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G. Nteliopoulos et al.
Table 2. Demographics and clinical/molecular characteristics of subjects with chronic phase-chronic myeloid leukemia at diagnosis.
N. of subjects (%)
Subtype of frontline TKI therapy
(IM/DAS/NIL/BOS)
(%)
Responders to TKI therapy (according to the 2013 ELN criteria of 2013)* (% of patients per subtype of frontline TKI therapy)
Non-responders to TKI therapy (according to the ELN criteria of 2013) (% of patients per subtype of frontline TKI therapy)
Age (years)
median (range)
Gender (male/female)
(%)
Sokal risk group at diagnosis (n=122)
Low/intermediate/high risk
(%)
ELTS risk group at diagnosis (n=122)
Low/intermediate/high risk
(%)
BCRABL1/ABL1 transcript before TKI-therapy
median (range)
BCRABL1 Transcript type
e13a2/e14a2/e13a2:e14a2/e1a2/e13a3
(%)
ACA besides Ph chromosome (n=61)†
classical Ph/additional ACA in Ph+/variant Ph/Ph-
(%)
Subsequent BCRABL1 KD mutations
(%)
Follow-up duration after TKI therapy (months)
median (range)
IM-treated subjects
62 (50)
62/0/0/0 (100/0/0/0)
33/0/0/0
(53/0/0/0) 29/0/0/0 (47/0/0/0) 50 (20.8-80.1)
38/24 (61/39) N=62 23/20/19 (37/32/31) N=62 32/18/12 (52/29/19) 20.1 (11.9-43.4)
23/32/7/1/0 (36/51/11/2/0)
n=41 34/2/4/1 (83/5/10/2)
6
(10)
95.6 (18-196.1)
2G-TKI-treated subjects
62 (50)
0/55/4/3 (0/89/6/5)
0/31/4/1
(0/56/100/33) 0/24/0/2 (0/44/0/67) 49.9 (20.2-85)
40/22 (65/35) N=60 19/21/20 (32/35/33) N=60 29/23/8 (48/38/14) 22.9 (7.1-51.8)
23/31/7/0/1 (37/50/11/0/2)
n=20 17/2/1/0 (85/10/5/0)
1
(2)
69.9 (9.5-112.8)
*Real-timequalitativepolymerasechainreaction ≤10%,≤1%,≤0.1%(InternationalScore)at3,6and12months,respectively.†Additionalcytogeneticabnormalities(ACA)data available only for subjects treated at Hammersmith Hospital, London, UK. BOS: bosutinib; DAS: dasatinib; ELN: European LeukemiaNet; ELTS: European Treatment and Outcome Study long-term survival; IM: imatinib; KD: kinase domain; NIL: nilotinib; Ph: Philadelphia; TKI: tyrosine kinase inhibitors; 2G: second-generation.
of 8-year EFS, PFS and CML-related survival compared with the non-variant subjects [28% (13, 59%) vs. 68% (55, 85%); P=0.003 for EFS; 61% (42, 88%) vs. 85% (74, 97%); P=0.025 for PFS; 58% (37, 92%) vs. 84% (73, 97%); P=0.039 for CML-related survival] (Figure 2 B-D). Somatic variants and Sokal score were independently predictive for PFS and CML-related survival whereas only somatic variants predicted EFS (Table 3). When compared with European Treatment and Outcome Study (EUTOS) long- term survival (ELTS) score, only ELTS score predicted MR3, PFS and CML-related survival while both ELTS and somatic variants predicted EFS (Table 3). Subjects with a low Sokal score or a low ELTS score and somatic variants had worse EFS (P=0.015 for Sokal; P=0.021 for ELTS) and PFS (P=0.040 for Sokal; P=0.031 for ELTS) than those without somatic variants (Online Supplementary Figure S4A and B). The trends towards poorer outcomes in subjects with somatic variants was also evident for intermediate- and high-Sokal/ELTS subjects. Somatic variants were a more accurate predictor of outcomes compared with
BCRABL1 transcript type (Table 3) and similarly compared with BCRABL1/ABL1 transcript levels before TKI-therapy, age and gender (data not shown).
Molecular response within the 1st year (calculated by BCRABL1/ABL1 transcripts at 3, 6, 12 months) (P<0.001) and somatic variants (P=0.044) were independently pre- dictive for EFS. Non-responders without somatic variants had a better EFS [23% (9, 59%)] compared to non-respon- ders with somatic variants at 0% (Online Supplementary Figure S5A). No association was detected between somatic variants in epigenetic modifiers at diagnosis and subse- quent BCRABL1 kinase domain (KD) mutations (P=0.81).
In all the above analyses, we included the subject with pre-leukemia variant. Excluding this subject did not alter our conclusions (Online Supplementary Table S4A).
Somatic variants and outcomes in the second-generation tyrosine kinase inhibitor cohort
There was no association between the presence of somatic variants and the 5-year rates of MR3 and 6-year
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