The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians ...and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.
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.
•Decitabine and azacitidine are valuable options in acute myeloid leukemia.•They are well tolerated, and complications most commonly relate to myelosuppression.•Antibiotic/antifungal use, regular ...monitoring, and patient education are essential.•Treatment should be continued for at least 4–6 cycles.•Genetic factors offer potential for better predicting response in future.
The hypomethylating agents (HMAs), decitabine and azacitidine, are valuable treatment options in acute myeloid leukemia patients who are not eligible for intensive chemotherapy. Both agents are generally well tolerated, and complications most commonly relate to myelosuppression. Antibiotic / antifungal use, regular monitoring, and proactive patient education are important to minimize these events, and reduce the need for dose delay. Responses to HMAs are often not evident for up to 6 cycles, and there is currently no validated clinical marker for predicting response. Hence, treatment should be continued for at least 4–6 cycles to ensure that patients have sufficient opportunity to respond. Delivery of insufficient numbers of cycles is a key reason for HMA failure, and premature discontinuation must be avoided. Genetic factors offer potential for better predicting responders to HMAs in future, but require further study.
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
We conducted a phase 3, randomized, ...double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.
A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this ...randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 116 eligible patients were randomly (1:1) assigned to either observation (N = 60) or azacitidine maintenance (N = 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks) until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with azacitidine was feasible. DFS was significantly better for the azacitidine treatment group (logrank; P = .04), as well as after adjustment for poor-risk cytogenetic abnormalities at diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression; hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P = .026). The 12-month DFS was estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups, with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often in the observation group (n = 32) than in the azacitidine maintenance group (n = 9). We conclude that azacitidine maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15).
•Azacitidine maintenance is feasible in intensively treated older patients with newly diagnosed AML.•Azacitidine maintenance, with adjustment for poor risk cytogenetic risk at diagnosis and platelet count at randomization, improves DFS.
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Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual ...patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.
•Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival.•Mutant TP53 AML/MDS-EB should be considered a single molecular disease entity.
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In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable ...progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target disease-associated molecular defects. Recent developments prompted an international expert panel to provide updated evidence- and expert opinion–based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.
The applicability of
-internal tandem duplications (
-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by ...patient-specific duplications and potential instability of
-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based
-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant
and multiparameter flow cytometry.
In 161 patients with de novo
-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment.
-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS).
NGS-based
-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of
-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75%
-ITD MRD
33% no
-ITD MRD;
< .001) and inferior OS (4-year OS, 31%
-ITD MRD
57% no
-ITD MRD;
< .001). In multivariate analysis, detection of
-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55;
< .001) and OS (hazard ratio 2.51;
= .002). Strikingly,
-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the
-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant
detection or multiparameter flow cytometry.
NGS-based detection of
-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for
-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.
Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European ...LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.
Measurable residual disease (MRD; previously termed minimal residual disease) is an independent, postdiagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk ...stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be evaluated using a variety of multiparameter flow cytometry and molecular protocols, but, to date, these approaches have not been qualitatively or quantitatively standardized, making their use in clinical practice challenging. The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRD in clinical practice. The work was accomplished over 2 years, during 4 meetings by a specially designated MRD Working Party of the European LeukemiaNet. The group included 24 faculty with expertise in AML hematopathology, molecular diagnostics, clinical trials, and clinical medicine, from 19 institutions in Europe and the United States.
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