial seems to support an alloSCT in first CR in adult ALL patients (reflected by a significantly reduced relapse rate with an improved disease-free survival). However, less than 30% of the patients have a matched sibling donor, the majority of the patients are over 40 years old, which makes them less suitable for conventional allograft, and even in those who have a matched sibling donor and are young and fit enough to receive it the treatment-related mortality (TRM) is about 20%. Strategies for expanding donor availability, meanwhile, to reduce the TRM, remain challenges. Data regarding the efficacy of reduced-intensity regimens in ALL patients are still scanty. Another way of improving patient outcome is to select patients for allograft more carefully. There are enough data to suggest now that children who achieved a clinical remission but failed to obtain a molecular/immunological remission are more prone to relapse. Similar data have recently been published for adult ALL. However, data are still limited, and the significance of minimal residual disease (MRD) has never been studied prospectively in adult ALL patients. A reasonable approach is to assign all patients with a matched related donor who has failed to achieve a molecular/immunological remission to receive a conventional alloSCT, whereas all others might be randomized to receive alloSCT versus chemotherapy/autologousSCT. However, patients with Ph(+) ALL who have a donor should receive an alloSCT in CR1, regardless of their MRD results. It appears that alloSCT provides the best chance for cure. However, by improving our ability to select those who have the highest risk for relapse, unnecessary toxicity/mortality might be prevented and the general outcome might improve.

Secondary leukaemias are common, accounting for more than 40% of all patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). A clinical history of exposure to haematotoxins or radiation is helpful; however, many older patients are diagnosed with leukaemia with no antecedent history of exposure. These patients' disease show a remarkably similar phenotype to classic therapy-related leukaemia. The specific cytogenetic abnormalities common to MDS, alkylating-agent-related AML and poor-prognosis AML (3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-, 12p-, -18, -19,20q-, +21, t(1;7), t(2;11)), probably reflect a common pathogenesis distinct from that of other de novo AMLs, although the pathogenetic pathway has yet to be elucidated. Possibly, tumour suppressor genes are implicated and genomic instability may be a cause of multiple unbalanced chromosomal translocations or deletions. Typically, these patients are either elderly or have a history of exposure to alkylating agents or environmental exposure 5-7 years prior to diagnosis. Another distinct entity affects the mixed lineage leukaemia (MLL) gene located on 11q23. These account for about 3% of patients with therapy-related leukaemia and have a short latency period from exposure, usually to an inhibitor of topoisomerase II. Other therapy-related patients with t(8:21), inv16 or t(15;17) translocations should be treated as any other de novo AML with similar cytogenetics. In summary, the major prognostic factor is related to the pathogenetic mechanisms of the leukaemia. Cytogenetics and molecular features are a better predictor of outcome than patient history. Patients should receive standard induction therapy. However, the long-term outcome is relatively poor; the best results being obtained among patients undergoing allogeneic transplantation., (Copyright 2001 Harcourt Publishers Ltd.)