Current and emerging strategies for the management of acute myeloid leukemia in the elderly

Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemias diagnosed in adults. The elderly are disproportionately affected by AML, as 35% of newly diagnosed patients are aged >or=75 and the median age at diagnosis is 67. Elderly individuals also respond less well to standard chemotherapy than do younger individuals, as reflected by lower complete remission and relapse-free survival rates in major clinical trials. A higher prevalence of comorbid conditions as well as the unique biological features of elderly AML patients account for the relatively poor response to therapy observed in this population. Compared with AML in younger individuals, for example, AML in the elderly more often emerges from a preceding myelodysplastic syndrome and is more frequently associated with poor-prognosis karyotypes such as 5q- or 7q-. The introduction of novel therapies over the past decade has already altered the treatment paradigm of elderly individuals with AML. The first of these to emerge was gemtuzumab ozogamicin. Other agents are currently under evaluation in clinical trials, including inhibitors of multidrug resistance, farnesyltransferase inhibitors, novel nucleoside analogues, and inhibitors of the FMS-like tyrosine kinase-3. This review describes the biological features of AML in the elderly and summarizes both the current and emerging strategies for the treatment of this disease in older individuals.     

New drugs in acute myeloid leukemia

The standard therapy for acute myeloid leukemia (AML) has not changed meaningfully for the past four decades. Improvements in supportive care and modifications to the dose and schedule of existing agents have led to steady improvements in outcomes. However, developing new therapies for AML has been challenging. Although there have been advances in understanding the biology of AML, translating this knowledge to viable treatments has been slow. Active research is currently ongoing to address this important need and several promising drug candidates are currently in the pipeline. Here, we review some of the most advanced and promising compounds that are currently in clinical trials and may have the potential to be part of our future armamentarium. These drug candidates range from cytotoxic chemotherapies, targeted small-molecule inhibitors, and monoclonal antibodies.     

Differentiation therapy for myeloid malignancies: beyond cytotoxicity

Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.Subject terms: Myelodysplastic syndrome, Acute myeloid leukaemia, Differentiation     

Clinical development of decitabine as a prototype for an epigenetic drug program

This review highlights decitabine as a prototype epigenetic modifying drug to show how the clinical development of epigenetic agents differs from that of traditional cytotoxic chemotherapies. Decitabine, a cytosine analogue, is cytotoxic at high doses but has selective DNA demethylating activity at low doses. The focus of current decitabine investigations is twofold: to elucidate all of the mechanisms of action and to determine the optimal dose, schedule, and concomitant therapies. New phase I trials have identified a "biologically effective dose," which is 1 to 2 logs lower than the cytotoxic dose. A clinical development program with low-dose decitabine in malignant diseases is focused on myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). A phase III trial in MDS showed objective responses (complete [CR] plus partial [PR] remission) and longer median time to progression to AML or death with decitabine than with supportive care alone. The optimal use of decitabine may be in combination with other agents that promote gene expression, namely, histone deacetylase (HDAC) inhibitors. Optimized decitabine doses and combinations with other epigenetic therapies that can be used at minimally toxic doses provide potentially safer therapeutic options and introduce novel combination therapies.     

Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia

Acute myeloid leukemia (AML) has posed significant therapeutic challenges to pediatric oncologists. Despite intensive therapy, half of the children with AML relapse and die from their disease. Efforts to identify risk factors in AML are directed toward defining populations who may benefit from alternative therapies. Patients at lower risk for relapse may benefit from treatment de-escalation, sparing them adverse side effects. Management of high-risk patients may prove more difficult, as the nearly myeloablative nature of AML therapy leaves little room for therapy escalation short of stem cell transplantation. This review evaluates prognostic factors in pediatric AML and discusses the feasibility of using these factors in risk-adapted therapy regimens.     

Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly

Acute myeloid leukemia (AML) is more prevalent in older adults, with an incidence in the United States of 17.6 per 100,000 for those 65 years of age, compared with an incidence of 1.8 per 100,000 for those <65 years of age. While there have been improvements in survival during the last decade for younger patients, prognosis in elderly patients is still poor; approximately 50% achieve complete responses, but many of them relapse. With increasing age, more patients are suboptimal candidates for standard induction chemotherapy due to poor performance status, pre-existing myelodysplasia, unfavorable cytogenetics, treatment-related AML, multidrug resistance protein expression, and CD34 positivity, which are often characteristic of this patient population. In addition, the presence of comorbid conditions make many treatment options less tolerable for elderly patients. Several investigators have described subgroups showing no benefit after intensive treatment approaches in recent years. However, several novel agents have been developed to treat elderly AML patients. These include new chemotherapeutic agents, such as nucleoside analogs, as well as targeted therapies like farnesyltransferase inhibitors, tyrosine kinase inhibitors, epigenetic drugs, and antibodies. On the other hand new insights into the biology of the disease lead to a better understanding of its heterogeneity. Thus, with a variety of novel substances at hand it is increasingly important to introduce a risk-adapted approach for the optimal management of patients. This review will identify subgroups not likely to benefit from intensive chemotherapy and highlight the efficacy and tolerability of new agents in the treatment of AML.     

SOHO State of the Art Updates and Next Questions |The Role of Maintenance Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive disease predominantly affecting the elderly population. Although, up to 65% of patients with AML achieve a complete remission with standard induction chemotherapy, the majority of patients will relapse and succumb to the disease. Although maintenance therapy is a component of standard management for various hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL) or multiple myeloma, past studies investigating the role of maintenance therapy in AML were unable to demonstrate an advantage in overall survival, and therefore, it has not been an established practice in the treatment of AML. For patients, who are not candidates for stem cell transplant, effective AML maintenance therapies are needed in order to reduce the risk of relapse. Over the past decades, many investigators have examined the role of various maintenance strategies in AML; with the intention to prolong remission and overall survival. This review will provide an overview of prior and ongoing approaches and strategies to maintenance therapy for AML.     

Therapeutic options for acute myelogenous leukemia

BACKGROUND: General therapeutic options for patients with acute myelogenous leukemia (AML) are reviewed and specific new therapies are described. METHODS: Data in this review came from the published literature and the M. D. Anderson Cancer Center's acute leukemia database. RESULTS: Outcome following standard therapy of AML is so variable that is best to speak of a range of outcomes determined by various prognostic factors. Therapy can (and usually does) fail because of treatment-induced mortality or (more usually) resistance to therapy. Performance status and age are the principal predictors of early death, whereas cytogenetics, a history of abnormal blood counts, and MDR1 expression are predictors of resistance. Using this information, physicians can categorize patients into those in whom 1) standard therapy is indicated, 2) either standard or investigational therapy is appropriate, and 3) investigational therapy is indicated. The majority of even newly diagnosed patients belong to Group 3. The availability of allogeneic or autologous transplantation does not alter this conclusion. Investigational therapies have been developed that are directed against the CD33 surface antigen, the multidrug-resistant MDR1 protein, and other targets. Because of the number of new therapies clinical research in AML should emphasize pilot trials rather than traditionally large Phase III studies. CONCLUSIONS: Most patients with newly diagnosed AML should be offered investigational regimens.     

Antimetastatic drugs in prostate cancer

Despite the benefits of local therapy with radical prostatectomy and radiation, many patients with prostate cancer require hormonal ablation. While chemotherapy has proven efficacy when the disease progresses to androgen-independent prostate cancer, patients ultimately succumb to the disease, thus the identification of other active therapies is needed. Future treatment modalities include molecular targeted therapies. Prostate cancer has been an ideal model to study the multiple steps required in the metastatic cascade. These steps have been utilized in the development of metastasis inhibitors. This review will present promising agents that have been tested preclinically or are undergoing clinical investigation for their abilities in preventing prostate cancer metastasis. Because prostate cancer metastasizes preferentially to the bone, special attention will be given to agents that interfere with this pattern of metastasis. Specifically, the efficacy of angiogenesis inhibitors, metalloproteinase inhibitors, inhibitors of prostate cancer cell- endothelial cell interactions, and bisphosphonates will be reported. In addition, the introduction of these novel agents has raised many questions as to the relevance and optimal utilization of current clinical trial designs. Issues regarding combination therapy with chemotherapy, optimal timing of treatment with metastatic inhibitors, and the need for surrogate endpoints for molecular targeted therapies will be discussed.     

A phase II study of the EGFR inhibitor gefitinib in patients with acute myeloid leukemia

Novel therapies for the treatment of acute myeloid leukemia are required to overcome disease resistance and to provide potentially less toxic therapies for older adults. Prior clinical trials involving patients with non-small cell lung cancer have demonstrated the safety and biologic activity of the administration of EGFR inhibitors in carefully selected patients. The potential efficacy of this approach in patients with acute myeloid leukemia is unknown. The effects of gefitinib on differentiation induction and cell viability in AML cell lines and primary patient AML cells were previously reported and cell viability was inhibited in a clinically achievable range. To determine if EGFR inhibitors would be therapeutically efficacious in advanced AML, we performed a phase II trial in which 18 patients with a median age of 72 (range, 57–84 years) were treated with gefitinib (750 mg orally daily). While there were no unexpected toxicities, no patients experienced an objective response, though one had stable disease lasting 16 months. We conclude that in spite of pre-clinical activity and anecdotal cases of response to EGFR inhibitors, routine use of the EGFR inhibitor gefitinib as a single agent for advanced AML is not appropriate.     

Elderly patients with acute myeloid leukaemia: characteristics in biology, patients and treatment. Recommendations of the Working Group Geriatric Oncology of the German Society for Haematology and Oncology (DGHO), the Austrian Society for Haematology and Oncology (OGHO) and the German Society for Geriatrics (DGG)

While the incidence rate of acute myeloid leukaemia (AML) is increasing with the age of the patients, the 5-year-survival rates are decreasing in an age-dependent manner. Patients with AML are considered to be old when they have reached the age of 60. This consideration is due to patient- and disease-specific parameters, which reveal differences between older and younger patients with AML. Standard of therapy is a dose-intensive chemotherapy aiming at the induction of complete remission, followed by different kinds of post-remission therapies. A small percentage of patients can be cured by this approach. However, most patients will die within the first 2 years after diagnosis due to resistance or relapse of the disease or therapy-related complications. The improvements achieved in the treatment of patients with AML are mainly restricted to the group of younger patients. The small percentage of patients who are cured, and the high rate of treatment-related mortality in elderly patients with AML give rise to the question which patients benefit from a primarily curative approach, and which should be treated with a palliative approach. The value of a palliative approach has not yet been consistently assessed in clinical trials. Geriatric assessment will be an important tool in clinical trials for elderly patients with AML to be used in the decision making process. There is hope that new classes of drugs and treatment modalities such as inhibitors of signal transduction, monoclonal antibodies, inhibitors of angiogenesis, or allogenic blood stem cell therapy after non-myeloablative conditioning regimens will improve the therapy of elderly patients with AML in the near future.     

New drugs in acute myeloid leukemia

Standard treatment of acute myeloid leukemia (AML) results in a median survival of approximately 1 year. Together with increasing understanding of the biology of AML, this has led to the introduction of many new anti-AML drugs. Here we discuss the most prominent of these: clofarabine, epigenetic-acting agents, gemtuzumab ozogamycin, and FLT3 inhibitors. All are indubitably active. However, their therapeutic efficacy relative to each other and to standard therapy is unclear. The future is likely to see combinations of the drugs with each other and with more standard therapies. There also will be a shift away from inquiring which therapy is best for the average patient to inquiring which therapy is best for a given patient with a specific constellation of disease markers.     

Novel Therapies Targeting the Apoptosis Pathway for the Treatment of Acute Myeloid Leukemia

Opinion statement Defects in the core regulators of the apoptosis pathway contribute to chemoresistance and poor outcomes in patients with acute myeloid leukemia (AML). To overcome these defects, novel molecules that target key proteins in the mitochondrial, death receptor, and convergence pathways of caspase activation are being developed. This review will highlight selected molecules including Bcl-2 and XIAP inhibitors that are advanced stages of development and have entered clinical trial for AML. In addition, this review will discuss how these novel therapies are being used as chemical probes to better understand the biology of the apoptosis pathway.     

Induction and postremission strategies in acute myeloid leukemia: state of the art and future directions

Although the past decade has brought improvements in the treatment of AML, particularly for younger individuals, most patients succumb to the disease. With current induction therapy, most patients achieve remission, but the optimal strategy for post-remission therapy is unclear. Refinements to risk classification systems that incorporate additional molecular markers may better guide physicians in recommendations for postremission therapy. The prognosis for older patients with AML remains uniformly poor, because only a minority can benefit from intensive chemotherapy and novel HCT strategies. Despite active investigation, no standard of care has emerged for patients who are not suitable candidates for standard induction therapy. The development of less toxic, more effective therapies for this population is sorely needed. Advances in molecular genetics, immunology, and the biology of normal and malignant hematopoiesis pathogenesis have led to an improved understanding of the pathogenesis of AML and to the discovery of potential therapeutic targets. Until a greater proportion of individuals with AML attain long-term survival, patients should routinely be referred to cancer centers and enrolled in investigational studies.     

Clinical potential of introducing next-generation sequencing in patients at relapse of acute myeloid leukemia

Relapse of acute myeloid leukemia (AML) remains a major determinant of outcome. A number of molecularly directed treatment options have recently emerged making comprehensive diagnostics an important pillar of clinical decision making at relapse. Acknowledging the high degree of individual genetic variability at AML relapse, next-generation sequencing (NGS) has opened the opportunity for assessing the unique clonal hierarchy of individual AML patients. Knowledge on the genetic makeup of AML is reflected in patient customized treatment strategies thereby providing improved outcomes. For example, the emergence of druggable mutations at relapse enable the use of novel targeted therapies, including FLT3 inhibitors or the recently approved IDH1/2 inhibitors ivosidenib and enasidenib, respectively. Consequently, some patients may undergo novel bridging approaches for reinduction before allogeneic stem cell transplantation, or the identification of an adverse prognostic marker may initiate early donor search. In this review, we summarize the current knowledge of NGS in identifying clonal stability, clonal evolution, and clonal devolution in the context of AML relapse. In light of recent improvements in AML treatment options, NGS-based molecular diagnostics emerges as the basis for molecularly directed treatment decisions in patients at relapse.     

Novel Therapies for Acute Myeloid Leukemia: Are We Finally Breaking the Deadlock?

Acute myeloid leukemia (AML) is one of the best studied malignancies, and significant progress has been made in understanding the clinical implications of its disease biology. Unfortunately, drug development has not kept pace, as the ‘7+3’ induction regimen remains the standard of care for patients fit for intensive therapy 40 years after its first use. Temporal improvements in overall survival were mostly confined to younger patients and driven by improvements in supportive care and use of hematopoietic stem cell transplantation. Multiple forms of novel therapy are currently in clinical trials and are attempting to bring bench discoveries to the bedside to benefit patients. These novel therapies include improved chemotherapeutic agents, targeted molecular inhibitors, cell cycle regulators, pro-apoptotic agents, epigenetic modifiers, and metabolic therapies. Immunotherapies in the form of vaccines; naked, conjugated and bispecific monoclonal antibodies; cell-based therapy; and immune checkpoint inhibitors are also being evaluated in an effort to replicate the success seen in other malignancies. Herein, we review the scientific basis of these novel therapeutic approaches, summarize the currently available evidence, and look into the future of AML therapy by highlighting key clinical studies and the challenges the field continues to face.

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Chemotherapy for patients with acute myeloid leukemia in first remission

Although the majority of patients with acute myeloid leukemia (AML) achieve a complete remission with induction chemotherapy, most will ultimately relapse. Therefore, the optimal postremission therapy for AML remains to be defined, and further improvements in treatment strategies are required. Clinical trials have demonstrated that early intensive consolidation therapy with high-dose cytarabine can produce prolonged responses in up to 40% of patients in remission after standard induction therapy. Equally, however, it has been shown that high-dose cytarabine used in induction therapy can deliver equivalent long-term results. Autologous and allogeneic stem cell transplantation in first remission are also valid alternatives, but the value of low-dose maintenance treatment seems confined to acute promyelocytic leukemia. Further improvement in the treatment of AML is likely to depend on the development of new strategies, such as molecularly targeted or immune therapies.     

Salvage Therapy Outcomes in a Historical Cohort of Patients With Relapsed or Refractory Acute Myeloid Leukemia

BackgroundThe prognosis of patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) is poor, with no universal standard salvage therapy currently available for most patients. Novel therapies with efficacy in patient subsets often have limited activity in alternative subsets, resulting in a majority of patients not gaining benefit from these therapies. This study systematically evaluated patient outcomes in a large cohort of R/R AML patients from a single institution across all salvage therapy lines, up to and including the third line.Patients and MethodsOutcomes of R/R AML patients treated at a single institution (MD Anderson Cancer Center, Houston, TX) between 2002 and 2016 were entered into a central database. Eligible patients received one or more lines of salvage therapy after first occurrence of R/R AML. Patients who received second- or third-line salvage treatment were also included in the first salvage analysis. Eligible patients were ≥ 18 years old at time of initial AML diagnosis, with no central nervous system involvement.ResultsA total of 818 eligible patients received one or more lines of salvage therapy, 809 received second-line salvage therapy, and 397 received third-line salvage therapy. Complete remission rates decreased from 14% after first salvage therapy to 9% after second salvage therapy and 3% after third salvage therapy. Median overall survival was 6.30, 4.07, and 2.98 months after first, second, and third salvage therapies, respectively.ConclusionThese data indicate that the best chance of obtaining long-term remission in AML is with a successful first induction. Strategies that improve initial response and decrease the likelihood of relapse should be pursued.     

Treating acute myeloid leukemia in the modern era: A primer

Recent years have seen tremendous advances in treating acute myeloid leukemia (AML), largely because of progress in understanding the genetic basis of the disease. The US Food and Drug Administration approved 7 agents for AML in the last 2 years: the first new drugs in decades. In this review, the authors discuss these new approvals in the backdrop of an overall strategy for treating AML today. Treating AML in the modern era requires: 1) access to and use of upfront genetic and cytogenetic testing, not only to describe prognosis but also to help identify the best available therapy; 2) effectively working new therapies into a conventional backbone of treatment, including transplantation; and 3) continued commitment to clinical trials designed to capitalize on advances in genetics and immunology to foster the next wave of drug approvals.