Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

Table 1 Clinico-biological and outcome characteristics of adult and pediatric T-ALL (GRAALL and FRALLE protocols) according to IDH1/2 status

Variable	IDH2^Mut (n = 10)	p value²	Overall (n = 476)	p value²	IDH1^Mut (n = 5)
Male	7/10 (70%)	0.72	357/476 (75%)	0.34	5/5 (100%)
Age (y)¹	47.6 (3.6–59.1)	0.01	15.3 (1.1–59.1)	0.26	21.6 (5.4–56.5)
WBC (G/L)¹	9 (1–400)	0.01	64 (0–980)	0.60	80 (4–110)
CNS involvement	1/10 (10%)	0.99	51/474 (11%)	0.99	0/5 (0%)
Immunophenotype
ETP phenotype	3/5 (60%)	0.04	56/307 (18%)	0.54	1/4 (25%)
Immature (IM0/δ/γ)	5/7 (71%)	0.006	89/419 (21%)	0.99	1/5 (20%)
Cortical (IMB, preαβ)	0/7 (0%)	0.007	211/419 (50%)	0.68	2/5 (40%)
Mature TCRαβ	1/7 (14%)	0.99	66/419 (16%)	0.99	0/5 (0%)
Mature TCRγδ	1/7 (14%)	0.99	53/419 (13%)	0.12	2/5 (40%)
Oncogenetic classification
TLX1	0/8 (0%)	0.60	54/415 (13%)	0.99	0/5 (0%)
TLX3	1/8 (12%)	0.99	72/415 (17%)	0.21	2/5 (40%)
SIL-TAL1	0/8 (0%)	0.61	57/415 (14%)	0.99	0/5 (0%)
CALM-AF10	0/8 (0%)	0.99	13/415 (3%)	0.99	0/5 (0%)
High-risk classifier	8/10 (80%)	0.03	209/476 (44%)	0.99	2/5 (40%)
Treatment response
Rapid prednisone response	3/10 (30%)	0.12	259/467 (55%)	0.66	2/5 (40%)
Complete Remission	9/10 (90%)	0.54	440/476 (92%)	0.32	4/5 (80%)
MRD1 > 10^–4	1/1 (100%)	0.36	123/340 (36%)	0.99	1/4 (25%)
Allo-HSCT	2/10 (20%)	0.99	101/456 (22%)	0.99	1/5 (20%)
Outcome
4-year CIR (95% CI)	78% (49;97)	< 0.001³	29% (25;33)	0.75³	25% (4;87)
4-year OS (95% CI)	30% (7;58)	0.001³	71% (67;75)	0.61³	80% (20;97)

Univariate and multivariate analysis³
	Univariate			Multivariate
CIR	SHR	95%CI	p	SHR	95%CI	p
Age	1.01	(0.98; 1.03)	0.57	-	-	-
CNS	1.57	(0.85; 2.59)	0.08	1.33	(0.80; 2.20)	0.28
Log(WBC)	1.62	(1.2; 2.18)	0.002	1.63	(1.20; 2.22)	0.002
Prednisone response	0.67	(0.47; 0.95)	0.03	1.00	(0.68; 1.46)	0.99
High-risk Classifier	2.78	(1.94; 3.99)	< 0.001	2.62	(1.81; 3.79)	< 0.001
IDH2^Mut	4.28	(1.99; 9.23)	< 0.001	4.06	(1.84; 8.96)	0.001
OS	HR	95%CI	p	HR	95%CI	p
Age	1.03	(1.01; 1.05)	0.001	1.04	(1.02; 1.07)	< 0.001
CNS	2.00	(1.28; 3.14)	0.002	1.67	(1.02; 1.07)	0.03
Log(WBC)	1.99	(1.48; 2.67)	< 0.001	2.00	(1.46; 2.76)	< 0.001
Prednisone response	0.54	(0.38; 0.76)	< 0.001	0.85	(0.59; 1.24)	0.41
High-risk Classifier	2.93	(2.06; 4.17)	< 0.001	2.90	(2.00; 4.19)	< 0.001
IDH2^Mut	3.56	(1.66; 7.65)	0.001	1.98	(0.86; 4.57)	0.11

p-values < 0.05 are indicated in bold
MRD1 correspond to MRD evaluation after induction and was performed by allele-specific oligonucleotides polymerase chain reaction. T-cell receptor status and oncogenic were performed as described in supplemental methods. IDH1^Mut and IDH2^Mut were statistically compared to IDH1^WT and IDH2^WT patients, respectively
T-ALL: T-cell acute lymphoblastic leukemia; WBC, white blood count; CNS, central nervous system; ETP, early thymic precursor; High Risk classifier, NOTCH1/FBXW7-RAS/PTEN classifier as previously described [3, 4]; CR, complete remission; MRD, minimal residual disease; Allo-HSCT, allogenic hematopoietic stem cell transplantation; CIR, cumulative incidence of relapse; OS, overall survival; HR: hazard ratio, SHR: specific hazard ratio, CI: confidence interval
¹Statistics presented: Median (Minimum–Maximum)
²Statistical tests performed: Fisher's exact test; Wilcoxon rank-sum test
³Univariate and multivariate Cox analyses stratified on protocol

ISSN: 1756-8722