Prognostic significance of ASXL1 mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: A meta-analysis

Figures & data

Figure 1 Flow diagram of selection process in the meta-analysis.

Table 1 Summary of the data extracted from the six studies included

Study	Gelsi-Boyer (2010)^Citation30	Bejar (2011)^Citation28	Thol (2011)^Citation29	Chen (2014)^Citation27	Itzykson (2013)^Citation31	Patnaik (2013)^Citation35
Journal	Br J Haematol	N Engl J Med	J Clin Oncol	Blood Cancer J	J Clin Oncol	Leukemia
Region	France	United States	Germany	Taiwan	United States	United States
Patients (n)	53	439	193	466	312	226
ASXL1 mutations	25	63	40	106	125	87
Frameshift mutation	20	—	28	—	—	—
Point mutation	5	—	12	—	—	—
Sex (male/female)	35/18	306/133	119/74	158/308	210/102	152/74
Age (years)	NR (41–88)	70 (NR/NR)	64.71 (36–92)	66 (18–98)	74 (41–93)	71 (20–90)
Criterion	FAB classification	FAB classification	WHO classification	FAB classification	WHO classification	WHO classification
IPSS-based karyotype
High	1	67	23	—	25	—
Intermediate	12	55	20	—	45	—
Favorable	38	310	109	—	242	—
Unknown	2	7	41	—	—	—
Acute transformation	11	—	—	—	79	87
IPSS classification
Low	—	110	39	254	—	—
Intermediate-1	—	185	57		—	—
Intermediate-2	—	101	38	181	—	—
High	—	32	13		—	—
Unknown	—	11	46	31	—	—

WHO, World Health Organization; FAB, French–American–British; CMML, chronic myelomonocytic leukemia; ASXL1, additional sex comb-like 1 gene; NR, Not Reported; IPSS, International Prognostic Scoring System.

Table 2 Determination of IPSS risk groups

	Score value
IPSS
Prognostic variable	0	0.5	1.0	1.5	2.0
Bone marrow blast percentage (%)	>5	5–10		11–20	21–30
Karyotype category	Good	Intermediate	Poor
Number of cytopenias	0 or 1	2 or 3
Karyotype categories
Good: normal, -Y, del(5q), del(20q)
Intermediate: other (not good or poor)
Poor: chromosome 7 anomalies or complex (≥3 abnormalities)
Cytopenia definitions
Hemoglobin: <10 g/dl
Absolute neutrophil counts: <1800/μl
Platelet count: <100 000/μl

Note: The IPSS risk group: low, 0; intermediate-1, 0.5–1.0; intermediate-2, 1.5–2.0; high, ≥2.5.

Each of three prognostic variables is assigned a score as outlined in this table. The total of these scores is used to determine the IPSS risk group (low, intermediate-1, intermediate-2, and high).

Table 3 Combined mutations of ASXL1 with IDH1/2, NPM1, RUNX1, and TET2 in MDSs

Selected research	Other mutations	ASXL1-mutated (%)	ASXL1-wild (%)	P-value
Chen et al.^Citation27	IDH1/2	11.4	2.5	<0.001
	RUNX1	32.4	6.8	<0.001
	EZH2	22.6	1.1	<0.001
Rocquain et al.^Citation15	IDH1	7.7	1.9
	IDH2	15.4	1.9
	RUNX1	23.1	3.8
	TET2	15.4	23.1
Thol et al.^Citation29	IDH	7.5	2.6	P = 0.141
Bejar et al.^Citation28	IDH1	4.8	0.8
	IDH2	6.3	1.3
	RUNX1	20.6	6.6
	EZH2	11.1	5.6
	TET2	28.6	19.1
MD Anderson Cancer Center^Citation41	EZH2	14.3	10
	TET2	50	40

Table 4 Quality assessment of individual study

	Selection					Outcome
Study	Representativeness of exposed cohort	Selection of non-exposed cohort	Ascertainment of exposure	Outcome not present at start	Comparability	Assessment of outcome	Follow-up length	Follow-up adequacy	Score
Gelsi-Boyer (2010)^Citation30	*		*	*	*	*	*	*	7
Bejar (2011)^Citation28	*	*	*	*	*	*	*	*	8
Thol (2011)^Citation29	*		*	*	*	*	*		6
Chen (2014)^Citation27	*		*	*	*	*	*	*	7
Itzykson (2013)^Citation31	*	*	*	*	*	*	*	*	7
Patnaik (2013)^Citation35	*		*	*	*	*	*	*	7

Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.

Figure 2 Forest plots of the HRs and 95% CIs for OS and LFS in FAB-defined MDS patients. The size of the blocks or diamonds represents the weight and the length of the straight line represents the width of 95% CI.

Figure 3 Begg's funnel plot with pseudo 95% confidence limits.

Figure 4 Forest plots of the HRs and 95% CIs for: OS in CMML patients. The size of the blocks or diamonds represents the weight and the length of the straight line represents the width of 95% CI.

Gelsi-Boyer V, Trouplin V, Roquain J, Adélaïde J, Carbuccia N, Esterni B, et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151:365–75. doi: 10.1111/j.1365-2141.2010.08381.x

 PubMed Web of Science ®Google Scholar

Bejar R, Stevenson K, Abdel-Wahab O, Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496–506. doi: 10.1056/NEJMoa1013343

 PubMed Web of Science ®Google Scholar

Thol F, Friesen I, Damm F, Yun H, Eva M, Weissinger E, et al. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol. 2011;29:2499–506. doi: 10.1200/JCO.2010.33.4938

 PubMed Web of Science ®Google Scholar

Chen T-C, Houl H-A, Chou W-C, Tang J-L, Kuo Y-Y, Chen C-Y, et al. Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome. Blood Cancer J. 2014;4:e177. doi: 10.1038/bcj.2013.74

 PubMed Web of Science ®Google Scholar

Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:2428–36. doi: 10.1200/JCO.2012.47.3314

 PubMed Web of Science ®Google Scholar

Patnaik MM, Padron E, LaBorde RR, Lasho TL, Finke CM, Hanson CA, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia. 2013;27:1504–10. doi: 10.1038/leu.2013.88

 PubMed Web of Science ®Google Scholar

Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2010;10:401–7. doi: 10.1186/1471-2407-10-401

 PubMed Web of Science ®Google Scholar

Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A, et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia. 2011;25:1200–2. doi: 10.1038/leu.2011.58

 PubMed Web of Science ®Google Scholar