Table 1

Longitudinal mutation status of patients with low-level mutations detected by MS at baseline

Pt IDDisease phase at study entryNumber of prior TKIsMutation history*Mutation status by Sanger sequencing at baselineLow-level mutations at baseline†Months on ponatinibOutcomeMutation status by Sanger sequencing at treatment failure or discontinuation (%)‡
109 CP-CML 3 No mutation detected No mutation detected E459K 4.2 Discontinued therapy§ Not evaluable 
210 CP-CML 3 E255K E255K G250E 10.7 Discontinued therapy§ Not evaluable 
239 CP-CML 3 M244V, E255K, T315I E255K, T315I M244V 17.6 Discontinued therapy‖ Not evaluable 
288 CP-CML 2 T315I No mutation detected T315I 21.9 Discontinued therapy‖ T315I (20) 
35 CP-CML 2 No mutation detected No mutation detected F359V 31.0 Maintained MCyR No mutation detected 
45 CP-CML 2 E255K, T315I E255K E255V, T315I 24.8 Maintained MCyR  
215 CP-CML 3 T240M, E255V, T315I T315I E255V 30.7 Maintained MCyR  
271 CP-CML 1 G250E, T315I G250E, E255V M244V, Y253H 26.3 Maintained MCyR  
253 CP-CML 2 F317L F317L F317L 27.8 Maintained MMR  
314 CP-CML 1 T315I No mutation detected M244V, G250E, F359I 28.3 Maintained MMR  
358 CP-CML 3 Y253F, D276G Y253F Q252H, T315I 28.5 Maintained MMR  
361 CP-CML 3 M244V, F359V F359V E355G 28.2 Maintained MMR  
365 CP-CML 2 T315I, F359V F359V T315I 28.4 Maintained MMR  
255 CP-CML 1 T315I T315I F317L 22.1 Lost MMR  
381 CP-CML 1 No mutation detected No mutation detected E255K 25.8 Lost MMR  
216 CP-CML 2 E355A, T315I E355A T315I 30.7 No MCyR T315I, E355A (10, 10) 
19 CP-CML 4 M351T, F359V F317L, E450G F359V 29.6 Progressive disease F317L, E450G (10, 10) 
26 CP-CML 3 V299L V299L E255K, F317L 32.2 Progressive disease E255K (70) 
47 CP-CML 2 T315I, F317L T315I F317L 3.1 Progressive disease T315I (100) 
96 CP-CML 3 T315I, F359C T315I, F359C V299L 0.9 Progressive disease Not evaluable 
97 CP-CML 3 No mutation detected No mutation detected F317L 0.9 Progressive disease Not evaluable 
153 CP-CML 3 No mutation detected No mutation detected T315I 8.2 Progressive disease No mutation detected 
168 CP-CML 3 T315I T315I F317L 3.9 Progressive disease T315I (100) 
228 CP-CML 2 T315I, F317L T315I, F317L F317L 8.0 Progressive disease T315I (100) 
258 CP-CML 4 M244V, F359V F359V M244V 7.3 Progressive disease Y253H, F359V (100, 100) 
281 CP-CML 3 G250E No mutation detected G250E 18.9 Progressive disease G250E (20) 
348 CP-CML 2 Y253H, F317L, H396R F317L, H396R G250E, T315I 2.7 Progressive disease F317L, H396R (60, 20) 
389 CP-CML 3 T315I, F359V F359V E255K, T315I 7.4 Progressive disease T315I (100) 
83 AP-CML 3 Y253F, E255K, T315I T315I Y253F, E255K 2.1 Discontinued therapy‖ T315I (50) 
150 AP-CML 3 E355G, L248V L248V E355G 27.5 Maintained MMR  
292 AP-CML 1 M244V, T315I M244V, T315I F359I 29.2 Lost MMR T315I (50) 
331 AP-CML 3 T315I, F317L, H396R H396R F317L 28.4 No MCyR H396R (50) 
127 AP-CML 2 T315I T315I E255V 24.8 Progressive disease Not evaluable 
130 AP-CML 2 T315I No mutation detected T315I 2.4 Progressive disease Not evaluable 
143 AP-CML 2 T315I No mutation detected F317L 20.0 Progressive disease Not evaluable 
208 AP-CML 2 T315I T315I E255V, H396R 6.2 Progressive disease T315I (100) 
278 AP-CML 2 T315I, F359C F359C T315I 31.0 Progressive disease Not evaluable 
290 AP-CML 3 T277A, F317L, M351T, L387F L387F F317L 30.9 Progressive disease Not evaluable 
301 AP-CML 2 T315I No mutation detected T315I 28.6 Progressive disease Not evaluable 
332 AP-CML 3 No mutation detected No mutation detected T315I 28.4 Progressive disease Not evaluable 
37 BP-CML 2  T315I E255K 3.2 Discontinued therapy# T315I (100) 
4 BP-CML 2 T315I T315I V299L, F317L 1.8 Progressive disease T315I (100) 
163 BP-CML 2 T315I, F359V T315I, F359V F317L 1.2 Progressive disease T315I, F359V (100, 100) 
1 BP-CML 3  No mutation detected L248V, G250E, Q252H, F317L, F359V 0.2 Death No mutation detected 
66 BP-CML 2 T315I E255K, T315I E255V 0.7 Death Not evaluable 
77 BP-CML 3 No mutation detected E255K E255V, T315I 0.0 Death Not evaluable 
88 BP-CML 3 E255K E255K E255V 2.9 Death E255K, E255V (20, 20) 
252 BP-CML 2 M244V, F317L M244V, F317L F317L 12.5 Death Not evaluable 
3 Ph+ ALL 2  F317I V299L 5.6 Progressive disease E255V, F317I (100, 100) 
93 Ph+ ALL 3 T315I T315I M351T 3.8 Progressive disease Not evaluable 
144 Ph+ ALL 2 No mutation detected E255V, T315I Q252H ×2, V299L ×2, F317L ×2 1.0 Progressive disease E255V, T315I (100, 60) 
171 Ph+ ALL 3 G250E, F317L G250E, F317L T315I, F359V 7.5 Progressive disease G250E, Y253H, E255V, T315I, F317L (10, 40, 10, 30, 100) 
167 Ph+ ALL 2 T315I No mutation detected Y253H, T315I 15.5 Death Not evaluable 
Pt IDDisease phase at study entryNumber of prior TKIsMutation history*Mutation status by Sanger sequencing at baselineLow-level mutations at baseline†Months on ponatinibOutcomeMutation status by Sanger sequencing at treatment failure or discontinuation (%)‡
109 CP-CML 3 No mutation detected No mutation detected E459K 4.2 Discontinued therapy§ Not evaluable 
210 CP-CML 3 E255K E255K G250E 10.7 Discontinued therapy§ Not evaluable 
239 CP-CML 3 M244V, E255K, T315I E255K, T315I M244V 17.6 Discontinued therapy‖ Not evaluable 
288 CP-CML 2 T315I No mutation detected T315I 21.9 Discontinued therapy‖ T315I (20) 
35 CP-CML 2 No mutation detected No mutation detected F359V 31.0 Maintained MCyR No mutation detected 
45 CP-CML 2 E255K, T315I E255K E255V, T315I 24.8 Maintained MCyR  
215 CP-CML 3 T240M, E255V, T315I T315I E255V 30.7 Maintained MCyR  
271 CP-CML 1 G250E, T315I G250E, E255V M244V, Y253H 26.3 Maintained MCyR  
253 CP-CML 2 F317L F317L F317L 27.8 Maintained MMR  
314 CP-CML 1 T315I No mutation detected M244V, G250E, F359I 28.3 Maintained MMR  
358 CP-CML 3 Y253F, D276G Y253F Q252H, T315I 28.5 Maintained MMR  
361 CP-CML 3 M244V, F359V F359V E355G 28.2 Maintained MMR  
365 CP-CML 2 T315I, F359V F359V T315I 28.4 Maintained MMR  
255 CP-CML 1 T315I T315I F317L 22.1 Lost MMR  
381 CP-CML 1 No mutation detected No mutation detected E255K 25.8 Lost MMR  
216 CP-CML 2 E355A, T315I E355A T315I 30.7 No MCyR T315I, E355A (10, 10) 
19 CP-CML 4 M351T, F359V F317L, E450G F359V 29.6 Progressive disease F317L, E450G (10, 10) 
26 CP-CML 3 V299L V299L E255K, F317L 32.2 Progressive disease E255K (70) 
47 CP-CML 2 T315I, F317L T315I F317L 3.1 Progressive disease T315I (100) 
96 CP-CML 3 T315I, F359C T315I, F359C V299L 0.9 Progressive disease Not evaluable 
97 CP-CML 3 No mutation detected No mutation detected F317L 0.9 Progressive disease Not evaluable 
153 CP-CML 3 No mutation detected No mutation detected T315I 8.2 Progressive disease No mutation detected 
168 CP-CML 3 T315I T315I F317L 3.9 Progressive disease T315I (100) 
228 CP-CML 2 T315I, F317L T315I, F317L F317L 8.0 Progressive disease T315I (100) 
258 CP-CML 4 M244V, F359V F359V M244V 7.3 Progressive disease Y253H, F359V (100, 100) 
281 CP-CML 3 G250E No mutation detected G250E 18.9 Progressive disease G250E (20) 
348 CP-CML 2 Y253H, F317L, H396R F317L, H396R G250E, T315I 2.7 Progressive disease F317L, H396R (60, 20) 
389 CP-CML 3 T315I, F359V F359V E255K, T315I 7.4 Progressive disease T315I (100) 
83 AP-CML 3 Y253F, E255K, T315I T315I Y253F, E255K 2.1 Discontinued therapy‖ T315I (50) 
150 AP-CML 3 E355G, L248V L248V E355G 27.5 Maintained MMR  
292 AP-CML 1 M244V, T315I M244V, T315I F359I 29.2 Lost MMR T315I (50) 
331 AP-CML 3 T315I, F317L, H396R H396R F317L 28.4 No MCyR H396R (50) 
127 AP-CML 2 T315I T315I E255V 24.8 Progressive disease Not evaluable 
130 AP-CML 2 T315I No mutation detected T315I 2.4 Progressive disease Not evaluable 
143 AP-CML 2 T315I No mutation detected F317L 20.0 Progressive disease Not evaluable 
208 AP-CML 2 T315I T315I E255V, H396R 6.2 Progressive disease T315I (100) 
278 AP-CML 2 T315I, F359C F359C T315I 31.0 Progressive disease Not evaluable 
290 AP-CML 3 T277A, F317L, M351T, L387F L387F F317L 30.9 Progressive disease Not evaluable 
301 AP-CML 2 T315I No mutation detected T315I 28.6 Progressive disease Not evaluable 
332 AP-CML 3 No mutation detected No mutation detected T315I 28.4 Progressive disease Not evaluable 
37 BP-CML 2  T315I E255K 3.2 Discontinued therapy# T315I (100) 
4 BP-CML 2 T315I T315I V299L, F317L 1.8 Progressive disease T315I (100) 
163 BP-CML 2 T315I, F359V T315I, F359V F317L 1.2 Progressive disease T315I, F359V (100, 100) 
1 BP-CML 3  No mutation detected L248V, G250E, Q252H, F317L, F359V 0.2 Death No mutation detected 
66 BP-CML 2 T315I E255K, T315I E255V 0.7 Death Not evaluable 
77 BP-CML 3 No mutation detected E255K E255V, T315I 0.0 Death Not evaluable 
88 BP-CML 3 E255K E255K E255V 2.9 Death E255K, E255V (20, 20) 
252 BP-CML 2 M244V, F317L M244V, F317L F317L 12.5 Death Not evaluable 
3 Ph+ ALL 2  F317I V299L 5.6 Progressive disease E255V, F317I (100, 100) 
93 Ph+ ALL 3 T315I T315I M351T 3.8 Progressive disease Not evaluable 
144 Ph+ ALL 2 No mutation detected E255V, T315I Q252H ×2, V299L ×2, F317L ×2 1.0 Progressive disease E255V, T315I (100, 60) 
171 Ph+ ALL 3 G250E, F317L G250E, F317L T315I, F359V 7.5 Progressive disease G250E, Y253H, E255V, T315I, F317L (10, 40, 10, 30, 100) 
167 Ph+ ALL 2 T315I No mutation detected Y253H, T315I 15.5 Death Not evaluable 
*

Mutation analysis performed by Sanger sequencing. Mutations detected at low levels at baseline are underlined.

†

Low-level mutations detected by MS alone (present below the detection limit of Sanger sequencing, ∼10%). Of the mutations detected by Sanger sequencing and included in the MS assay design, all except 6 were detected.

‡

Percent mutant at therapy failure/discontinuation estimated by Sanger sequencing, mutations detected at low levels at baseline are underlined; mutations not detected at baseline by either method (“new mutations”) are bold.

§

Reason for discontinuation: withdrawal by subject (n = 2).

‖

Reason for discontinuation: adverse event (n = 3).

MS detected 2 different nucleotide substitutions that both resulted in an F317L mutation in these samples, only 1 of which was also detected by Sanger sequencing.

#

Reason for discontinuation: other (n = 1).

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