Interleukin‐2 as maintenance therapy for children and adults with acute myeloid leukaemia in first complete remission

Chen Mao; Xiao‐Hong Fu; Jin‐Qiu Yuan; Zu‐Yao Yang; Ya‐Fang Huang; Qian‐Ling YE; Xin‐Yin Wu; Xue‐Feng Hu; Zhi‐Min Zhai; Jin‐Ling Tang

doi:10.1002/14651858.CD010248.pub2

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Figure 1

Flow diagram of literature search

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 IL‐2 vs. Control, outcome: 1.1 Disease‐free survival.

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Figure 5

Forest plot of comparison: 1 IL‐2 vs. Control, outcome: 1.2 Overall survival.

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Analysis 1.1

Comparison 1 IL‐2 versus control, Outcome 1 Disease‐free survival.

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Analysis 1.2

Comparison 1 IL‐2 versus control, Outcome 2 Overall survival.

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Analysis 1.3

Comparison 1 IL‐2 versus control, Outcome 3 Adverse events.

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Analysis 1.4

Comparison 1 IL‐2 versus control, Outcome 4 Subgroup analysis of DFS: age<60 versus age ≥60.

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Analysis 1.5

Comparison 1 IL‐2 versus control, Outcome 5 Subgroup analysis of DFS: >20% blasts versus ≥30% blasts.

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Analysis 1.6

Comparison 1 IL‐2 versus control, Outcome 6 Subgroup analysis of DFS: chemotherapy alone versus autologous stem cell transplantation.

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Analysis 1.7

Comparison 1 IL‐2 versus control, Outcome 7 Subgroup analysis of DFS: IL‐duration ≤3months versus >3 months.

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Analysis 1.8

Comparison 1 IL‐2 versus control, Outcome 8 Subgroup analysis of OS: age<60 versus age ≥60.

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Analysis 1.9

Comparison 1 IL‐2 versus control, Outcome 9 Subgroup analysis of OS: >20% blasts versus ≥30% blasts.

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Analysis 1.10

Comparison 1 IL‐2 versus control, Outcome 10 Subgroup analysis of OS: IL‐duration ≤3months versus 12 months.

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Analysis 1.11

Comparison 1 IL‐2 versus control, Outcome 11 Subgroup analysis of OS: chemotherapy alone versus autologous stem cell transplantation.

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Analysis 1.12

Comparison 1 IL‐2 versus control, Outcome 12 Sensitivity analysis of DFS (random‐effects model).

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Analysis 1.13

Comparison 1 IL‐2 versus control, Outcome 13 Sensitivity analysis of DFS (excluding abstracts).

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Analysis 1.14

Comparison 1 IL‐2 versus control, Outcome 14 Sensitivity analysis of OS (excluding abstracts).

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Analysis 1.15

Comparison 1 IL‐2 versus control, Outcome 15 Sensitivity analysis of OS (random‐effects model).

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Analysis 1.16

Comparison 1 IL‐2 versus control, Outcome 16 Sensitivity analysis including DFS and EFS.

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IL‐2 compared with no treatment for people with AML in first complete remission
Patient or population: People with AML in first complete remission Settings: Maintenance therapy Intervention: IL‐2 Comparison: No treatment
Outcomes	Illustrative comparative risks^[1]		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment	IL‐2
Relapses/death (instead of disease‐free survival）^[2] Follow‐up at median 5 years	590 per 1000	571 per 1000 (535 to 611)	HR 0.95 (0.86 to 1.06)	1426 (6 studies)	⊕⊕⊝⊝^[3] Low
Mortality (instead of overall survival)^[2] Follow‐up at median 5 years	480 per 1000	497 per 1000 (463 to 532)	HR 1.05 (0.95 to 1.16)	1355 (5 studies)	⊕⊕⊕⊝^[4] Moderate
Death/progress (instead of event‐free survival)^[2] Follow‐up at 5 years	280 per 1000	285 per 1000 (229 to 352)	HR 1.02 (0.79 to 1.32)	161 (1 study)	⊕⊕⊝⊝^[3] Low
Treatment‐related mortality	See comments	See comments	Not estimable	0 (0)	See comments	None of the studies reported treatment‐related mortality
Adverse events: hypersensitivity Follow‐up at median 6 years	See comments	See comments	RR 17.13 (0.99 to 295.26)	528 (1 study)	⊕⊝⊝⊝^[3,5] Very low	Illustrative comparative risks are not estimable as the assumed risk is zero
Adverse events: fatigue Follow‐up at median 6 years	10 per 1000	71 per 1000 (21 to 233)	RR 7.05 (2.13 to 23.36)	528 (1 study)	⊕⊝⊝⊝^[3,5] Very low
Adverse events: rigor/chills Follow‐up at median 6 years	See comments	See comments	RR 33.25 (2.01 to 551.36)	528 (1 study)	⊕⊝⊝⊝^[3,5] Very low	Illustrative comparative risks are not estimable as the assumed risk is zero
Adverse events: arthralgia/myalgia Follow‐up at median 6 years	See comments	See comments	RR 19.14 (1.12 to 327.24)	528 (1 study)	⊕⊝⊝⊝^[3,5] Very low	Illustrative comparative risks are not estimable as the assumed risk is zero
Quality of life	See comments	See comments	Not estimable	0 (0)	See comments	None of the studies reported quality of life
CI: confidence interval; HR: hazard ratio; IL‐2: interleukin‐2; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
1. The basis for the assumed risk is the median control group risk across studies (The absolute effects come directly from the included study if only one study was included). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The HRs are first converted to RRs and the corresponding risks are then calculated from the RRs. Corresponding intervention risk, per 1000 people = 1000 × assumed control risk× RR. 2. Absolute effects were estimated from the HRs, and both are reported in the same row. 3. Downgrading two points for study limitations (high risk of detection bias due to lack of blinding; sequence generation and allocation concealment in some studies were not reported, leading to potential selection bias). 4. Downgrading one point for study limitations (sequence generation and allocation concealment in some studies were not reported, leading to potential selection bias). 5. Downgrading one point for imprecision (wide confidence interval).

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Table 1. Adverse events

Adverse events	Thrombocytopenia	Neutropenia	Malaise/fatigue	Infection/fever
Baer 2008	65%	64%	15%	24%
Kolitz 2014	24%	20%	12%	5%
Pautas 2010	11%	3%	5%	57%

Table 1. Adverse events

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Table 2. Subgroup analyses for disease‐free survival

Groups		No. of studies	HR [95% CI]	Test for subgroup differences
Age	< 60 years	3	0.92 [0.78, 1.08]	P = 0.76, I² = 0%
Age	≥ 60 years	1	0.95 [0.80, 1.13]	P = 0.76, I² = 0%
AML classification	> 20% blasts	2	0.86 [0.68, 1.09]	P = 0.37, I² = 0%
AML classification	≥ 30% blasts	3	0.98 [0.86, 1.10]	P = 0.37, I² = 0%
Treatment before IL‐2	Chemotherapy alone	3	0.98 [0.86, 1.12]	P = 0.86, I² = 0%
Treatment before IL‐2	Autologous stem cell transplantation	2	0.96 [0.80, 1.15]	P = 0.86, I² = 0%
IL‐2 duration	≤ 3 months	4	0.95 [0.84, 1.08]	P = 0.98, I² = 0%
IL‐2 duration	> 3 months	2	0.95 [0.80, 1.14]	P = 0.98, I² = 0%
CI: confidence interval HR: hazard ratio IL: interleukin‐2

Table 2. Subgroup analyses for disease‐free survival

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Table 3. Subgroup analyses for overall survival

Groups		No. of studies	HR [95% CI]	Test for subgroup differences
Age	< 60 years	2	0.93 [0.77, 1.11]	P = 0.25, I² = 25.4%
Age	≥ 60 years	1	1.11 [0.87, 1.40]	P = 0.25, I² = 25.4%
AML classification	> 20% blasts	1	0.88 [0.68, 1.13]	P = 0.13, I² = 55.7%
AML classification	≥ 30% blasts	4	1.09 [0.97, 1.22]	P = 0.13, I² = 55.7%
Treatment before IL‐2	Chemotherapy alone	3	1.11 [0.98, 1.26]	P = 0.38, I² = 0%
Treatment before IL‐2	Autologous stem cell transplants	1	0.98 [0.76, 1.26]	P = 0.38, I² = 0%
IL‐2 duration	≤ 3 months	3	1.00 [0.85, 1.18]	P = 0.46, I² = 0%
IL‐2 duration	> 3 months	2	1.08 [0.95, 1.24]	P = 0.46, I² = 0%
CI: confidence interval HR: hazard ratio IL: interleukin‐2

Table 3. Subgroup analyses for overall survival

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Table 4. Sensitivity analyses

Outcomes	Sensitivity analyses	No. of studies	HR [95% CI]
Disease‐free survival	Excluding 2 abstracts	4	0.95 [0.84, 1.08]
Disease‐free survival	Random‐effects model	6	0.95 [0.86, 1.06]
Overall survival	Excluding 2 abstracts	4	1.06 [0.95, 1.19]
Overall survival	Random‐effects model	5	1.05 [0.95, 1.16]
Disease‐free survival and event‐free survival	Excluding event‐free survival	6	0.95 [0.86, 1.06]
Disease‐free survival and event‐free survival	Including event‐free survival	7	0.96 [0.87, 1.06]
CI: confidence interval HR: hazard ratio

Table 4. Sensitivity analyses

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Comparison 1. IL‐2 versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	6	1426	Hazard Ratio (Fixed, 95% CI)	0.95 [0.86, 1.06]

2 Overall survival Show forest plot	5	1355	Hazard Ratio (Fixed, 95% CI)	1.05 [0.95, 1.16]

3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Hypersensitivity	1	528	Risk Ratio (M‐H, Fixed, 95% CI)	17.13 [0.99, 295.26]
3.2 Fatigue	1	528	Risk Ratio (M‐H, Fixed, 95% CI)	7.05 [2.13, 23.36]
3.3 Rigor/Chills	1	528	Risk Ratio (M‐H, Fixed, 95% CI)	33.25 [2.01, 551.36]
3.4 Arthralgia/Myalgia	1	528	Risk Ratio (M‐H, Fixed, 95% CI)	19.14 [1.12, 327.24]
4 Subgroup analysis of DFS: age<60 versus age ≥60 Show forest plot	4	983	Hazard Ratio (Fixed, 95% CI)	0.93 [0.83, 1.05]

4.1 Younger adults age<60	3	820	Hazard Ratio (Fixed, 95% CI)	0.92 [0.78, 1.08]
4.2 Older adults age ≥ 60	1	163	Hazard Ratio (Fixed, 95% CI)	0.95 [0.80, 1.13]
5 Subgroup analysis of DFS: >20% blasts versus ≥30% blasts Show forest plot	5	1348	Hazard Ratio (Fixed, 95% CI)	0.95 [0.85, 1.06]

5.1 >20% blasts	2	368	Hazard Ratio (Fixed, 95% CI)	0.86 [0.68, 1.09]
5.2 ≥30% blasts	3	980	Hazard Ratio (Fixed, 95% CI)	0.98 [0.86, 1.10]
6 Subgroup analysis of DFS: chemotherapy alone versus autologous stem cell transplantation Show forest plot	5	1212	Hazard Ratio (Fixed, 95% CI)	0.97 [0.87, 1.08]

6.1 Chemotherapy alone	3	606	Hazard Ratio (Fixed, 95% CI)	0.98 [0.86, 1.12]
6.2 Autologous stem cell transplants	2	606	Hazard Ratio (Fixed, 95% CI)	0.96 [0.80, 1.15]
7 Subgroup analysis of DFS: IL‐duration ≤3months versus >3 months Show forest plot	6	1426	Hazard Ratio (Fixed, 95% CI)	0.95 [0.86, 1.06]

7.1 IL‐2 duration ≤3 months	4	744	Hazard Ratio (Fixed, 95% CI)	0.95 [0.84, 1.08]
7.2 IL‐2 duration >3 months	2	682	Hazard Ratio (Fixed, 95% CI)	0.95 [0.80, 1.14]
8 Subgroup analysis of OS: age<60 versus age ≥60 Show forest plot	3	905	Hazard Ratio (Fixed, 95% CI)	0.99 [0.86, 1.14]

8.1 Younger adults age <60	2	742	Hazard Ratio (Fixed, 95% CI)	0.93 [0.77, 1.11]
8.2 Older adults age ≥ 60	1	163	Hazard Ratio (Fixed, 95% CI)	1.11 [0.87, 1.40]
9 Subgroup analysis of OS: >20% blasts versus ≥30% blasts Show forest plot	5	1355	Hazard Ratio (Fixed, 95% CI)	1.05 [0.95, 1.16]

9.1 >20% blasts	1	214	Hazard Ratio (Fixed, 95% CI)	0.88 [0.68, 1.13]
9.2 ≥30% blasts	4	1141	Hazard Ratio (Fixed, 95% CI)	1.09 [0.97, 1.22]
10 Subgroup analysis of OS: IL‐duration ≤3months versus 12 months Show forest plot	5	1355	Hazard Ratio (Fixed, 95% CI)	1.05 [0.95, 1.16]

10.1 IL‐duration ≤3months	3	666	Hazard Ratio (Fixed, 95% CI)	1.00 [0.85, 1.18]
10.2 IL‐duration 12 months	2	689	Hazard Ratio (Fixed, 95% CI)	1.08 [0.95, 1.24]
11 Subgroup analysis of OS: chemotherapy alone versus autologous stem cell transplantation Show forest plot	4	1141	Hazard Ratio (Fixed, 95% CI)	1.09 [0.97, 1.22]

11.1 Chemotherapy alone	3	613	Hazard Ratio (Fixed, 95% CI)	1.11 [0.98, 1.26]
11.2 Autologous stem cell transplants	1	528	Hazard Ratio (Fixed, 95% CI)	0.98 [0.76, 1.26]
12 Sensitivity analysis of DFS (random‐effects model) Show forest plot	6	1426	Hazard Ratio (Random, 95% CI)	0.95 [0.86, 1.06]

13 Sensitivity analysis of DFS (excluding abstracts) Show forest plot	4	744	Hazard Ratio (Fixed, 95% CI)	0.95 [0.84, 1.08]

14 Sensitivity analysis of OS (excluding abstracts) Show forest plot	4	821	Hazard Ratio (Fixed, 95% CI)	1.06 [0.95, 1.19]

15 Sensitivity analysis of OS (random‐effects model) Show forest plot	5	1355	Hazard Ratio (Random, 95% CI)	1.05 [0.95, 1.16]

16 Sensitivity analysis including DFS and EFS Show forest plot	7	1587	Hazard Ratio (Fixed, 95% CI)	0.96 [0.87, 1.06]

Comparison 1. IL‐2 versus control

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