Efficacy and safety of cladribine addition to induction treatment of newly diagnosed acute myeloid leukemia: a systematic review and meta-analysis

Figures & data

Figure 1. PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of the study selection process. Abbreviations: AML, acute myeloid leukemia.

Table 1 Characteristics of the included studies

First Author	Year	Country	Study type	Induction chemotherapy regimen	Dosage
DAC
Holowiecki et al[5]	2004	Poland	phase III	DAC vs DA	cladribine 5 mg/m^2 d1-5; DNR 60 mg/m^2 d1-3; Ara-C 200 mg/m^2 d1-7
Holowiecki et al[6]	2012	Poland	phase III	DAC vs DA/DAF	cladribine 5 mg/m^2 d1-5; DNR 60 mg/m^2 d1-3; Ara-C 200 mg/m^2 d1-7
Doma et al[17]	2020	Slovenia	retrospective	DAC vs DA	cladribine 5 mg/m^2 d1-5; DNR 60 mg/m^2 d1,3,5; Ara-C 200 mg/m^2 d1-7
IAC
Woelich et al[18]	2017	U.S.A.	retrospective	IAC	cladribine 5 mg/m^2 d1-5; IDA 12 mg/m^2 d1-3; Ara-C 200 mg/m^2 d1-7
Shen et al[9]	2014	China	retrospective	IAC vs IA-L/IA-H	cladribine 5 mg/m^2 d1-5; IDA 8 mg/m^2 d1-3; Ara-C 100 mg/m^2 d1-7
Wiedower et al[8]	2015	U.S.A.	retrospective	ICC	cladribine 5 mg/m^2 d1-5; IDA 12 mg/m^2 d1-3; Ara-C 100-200 mg/m^2 d1-7
Schoen et al[19]	2018	U.S.A.	retrospective	Cladribine + IA	cladribine 5 mg/m^2 d1-5; IDA 12 mg/m^2 d1-3; Ara-C 200 mg/m^2 d1-7
Seligson et al[10]	2017	U.S.A.	retrospective	Cladribine + IA vs IA	as NCCN recommended
CLAG ± M
Martin et al[12]	2009	U.S.A.	retrospective	CLAG ± M	cladribine 5 mg/m^2 d1-5; cytarabine 2 g/m^2 d1-5; G-CSF 300 μg d1-5; or mito 10 mg/m^2 d1-3
Seiter et al[20]	2016	U.S.A.	retrospective	CLAG	cladribine 5 mg/m^2 d1-5; cytarabine 2 g/m^2 d1-5; G-CSF 300 μg d1-5; mito or IDA 12 mg/m^2 d1-3
Halpern et al [13]	2018	U.S.A.	prospective	GCLAM vs DA/IA	cladribine 5 mg/m^2 d1-5; cytarabine 2 g/m^2 d1-5; G-CSF 300 μg d0-5; mito 18 mg/m^2 d1-3
Elderly patients
Pluta et al[15]	2017	Poland	prospective	DAC vs DA	cladribine 5 mg/m^2 d1-5; DNR 45 mg/m^2 d1-3; Ara-C 100 mg/m^2 d1-7
Juliusson et al[16]	2003	Sweden	prospective	CCI vs CI	cladribine 5 mg/m^2 twice d1-4; IDA 10 mg/m^2 d1-2; Ara-C 1 g/m^2 d1-4
Kadia et al[14]	2018	U.S.A.	phase II	Cladribine + cytarabine	cladribine 5 mg/m^2 d1-5; cytarabine 20 mg SQ Bid1-10

Abbreviations: DAC, daunorubicin, Ara-C, and cladribine; DA, daunorubicin and Ara-C; DAF, daunorubicin, Ara-C, and fludarabine; IAC, idarubicin, Ara-C, and cladribine; IA, idarubicin and Ara-C; IA-L, idarubicin (10 mg/m²) and Ara-C; IA-H, idarubicin (12 mg/m²) and Ara-C; ICC, idarubicin, Ara-C, and cladribine; Cladribine + IA, idarubicin, Ara-C, and cladribine; CLAG ± M, cladribine, Ara-C, G-CSF ± mitoxantrone; CLAG, cladribine, Ara-C, and G-CSF; CCI, cladribine, Ara-C and idarubicin; CI, intermediate-dose Ara-C and idarubicin.

Table 2 Characteristics of the included studies

First Author	No. of patients	Median age in years (range)	Sex (M/F)	CR (%)	ED (%)	OS	DFS	Days for neutrophils <0.5 × 10^9/L	Days for platelets <50 × 10^9/L	Duration of hospital stay
DAC
Holowiecki et al[5]	200	44 (16–60)	98/102	63.5%	15.5%	34% (3 y)	43% (3 y)	19 (5–37)	21 (3–37)	33 (20–111)
Holowiecki et al[6]	222	48 (18–60)	112/110	62%	11%	45 ± 4% (3 y)	45 ± 5% (3 y)	20 (0–42)	22 (10–52)	33 (18–111)
Doma et al[17]	58	54.5 (20–60)	27/31	79%	5.2%	NA	NA	NR	NR	NR
IAC
Woelich et al[18]	38	61 (20–78)	27/11	63%	11%	NR	NR	30.5 (21–75)	NR	33 (24–98)
Shen et al[9]	27	43 (19–53)	15/12	77.8%	NR	NR	NR	20 (8–30)	15 (10–20)	28 (21–51)
Wiedower et al[8]	24	58 (24–68)	16/8	79.2%	8.3%	56% (33 m)	36% (33 m)	NR	NR	NR
Schoen et al[19]	107	60 (20–81)	67/40	65%	11%	17.3 m	NR	30 (19–75)	27 (19–131)	30 (14–98)
Seligson et al[10]	12	58 (36–71)	6/6	42%	8%	NR	NR	28.7	NR	26.6
CLAG ± M
Martin et al[12]	15	63 (23–80)	NR	53%	20%	NR	NR	20 (11–33)	23 (7–27)	NR
Seiter et al[20]	20	64 (42–79)	13/7	65%	NR	29.0 m	NR	NR	NR	NR
Halpern et al[13]	94	60 (21–81)	53/41	79%	2%	69% (12 m)	NR	26 (23–30)	23 (20–28)	NR
Elderly patients
Pluta et al[15]	80	66 (60–79)	44/36	44%	23%	8.6 m	NR	16 (0–42)	17 (0–55)	33 (16–92)
Juliusson et al[16]	43	70 (64–75)	19/24	51%	12%	NR	NR	22 (19–25)	17 (16–20)	NR
Kadia et al[14]	118	69 (49–85)	NR	58%	1%	13.8 m	10.8 m	NR	NR	NR

Abbreviations: CR, complete remission; ED, early death; OS, overall survival; DFS, disease-free survival; DAC, daunorubicin, Ara-C, and cladribine; IAC, idarubicin, Ara-C, and cladribine; CLAG ± M, cladribine, Ara-C, G-CSF ± mitoxantrone; NR, not reported; NA, not achieved.

Figure 2. A forest graph showing the overall and subgroup CR rates achieved in the meta-analysis. Abbreviations: DAC, daunorubicin, Ara-C, and cladribine; IAC, idarubicin, Ara-C, and cladribine; CLAG ± M, cladribine, Ara-C, G-CSF ± mitoxantrone.

Figure 3. A forest graph showing the comparison of the CR rate between the cladribine-containing regimen and the control group. Abbreviations: DAC, daunorubicin, Ara-C, and cladribine; IAC, idarubicin, Ara-C, and cladribine; CLAG ± M, cladribine, Ara-C, G-CSF ± mitoxantrone; DA, daunorubicin and Ara-C; IA, idarubicin and Ara-C.

Figure 4. A forest graph showing the overall and subgroup ED rates achieved in the meta-analysis. Abbreviations: DAC, daunorubicin, Ara-C, and cladribine; IAC, idarubicin, Ara-C, and cladribine; CLAG ± M, cladribine, Ara-C, G-CSF ± mitoxantrone.

Figure 5. A forest graph showing the comparison of the ED rate between the cladribine-containing regimen and the control group. Abbreviations: DAC, daunorubicin, Ara-C, and cladribine; IAC, idarubicin, Ara-C, and cladribine; CLAG ± M, cladribine, Ara-C, G-CSF ± mitoxantrone; DA, daunorubicin and Ara-C; IA, idarubicin and Ara-C.

Figure 6. Begg’s funnel plot for assessing publication bias.

Table 3 Risk of bias in the prospective randomized controlled studies

Study	Adequate random sequence generation	Allocation concealment	Blinding of participants and personnel	Adequate assessment of each outcome	Selective outcome reporting avoided	Other sources of bias
Holowiecki et al[5]	Unclear	Unclear	Unclear	Yes	No	No
Holowiecki et al[6]	Unclear	Unclear	Unclear	Yes	No	No
Juliusson et al[16]	Unclear	Unclear	Unclear	Yes	No	No
Pluta et al[15]	Unclear	Unclear	Unclear	Yes	No	No

Table 4 Risk of bias in retrospective studies using a modified Newcastle-Ottawa scale

Study	Selection			Comparability		Outcome		Quality score
	Assignment for treatment*	Representative treatment group	Representative reference group	Comparable for 1,2,3,4	Comparable for 5,6	Assessment of outcome	Adequate follow-up
Doma et al[17]	No	Yes	Yes	Yes	5,6	Yes	Yes	★★★★★★
Woelich et al[18]	No	Yes	No	No	No	Yes	No	★★
Shen et al[9]	No	Yes	Yes	1,2,3	5	Yes	No	★★★★★
Wiedower et al[8]	No	Yes	No	No	No	Yes	Yes	★★★
Schoen et al[19]	No	Yes	No	No	No	Yes	Yes	★★★
Seligson et al[10]	No	Yes	Yes	1,2,3	5,6	Yes	Yes	★★★★★★
Martin et al[12]	No	Yes	No	No	No	Yes	No	★★
Seiter et al[20]	No	Yes	No	No	No	Yes	Yes	★★★
Halpern et al[13]	No	Yes	Yes	1,2,3	5,6	Yes	Yes	★★★★★★
Kadia et al[14]	No	Yes	No	No	No	Yes	Yes	★★★

Comparability variables: 1 = age, 2 = sex, 3 = WBC at diagnosis, 4 = blasts in BM at diagnosis, 5 = risk category, 6 = secondary AML.

*Details of criteria for adequate random assignment of patients to treatments were provided.

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