Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary?

Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P = .00004), the German AMLCG requestioned the effect of maintenance randomly compared with sequential high-dose cytosine arabinoside (Ara-C) and mitoxantrone in patients who received intensified induction treatment. The results show an advantage for maintenance treatment (RFS rate of 32%) versus the sequential Ara-C and mitoxantrone treatment (RFS rate of 25%) (P = .021). We conclude that maintenance treatment continues to substantially contribute to the management of adult patients with AML, even as part of recent strategies using intensified induction treatment, and thus appears necessary in these settings.     

What is the potential for thrombopoietic agents in acute leukemia?

In the 16 years since thrombopoietin was identified and cloned, much has been learned about its biochemistry, how it is regulated, and its involvement in a wide range of functions in a variety of cell lineages. The first generation of recombinant human thrombopoietins, rHuTPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), were shown to increase platelet counts in patients with immune thrombocytopenia, in platelet apheresis donors, and in patients receiving nonmyeloablative chemotherapy. Their effects in patients with acute myeloid leukemia (AML) showed no benefit at a wide range of doses and schedules. The two second-generation TPO mimetics approved by the US Food and Drug Administration (FDA) for the treatment of ITP, romiplostim and eltrombopag, are now being studied in a number of thrombocytopenic disorders including those due to chemotherapy and hepatitis C. Since romiplostim is comparable to the first-generation recombinant thrombopoietins, it may not be beneficial in AML treatment; however, given its novel mechanism of action, eltrombopag may be a TPO potentiator and if given at the proper time during chemotherapy, may enable AML patients to recover platelet counts sooner.     

Amonafide: a future in treatment of resistant and secondary acute myeloid leukemia?

Development of the novel topoisomerase II inhibitor, amonafide, began almost 40 years ago. The drug was selected for further investigation owing to evidence of marked antineoplastic efficacy in preclinical models of cancer. When its usefulness in the treatment of various solid malignancies proved limited, focus was shifted to establishing its use as an antileukemic agent, specifically against secondary and treatment-associated acute myeloid leukemia (AML). While Phase I and II studies gave rise to hopes that amonafide might hold the key to treating older patients, including those with multidrug resistant, cytogenetically unfavorable secondary and treatment-associated AML, when used in combination with cytarabine, it failed to demonstrate a survival advantage over standard-of-care therapy in randomized studies. This article will outline the development of amonafide from the laboratory to the bedside and discuss the potential place that this agent has in the current management of AML.     

Post-remission therapy in acute myeloid leukemia: Are we ready for an individualized approach?

Recent advances in remission induction treatment strategies for acute myeloid leukemia (AML) have improved the rates of complete remission (CR) and overall survival (OS), owing to a concerted effort to tailor therapies toward specific AML subtypes. However, without effective post-remission therapy, most patients will relapse. The extent to which post-remission therapies is individualized in the current paradigm is quite varied. Core binding factor (CBF) AML is typically treated with post-remission high-dose cytarabine (HiDAC) without allogeneic hematopoietic stem cell transplantation (HSCT), whereas those with intermediate or adverse-risk cytogenetics are treated with post-remission cytarabine followed by allogeneic HSCT in CR1 when feasible. A lack of clarity regarding the proper dosing of post-remission cytarabine has made consensus building on dosing and schedule a challenge. CBF AML benefits most from high-dose cytarabine (HiDAC), and dasatinib appears promising as an adjunct for those for KIT-mutated CBF AML. Other than series using CPX-351 or lomustine in older adults, multiagent chemotherapy approaches have resulted in excess toxicity without a survival benefit. Neither hypomethylating agents nor gemtuzumab ozogamicin have shown a material OS benefit. Targeted agents such as FLT3 inhibitors and IDH1/IDH2 inhibitors show potential for the patients who harbor these druggable targets, but few data are available. Many studies evaluating post-remission strategies to target AML in the MRD-positive state are already underway, and these remain a promising area of investigation.     

Patient-reported outcomes in acute myeloid leukemia: Where are we now?

Outcomes for acute myeloid leukemia remain poor, and treatment decisions must consider not just quantity, but also quality of life (QOL). We conducted a systematic review of studies in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that incorporated patient-reported outcome (PRO) measures. PubMed and PsycINFO were searched for articles published from January 2000 through June 2016. Forty-one were relevant for our review with more published in recent years. There was considerable inter-study heterogeneity in which instruments were used, and many studies employed multiple (often overlapping) instruments. Longitudinal studies in particular suffered from both high attrition rates due to disease-related mortality as well as waning compliance with questionnaire completion. There remain significant challenges to incorporation of PROs into leukemia trials. Despite these limitations, however, well-implemented PROs can provide important information beyond objective response outcomes and highlight areas of focus for clinicians caring for patients and for future research endeavors.     

Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia?

Secondary leukemia is a poorly defined term that often refers to the development of acute myeloid leukemia (AML) following the history of a previous disease, such as a myelodysplastic syndrome or a chronic myeloproliferative disorder. Secondary leukemia can also be a consequence of treatment with chemotherapy, including alkylating agents and topoisomerase II inhibitors, and/or radiotherapy, or due to exposure to environmental carcinogens. Outcomes for this large and variable group of patients with secondary AML have been poor compared to people who develop AML de novo. The question arises whether a diagnosis of secondary leukemia per se indicates a poor prognosis or whether their bad outcomes result from an association with certain morphologic and biologic characteristics. Morphologic dysplasia in de novo AML is related to unfavorable cytogenetics, but has no independent prognostic relevance under the conditions of intensive chemotherapy. While there is no significant correlation between cytogenetic risk groups and dysplasia, cytogenetic features do have an impact on outcome among both de novo and secondary AML patients. In various subgroups of secondary AML, the spectrum of cytogenetic abnormalities is similar to de novo AML, but the frequency of abnormalities associated with unfavorable and intermediate risk cytogenetics, such as a complex karyotype, trisomy 8, monosomy 7, and others, is higher in secondary AML. The survival of patients with therapy-related myeloid leukemia (t-AML) is generally shorter than for those with de novo AML within the same cytogenetic risk group. Across the population of t-AML, however, survival varies according to cytogenetic risk group, with longer survival in patients with favorable-risk karyotypes. The term secondary AML is too broad and imprecise to be of importance and should not be used. These AML patients should be enrolled on front-line chemotherapy trials and should be stratified by pretreatment disease status and exposure history, if necessary. Most importantly, the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.     

The immunophenotype of acute myeloid leukemia: is there a relationship with prognosis?

Immunophenotyping of acute myeloid leukemia has controversial implications with regards to prognosis. Many associations have been described between individual antigen expression on myeloid blasts and prognosis, however few are consistent. Markers with a consistent prognostic association that have been demonstrated in more than one study have been CD13, CD14, and CD15. The association of the expression of CD11b with poor prognosis appears definite, as does CD7 expression. When compared with the expression of a single antigen, a pattern of antigen expression is likely to have a more significant relationship to prognosis. This is exemplified by the panmyeloid phenotype (expression of 5 myeloid antigens) which appears to be associated with a good prognosis and may differentiate a subgroup within an otherwise intermediate prognosis group of patients. Further analysis with the inclusion of novel antibodies and the combination of multiple antibodies to create further subgroups such as the panmyeloid phenotype will continue to enhance knowledge in this area.