Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: A systematic review.

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.

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.

Fig 1

Eligibility assessment PRISMA flow diagram.

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.

Table 1

Characteristics of included studies.

Author (year)	Sample Size	Median age (range, year)	Sex, female, n (%)	People with intermediate or adverse cytogenetics, n (%)	Performance status, tool, n (%)	Intensive antileukemic therapy arm	Less-intensive antileukemic therapy arm	Follow-up duration, median (months)
Almeida et al. (2017) [32]	163	63 (20–88)	49 (30.1)	143 (87.7)	NR	cytarabine-based + daunorubicin/idarubicin	HMA	7.7
Boddu et al. (2017) [30]	802	68 (60–75)	NR	728 (90.8)	ECOG PSLevel 0–1, 576 (71.8)Level 2, 131 (16.3)Unknown, 95 (11.9)	cytarabine-based	1. LDAC; 2. HMA-based	6.7
Bories et al. (2014) [39]	210	72 (60–89)	77 (36.7)	199 (94.8)	Tool NR; PS Level 0–1, 136 (64.8)Level 2–4, 44 (21.0)Unknown, 30 (14.3)	cytarabine-based + daunorubicin/idarubicin	AZA	36
Cannas et al. (2015) [38]	138	74 (70–86)	62 (44.9)	114 (82.6)	WHO PS >2, 4 (2.9)other categories NR	cytarabine-based + anthracycline	mixed †	13.3
Chen et al. (2016) [44]	248	67 (60–87)	111 (44.8)	119 (48.0)	ECOG PS scoreLevel 0 and 1, 85 (34.3)Level 2, 163 (65.7)	1. IA; 2. DA	CAG	27.1
Dumas et al. (2017) [37]	199	72 (61–88)	82 (41.2)	199 (100)	Tool NR; PS Level 0–1, 123 (61.8)Level 2–3, 49 (24.6)Unknown, 27 (13.6)	cytarabine-based	AZA	40.8
El-Jawahri et al. (2015) [33]	330	70 (7)*	135 (40.9)	305 (92.4)	ECOG PS mean (SD), 0.88 (0.56)	cytarabine-based + anthracycline	mixed ††	NR (a minimum of 2-year follow-up)
Estey et al. (2002) [14]	82	72 (65–89)	NR	82 (100)	ECOG PS 3 or 4, 11 (13.4)	IA	1. GO with IL; 2. GO without IL	4.5
Fattoum et al. (2015) [36]	183	74 (70–86)	79 (43.2)	143 (78.1)	WHO PS = < 2, 183 (100)	cytarabine-based + anthracycline	LDAC/AZA/decitabine	36
Heiblig et al. (2017) [35]	195	74 (70–86)	85 (43.6)	149 (76.4)	WHO PS > = 2, 6 (3.1)	cytarabine-based + anthracycline	LDAC	36
Maurillo et al. (2018) [12]	199	70 (61–80)	86 (43.2)	157 (78.9)	ECOG PSLevel 0, 89 (44.7)Level 1, 80 (40.2)Level 2, 30 (15.1)	MICE	AZA	8.5
Michalski et al. (2019) [34]	211	NR (60–69)	101 (47.9)	180 (85.3)	55.9% patients had a KPS score of 90–100; other details NR.	cytarabine-based + anthracycline	1. mixed; § 2. decitabine	NR (reported outcomes at 1-year follow-up)
Oh et al. (2017) [42]	86	73 (65–86)	44 (51.2)	82 (95.3)	ECOG PSLevel 0–1, 59 (68.6)Level 2–4, 25 (29.1)Unknown, 2 (2.3)	cytarabine-based + daunorubicin/idarubicin	HMA	20
Osterroos et al. (2020) [46]	1831	71 (60–94)	812 (44.3)	1630 (89.0)	WHO PSLevel 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)	IC, unspecified	HMA	60
Quintas-Cardama et al. (2012) [47]	671	72 (65–89)	235 (35.0)	521 (77.6)	ECOG PSLevel 0–2, 635 (94.6)	IA	AZA or decitabine	24
Scappaticci et al. (2018) [31]	64	71 (60–83)	NR	60 (93.8)	NR	FLAG	clofarabine	20
Solomon et al. (2020) [48]	262	70 (60–88)	108 (41.2)	220 (84.0)	NR	FLAG	HMA	34.2
1Takahashi et al. (2016) [45]	190	68 (60–85)	65 (34.2)	186 (97.9)	ECOG PSLevel 0–1, 161 (84.7)Level 2–3, 29 (15.3)	IA	LDAC + clofarabine	60
Talati et al. (2020) [49]	706	75 (70–95)	230 (32.6)	629 (89.1)	ECOG PSLevel 0–1, 593 (84.0)Level 2–4, 99 (14.0)Unknown, 14 (2.0)	IA	1. HMA; 2. LDAC	20.5
Tasaki et al. (2014) [43]	41	74 (65–90)	17 (41.5)	36 (87.8)	NR	cytarabine-based	LDAC	9.5
Vachhani et al. (2018) [4]	201	71 (60–93)	67 (33.3)	181 (90.0)	NR	cytarabine-based + anthracycline	HMA	60
van der Helm et al. (2013) [40]	116	67 (60–81)	52 (44.8)	109 (94.0)	WHO PS score > = 2, 52 (44.8)	cytarabine-based	AZA	12
Yi et al. (2014) [41]	168	70 (65–89)	83 (49.4)	138 (82.1)	ECOG PSLevel 0–1, 68 (40.5)Level 2–4, 100 (59.5)	mixed §§	mixed¶	12
Dombret et al.** (2015) [15]	443	75 (64–91)	184 (41.5)	440 (99.3)	ECOG PSLevel 0–1, 345 (77.9)Level 2, 98 (22.1)	cytarabine-based + daunorubicin/idarubicin	1. AZA; 2. LDAC	24.4
Fenaux et al.** (2009) [29]	86	70 (50–83)	24 (27.9)	81 (94.2)	ECOG PSLevel 0, 33 (38.4)Level 1, 48 (55.8)Level 2, 4 (4.6)Unknown, 1 (1.2)	cytarabine-based + anthracycline	1. AZA; 2. LDAC	20.1

* 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.

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).

Fig 2

Risk of bias in observational studies.

Fig 3

Risk of bias in RCTs.

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).

Table 2

GRADE summary of findings: Intensive versus less-intensive antileukemic therapy among older patients with acute myeloid leukemia, evidence from observational studies.

Outcomes	Relative effects and source of evidence	Absolute effect estimates		Certainty of evidence	Plain languages summary
		Baseline risk for control group (per 1000)	Difference (95% CI) (per 1000)
Mortality	HR 0.87 (95%CI 0.76 to 0.99)Based on data from 5365 patients in 16 observational studies	5871	-50 (-98 to -4)	Low ⨁⨁◯◯(Very serious risk of bias)2	Intensive antileukemic therapy may reduce mortality.
Mortality at 30 days	RR 1.23 (95%CI 0.79 to 1.92)Based on data from 5345 patients in 16 observational studies	723	16 (-15 to 66)	Very low ⨁◯◯◯(Very serious risk of bias and serious inconsistency)4	We are very uncertain of the effect of intensive antileukemic therapy on reducing mortality.
Mortality at 1 year	RR 0.93 (95%CI 0.85 to 1.02)Based on data from 5724 patients in 18 observational studies	5873	-41 (-88 to 12)	Very low ⨁◯◯◯(Very serious risk of bias and serious imprecision)5	We are very uncertain of the effect of intensive antileukemic therapy on reducing mortality.
Allogeneic hematopoietic stem cell transplantation (AlloHCT/AlloSCT)	RR 6.14 (95%CI 4.03 to 9.35)Based on data from 1490 patients in 9 observational studies	353	182 (107 to 295)	⨁⨁⨁◯ Moderate(Very serious risk of bias but strong association)6	Intensive antileukemic therapy likely increases AlloHCT/AlloSCT.
Serious treatment-emergent adverse events (TEAEs)	RR 1.34 (95%CI 1.03 to 1.75)Based on data from 190 patients in 1 observational study	4633	157 (14 to 347)	Low ⨁⨁◯◯(Very serious risk of bias)2	Intensive antileukemic therapy may increase TEAEs.
Febrile neutropenia (specific TEAE)	RR 1.04 (95%CI 0.93 to 1.15)Based on data from 495 patients in 2 observational studies	3373	13 (-24 to 51)	Very low ⨁◯◯◯(Very serious risk of bias and serious imprecision)5	We are very uncertain of the effect of intensive antileukemic therapy on febrile neutropenia.
Anemia (specific TEAE)	RR 0.75 (95%CI 0.35 to 1.63)Based on data from 431 patients in 1 observational study	1853	-46 (-120 to 117)	Very low ⨁◯◯◯(Very serious risk of bias and serious imprecision)5	We are very uncertain of the effect of intensive antileukemic therapy on anemia.
Neutropenia (specific TEAE)	RR 1.30 (95%CI 0.82 to 2.07)Based on data from 431 patients in 1 observational study	2573	-77 (-46 to 275)	Very low ⨁◯◯◯(Very serious risk of bias and serious imprecision)5	We are very uncertain of the effect of intensive antileukemic therapy on neutropenia.
Thrombocytopenia (specific TEAE)	RR 0.86 (95%CI 0.47 to 1.56)Based on data from 431 patients in 1 observational study	2523	-35 (-134 to 141)	Very low ⨁◯◯◯(Very serious risk of bias and serious imprecision)5	We are very uncertain of the effect of intensive antileukemic therapy on thrombocytopenia.
Pneumonia (specific TEAE)	RR 0.25 (95%CI 0.06 to 0.98)Based on data from 431 patients in 1 observational study	1903	-143 (-179 to -4)	Low ⨁⨁◯◯(Very serious risk of bias)2	Intensive antileukemic therapy may reduce TEAEs.
ICU admission	RR 1.61 (95%CI 0.43 to 6.06)Based on data from 394 patients in 2 observational studies	1763	107 (-100 to 889)	Low ⨁⨁◯◯(Very serious risk of bias)2	Intensive antileukemic therapy may increase ICU admission.

CI, confidence interval; HR, hazard ratio; RR, risk ratio.

1We used event rate from 1-year mortality of the less-intensive therapy (from observational study).

2Observational studies started at high certainty in the evidence as we used ROBINS-I for assessing risk of bias in individual studies. We have rated down two levels for risk of bias.

3We used event rate from the less-intensive therapy to serve as baseline risk.

4Observational studies started at high certainty in the evidence as we used ROBINS-I for assessing risk of bias in individual studies. We have rated down two levels for risk of bias. In addition, we rated down for inconsistency (CIs of several studies show minimal or no overlap; I2 = 68%).

5Observational studies started at high certainty in the evidence as we used ROBINS-I for assessing risk of bias in individual studies. We have rated down three levels for risk of bias. In addition, we rated down for imprecision (wide confidence interval includes no difference).

6Observational studies started at high certainty in the evidence as we used ROBINS-I for assessing risk of bias in individual studies. We have rated down two levels for risk of bias. The large magnitude of effect (strong association) increased certainty in the evidence.

Table 3

GRADE summary of findings: Intensive versus less-intensive antileukemic therapy among older patients with acute myeloid leukemia, evidence from RCTs.

Outcomes	Relative effects and source of evidence	Absolute effect estimates		Certainty of evidence	Plain languages summary
		Baseline risk for control group (per 1000)	Difference (95% CI) (per 1000)
Mortality at 1 year	RR 0.90 (95%CI 0.60 to 1.33)Based on data from 87 patients in 1 RCT	5581	-56 (-223 to 184)	Low ⨁⨁◯◯(Very serious imprecision)2	Intensive antileukemic therapy may reduce mortality.
Anemia (specific TEAE)	RR 0.60 (95%CI 0.28 to 1.31)Based on data from 81 patients in 1 RCT	6201	-248 (-446 to 192)	Very low ⨁◯◯◯(Serious risk of bias and very serious imprecision)3	We are very uncertain of the effect of intensive antileukemic therapy on anemia.
Neutropenia (specific TEAE)	RR 0.96 (95%CI 0.77 to 1.20)Based on data from 81 patients in 1 RCT	9301	-37 (-214 to 186)	Very low ⨁◯◯◯(Serious risk of bias and very serious imprecision)3	We are very uncertain of the effect of intensive antileukemic therapy on neutropenia.
Thrombocytopenia (specific TEAE)	RR 0.94 (95%CI 0.71 to 1.24)Based on data from 81 patients in 1 RCT	9301	-56 (-270 to 223)	Very low ⨁◯◯◯(Serious risk of bias and very serious imprecision)3	We are very uncertain of the effect of intensive antileukemic therapy on thrombocytopenia.

CI, confidence interval; RR, risk ratio; TEAE, treatment-emergent adverse event.

1We used event rate from the less-intensive therapy to serve as baseline risk.

2We rated down two levels for imprecision (very wide confidence interval includes important benefit and harm).

3We rated down three levels: one for risk of bias (high risk of bias for random sequence generation and allocation concealment), two for imprecision (very wide confidence interval includes important benefit and harm).

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.

Fig 4

All-cause mortality assessed with risk of death (all from observational studies).

Intensive, intensive antileukemic therapy; Less-intensive, less-intensive antileukemic therapy; df, degree of freedom; SE, standard error; IV, inverse variance.

Fig 5

Funnel plot to detect publication 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.

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.

D. Quality of life (QOL) and functional outcomes

Eligible studies did not report pre-specified outcomes of quality of life impairment, functional status impairment and burden on caregivers.

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.

(DOCX)

Click here for additional data file.

MEDLINE search strategy.

MEDLINE search strategy for intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia.

(DOCX)

Click here for additional data 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.

(DOCX)

Click here for additional data file.

15 Jan 2021

PONE-D-20-39802

Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: a systematic review

PLOS ONE

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Reviewer #1: The authors present a comprehensive meta-analysis of studies collected through literature in Medline, Embase and CENTRAL to compare the safety and effectiveness of intensive and less-intensive antileukemic therapies in acute myeloid leukemia. The information of the studies and the statistical approaches are extremely well described along the methods and manuscript. The study contains useful information for the readers and the clinical community. In the future it would be great to have a similar analysis accounting for the genetic background of the patients and how it might impact the response to therapies.

I consider this manuscript relevant for clinicians and an excellent guide for the readers. I have no comments.

Reviewer #2: Peer review comments:

Thank you for letting me peer-review this paper. I am a systematic reviewer and have done a couple of reviews on AML therapy, so can appreciate the amount of work that has gone into this review, particularly as the majority of studies are observational.

Overall it is a very well conducted review, using appropriate standard systematic review methods. The writing is clear, however, I think you need to emphasise more strongly the fact that there were only 2 small RCTs and the majority of the results came from observational studies. This is likely to have introduced selection bias particularly as within this disease and within the age groups under study, treatment is often determined by fitness to receive intensive chemotherapy.

Abstract

Reads well, BUT A MAJOR REVISION SHOULD TAKE PLACE REGARDING MORE EMPHASIS ON THE FACT THAT ALL BUT TWO STUDIES ARE OBSERVATIONAL AND THEREFORE THERE WILL BE INHERENT SELECTION BIAS WITHIN THE STUDIES THAT COULD AFFECT THE RESULTS IN FAVOUR OF THE INTENSIVE THERAPY AND THEREFORE THE RESULTS SHOULD BE VIEWED WITH APPROPRIATE CAUTION.

Introduction

A minor comment for the introduction is that you could introduce the origins of the review in that it was undertaken as part of an ASH guideline development, this would then relate to paragraph which talks about it in the discussion. It is always good to see systematic reviews borne from guidelines being published.

Methods

The methods look standard and appear to have been well conducted.

Results

Major comment - there isn’t a separate section for reporting the risk of bias assessment.

It is obvious a lot of work has gone into the risk of bias assessment and I think it is key to understanding the context of the review results. Whether a separate section is inserted or more detail is given within the reporting of the outcome results is a matter for you, but at the moment comments at the bottom of these sections are too vague – saying there is a ‘serious risk of bias’ or ‘series imprecision’ is not telling the reader what the problem is, and the bias could be different depending upon the outcome - especially so with the Robins tool. Many readers, who will hopefully use this in clinical practice, may well be unfamiliar with biases in observational studies and will be unlikely to be able to interpret the Robins tool, so maybe a separate section on the biases might be better. You really need to highlight the main bias at play – looks like its confounding in most of the observational studies – and explain why you are concerned and how this affects the interpretation of the results i.e. cautiously.

Results – minor comment – it would have been helpful if you had put the age ranges as well as the mean age in this table, especially given the review focus is on age.

Results – minor comment – you looked for ongoing trials, did you find any, if so maybe comment on them in the discussion where you talk about future research.

Discussion

The points within Paragraph 2 in the discussion needs more emphasis and the second from last paragraph in the discussion – or something similar - should be in the abstract: ‘The quality 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 the review’.

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Reviewer #2: Yes: Jayne Wilson

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23 Feb 2021

Dear Dr. Bertolini and reviewers,

Thank you for taking the time to review our manuscript, and for the positive reviews. Please see below our responses (in red) for the peer review comments regarding our manuscript ID PONE-D-20-39802, “Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: a systematic review”. Any changes in the manuscript are tracked. Changes including the additional references were highlighted within the document.

Please let us know if anything requires further clarification.

Sincerely,

Yaping Chang and Romina Brignardello-Petersen

On behalf of the authors

Journal Requirements:

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We adjusted the format in manuscript and file names according to PLOS ONE’s style requirements.

2. We noticed you have some minor occurrence of overlapping text with the following previous publication by some of the authors of the present study, which needs to be addressed:

- https://ashpublications.org/bloodadvances/article/4/15/3528/461693/American-Society-of-Hematology-2020-guidelines-for

OPTIONAL: The text that needs to be addressed is throughout the discussion.

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section.

We revised the sections and sentences throughout the manuscript, especially in Discussion, to avoid any overlapping text with a previous publication Sekeres et al., 2020. We have also cited the manuscript to make it clear that these clinical considerations come from that work.

3. We note that your review includes a meta-analysis; please describes any analyses conducted for the assessment of bias across publications using graphical and statistical methods (e.g. funnel plot, Begg/Egger test), or explain the reasons for not doing so.

We added a sentence in the methods section describing when we used funnel plots between Lines 365-366 on Page 10.

“We used funnel plots to address publication bias whenever there were 10 or more studies in a meta-analysis.”

We also added a funnel plot to detect publication bias for the outcome of the risk of death as Fig 5 and sentences between Lines 595-596 on Page 22.

“We did not detect publication bias for the risk of death over time and presented the funnel plot in Fig 5.”

4. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

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'The authors received no specific funding for this work.'

b. Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

We have removed any funding information in the manuscript.

We would like to update our funding statement as follows “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”.

5. PLOS requires an ORCID ID for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager.

We added the ORCID ID for the corresponding author Editorial Manager.

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We added the sentence in Results between Lines 551-554 on Page 18.

“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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We added the Supporting Information on Page 42, revised their in-text citations and uploaded the files accordingly.

Reviewer comments:

Reviewer #1: The authors present a comprehensive meta-analysis of studies collected through literature in Medline, Embase and CENTRAL to compare the safety and effectiveness of intensive and less-intensive antileukemic therapies in acute myeloid leukemia. The information of the studies and the statistical approaches are extremely well described along the methods and manuscript. The study contains useful information for the readers and the clinical community. In the future it would be great to have a similar analysis accounting for the genetic background of the patients and how it might impact the response to therapies.

I consider this manuscript relevant for clinicians and an excellent guide for the readers. I have no comments.

Thank you for your comments.

Reviewer #2: Peer review comments:

Thank you for letting me peer-review this paper. I am a systematic reviewer and have done a couple of reviews on AML therapy, so can appreciate the amount of work that has gone into this review, particularly as the majority of studies are observational.

Overall it is a very well conducted review, using appropriate standard systematic review methods. The writing is clear, however, I think you need to emphasise more strongly the fact that there were only 2 small RCTs and the majority of the results came from observational studies. This is likely to have introduced selection bias particularly as within this disease and within the age groups under study, treatment is often determined by fitness to receive intensive chemotherapy.

Abstract

Reads well, BUT A MAJOR REVISION SHOULD TAKE PLACE REGARDING MORE EMPHASIS ON THE FACT THAT ALL BUT TWO STUDIES ARE OBSERVATIONAL AND THEREFORE THERE WILL BE INHERENT SELECTION BIAS WITHIN THE STUDIES THAT COULD AFFECT THE RESULTS IN FAVOUR OF THE INTENSIVE THERAPY AND THEREFORE THE RESULTS SHOULD BE VIEWED WITH APPROPRIATE CAUTION.

We believe our assessment of certainty of the evidence assessment deals with the problem of study design and potential biases. We agree, however, that this was not explicit for readers, and so we have made this clearer in the discussion. We added a sentence in Abstract between Lines 159-162 on Page 3.

“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

A minor comment for the introduction is that you could introduce the origins of the review in that it was undertaken as part of an ASH guideline development, this would then relate to paragraph which talks about it in the discussion. It is always good to see systematic reviews borne from guidelines being published.

We added sentences between Lines 230-232 on Page 5.

“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].”

Methods

The methods look standard and appear to have been well conducted.

Thank you for your comment.

Results

Major comment - there isn’t a separate section for reporting the risk of bias assessment.

It is obvious a lot of work has gone into the risk of bias assessment and I think it is key to understanding the context of the review results. Whether a separate section is inserted or more detail is given within the reporting of the outcome results is a matter for you, but at the moment comments at the bottom of these sections are too vague – saying there is a ‘serious risk of bias’ or ‘series imprecision’ is not telling the reader what the problem is, and the bias could be different depending upon the outcome - especially so with the Robins tool. Many readers, who will hopefully use this in clinical practice, may well be unfamiliar with biases in observational studies and will be unlikely to be able to interpret the Robins tool, so maybe a separate section on the biases might be better. You really need to highlight the main bias at play – looks like its confounding in most of the observational studies – and explain why you are concerned and how this affects the interpretation of the results i.e. cautiously.

We added contents in Materials and methods between Lines 318-326 on Page 9.

“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].”

We added a separate section in Results between Lines 491-554 on Pages 17-18.

“Risk of bias of included studies

We present risk of bias assessments of the observational studies and RCTs in Fig 2 and Fig 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 [30,33,34,35,37,40,42,46,47,48,49], 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).”

We have also added a sentence about this in the Discussion between Lines 756-759 on Page 27.

“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.”

Results – minor comment – it would have been helpful if you had put the age ranges as well as the mean age in this table, especially given the review focus is on age.

We added age ranges in Table 1 on Pages 14-16 and contents between Lines 448-449 on Page 13.

“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.”

Results – minor comment – you looked for ongoing trials, did you find any, if so maybe comment on them in the discussion where you talk about future research.

We added a sentence in Results between Lines 397-398 on Page 12.

“We did not find any ongoing studies.”

Discussion

The points within Paragraph 2 in the discussion needs more emphasis and the second from last paragraph in the discussion – or something similar - should be in the abstract: ‘The quality 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 the review’.

We added a sentence in Abstract between Lines 159-162. We added sentences in Discussion between Lines 756-759 on Page 27, and between Lines 836-839, and 849-850 on Page 30.

“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.”

“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].”

11 Mar 2021

Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: a systematic review

PONE-D-20-39802R1

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Reviewer #2: Good publication, good that it relates to the guidelines that it supports, but offers the science behind the guideline recommendations. This is rarely done even for national and international guidelines as it is seen as 'dual publication' or 'salami slicing' for many journals. Guidelines should have the systematic reviews which support them published in full, otherwise a 'black hole' of evidence exists, that is unhelpful in clinical and patient decision making. Congratulations to the authors and PLOS ONE for - hopefully - getting this published.

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Reviewer #1: No

Reviewer #2: Yes: Jayne Wilson

17 Mar 2021

PONE-D-20-39802R1

Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: a systematic review

Dear Dr. Brignardello-Petersen:

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