Page 147 - Haematologica Vol. 109 - July 2024

ARTICLE - Patterns of lower risk MDS progresion A.G. Jain et al. Table 2. Mutational profile of the 4 cohorts.
Mutation
LR-LR, N (%) N=1,300
LR-HR, N (%) N=317
LR-HR-AML, N (%) N=124
LR-AML, N (%) N=173
P
SF3B1
259 (38.1)
47 (28.8)
5 (10.2)
13 (16.7)
<0.0001
SRSF2
60 (8.9)
22 (13.7)
16 (32.7)
20 (25.6)
<0.0001
U2AF1
68 (10.1)
19 (11.7)
10 (20.8)
11 (14.1)
0.1127
ZRSR2
50 (7.4)
11 (6.8)
5 (10.4)
10 (12.8)
0.3222
TET2
193 (28.7)
49 (30.2)
15 (30)
28 (34.1)
0.7723
IDH1
16 (2.4)
0
1 (2)
8 (9.5)
0.0001
IDH2
13 (1.9)
7 (4.3)
2 (4)
6 (7.1)
0.0290
DNMT3A
88 (13.1)
23 (14.3)
6 (12.2)
12 (14.6)
0.9575
EZH2
43 (13.1)
13 (14.3)
4 (12.2)
11 (14.6)
0.0855
ASXL1
133 (18.8)
39 (23.2)
18 (32.1)
26 (31)
0.0092
SETBP1
28 (4.2)
7 (4.4)
3 (6.1)
5 (6.4)
0.7698
TP53
26 (3.7)
20 (12)
6 (10.9)
11 (13.8)
<0.0001
PHF6
6 (0.9)
1 (0.6)
3 (6.1)
1 (0.2)
0.0093
RUNX1
37 (5.2)
17 (10.1)
10 (18.2)
20 (25)
<0.0001
ETV6
9 (1.3)
12 (7.2)
6 (10.9)
1 (1.3)
<0.0001
CBL
16 (2.4)
9 (5.6)
3 (6.1)
7 (9)
0.0074
NRAS
6 (0.9)
4 (2.5)
3 (6.1)
4 (5.1)
0.0030
JAK2
46 (6.8)
10 (6.2)
3 (6.1)
1 (1.3)
0.3012
NPM1
0
1 (0.6)
1 (2)
7 (8)
<0.0001
LR-LR: patients who remained in the low-risk (LR) myelodysplastic syndrome (MDS) category throughout their period of follow-up; LR-HR: patients who progressed from LR to high-risk (HR) MDS without acute myeloid leukemia (AML) transformation; LR-HR-AML: patients who progressed from LR to HR MDS and then AML; LR-AML: patients who directly progressed from LR MDS to AML.
In a study on 107 LR MDS patients, Kawabata et al. showed that the 3-year OS for the high ferritin group (ferritin >210 ng/mL) was significantly shorter than the low ferritin group (66% vs. 79%), while the rates of leukemic progression were similar between the 2 groups.10 In contrast, we noted higher ferritin in patients that progressed to HR-MDS, HR-AML, and directly to AML, but this may reflect the severity of the anemia as the disease progresses, and is most likely the result of progression rather than its cause. Considering high ferritin levels, iron chelation therapy (ICT) has been sug- gested to improve EFS and OS.11,12 In our study, the LR-HR cohort had the most patients that were treated with ICT, probably because this group included patients that could tolerate ICT, while the other two groups, LR-HR-AML and LR-AML, were patients in a poorer medical condition, with progression to AML, and so a smaller number of patients were treated with ICT.
Mutations that were associated with increased risk of pro- gression to AML in our study were SRSF2 and NRAS. Mu- tations associated with progression to higher risk disease only, without AML and/or direct/indirect AML, were ASXL1, TP53, RUNX1, and CBL. The presence of an ETV6 mutation was associated with progression to HR-MDS, but not to
AML. Similar to our study, Bejar et al., in their study vali- dating LR-MDAS in lower risk patients, reported that ASXL1, U2AF1, SRSF2, RUNX1, NRAS, and CBL were over-represented in the highest-risk LR-PSS category.13 In their study, ASXL1, RUNX1, EZH2, SRSF2, U2AF1, and NRAS mutations were also associated with shorter OS.13 We also found that IDH1, IDH2, and NPM1 were more common in patients with direct AML transformation. Similar to our study, Bejar et al. reported that SF3B1 mutation was significantly under-represented in the higher risk LR-MDS category and showed a non-signifi- cant trend toward longer OS.13 Recently, the molecular IPSS (IPSS-M) was introduced, which combines mutations with other hematologic and cytogenetic parameters.14 Using the IPSS-M, Bernard et al. were able to re-stratify 46% patients. We validated the IPSS-M at our center and found that 45% of patients were re-stratified, including approximately 75% of patients that the IPSS-R classified as very-low (VL) who were upstaged (the majority to IPSS-M low and ML/MH).15 In our study, at a median follow up of 99 months, the median OS for the LR-LR, LR-HR, LR-HR-AML, and LR-AML groups was 80.7, 61.2, 48.3, and 42.8 months, respectively. In the study by Greenberg et al. on the IPSS-R, the OS for the VL and LR IPSS-R categories was 8.8 and 5.3 years, which is
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