https://orcid.org/0000-0002-0549-5087
Figures
Abstract
To compare the effectiveness and safety of intensive antileukemic therapy to less-intensive therapy in older adults with acute myeloid leukemia (AML) and intermediate or adverse cytogenetics, we searched the literature in Medline, Embase, and CENTRAL to identify relevant studies through July 2020. We reported the pooled hazard ratios (HRs), risk ratios (RRs), mean difference (MD) and their 95% confidence intervals (CIs) using random-effects meta-analyses and the certainty of evidence using the GRADE approach. Two randomized trials enrolling 529 patients and 23 observational studies enrolling 7296 patients proved eligible. The most common intensive interventions included cytarabine-based intensive chemotherapy, combination of cytarabine and anthracycline, or daunorubicin/idarubicin, and cytarabine plus idarubicin. The most common less-intensive therapies included low-dose cytarabine alone, or combined with clofarabine, azacitidine, and hypomethylating agent-based chemotherapy. Low certainty evidence suggests that patients who receive intensive versus less-intensive therapy may experience longer survival (HR 0.87; 95% CI, 0.76–0.99), a higher probability of receiving allogeneic hematopoietic stem cell transplantation (RR 6.14; 95% CI, 4.03–9.35), fewer episodes of pneumonia (RR, 0.25; 95% CI, 0.06–0.98), but a greater number of severe, treatment-emergent adverse events (RR, 1.34; 95% CI, 1.03–1.75), and a longer duration of intensive care unit hospitalization (MD, 6.84 days longer; 95% CI, 3.44 days longer to 10.24 days longer, very low certainty evidence). Low certainty evidence due to confounding in observational studies suggest superior overall survival without substantial treatment-emergent adverse effect of intensive antileukemic therapy over less-intensive therapy in older adults with AML who are candidates for intensive antileukemic therapy.
Citation: Chang Y, Guyatt GH, Teich T, Dawdy JL, Shahid S, Altman JK, et al. (2021) Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: A systematic review. PLoS ONE 16(3): e0249087. https://doi.org/10.1371/journal.pone.0249087
Editor: Francesco Bertolini, European Institute of Oncology, ITALY
Received: December 18, 2020; Accepted: March 8, 2021; Published: March 30, 2021
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: All relevant data are within the manuscript and its Supporting information files.
Funding: This systematic review was performed as part of the American Society of Hematology (ASH) guidelines for the treatment of older adults with acute myeloid leukemia. The entire guideline development process was funded by ASH. None of the authors received funding specifically for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Acute myeloid leukemia (AML), the most common type of acute leukemia occurring in adults, presents with a median age of onset of 68 years—more than 75% aged 55 or older [1]—and incurs a 5-year survival of approximately 30% [2,3]. High-risk AML, characterized by advanced patient age, secondary AML, AML with myelodysplastic-related changes or disease carrying adverse cytogenetic or molecular profiles, portends worse survival than disease with favorable or intermediate risk cytogenetic profiles [4,5].
Current standard therapy, typically an intensive chemotherapy (IC) regimen including 3 days of an anthracycline and 7 days of cytarabine (ARA-C), induces remission in 30 to 50% of older patients [6]. Long-term prognosis is, however, poor, with fewer than 10% of individuals over 60 years of age at diagnosis surviving at 5 years post-diagnosis [6–8]. Patients with unfavorable karyotype have minimal or no response to IC and hence an even worse outcome [9]. There are subgroups of AML (e.g., p53 mutated [p53m]) that, regardless of age, have a lower likelihood of responding to IC [10]. For patients with p53m AML, intensive therapy may be inferior to less-intensive therapy [11].
Historically, clinical trials have excluded approximately 40% of older patients on the basis of ineligibility for IC due to comorbidities, age over 75 years, and physician reluctance to aggressively treat older patients [6–9,12].
Azacitidine (AZA), a less-intensive therapy, has also demonstrated efficacy in myelodysplastic syndromes (MDS) and in older patients with AML [12–14]. Subgroup analysis of two prospective randomized trials in older AML patients detected no difference in overall survival (OS) between those treated with AZA or IC [15]. Results from observational studies also suggested that AZA resulted in acceptable median survival times and a survival advantage even in the absence of a complete remission (CR) [16–18]. Therefore, whether AZA or other less-intensive approaches might indeed represent an alternative to IC for the treatment of older patients with AML remains uncertain [19].
The objective of this systematic review was to compare efficacy, safety and quality of life of intensive antileukemic therapy compared to less-intensive antileukemic therapy for patients 55 years and older experiencing newly diagnosed AML with intermediate and adverse cytogenetic or molecular markers and considered appropriate for intensive antileukemic therapy. This systematic review was undertaken to inform the development of the American Society of Hematology (ASH) 2020 Guidelines for Treating Newly Diagnosed Acute Myeloid Leukemia in Older Adults [20].
Materials and methods
We conducted this systematic review to inform the development of recommendations regarding the treatment of AML in elderly patients from the ASH 2020 Guidelines for Treating Newly Diagnosed Acute Myeloid Leukemia in Older Adults [20]. As described in detail below, we conducted the study in accordance with the Cochrane Handbook [21] and report the results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [22].
Eligibility criteria
Patients.
We included studies enrolling patients ≥ 55 years of age with newly diagnosed AML including de novo AML, treatment-related AML and secondary AML, with adverse- or intermediate-risk cytogenetics and who were considered appropriate for intensive antileukemic therapy. We excluded studies if more than 25% of the patients had one or more of the following characteristics: refractory, recurrent or relapsed AML; acute promyelocytic leukemia, or myeloid conditions related to Down syndrome. We chose 55 years as the age cutoff for our eligibility criterion based on the experts’ opinion from ASH guideline panel [20].
Intervention.
Intensive antileukemic therapy included the following therapies: “7+3” an anthracycline (e.g. daunorubicin, idarubicin, or mitoxantrone) and cytarabine, with or without a third agent (gemtuzumab ozogamicin, vorinostat, bortezomib or midostaurin), with or without hematopoietic growth factor (HGFs, granulocyte colony-stimulating factor [G-CSF], granulocyte-monocyte colony-stimulating factor [GM-CSF], ESAs, or TPO mimetics); FLAG (fludarabine + cytarabine + G-CSF); or CLAG (cladribine + cytarabine + G-CSF). We also included any other antileukemic therapy labelled as intensive by our clinical expert panel (R.M.S, J.K.A. and M.A.S.).
Comparison.
Less-intensive antileukemic therapy included monotherapy of any one of 5- or 10- day decitabine, gemtuzumab ozogamicin, 5- or 7-day azacitidine, cytarabine that the authors considered “low-dose”, clofarabine (if the authors of the study labelled it as a less-intensive therapy), or any of these therapies in combination with other agents. Secondary agents in combinations could include, but were not limited to venetoclax, sorafenib, and HGFs.
Outcomes.
We included studies in which researchers reported any of the following outcomes: mortality, allogeneic hematopoietic cell transplantation, duration of first morphologic complete remission, severe toxicity, quality of life impairment, functional status impairment, recurrence (or duration of response) and burden on caregivers. We did not address responses less than complete remission, such as partial remission.
Study designs.
We included randomized controlled trials (RCTs) and comparative observational studies (prospective and retrospective observational studies, before-after studies, and studies in which the comparator was a historical cohort). We excluded studies with less than 10 participants in each arm, and studies published only as conference abstracts.
Search strategy
For the evidence synthesis supporting the development of recommendations, we searched Medline (via Ovid), Embase (via Ovid), and the Cochrane Central Register of Trials (CENTRAL) from inception to May 2019. For this publication, we updated the search through July 31st, 2020. We conducted an umbrella search encompassing all the questions addressed in the guidelines. We developed structured, database-specific search strategies [23] using terms related to “AML”, “chemotherapy” OR “antileukemic therapy”, “intensive”, “cytarabine”, “anthracycline”, “idarubicin”, “low-intensity treatment”, “azacitidine”, “decitabine”, “aclarubicin” and “LD-AraC”, and utilizing Medical Subject Heading (MeSH) terms wherever possible. We included the Medline search strategy as S1 Material in S1 File. We conducted a search of recently completed or ongoing studies using online trial registries (clinicaltrials.gov, TrialsCentral.org). We further searched the references lists of included studies and previously performed related reviews, and grey literature of dissertations for additional eligible articles.
Study selection
Pairs of reviewers independently screened titles and abstracts and identified those potentially relevant to this topic. A team of reviewers (Y.C., T.T., J.L.D. and S.S.), working in pairs, screened full texts independently. We conducted calibration exercises before screening and resolved disagreements by discussion and, if necessary, by consulting a third reviewer (R.B.P.).
Data abstraction and risk of bias assessment
We pilot-tested the data extraction forms, and confirmed in duplicate all abstracted data. To assess the risk of bias for each outcome in each included study, we used the Cochrane Risk of Bias tool 2.0 for RCTs by considering low, unclear, or high risk of bias for domains of random sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias [21]. We used the Risk of Bias in Non-randomized studies of interventions (ROBINS-I) for observational studies by considering low, moderate, serious, or critical risk of bias for domains of confounding, selection bias, classification of intervention, deviation from intended interventions, outcome measurement, missing data and selection of reporting result [24]. Reviewers resolved discrepancies through discussion or by a third reviewer when needed (R.B.P.). We collected study and patient demographic information (author, year of publication, country, funding, study design, length of follow-up, sample size, median age, sex distribution, proportion of people with intermediate or adverse cytogenetic, performance status), as well as information regarding each of the treatment arms (regimen, dose, route of administration, cycle) and outcomes of interest. We classified each group as intensive or less-intensive based on eligibility criteria and how the researchers labeled them.
Effect measures and data analysis
For dichotomous outcomes, we calculated the relative effect of therapies using risk ratios (RRs) and 95% confidence intervals (CIs), which we pooled across studies using random-effects models including the Mantel-Haenszel method [25] and the DerSimonian-Laird estimate of heterogeneity [26]. For continuous outcomes, we used the mean difference (MD) and 95% CI. When a meta-analysis was not possible, we summarized the continuous outcomes by reporting number of intensive- versus less-intensive-therapy comparisons with better and worse outcomes; and by reporting a difference of medians with the method of subtracting the medians from the two arms. For time-to-event outcomes, we used the hazard ratios (HR).
If missing, as is standard, we imputed standard deviations (SD) using median values across similar study characteristics (intervention, follow-up duration) [21]. In order to avoid double counting for studies with more than two treatment arms, we divided the data in the control arm by the number of intervention arms [21]. We performed all analyses using Review Manager 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Copenhagen, Denmark).
Assessment of certainty of the evidence
We evaluated the certainty of the evidence following the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach [27]. According to GRADE, data from randomized controlled trials begin as high certainty evidence but can be rated down due to moderate, low, or very low due to concerns of risk of bias, imprecision, inconsistency, indirectness, and publication bias [27]. Data from observational studies begin as low certainty of evidence but can be rated down for the same issues as in randomized trials and rated up for large magnitude of effect or dose-response relation [24,27]. We used funnel plots to address publication bias whenever there were 10 or more studies in a meta-analysis. We used GRADE summary of finding tables to present the main findings [28].
Subgroup and sensitivity analyses
We pooled and reported results from RCTs and observational studies separately.
We prespecified one subgroup analysis: Patients who had intermediate cytogenetic status versus patients who had adverse cytogenetic status, hypothesizing that less-intensive therapy would have larger benefits among patients with intermediate cytogenetic status than among those with adverse cytogenetic profile.
To account for potential reporting bias (i.e. when authors did not report the magnitude of the effect because of lack of statistical significance), we planned a sensitivity analysis for mortality over time. In this analysis, we included studies in which researchers reported that the effect of the therapies was “not statistically significantly different”, but did not provide the HR. In the sensitivity analyses we included these studies using a HR of 1 and a CI based on the sample size of the studies.
Results
Search results
Following the removal of duplicates, we identified 15615 potential eligible studies of which 231 proved potentially relevant based on title and abstract screening, and 25 studies (7825 patients) proved eligible on full-text review (Fig 1). From the included studies, published between published 2002 and 2020, 21 were included after the first search and informed the development of the recommendations [4,12,14,15,29–45], and 4 were included later [46–49]. We did not find any ongoing studies.
Study characteristics
Table 1 presents the study characteristics. Two studies (529 patients) were prospective, multicenter RCTs conducted in France, the United Kingdom, Sweden, Italy, Germany, Spain, Australia, the United States, Poland, Belgium, Republic of Korea and Canada [15,29]. Twenty-one were retrospective observational studies (retrospective cohort study, case-control study and case series) (7296 patients) conducted in the United States [4,30–34,47–49], France [33,35–39], the Netherlands [33,40], Republic of Korea [41,42], Japan [43], China [44], Sweden [46], Italy [12,33], Austria, Germany, Portugal and Spain [33]. Two articles reported analyses of data from two trials [14] or three trials [45] in the United States. Since the researchers did not randomize patients for the comparison of interest, we treated the data from these two articles [14,45] as observational studies. Median age of patients in the included studies varied from 63 years to 75 years of age and age range in majority of the studies was between 60 and 90 years.
AML was diagnosed by the World Health Organization (WHO) 2008 criteria (the presence of at least 20% myeloblasts in the bone marrow (BM) or peripheral blood [50]) in 10 studies [4,12,30–32,35–37,42,48], the French-American-British (FAB) criteria (AML was defined by the presence of ≥30% myeloblasts in the marrow or peripheral blood [14,51,52]) in 3 studies [14,38,43], or a combination of WHO and FAB criteria in 3 studies [29,40,44]. In 1 study > 30% BM blasts was used for the diagnosis of AML [15]. Eight studies did not report criteria used for AML diagnosis [33,34,39,41,45–47,49].
Of the 25 eligible studies, 17 with two-arm parallel comparisons [4,12,31–33,35,37–43,45–48] and 5 from three-arm studies [15,29,34,44,49] provided data suitable for meta-analysis; three articles reported data unsuitable for pooling [14,30,36]. Intensive interventions included cytarabine-based intensive chemotherapy [30,37,40,43], combination of high or intermediate dose of cytarabine and anthracycline [4,29,33–36,38], or daunorubicin/idarubicin [15,32,39,42], FLAG [31,48], IA [14,44,45,47,49], DA [44], MICE [12], or the combinations of intensive chemotherapy agents [41,46]. Less-intensive therapies included LDAC alone [15,29,30,35,43,49], or combined with clofarabine [45], AZA [12,15,29,37,39,40,47], hypomethylating agent (HMA)-based chemotherapy [4,30,32,42,46,48,49], clofarabine [31], decitabine [34,47], gemtuzumab ozogamicin (GO) with or without interleukin (IL)-11 [14], and the various types of less-intensive chemotherapies [33,36,38,41].
Risk of bias of included studies
We present risk of bias assessments of the observational studies and RCTs in Figs 2 and 3, respectively. Nineteen of the 23 observational studies (82.6%) had moderate to critical risk of bias due to confounding since one or several patient baseline characteristics differed importantly between the treatment groups. Available data indicated that patients in the intensive therapy group were younger in age [30,33–35,37,40,42,46–49], had higher bone marrow blasts (%) [30,37,39,46,47,49], had higher level of white blood cells [30,39,45,46,48,49], or had superior performance status or karyotypic status than patients in the less-intensive therapy group [33,36,37,39,40,42,49]. Ten studies had moderate to serious risk of bias due to deviation from the intended interventions (Fig 2). Of the 2 included RCTs, one had high risk of bias due to problems in random sequence generation and lack of information about allocation concealment [29]; the other had serious high of bias due to lack of blinding of personnel [15] (Fig 3).
RCT, randomized controlled trial.
Relative effects of the interventions
We summarize the effects of the interventions and the certainty of the evidence in GRADE summary of findings tables (Tables 2 and 3).
All-cause mortality.
a. Risk of death over time. Sixteen observational studies (5365 patients) reported hazard ratios (HRs) assessed in a median follow-up time range of 7.7 to 60 months [4,29,31–35,37–40,45–49]. The meta-analysis showed a lower risk of death from any causes with intensive versus less-intensive therapy (HR, 0.87 [95% CI, 0.76–0.99], 50 fewer deaths per 1000, Fig 4, Table 2). We did not detect publication bias for the risk of death over time and presented the funnel plot in Fig 5. The certainty of the evidence was low due to very serious risk of bias.
Intensive, intensive antileukemic therapy; Less-intensive, less-intensive antileukemic therapy; df, degree of freedom; SE, standard error; IV, inverse variance.
b. All-cause mortality at 30 days. Sixteen observational studies (18 comparisons, 5345 patients) reported all-cause mortality as the proportion of patients who died at 30 days [4,31,32,34,35,37–42,45–49]. The pooled result showed a confidence interval that included a 21% reduction in death and a 92% relative increase (RR, 1.23 [95% CI, 0.79–1.92], S2 Material e-Fig 1 in S2 File, Table 2). The certainty of the evidence was very low due to very serious risk of bias and serious inconsistency.
c. All-cause mortality at 1 year. Eighteen observational studies (21 comparisons, 5724 patients) reported all-cause mortality as the proportion of patients who died at 1 year [4,9,12,31,34,35,38–42,44,46–49]. Results suggested a lower risk of death with intensive therapy over less-intensive therapy (RR, 0.93 [95% CI, 0.85–1.02], S2 Material e-Fig 2 in S2 File, Table 2). The certainty of the evidence was very low due to very serious risk of bias and serious imprecision.
One RCT (87 patients) provided a confidence interval that included a 40% relative reduction in death and a 33% relative increase (RR, 0.90 [95% CI, 0.60–1.33], S2 Material e-Fig 2 in S2 File) [15]. The certainty of the evidence was low due to very serious imprecision.
d. Overall survival duration. Pooled estimates were not possible. Eighteen observational studies (22 arm-level comparisons, 6523 patients) reported the median OS duration [4,12,30–37,39,41,42,44–47,49]. Eight reported a shorter overall survival (OS) with intensive therapy compared to less-intensive [30,32,36,37,41,45,49], 13 reported a longer OS with intensive therapy [4,12,31,33–35,39,44,46,47,49], and one reported similar OS durations between the two groups [42]. The difference in OS duration ranged from 3.6 months shorter to 7.6 months longer when patients received intensive therapy versus less-intensive therapy. Certainty of evidence was very low due to very serious risk of bias, serious inconsistency, and very serious imprecision.
Two RCTs (4 arm-level comparisons, 529 patients) reported the OS duration [15,29]. Three of the four comparisons reported a shorter OS with intensive therapy [29] and one comparison [15] reported a longer OS with intensive therapy. The difference in OS duration ranged from 10.3 months shorter to 5.8 months longer when patients received intensive therapy versus less-intensive therapy. Certainty of evidence was very low due to serious risk of bias, serious inconsistency, and serious imprecision.
A. Allogeneic hematopoietic (AlloHCT/AlloSCT) stem cell transplantation.
Nine observational studies (10 comparisons, 1490 patients) reported the proportion of people who received AlloHCT/AlloSCT following initial AML therapy [4,12,31,33,34,37,39,40,43]. The meta-analysis showed a higher likelihood of AlloHCT/AlloSCT stem cell transplantation being performed after intensive AML therapy compared to less-intensive therapy (RR, 6.14 [95% CI, 4.03–9.35], 182 more per 1000, S2 Material e-Fig 3 in S2 File, Table 2). The certainty of the evidence was moderate because of strong association in result, though risk of bias was very serious.
B. Complete remission assessed with time to relapse in months.
Pooled estimates were not possible. Four observational studies (593 patients) reported the time to relapse [4,31,38,45]. Three reported a shorter remission with intensive therapy compared to less-intensive therapy [4,38,45]. The difference in CR duration ranged from 3.1 months shorter to 0.03 months longer when patients received intensive therapy versus less-intensive therapy. One reported similar CR durations between the two groups [31]. The certainty of evidence was very low due to very serious risk of bias, and serious imprecision.
C. Treatment-emergent adverse events (TEAEs).
a. Serious TEAEs (Grade 3 to 4 severe toxicity). One observational study (190 patients) showed a higher risk of the treatment-emergent Grade 3 to 4 adverse events with intensive therapy over less-intensive therapy at a median follow-up length of 5 years (RR, 1.34 [95% CI, 1.03–1.75], 157 more per 1000, S2 Material e-Fig 4 in S2 File, Table 2) [45]. The certainty of the evidence was low due to very serious risk of bias.
b. Specific serious TEAEs. We did not find statistically significant differences between the intensive and less-intensive therapies with respect to the proportion of patients experiencing the specific TEAEs including febrile neutropenia [15,31], anemia [15], neutropenia [29], thrombocytopenia [29] (S2 Material e-Figs 5–8 in S2 File), admission to Intensive Care Unit (ICU) [31,33] (S2 Material e-Fig 10 in S2 File), and duration of hospitalization in days [31,40,45] (S2 Material e-Fig 12 in S2 File), all with low to very low certainty of evidence due to serious imprecision and (or) very serious risk of bias. Tables 2 and 3 present detailed results.
c. Pneumonia. One study (RCT that recorded this outcome as a non-randomized manner) (431 patients) showed a lower risk of pneumonia with intensive therapy over less-intensive therapy (RR, 0.25 [95% CI, 0.06–0.98], 143 fewer per 1000, S2 Material e-Fig 9 in S2 File, Table 3) [15]. The certainty of the evidence was low due to very serious risk of bias.
d. Duration of ICU hospitalization. Pooled estimates were not possible. One observational study (64 patients) reported a longer ICU hospitalization with intensive therapy over less-intensive therapy (mean difference, 6.84 days longer [95% CI, 3.44 days longer to 10.24 days longer], S2 Material e-Fig 11 in S2 File) [31]. The certainty of the evidence was very low due to very serious risk of bias and very serious imprecision.
Subgroup and sensitivity analyses results
Because the studies did not provide sufficient information to be categorized in subgroups, nor presented outcome data separately according to the cytogenetic status. we did not conduct the preplanned subgroup analysis for patients who had intermediate cytogenetic status versus patients who had adverse cytogenetic status.
For the sensitivity analysis for the outcome risk of death over time, we found 4 observational studies [12,30,42,43] in which researchers reported that the effect of the therapies was not statistically significantly different, but did not provide the HR. We used a HR of 1 and a CI based on sample size and added them to the meta-analysis with the 16 observational studies that reported specific HRs. The meta-analysis of 20 observational studies (6438 patients) showed a lower risk of death with intensive therapy compared to less-intensive therapy (HR, 0.90 [95% CI, 0.82–1.00], S2 Material e-Fig 13 in S2 File), thus not materially different than the initial analysis [4,9,12,29,30,31,33–35,37–40,42,43,45–49]. The certainty of the evidence was low due to very serious risk of bias.
Discussion
Clinicians and patients considering how aggressively to treat an older adult with AML face a complicated decision. The choice between more or less-intensive chemotherapy is influenced by age, comorbidities, performance status, and most importantly, patient goals of care. Studies to help guide this decision are limited, at times contradictory in their findings, and may be underpowered or prone to bias. Analytic approaches such as meta-analyses can be used to clarify and inform treatment approaches.
Most of the evidence we found comes from observational studies, which resulted in having low certainty evidence due to the high risk of bias owing to confounding: patients who in practice were provided intensive antileukemic therapy are likely to be different from those who were provided less-intensive therapy. This low certainty evidence from observational studies suggests that older patients with newly diagnosed acute myeloid leukemia and with intermediate and adverse cytogenetics who receive intensive antileukemic therapy may be at 23% lower risk of death than those who receive less-intensive antileukemic therapy (Table 2) [4,29,31–35,37–40,45]. Although those who receive more intensive antileukemic therapy are more likely to proceed with stem cell transplant than those who receive less-intensive therapy, the difference may be due to patient and/or disease-related factors influencing the decision regarding initial treatment rather than a higher success rate with intensive chemotherapy, although a higher efficacy (e.g., remission) enabling transplant remains possible.
Because the studies did not provide all data necessary, we were not able to pool results quantifying the difference in survival time between patients who receive intensive versus those who received less intensive antileukemic therapy. Very low certainty evidence reported inconsistent results from both observational studies (shorter survival duration in 7 comparisons [30,32,36,37,41,45] but longer duration in 10 comparisons [4,12,31,33–35,39,44] with intensive therapy; difference ranged from 2.2 months shorter to 7.6 months longer with intensive therapy) and RCTs (shorter survival duration in 3 comparisons [29] and longer duration in 1 comparison [15] with intensive therapy; duration ranged from 10.3 months shorter to 5.8 months longer with intensive therapy). With available data from the included studies, we were not able to do subgroup analyses for age, cytogenetic status and comorbidities, which might influence the survival durations [6,53].
Low certainty evidence suggests that patients who receive more intensive therapy may be one third more likely (an absolute increase of almost 16%) to experience a grade 3 or worse treatment emergent adverse event, and experience an ICU stay of almost 7 days longer [31], but may be 75% less likely to experience pneumonia (an absolute difference of over 14%) [22] (Table 2). The importance of reduction in pneumonia is unclear in the context of evidence suggesting an increased risk of grade 3 or worse toxicity and prolonged ICU stay.
Our review found almost no data on the impact of different intensities of AML treatment on patient-reported outcomes or functional outcomes such as independence in daily activities. Given the poor long-term survival of many older adults with AML regardless of the intensity of therapy, the impact of treatment intensity on QOL and function represents an important area for further study. Indeed, American Society of Clinical Oncology (ASCO) guidelines [54] recommend that geriatric assessment be employed to identify older adults with cancers such as AML who are at increased risk for poor treatment outcomes, and assessing the effects of intensive versus non-intensive strategies on frailty itself as well as QOL seems a logical next step.
We conducted a rigorous systematic review, using a comprehensive search based on explicit eligibility criteria and multiple independent reviewers for study selection, data abstraction and risk of bias evaluation [21–23]. We applied the GRADE approach to assess the certainty of evidence [27,28], and took additional methodological steps to avoid double counting of studies with multiple treatment arms.
Despite these strengths, due to the nature of the evidence, the certainty of evidence for most outcomes was low to very low based on the non-randomized data; a paucity of randomized data addressed the critical question of whether older patients considered fit for chemotherapy actually have superior outcomes than similar patients receiving less-intensive therapy. Age of 55 years is relatively young, and there were too few data allowing us to dissect out risks of conventionally advanced age (e.g. 70 or 75 years) versus 55–70 or 55–75 years of age in the studies. The evidence includes patients with both intermediate and adverse cytogenetic status. Because of the way in which studies are reported, we could not separate these patients as subgroups and were unable to determine whether treatment would impact differently on the two groups.
For this publication, we updated the original search that informed the development of the recommendations. We included 4 new studies [46–49]. The inclusion of these studies did result in important change in results or certainty of the evidence.
In practice, the physician’s assessment of disease, patient characteristics and an analysis of patient goals in the context of anticipated outcomes with each treatment approach are part of the holistic assessment of whether an older adult with AML is considered fit for intensive antileukemic therapy and what is most appropriate induction regimen [53,55].
Intensive antileukemic therapy typically must be delivered in the hospital, representing a burden to the patients and the healthcare system. Intensive chemotherapy, which requires hospitalization due to its effects on myelosuppression and gastrointestinal, may also lead to a longer time in the hospital and greater chance of admission to the ICU [56,57]. However, our review did not find a difference between the two groups for duration of hospitalization ICU hospitalization. Although less-intensive antileukemic therapy can more often be administered in the outpatient setting, it may include more repetitive cycles of therapy than the relatively brief intensive therapy. This ongoing therapy can be difficult for patients to tolerate both psychologically and physically, and may still require hospitalization. The estimates of effect presented in this review, the low certainty of the evidence, and all these considerations resulted in the ASH guideline panel issuing a conditional recommendation for intensive antileukemic therapy over less-intensive antileukemic therapy [20,54].
In conclusion, our results suggest superior overall survival without substantial treatment-emergent adverse effect of intensive antileukemic therapy over less-intensive therapy in older adults with AML who are candidates for intensive antileukemic therapy. The certainty of evidence is almost uniformly low or very low, mainly due to the inherent bias in the selection of intensive chemotherapy for more fit and/or responsive patients in the observational studies that dominated this review. Studies did not address function or QOL [20].
The combination of less-intensive hypomethylating agent therapy with adjunctive agents such as venetoclax therapies [58] targeted against molecular abnormalities such as FLT3 and IDH1/2, and/or the sequencing of less-intensive therapy after initial intensive therapy [59] seem promising and could change the conclusion of similar analyses in the future. Confident resolution of the relative impact of more versus less-intensive chemotherapy for this population will require large, well designed randomized clinical trials reporting subgroup results of patients with varying but prespecified cytogenetic or molecular genetic risks.
Supporting information
S1 File. MEDLINE search strategy.
MEDLINE search strategy for intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia.
https://doi.org/10.1371/journal.pone.0249087.s002
(DOCX)
S2 File. Forest plots.
e-Fig 1. All-cause mortality at 30 days after treatment initiation. e-Fig 2. All-cause mortality at 1 year after treatment initiation. e-Fig 3. Proportion of patients who received allogeneic hematopoietic stem cell transplantation. e-Fig 4. Proportion of patients who had serious treatment-emergent adverse events. e-Fig 5. Proportion of patients who had febrile neutropenia. e-Fig 6. Proportion of patients who had anemia. e-Fig 7. Proportion of patients who had neutropenia. e-Fig 8. Proportion of patients who had thrombocytopenia. e-Fig 9. Proportion of patients who had pneumonia. e-Fig 10. Proportion of patients who admitted to intensive care unit (ICU). e-Fig 11. Duration of ICU hospitalization (days). e-Fig 12. Duration of overall hospitalization in days. e-Fig 13. Sensitivity analysis of all-cause mortality assessed with risk of death.
https://doi.org/10.1371/journal.pone.0249087.s003
(DOCX)
Acknowledgments
This systematic review was performed as part of the American Society of Hematology (ASH) guidelines for Treating Newly Diagnosed Acute Myeloid Leukemia in Older Adults. We thank the clinical experts who were part of the panel for critical feedback on population and outcome selection, and treatment grouping: Harry Erba, Hannah Choe, Kristen Odwyer and Ashley Rosko for inputs on the research panel meetings. We thank Shiyun Hu, Thomas Agoritsas, Wojtek Wiercioch, Linn Brandt, Nicolás Yanine for screening full-text studies that were published in non-English languages.
References
- 1. Qaseem A, Forland F, Macbeth F, Ollenschlager G, Phillips S, Van der Wees P. Board of Trustees of the Guidelines International N: guidelines International Network: toward international standards for clinical practice guidelines. Ann Intern Med. 2012;156(7):525–31. pmid:22473437
- 2. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood cancer journal. 2016;6(7):e441. pmid:27367478
- 3. Visser O, Trama A, Maynadié M, Stiller C, Marcos-Gragera R, De Angelis R, et al. Incidence, survival and prevalence of myeloid malignancies in Europe. European journal of cancer. 2012;48(17):3257–3266. pmid:22770878
- 4. Vachhani P, Al Yacoub R, Miller A, Zhang F, Cronin TL, Ontiveros EP, et al. Intensive chemotherapy vs. hypomethylating agents in older adults with newly diagnosed high-risk acute myeloid leukemia: A single center experience. Leukemia research. 2018;75:29–35. pmid:30445237
- 5. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–447. pmid:27895058
- 6. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97(12):1916–1924. pmid:22773600
- 7. Juliusson G, Lazarevic V, Hörstedt AS, Hagberg O, Höglund M. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood. 2012;119(17):3890–3899. pmid:22383796
- 8. Ferrara F. Treatment of unfit patients with acute myeloid leukemia: a still open clinical challenge. Clinical Lymphoma Myeloma and Leukemia. 2011;11(1):10–16. pmid:21454185
- 9. Alibhai SM, Leach M, Minden MD, Brandwein J. Outcomes and quality of care in acute myeloid leukemia over 40 years. Cancer. 2009;115(13):2903–2911. pmid:19452536
- 10. Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012 Mar 1;119(9):2114–21. pmid:22186996
- 11. Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. New England Journal of Medicine. 2016 Nov 24;375(21):2023–36. pmid:27959731
- 12. Maurillo L, Buccisano F, Spagnoli A, Voso MT, Fianchi L, Papayannidis C, et al. Comparative analysis of azacitidine and intensive chemotherapy as front-line treatment of elderly patients with acute myeloid leukemia. Annals of hematology. 2018;97(10):1767–1774. pmid:29947973
- 13. Deschler B, de Witte T, Mertelsmann R, Lubbert M. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica. 2006;91(11):1513–1522. pmid:17082009
- 14. Estey EH, Thall PF, Giles FJ, Wang XM, Cortes JE, Beran M, et al. Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside. Blood. 2002;99(12):4343–4349. pmid:12036860
- 15. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with> 30% blasts. Blood. 2015;126(3):291–299. pmid:25987659
- 16. Thépot S, Itzykson R, Seegers V, Recher C, Raffoux E, Quesnel B, et al. Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. American journal of hematology. 2014;89(4):410–416. pmid:24375487
- 17. Santini V, Fenaux P, Mufti GJ, Hellström-Lindberg E, Silverman LR, List A, et al. Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine. European journal of haematology. 2010;85(2):130–138. pmid:20394651
- 18. Kumar A, List AF, Mhaskar R, Djulbegovic B. Efficacy of Hypo-methylating agents in the treatment of myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. Blood. 2008;112 (11):3632.
- 19. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–474. pmid:19880497
- 20. Sekeres MA, Guyatt G, Abel G, Alibhai S, Altman JK, Buckstein R, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood advances. 2020 Aug 11;4(15):3528–49. pmid:32761235
- 21.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. www.training.cochrane.org/handbook.
- 22. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. International Journal of Surgery. 2010;8(5):336–341. pmid:20171303
- 23.
Haynes RB, Sackett DL, Guyatt GH, Tugwell P. Clinical epidemiology: how to do clinical practice research. 3rd ed. Philadelphia: Lippincott, Williams & Wilkins; 2006.
- 24. Schünemann HJ, Cuello C, Akl EA, Mustafa RA, Meerpohl JJ, Thayer K, et al. GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. Journal of clinical epidemiology. 2019;111:105–114. pmid:29432858
- 25. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute. 1959;22(4):719–748. pmid:13655060
- 26. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. pmid:3802833
- 27. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–926. pmid:18436948
- 28. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013;66(2):158–172. pmid:22609141
- 29. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. Journal of Clinical Oncology. 2009;28(4):562–569. pmid:20026804
- 30. Boddu PC, Kantarjian HM, Ravandi F, Garcia-Manero G, Verstovsek S, Jabbour EJ, et al. Characteristics and outcomes of older patients with secondary acute myeloid leukemia according to treatment approach. Cancer. 2017;123(16):3050–3060. pmid:28387922
- 31. Scappaticci GB, Marini BL, Nachar VR, Uebel JR, Vulaj V, Crouch A, et al. Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG. Annals of hematology. 2018;97(4):573–584. pmid:29288428
- 32. Almeida A, Prebet T, Itzykson R, Ramos F, Al-Ali H, Shammo J, et al. Clinical outcomes of 217 patients with acute erythroleukemia according to treatment type and line: a retrospective multinational study. International journal of molecular sciences. 2017;18(4):837. pmid:28420120
- 33. El-Jawahri AR, Abel GA, Steensma DP, LeBlanc TW, Fathi AT, Graubert TA, et al. Health care utilization and end‐of‐life care for older patients with acute myeloid leukemia. Cancer. 2015;121(16):2840–2848. pmid:25926135
- 34. Michalski JM, Lyden ER, Lee AJ, Al-Kadhimi ZS, Maness LJ, Gundabolu K, et al. Intensity of chemotherapy for the initial management of newly diagnosed acute myeloid leukemia in older patients. Future Oncology. 2019;15(17):1989–1995. pmid:31170814
- 35. Heiblig M, Le Jeune C, Elhamri M, Balsat M, Tigaud I, Plesa A, et al. Treatment patterns and comparative effectiveness in elderly acute myeloid leukemia patients (age 70 years or older): the Lyon-university hospital experience. Leukemia & lymphoma. 2017 Jan 2;58(1):110–117. pmid:27184036
- 36. Fattoum J, Cannas G, Elhamri M, Tigaud I, Plesa A, Heiblig M, et al. Effect of age on treatment decision-making in elderly patients with acute myeloid leukemia. Clinical Lymphoma Myeloma and Leukemia. 2015;15(8):477–483. pmid:25843415
- 37. Dumas PY, Bertoli S, Bérard E, Médiavilla C, Yon E, Tavitian S, et al. Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia. Oncotarget. 2017;8(45):79126. pmid:29108292
- 38. Cannas G, Fattoum J, Boukhit M, Thomas X. Economic analysis of blood product transfusions according to the treatment of acute myeloid leukemia in the elderly. Transfusion Clinique et Biologique. 2015;22(5–6):341–347. pmid:26184429
- 39. Bories P, Bertoli S, Bérard E, Laurent J, Duchayne E, Sarry A, et al. Intensive chemotherapy, azacitidine, or supportive care in older acute myeloid leukemia patients: an analysis from a regional healthcare network. American journal of hematology. 2014;89(12):E244–252. pmid:25195872
- 40. van der Helm LH, Scheepers ER, Veeger NJ, Daenen SM, Mulder AB, van den Berg E, et al. Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients. Journal of hematology & oncology. 2013;6(1):29.
- 41. Yi HG, Lee MH, Kim CS, Hong J, Park J, Lee JH, et al. Clinical characteristics and treatment outcome of acute myeloid leukemia in elderly patients in Korea: a retrospective analysis. Blood research. 2014;49(2):95–99. pmid:25025010
- 42. Oh SB, Park SW, Chung JS, Lee WS, Lee HS, Cho SH, et al. Therapeutic decision-making in elderly patients with acute myeloid leukemia: conventional intensive chemotherapy versus hypomethylating agent therapy. Annals of hematology. 2017;96(11):1801–1809. pmid:28828639
- 43. Tasaki T, Yamauchi T, Matsuda Y, Takai M, Ookura M, Lee S, et al. The response to induction therapy is crucial for the treatment outcomes of elderly patients with acute myeloid leukemia: single-institution experience. Anticancer research. 2014;34(10):5631–5636. pmid:25275066
- 44. Chen Y, Yang T, Zheng X, Yang X, Zheng Z, Zheng J, et al. The outcome and prognostic factors of 248 elderly patients with acute myeloid leukemia treated with standard-dose or low-intensity induction therapy. Medicine. 2016;95(30). pmid:27472687
- 45. Takahashi K, Kantarjian H, Garcia-Manero G, Borthakur G, Kadia T, DiNardo C, et al. Clofarabine plus low-dose cytarabine is as effective as and less toxic than intensive chemotherapy in elderly AML patients. Clinical Lymphoma Myeloma and Leukemia. 2016;16(3):163–168.
- 46. Österroos A, Eriksson A, Antunovic P, Cammenga J, Deneberg S, Lazarevic V, et al. Real-world data on treatment patterns and outcomes of hypomethylating therapy in patients with newly diagnosed acute myeloid leukaemia aged≥ 60 years. British Journal of Haematology. 2020 Apr;189(1):e13. pmid:32103493
- 47. Quintás-Cardama A, Ravandi F, Liu-Dumlao T, Brandt M, Faderl S, Pierce S, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood. 2012 Dec 6;120(24):4840–5. pmid:23071272
- 48. Solomon SR, Solh M, Jackson KC, Zhang X, Holland HK, Bashey A, et al. Real-world outcomes of unselected elderly acute myeloid leukemia patients referred to a leukemia/hematopoietic cell transplant program. Bone Marrow Transplantation. 2020 Jan;55(1):189–98. pmid:31527818
- 49. Talati C, Dhulipala VC, Extermann M, Al Ali N, Kim J, Komrokji R, et al. Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia. Haematologica. 2020 Jan 1;105(2):398–406. pmid:31073071
- 50. Vardiman J, Thiede J, Arber D, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the world health organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–951. pmid:19357394
- 51. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukaemia. A report of the French-American-British Cooperative Group. Ann Intern Med. 1985;103: 620–625. pmid:3862359
- 52. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gral-nick HR, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) Co-operative Group. Br J Haematol. 1976;33:451–458. pmid:188440
- 53. Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC cancer. 2017;17(1):852. pmid:29241450
- 54. Mohile SG, Dale W, Somerfield MR, Schonberg MA, Boyd CM, Burhenn PS, et al. Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology. J Clin Oncol. 2018 Aug 1;36(22):2326–2347. pmid:29782209
- 55. Bashey A, Liu L, Ihasz A, Medina B, Corringham S, Keese K, et al. Non-anthracycline based remission induction therapy for newly diagnosed patients with acute myeloid leukemia aged 60 or older. Leukemia research. 2006;30(4):503–506. pmid:16303178
- 56. Jackson G, Taylor P, Smith GM, Marcus R, Smith A, Chu P, et al. A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. British journal of haematology. 2001;112(1):127–137. pmid:11167793
- 57. Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leukemia research reports. 2016;6:1–7. pmid:27408788
- 58. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. New England Journal of Medicine. 2020 Aug 13;383(7):617–29. pmid:32786187
- 59. Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al. The QUAZAR AML-001 Maintenance Trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Blood. 2019; 134 (Supplement_2): LBA–3.