The prognostic value of the interaction between ASXL1 and TET2 gene mutations in patients with chronic myelomonocytic leukemia: a meta-analysis

Figures & data

Figure 1. Flow chart based on PRISMA guidelines.

Table 1. Summary of the data extracted from the 16 studies included.

Study Cohort	Year	Journal	Region	Patients (n)	Mean ages	Male/(%)	Mutated gene	Mutations (n)	Criterion	Therapy	Outcome	NOS score
Veronique Gelsi-Boyer [17]	2010	Br J Haematol	France	53	NR(41-88)	35/(66)	A	25	FAB	C/U	OS	7
MM Patnaik [22]	2013	Leukemia	US	226	71(20-90)	152/(67)	A	87	WHO	–	OS	7
Raphael Itzykson [21]	2013	J Clin Oncol	US	312	74(41-93)	210/(67)	A	125	WHO	C	OS	7
MM Patnaik [19]	2014	Leukemia	US	466	73(20-93)	309/(66)	A	164	WHO	–	OS	7
David A Sallman [20]	2017	Blood Cancer J	US	60	74(48-94)	41/(68)	A	28	WHO	C/S	OS	8
Yajuan Cui [28]	2015	Exp Hematol Oncol	China	145	63(18-85)	98/(68)	A	65	WHO/FAB	C/S	OS	7
Sandrine Niyongere [29]	2018	Leukemia	US	215	74(29-91)	139/(65)	A	49	WHO/FAB	–	OS	7
Hyun-Young Kim, M.D. [30]	2018	Ann Lab Med	Korea	36	71(38-83)	26/(72.2)	A	18	WHO	C	OS	7
MM Patnaik [31]	2016	Blood Cancer J	US	261	70(28-91)	168/(65)	T	109	WHO	–	OS	7
Olivier Kosmider [32]	2009	Haematologica	France	88	76(54-93)	61/(69)	T	44	WHO	C	OS	7
Alexander Kohlmann [3]	2010	J Clin Oncol	Germany	81	72.8(40-85.5)	–	T	36	WHO	–	OS	8
Thorsten Braun [12]	2011	Blood	France	39	71(54-88)	30/(77)	T/A	13/19	WHO	C	OS	8
MM Patnaik [23]	2016	Blood Cancer J	US	175	70(18-90)	116/(66)	T/A	80/82	WHO	–	OS	7
Yajuan Cui [33]	2016	Stem Cell Invest	China	141	63(16-85)	95/(67)	T/A	46/65	WHO	–	OS	8
Matthieu Duchmann [25]	2018	EBioMedicine	France	174	72(66-78)	118/(68)	T/A	66/75	WHO	C	OS	8
Giacomo Coltro [26]	2019	Leukemia	US	1084	72(18-95)	714/(68)	T/A	604/442	WHO/FAB	C	OS	8

Study design is case control study. A: ASXL1, T: TET2, C: Chemotherapy, U: Untreated, S: Surgery, WHO: World Health Organization, FAB: French-American-British, NR: not reported

Figure 2. Forest plot of the risk ratio (HR) and 95% confidence interval of the overall survival (OS) of patients with TET2 mutation and non-mutation CMML. The size of the square or square represents the weight, and the length of the line represents the width of the 95% CI.

Table 2. Subgroup analysis of pooled HRs for OS with or without TET2 mutation.

Categories	Studies (n)	Patients (n)	Pooled HR (95%CI)	Heterogeneity
				I²	P-value
Gene type
TET2 mutation	5	643	0.74(0.61 - 0.91)	0.0%	0.760
Sample size
≥100	2	435	0.75(0.61 - 0.93)	0.0%	0.699
＜100	3	208	0.68(0.33 - 1.40)	0.0%	0.439
Analysis method
Univariate	2	435	0.75(0.61 - 0.93)	0.0%	0.699
Multivariate	3	208	0.68(0.33 - 1.40)	0.0%	0.439

Table 3. The effect of TET2 mutation status on the acute transformation and death rate of CMML patients.

Event	TET2 Mutation		TET2 Wild Type		Total
	E/M	E Rates	E/W	E Rates	E/Total	E Rates
Acute Transformation
Giacomo Coltro [26]	85/604	0.14	103/480	0.21	188/1084	0.17
MM Patnaik [31]	4/109	0.04	33/152	0.22	37/261	0.14
MM Patnaik [23]	11/80	0.14	14/95	0.15	25/175	0.14
Death
Giacomo Coltro [26]	234/604	0.39	275/480	0.57	509/1084	0.47
Alexander E. Smith [35]	33/55	0.60	137/300	0.46	170/355	0.48
MM Patnaik [23]	62/80	0.78	84/95	0.88	146/175	0.83

E: Events, M: Mutation, W: Wild type

Table 4. Combining Table 3 to calculate the difference between the two rates (Incidence of events with or without mutation) in different events.

	d	p	p(1-p)	wi	wi*d	wi*p(1-p)
Acute Transformation
Giacomo Coltro [26]	0.07	0.17	0.14	267.45	19.76	38.34
MM Patnaik [31]	0.18	0.14	0.12	63.48	11.45	7.72
MM Patnaik [23]	0.01	0.14	0.12	43.43	0.43	5.32
Total				374.36	31.64	51.38
Death
Giacomo [26]	0.19	0.47	0.25	267.45	49.61	66.62
Alexander E. Smith [35]	−0.14	0.48	0.25	46.48	−6.66	11.60
MM Patnaik [23]	0.11	0.83	0.14	43.43	4.74	6.00
Total				357.36	47.69	84.22

d: Difference between two rates, p: Total rate, w_i: Weights

Figure 3. Forest plot of the risk ratio (HR) and 95% confidence interval of the overall survival (OS) of patients with ASXL1 mutation and non-mutation CMML. The size of the square or square represents the weight, and the length of the line represents the width of the 95% CI.

Table 5. Results of subgroup analyses of pooled HRs for OS with or without ASXL1 mutation.

Categories	Number of studies	Number of patients	Pooled HR (95%CI)	Heterogeneity
				I²	P-value
Gene type
ASXL1 mutation	10	1726	1.56(1.34 - 1.80)	26.8%	0.197
Sample size
≥100	6	1538	1.58(1.28 - 1.93)	38.6%	0.149
＜100	4	188	1.90(1.10 - 3.26)	12.2%	0.332
Analysis method
Univariate	2	210	1.52(1.02 - 2.26)	10.8%	0.29
Multivariate	8	1516	1.65(1.31 - 2.08)	37.0%	0.134

Table 6. The effect of ASXL1 mutation status on the acute transformation and death rate of CMML patients.

Event	ASXL1 Mutation		ASXL1 Wild Types		Total
	E/M	E Rates	E/W	E Rates	E/Total	E Rates
Acute Transformation
MM Patnaik [23]	13/82	0.16	12/93	0.13	15/175	0.09
MM Patnaik [19]	26/164	0.16	44/256	0.17	70/420	0.17
Veronique Gelsi-Boyer [17]	11/25	0.44	0/26	0.00	11/51	0.22
Hyun-Young Kim, M.D. [30]	8/16	0.50	4/17	0.24	12/33	0.36
Death
MM Patnaik [23]	71/82	86.59	75/93	80.65	146/175	0.83
MM Patnaik[19]	117/164	71.34	137/256	53.51	254/420	0.60
Hyun-Young Kim, M.D. [30]	15/18	83.33	11/18	61.11	26/36	0.72

E: Events, M: Mutation, W: Wild type

Table 7. Combining Table 6 to calculate the difference between the two rates (Incidence of events with or without mutation) in different events.

	d	p	p(1-p)	wi	wi*d	wi*p(1-p)
Acute Transformation
MM Patnaik[23]	−0.03	0.09	0.08	43.58	−1.29	3.42
MM Patnaik [19]	0.01	0.17	0.14	99.96	1.34	13.88
Veronique Gelsi-Boyer [17]	−0.44	0.22	0.17	16.78	−7.38	2.84
Hyun-Young Kim, M.D. [30]	−0.27	0.36	0.23	10.78	−2.86	2.49
Total				171.09	−10.18	22.63
Death
MM Patnaik [23]	−0.06	0.83	0.14	44.98	−2.67	6.22
MM Patnaik[19]	−0.18	0.60	0.24	99.96	−17.82	23.89
Hyun-Young Kim, M.D. [30]	−0.22	0.72	0.20	9.00	−2.00	1.81
Total				153.94	−22.49	31.92

d: Difference between two rates, p: Total rate, w_i: Weights

Figure 4. Funnel plot analysis of publication bias in research on different genes (A) TET2 gene (B) ASXL1 gene.

Figure 5. Sensitivity analysis of individual research results (A) The effect of TET2 gene mutation status on the overall survival of CMML patients (B) The effect of ASXL1 gene mutation status on the overall survival of CMML patients.

Figure 6. Forest plot of the risk ratio (HR) and 95% confidence interval of the overall survival (OS). The size of the square or square represents the weight, and the length of the line represents the width of the 95% CI. (A) Patients with TET2 mutation ASXL1 without mutation and TET2&ASXL1 mutations (B) Patients with TET2 mutation ASXL1 without mutation and TET2&ASXL1 without mutation (C) Patients with TET2 mutation ASXL1 without mutation and TET2 without mutation ASXL1 mutation.

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