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IDH1/2 mutations in remission predict AML relapse
were treated with intensive chemotherapy (n=10), hypomethylating agents (n=23) or low-dose cytarabine with or without nucleoside analogs (n=6). The median clinical follow-up was 17.5 months (range, 4.9 to 77.5 months).
IDH mutations in pretreatment samples
All 80 patients harbored IDH1 and/or IDH2 mutations:
78 patients had a single IDH1 or IDH2 mutation and two patients had both IDH1 and IDH2 mutations. The two patients who had two different IDH1/2 mutations had major (20~34%) and minor (1~14%) clones represented by MAF. As a single mutation, IDH2 R140 mutations were most common (n=46), followed by IDH1 R132 (n=24) and IDH2 R172 (n=7) mutations. IDH2 R172_H173delinsSA was found in one patient. Detailed information regarding the IDH1/2 mutations is presented in Table 1. The median MAF of IDH1/2 mutations in pretreatment samples was 43.8% (range, 12.3% to 62.7%). The median MAF of the IDH1 R132 mutation (39.2%) was similar to that of IDH2 R140 (44.1%) and IDH2 R172 (42.5%) mutation (P=0.31). There were no significant differences in median bone mar- row blast count among the three groups (P=0.54).
Persistent IDH mutations in complete remission
or complete remission with incomplete hematologic remission
The mutational status of IDH1/2 was available in first CR (n=36) or CRi (n=44) for all patients. In 51 patients treated with intensive chemotherapy, analysis of IDH1/2 was performed after the first, second and third or beyond cycles of therapy in 21, 16 and 14 patients, respectively. In 23 patients treated with hypomethylating agents, analysis of IDH1/2 was performed before and after the fourth cycle of therapy in nine and 15 patients, respectively. The latter also included six patients who had received six or more cycles of therapy. In patients treated with low-dose cytarabine with or without additional drugs (n=6), one, one and four patients were tested for IDH1/2 after, respec- tively, their first, second and fourth or beyond cycles of therapy. A total of 31 (39%) patients had persistent IDH1/2 mutations in CR or CRi (CRIDH+). Among the patients in CR (n=36), 12 (33%) had persistent IDH1/2 mutations. Similarly, among patients in CRi (n=44), 19 (43%) had persistent IDH1/2 mutations (P=0.49). IDH1 R132, IDH2 R140 and IDH2 R172 mutations were observed in, respectively, ten (38.5%), 19 (41.3%), and two (25%) patients with mutations in a pretreatment bone marrow specimen (P=0.68) (Figure 1A). Compared to the MAF values in pretreatment samples, the MAF of IDH1/2 mutations in CR or CRi were reduced in all patients (median MAF: 10.2%, range, 1% to 34.3%) (Figure 1B). CRIDH+ was not correlated with cytogenetic abnormalities. CRIDH+ was observed in patients with diploid karyotype and those with any cytogenetic abnor- malities with similar frequency (40.4% and 37.5%, respectively; P=0.99). Of 24 patients with cytogenetic abnormalities in pretreatment samples, only two had per- sistent cytogenetic abnormalities.
IDH mutations in remission are associated with an increased risk of relapse
The cumulative incidence rate of relapse in patients with CRIDH+ was 59% at 12 months and 80% at 24 months. The cumulative incidence rate was significantly
higher in patients with CRIDH+ than in patients without a detectable IDH1/2 mutation in remission (CRIDH-) (Figure 2A). Using the Fine and Gray regression model, the risk of relapse at 1 year of follow-up was higher for patients with CRIDH+ than patients in the CRIDH- group (59% versus 24%; hazard ratio, 3.89; 95% confidence interval: 1.98 to 7.62; P<0.01) (Table 2). Regarding mutation type, 90%, 74% and 100% of patients with persistent IDH1 R132, IDH2 R140 and IDH2 R172 clones relapsed, respectively (P=0.44). There were no differences regarding relapse between patients treated with intensive chemotherapy and hypomethylating agents (47.1% and 43.5%, respec- tively) (P=0.77). The median time to relapse in patients with CRIDH+ was not significantly different from that of CRIDH- patients (median: 8.1 and 6.9 months, respectively) (P=0.71).
IDH1/2 mutation burden does not correlate with relapse
Among patients with CRIDH+, the MAF values for CRIDH+ were not significantly different between relapsed (median MAF: 10.0%) and non-relapsed patients (median MAF: 20.5%) (P=0.19). To further evaluate the correlation between IDH1/2 mutation burden and relapse, we arbi- trarily divided patients according to whether they had a high MAF (≥10%) or low MAF (<10%). Among 17 patients with a high MAF, 13 (77%) patients relapsed, whereas 12 of 14 (86%) patients with a low MAF relapsed (P=0.66). The difference in the median time to relapse
Table 1. Laboratory, cytogenetic and IDH1/2 mutation data of patients with acute myeloid leukemia (n=80).
Age (years)
Hemoglobin (g/dL) White blood cells, x109 L Platelets, x109 L
Bone marrow blasts (%)
Cytogenetic risk Favorable Intermediate Adverse
Treatment
Intensive chemotherapy Hypomethylating agent Low-dose cytarabine
IDH1/2 mutation Single
p.R132C
p.R132H
p.R132S
p.R132L
p.R132G
p.R140Q
p.R140L
p.R140W
p.R172K
p.R172G p.R172_H173delinsSA
Double
p.R132C and p.R140Q
Median
59
9.0 7.9 58 62
Number of patients
0 67 9
51 23 6
13 5 3 2 1 44 1 1 6 1 1
Range
31 to 90
6.3 to 13.9 0.4 to 263.1 1 to 1,069 21 to 95
(%)
0 88 12
64 29 7
16.7 6.4 3.8 2.6 1.3 56.4 1.3 1.3 7.7 1.3 1.3
2
NA
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