Intensive versus less-intensive antileukemic therapy in older
Transcript Of Intensive versus less-intensive antileukemic therapy in older
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RESEARCH ARTICLE
Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: A systematic review
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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
Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0249087
Copyright: 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 Statement: All relevant data are within the manuscript and its Supporting information files.
Yaping ChangID1, Gordon H. Guyatt1, Trevor Teich2, Jamie L. Dawdy3, Shaneela Shahid1,4, Jessica K. Altman5, Richard M. Stone6, Mikkael A. Sekeres7, Sudipto Mukherjee7, Thomas W. LeBlanc8, Gregory A. Abel9, Christopher S. Hourigan10, Mark R. Litzow11, Laura C. Michaelis12, Shabbir M. H. Alibhai13, Pinkal Desai14, Rena Buckstein15, Janet MacEachern16, Romina Brignardello-Petersen1*
1 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada, 2 Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America, 3 School of Nursing, McMaster University, Hamilton, Ontario, Canada, 4 Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada, 5 Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America, 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 7 Leukemia Program, Cleveland Clinic, Cleveland, Ohio, United States of America, 8 Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America, 9 Division of Hematologic Malignances and Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 10 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 11 Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States of America, 12 Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America, 13 Department of Medicine, University Health Network & University of Toronto, Toronto, Ontario, Canada, 14 Weill Cornell Medicine, New York City, New York, United States of America, 15 Odette Cancer Centre, Division of Medical Oncology and Hematology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, 16 Grand River Regional Cancer Centre, Kitchener, Ontario, Canada
* [email protected]
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 metaanalyses 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 agentbased 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–
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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.
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.
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 lessintensive 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
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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 5or 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 lessintensive 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,
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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 randomeffects 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
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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
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Fig 1. Eligibility assessment PRISMA flow diagram.
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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).
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Table 1. Characteristics of included studies.
Author (year)
Sample Size
Median age (range, year)
Sex, female, n
(%)
Almeida et al. (2017) [32]
163 63 (20–88) 49 (30.1)
Boddu et al. (2017) [30]
802 68 (60–75) NR
Bories et al. (2014) [39]
210 72 (60–89) 77 (36.7)
Cannas et al. (2015) [38]
Chen et al. (2016) [44]
138 74 (70–86) 62 (44.9) 248 67 (60–87) 111 (44.8)
Dumas et al. (2017) [37]
199 72 (61–88) 82 (41.2)
El-Jawahri et al. 330 (2015) [33]
70 (7)� 135 (40.9)
Estey et al. (2002) [14]
Fattoum et al. (2015) [36]
Heiblig et al. (2017) [35]
Maurillo et al. (2018) [12]
82 72 (65–89) NR 183 74 (70–86) 79 (43.2) 195 74 (70–86) 85 (43.6) 199 70 (61–80) 86 (43.2)
Michalski et al. (2019) [34]
211 NR (60–69) 101 (47.9)
Oh et al. (2017) 86 73 (65–86) 44 (51.2) [42]
Osterroos et al. (2020) [46]
1831 71 (60–94) 812 (44.3)
QuintasCardama et al. (2012) [47]
671 72 (65–89) 235 (35.0)
People with intermediate or adverse cytogenetics,
n (%)
143 (87.7)
Performance status, tool, n (%)
NR
728 (90.8) 199 (94.8) 114 (82.6) 119 (48.0) 199 (100) 305 (92.4) 82 (100) 143 (78.1) 149 (76.4) 157 (78.9) 180 (85.3) 82 (95.3) 1630 (89.0)
521 (77.6)
ECOG PS Level 0–1, 576 (71.8) Level 2, 131 (16.3) Unknown, 95 (11.9)
Tool NR; PS Level 0–1, 136 (64.8) Level 2–4, 44 (21.0) Unknown, 30 (14.3)
WHO PS >2, 4 (2.9) other categories NR
ECOG PS score Level 0 and 1, 85 (34.3) Level 2, 163 (65.7)
Tool NR; PS Level 0–1, 123 (61.8) Level 2–3, 49 (24.6) Unknown, 27 (13.6)
ECOG PS mean (SD), 0.88 (0.56)
ECOG PS 3 or 4, 11 (13.4)
WHO PS = < 2, 183 (100)
WHO PS > = 2, 6 (3.1)
ECOG PS Level 0, 89 (44.7) Level 1, 80 (40.2) Level 2, 30 (15.1)
55.9% patients had a KPS score of 90–100; other details NR.
ECOG PS Level 0–1, 59 (68.6) Level 2–4, 25 (29.1) Unknown, 2 (2.3)
WHO PS Level 0, 462 (25.2) Level 1, 968 (52.9) Level 2, 229 (12.5) Level 3, 76 (4.2) Level 4, 31 (1.7) Unknown, 65 (3.5)
ECOG PS Level 0–2, 635 (94.6)
Intensive antileukemic therapy arm
cytarabine-based + daunorubicin/ idarubicin cytarabine-based
Less-intensive antileukemic therapy arm
HMA
1. LDAC; 2. HMAbased
Follow-up duration, median (months)
7.7
6.7
cytarabine-based
AZA
36
+ daunorubicin/
idarubicin
cytarabine-based
mixed †
13.3
+ anthracycline
1. IA; 2. DA
CAG
27.1
cytarabine-based
AZA
40.8
cytarabine-based + anthracycline
IA
cytarabine-based + anthracycline cytarabine-based + anthracycline MICE
mixed ††
1. GO with IL; 2. GO without IL LDAC/AZA/ decitabine LDAC
AZA
NR (a minimum of 2-year follow-
up) 4.5
36
36
8.5
cytarabine-based + anthracycline
1. mixed; § 2. decitabine
cytarabine-based + daunorubicin/ idarubicin
IC, unspecified
HMA HMA
NR (reported outcomes at 1-year follow-
up) 20
60
IA
AZA or decitabine
24
(Continued )
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Table 1. (Continued)
Author (year)
Scappaticci et al. (2018) [31] Solomon et al. (2020) [48] 1 Takahashi et al. (2016) [45] Talati et al. (2020) [49]
Tasaki et al. (2014) [43] Vachhani et al. (2018) [4] van der Helm et al. (2013) [40] Yi et al. (2014) [41]
Dombret et al.�� (2015) [15] Fenaux et al.�� (2009) [29]
Sample Size
64
Median age (range, year)
71 (60–83)
Sex, female, n
(%)
NR
People with intermediate or adverse cytogenetics,
n (%)
60 (93.8)
Performance status, tool, n (%)
NR
Intensive
Less-intensive
antileukemic therapy antileukemic
arm
therapy arm
FLAG
clofarabine
Follow-up duration, median (months)
20
262 70 (60–88) 108 (41.2)
220 (84.0)
NR
FLAG
HMA
34.2
190 68 (60–85) 65 (34.2)
186 (97.9)
ECOG PS
IA
Level 0–1, 161 (84.7)
Level 2–3, 29 (15.3)
LDAC
60
+ clofarabine
706 75 (70–95) 230 (32.6)
629 (89.1)
ECOG PS
IA
Level 0–1, 593 (84.0)
Level 2–4, 99 (14.0)
Unknown, 14 (2.0)
1. HMA; 2. LDAC
20.5
41 74 (65–90) 17 (41.5)
36 (87.8)
NR
cytarabine-based
LDAC
9.5
201 71 (60–93) 67 (33.3)
181 (90.0)
NR
cytarabine-based
HMA
60
+ anthracycline
116 67 (60–81) 52 (44.8)
109 (94.0)
WHO PS score > = 2, cytarabine-based
AZA
12
52 (44.8)
168 70 (65–89) 83 (49.4)
138 (82.1)
ECOG PS
mixed §§
mixed
12
Level 0–1, 68 (40.5)
Level 2–4, 100 (59.5)
443 75 (64–91) 184 (41.5)
440 (99.3)
ECOG PS
cytarabine-based
1. AZA; 2. LDAC
24.4
Level 0–1, 345 (77.9) + daunorubicin/
Level 2, 98 (22.1)
idarubicin
86 70 (50–83) 24 (27.9)
81 (94.2)
ECOG PS
cytarabine-based
1. AZA; 2. LDAC
20.1
Level 0, 33 (38.4)
+ anthracycline
Level 1, 48 (55.8)
Level 2, 4 (4.6)
Unknown, 1 (1.2)
� Mean (standard deviation) age. �� Randomized controlled trials. † LDAC(39 patients), AZA (16 patients), decitabine (11 patients), tipifarnib (3 patients), or all-trans retinoic acid (ATRA) (1 patient). †† Hypomethylating agents, low-dose cytarabine, or single-agent therapy. Single agents included: SNS595 (a topoisomerase II inhibitor), heat-shock protein 90 (HSP90)
inhibitor, panobinostat (a histone deacetylase inhibitor), cloretazine, lenalidomide, NEDD-8 activating enzyme inhibitor, sorafenib, PKC-412 inhibitor, and bortezomib. § Five days of decitabine, 5- or 7-day AZA or low-dose cytarabine. §§ Anthracycline, high dose cytarabine and fludarabine. Low dose cytarabine, hypomethylating agent, arsenic trioxide and all-trans retinoic acid (ATRA). NR, not reported; PS, performance status; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; HMA, hypomethylating agent; LDAC, low-dose cytarabine; AZA, azacitidine; IA, standard-dose cytarabine plus idarubicin; DA, standard-dose cytarabine plus daunorubicin; CAG, cytarabine, aclarubicin,
and granulocyte colony-stimulating factor; GO, gemtuzumab ozogamicin; IL, interleukin-11; MICE, mitoxantrone, idarubicin, cytarabine, and etoposide; FLAG,
fludarabine, cytarabine, and granulocyte colony-stimulating factor; IC, intensive chemotherapy.
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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
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Fig 2. Risk of bias in observational studies.
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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.
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.
Fig 3. Risk of bias in RCTs. RCT, randomized controlled trial. https://doi.org/10.1371/journal.pone.0249087.g003
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Table 2. GRADE summary of findings: Intensive versus less-intensive antileukemic therapy among older patients with acute myeloid leukemia, evidence from observational studies.
Outcomes
Mortality
Mortality at 30 days
Mortality at 1 year
Allogeneic hematopoietic stem cell transplantation (AlloHCT/ AlloSCT) Serious treatment-emergent adverse events (TEAEs)
Febrile neutropenia (specific TEAE)
Anemia (specific TEAE)
Neutropenia (specific TEAE)
Thrombocytopenia (specific TEAE)
Pneumonia (specific TEAE)
Relative effects and source of evidence
HR 0.87 (95%CI 0.76 to 0.99) Based on data from 5365 patients in 16 observational studies
RR 1.23 (95%CI 0.79 to 1.92) Based on data from 5345 patients in 16 observational studies
RR 0.93 (95%CI 0.85 to 1.02) Based on data from 5724 patients in 18 observational studies
RR 6.14 (95%CI 4.03 to 9.35) Based on data from 1490 patients in 9 observational studies
RR 1.34 (95%CI 1.03 to 1.75) Based on data from 190 patients in 1 observational study
RR 1.04 (95%CI 0.93 to 1.15) Based on data from 495 patients in 2 observational studies
RR 0.75 (95%CI 0.35 to 1.63) Based on data from 431 patients in 1 observational study
RR 1.30 (95%CI 0.82 to 2.07) Based on data from 431 patients in 1 observational study
RR 0.86 (95%CI 0.47 to 1.56) Based on data from 431 patients in 1 observational study
RR 0.25 (95%CI 0.06 to 0.98) Based on data from 431 patients in 1 observational study
Absolute effect estimates
Baseline risk for control group (per 1000)
5871
Difference (95% CI) (per 1000)
-50 (-98 to -4)
Certainty of evidence
LL Low �� (Very serious risk of bias)2
Plain languages summary
Intensive antileukemic therapy may reduce mortality.
723 16 (-15 to 66) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious inconsistency)4
reducing mortality.
5873 -41 (-88 to 12) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
reducing mortality.
353 182 (107 to 295) LLL� Moderate Intensive antileukemic therapy likely
(Very serious risk of bias increases AlloHCT/AlloSCT. but strong association)6
4633 157 (14 to 347) Low LL�� Intensive antileukemic therapy may
(Very serious risk of bias)2
increase TEAEs.
3373 13 (-24 to 51) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
febrile neutropenia.
1853 -46 (-120 to 117) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
anemia.
2573 -77 (-46 to 275) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
neutropenia.
2523 -35 (-134 to 141) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
thrombocytopenia.
1903 -143 (-179 to -4) Low LL�� Intensive antileukemic therapy may
(Very serious risk of bias)2
reduce TEAEs.
(Continued )
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RESEARCH ARTICLE
Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: A systematic review
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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
Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0249087
Copyright: 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 Statement: All relevant data are within the manuscript and its Supporting information files.
Yaping ChangID1, Gordon H. Guyatt1, Trevor Teich2, Jamie L. Dawdy3, Shaneela Shahid1,4, Jessica K. Altman5, Richard M. Stone6, Mikkael A. Sekeres7, Sudipto Mukherjee7, Thomas W. LeBlanc8, Gregory A. Abel9, Christopher S. Hourigan10, Mark R. Litzow11, Laura C. Michaelis12, Shabbir M. H. Alibhai13, Pinkal Desai14, Rena Buckstein15, Janet MacEachern16, Romina Brignardello-Petersen1*
1 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada, 2 Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America, 3 School of Nursing, McMaster University, Hamilton, Ontario, Canada, 4 Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada, 5 Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America, 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 7 Leukemia Program, Cleveland Clinic, Cleveland, Ohio, United States of America, 8 Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America, 9 Division of Hematologic Malignances and Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 10 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 11 Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States of America, 12 Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America, 13 Department of Medicine, University Health Network & University of Toronto, Toronto, Ontario, Canada, 14 Weill Cornell Medicine, New York City, New York, United States of America, 15 Odette Cancer Centre, Division of Medical Oncology and Hematology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, 16 Grand River Regional Cancer Centre, Kitchener, Ontario, Canada
* [email protected]
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 metaanalyses 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 agentbased 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–
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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.
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.
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 lessintensive 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
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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 5or 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 lessintensive 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,
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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 randomeffects 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
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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
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Fig 1. Eligibility assessment PRISMA flow diagram.
https://doi.org/10.1371/journal.pone.0249087.g001
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).
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Table 1. Characteristics of included studies.
Author (year)
Sample Size
Median age (range, year)
Sex, female, n
(%)
Almeida et al. (2017) [32]
163 63 (20–88) 49 (30.1)
Boddu et al. (2017) [30]
802 68 (60–75) NR
Bories et al. (2014) [39]
210 72 (60–89) 77 (36.7)
Cannas et al. (2015) [38]
Chen et al. (2016) [44]
138 74 (70–86) 62 (44.9) 248 67 (60–87) 111 (44.8)
Dumas et al. (2017) [37]
199 72 (61–88) 82 (41.2)
El-Jawahri et al. 330 (2015) [33]
70 (7)� 135 (40.9)
Estey et al. (2002) [14]
Fattoum et al. (2015) [36]
Heiblig et al. (2017) [35]
Maurillo et al. (2018) [12]
82 72 (65–89) NR 183 74 (70–86) 79 (43.2) 195 74 (70–86) 85 (43.6) 199 70 (61–80) 86 (43.2)
Michalski et al. (2019) [34]
211 NR (60–69) 101 (47.9)
Oh et al. (2017) 86 73 (65–86) 44 (51.2) [42]
Osterroos et al. (2020) [46]
1831 71 (60–94) 812 (44.3)
QuintasCardama et al. (2012) [47]
671 72 (65–89) 235 (35.0)
People with intermediate or adverse cytogenetics,
n (%)
143 (87.7)
Performance status, tool, n (%)
NR
728 (90.8) 199 (94.8) 114 (82.6) 119 (48.0) 199 (100) 305 (92.4) 82 (100) 143 (78.1) 149 (76.4) 157 (78.9) 180 (85.3) 82 (95.3) 1630 (89.0)
521 (77.6)
ECOG PS Level 0–1, 576 (71.8) Level 2, 131 (16.3) Unknown, 95 (11.9)
Tool NR; PS Level 0–1, 136 (64.8) Level 2–4, 44 (21.0) Unknown, 30 (14.3)
WHO PS >2, 4 (2.9) other categories NR
ECOG PS score Level 0 and 1, 85 (34.3) Level 2, 163 (65.7)
Tool NR; PS Level 0–1, 123 (61.8) Level 2–3, 49 (24.6) Unknown, 27 (13.6)
ECOG PS mean (SD), 0.88 (0.56)
ECOG PS 3 or 4, 11 (13.4)
WHO PS = < 2, 183 (100)
WHO PS > = 2, 6 (3.1)
ECOG PS Level 0, 89 (44.7) Level 1, 80 (40.2) Level 2, 30 (15.1)
55.9% patients had a KPS score of 90–100; other details NR.
ECOG PS Level 0–1, 59 (68.6) Level 2–4, 25 (29.1) Unknown, 2 (2.3)
WHO PS Level 0, 462 (25.2) Level 1, 968 (52.9) Level 2, 229 (12.5) Level 3, 76 (4.2) Level 4, 31 (1.7) Unknown, 65 (3.5)
ECOG PS Level 0–2, 635 (94.6)
Intensive antileukemic therapy arm
cytarabine-based + daunorubicin/ idarubicin cytarabine-based
Less-intensive antileukemic therapy arm
HMA
1. LDAC; 2. HMAbased
Follow-up duration, median (months)
7.7
6.7
cytarabine-based
AZA
36
+ daunorubicin/
idarubicin
cytarabine-based
mixed †
13.3
+ anthracycline
1. IA; 2. DA
CAG
27.1
cytarabine-based
AZA
40.8
cytarabine-based + anthracycline
IA
cytarabine-based + anthracycline cytarabine-based + anthracycline MICE
mixed ††
1. GO with IL; 2. GO without IL LDAC/AZA/ decitabine LDAC
AZA
NR (a minimum of 2-year follow-
up) 4.5
36
36
8.5
cytarabine-based + anthracycline
1. mixed; § 2. decitabine
cytarabine-based + daunorubicin/ idarubicin
IC, unspecified
HMA HMA
NR (reported outcomes at 1-year follow-
up) 20
60
IA
AZA or decitabine
24
(Continued )
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Table 1. (Continued)
Author (year)
Scappaticci et al. (2018) [31] Solomon et al. (2020) [48] 1 Takahashi et al. (2016) [45] Talati et al. (2020) [49]
Tasaki et al. (2014) [43] Vachhani et al. (2018) [4] van der Helm et al. (2013) [40] Yi et al. (2014) [41]
Dombret et al.�� (2015) [15] Fenaux et al.�� (2009) [29]
Sample Size
64
Median age (range, year)
71 (60–83)
Sex, female, n
(%)
NR
People with intermediate or adverse cytogenetics,
n (%)
60 (93.8)
Performance status, tool, n (%)
NR
Intensive
Less-intensive
antileukemic therapy antileukemic
arm
therapy arm
FLAG
clofarabine
Follow-up duration, median (months)
20
262 70 (60–88) 108 (41.2)
220 (84.0)
NR
FLAG
HMA
34.2
190 68 (60–85) 65 (34.2)
186 (97.9)
ECOG PS
IA
Level 0–1, 161 (84.7)
Level 2–3, 29 (15.3)
LDAC
60
+ clofarabine
706 75 (70–95) 230 (32.6)
629 (89.1)
ECOG PS
IA
Level 0–1, 593 (84.0)
Level 2–4, 99 (14.0)
Unknown, 14 (2.0)
1. HMA; 2. LDAC
20.5
41 74 (65–90) 17 (41.5)
36 (87.8)
NR
cytarabine-based
LDAC
9.5
201 71 (60–93) 67 (33.3)
181 (90.0)
NR
cytarabine-based
HMA
60
+ anthracycline
116 67 (60–81) 52 (44.8)
109 (94.0)
WHO PS score > = 2, cytarabine-based
AZA
12
52 (44.8)
168 70 (65–89) 83 (49.4)
138 (82.1)
ECOG PS
mixed §§
mixed
12
Level 0–1, 68 (40.5)
Level 2–4, 100 (59.5)
443 75 (64–91) 184 (41.5)
440 (99.3)
ECOG PS
cytarabine-based
1. AZA; 2. LDAC
24.4
Level 0–1, 345 (77.9) + daunorubicin/
Level 2, 98 (22.1)
idarubicin
86 70 (50–83) 24 (27.9)
81 (94.2)
ECOG PS
cytarabine-based
1. AZA; 2. LDAC
20.1
Level 0, 33 (38.4)
+ anthracycline
Level 1, 48 (55.8)
Level 2, 4 (4.6)
Unknown, 1 (1.2)
� Mean (standard deviation) age. �� Randomized controlled trials. † LDAC(39 patients), AZA (16 patients), decitabine (11 patients), tipifarnib (3 patients), or all-trans retinoic acid (ATRA) (1 patient). †† Hypomethylating agents, low-dose cytarabine, or single-agent therapy. Single agents included: SNS595 (a topoisomerase II inhibitor), heat-shock protein 90 (HSP90)
inhibitor, panobinostat (a histone deacetylase inhibitor), cloretazine, lenalidomide, NEDD-8 activating enzyme inhibitor, sorafenib, PKC-412 inhibitor, and bortezomib. § Five days of decitabine, 5- or 7-day AZA or low-dose cytarabine. §§ Anthracycline, high dose cytarabine and fludarabine. Low dose cytarabine, hypomethylating agent, arsenic trioxide and all-trans retinoic acid (ATRA). NR, not reported; PS, performance status; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; HMA, hypomethylating agent; LDAC, low-dose cytarabine; AZA, azacitidine; IA, standard-dose cytarabine plus idarubicin; DA, standard-dose cytarabine plus daunorubicin; CAG, cytarabine, aclarubicin,
and granulocyte colony-stimulating factor; GO, gemtuzumab ozogamicin; IL, interleukin-11; MICE, mitoxantrone, idarubicin, cytarabine, and etoposide; FLAG,
fludarabine, cytarabine, and granulocyte colony-stimulating factor; IC, intensive chemotherapy.
https://doi.org/10.1371/journal.pone.0249087.t001
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
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Antileukemic therapy for AML in older adults
Fig 2. Risk of bias in observational studies.
https://doi.org/10.1371/journal.pone.0249087.g002
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.
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.
Fig 3. Risk of bias in RCTs. RCT, randomized controlled trial. https://doi.org/10.1371/journal.pone.0249087.g003
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Antileukemic therapy for AML in older adults
Table 2. GRADE summary of findings: Intensive versus less-intensive antileukemic therapy among older patients with acute myeloid leukemia, evidence from observational studies.
Outcomes
Mortality
Mortality at 30 days
Mortality at 1 year
Allogeneic hematopoietic stem cell transplantation (AlloHCT/ AlloSCT) Serious treatment-emergent adverse events (TEAEs)
Febrile neutropenia (specific TEAE)
Anemia (specific TEAE)
Neutropenia (specific TEAE)
Thrombocytopenia (specific TEAE)
Pneumonia (specific TEAE)
Relative effects and source of evidence
HR 0.87 (95%CI 0.76 to 0.99) Based on data from 5365 patients in 16 observational studies
RR 1.23 (95%CI 0.79 to 1.92) Based on data from 5345 patients in 16 observational studies
RR 0.93 (95%CI 0.85 to 1.02) Based on data from 5724 patients in 18 observational studies
RR 6.14 (95%CI 4.03 to 9.35) Based on data from 1490 patients in 9 observational studies
RR 1.34 (95%CI 1.03 to 1.75) Based on data from 190 patients in 1 observational study
RR 1.04 (95%CI 0.93 to 1.15) Based on data from 495 patients in 2 observational studies
RR 0.75 (95%CI 0.35 to 1.63) Based on data from 431 patients in 1 observational study
RR 1.30 (95%CI 0.82 to 2.07) Based on data from 431 patients in 1 observational study
RR 0.86 (95%CI 0.47 to 1.56) Based on data from 431 patients in 1 observational study
RR 0.25 (95%CI 0.06 to 0.98) Based on data from 431 patients in 1 observational study
Absolute effect estimates
Baseline risk for control group (per 1000)
5871
Difference (95% CI) (per 1000)
-50 (-98 to -4)
Certainty of evidence
LL Low �� (Very serious risk of bias)2
Plain languages summary
Intensive antileukemic therapy may reduce mortality.
723 16 (-15 to 66) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious inconsistency)4
reducing mortality.
5873 -41 (-88 to 12) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
reducing mortality.
353 182 (107 to 295) LLL� Moderate Intensive antileukemic therapy likely
(Very serious risk of bias increases AlloHCT/AlloSCT. but strong association)6
4633 157 (14 to 347) Low LL�� Intensive antileukemic therapy may
(Very serious risk of bias)2
increase TEAEs.
3373 13 (-24 to 51) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
febrile neutropenia.
1853 -46 (-120 to 117) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
anemia.
2573 -77 (-46 to 275) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
neutropenia.
2523 -35 (-134 to 141) Very low L��� We are very uncertain of the effect of
(Very serious risk of bias intensive antileukemic therapy on
and serious imprecision)5
thrombocytopenia.
1903 -143 (-179 to -4) Low LL�� Intensive antileukemic therapy may
(Very serious risk of bias)2
reduce TEAEs.
(Continued )
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