Key risk factors in patients with standard-risk relapsed B-cell precursor ALL
| . | Total . | Cytogenetic goodrisk . | Cytogenetic intermediate risk . | Cytogenetic high risk . | ETV6-RUNX1 . | High hyperdiploidy . | B-other . | iAMP21 . | CDKN2A/B deletion . | IKZF1 deletion . | PAX5 alteration . | ETV6 deletion . | KRAS mutation . | NRAS mutation . | PTPN11 mutation . | P2RY8-CRLF2 . | TP53 alteration . | RB1 deletion . | NR3C1 deletion . | NR3C1/BTG1 deletion . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total, n (%)† | 343 | 186 | 112 | 25 | 76 | 110 | 104 | 16 | 67 | 39 | 33 | 32 | 19 | 16 | 16 | 15 | 13 | 11 | 10 | 17 |
| Sex ratio (% males) | 61% | 60% | 66% | 48% | 71%* | 53%* | 68% | 56% | 61% | 46% | 58% | 53% | 42% | 63% | 31%* | 60% | 38% | 73% | 50% | 59% |
| Age at relapse, n (%) | ||||||||||||||||||||
| 1-9 y | 194 (57) | 127 (68) | 46 (41) | 9 (36) | 52 (68)* | 75 (68)** | 46 (44)** | 0 (0) | 31 (46) | 11 (28) | 18 (55) | 15 (47) | 12 (63) | 12 (75) | 5 (31) | 9 (60) | 5 (38) | 4 (36) | 6 (60) | 7 (41) |
| 10-14 y | 107 (31) | 49 (26) | 42 (38) | 10 (40) | 20 (26) | 29 (26) | 38 (37) | 10 (63) | 26 (39) | 18 (46) | 11 (33) | 12 (38) | 4 (21) | 3 (19) | 8 (50) | 3 (20) | 4 (31) | 4 (36) | 2 (20) | 5 (29) |
| 15-18 y | 42 (12) | 10 (5) | 24 (21) | 6 (24) | 4 (5) | 6 (5) | 20 (19) | 6 (38)*** | 10 (15) | 10 (26) | 4 (12) | 5 (16) | 3 (16) | 1 (6) | 3 (19) | 3 (20) | 4 (31) | 3 (27) | 2 (20) | 5 (29) |
| Time to first relapse, n (%)‡ | ||||||||||||||||||||
| Very early | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Early | 86 (25) | 36 (19) | 34 (30) | 8 (32) | 13 (17) | 23 (21) | 33 (32) | 5 (31) | 10 (15) | 2 (5) | 6 (18) | 4 (13) | 1 (5) | 0 (0) | 1 (6) | 3 (20) | 2 (15) | 0 (0) | 1 (10) | 1 (6) |
| Late | 257 (75) | 150 (81) | 78 (70) | 17 (68) | 63 (82) | 87 (79) | 71 (68)* | 11 (69) | 57 (85)** | 37 (95) | 27 (82) | 28 (88) | 18 (95) | 16 (100) | 15 (94) | 12 (80)* | 11 (85) | 11 (100) | 9 (90) | 16 (94) |
| Site of first relapse, n (%)§ | ||||||||||||||||||||
| Isolated BM | 188 (55) | 107 (58) | 59 (53) | 14 (56) | 45 (59) | 62 (56) | 53 (51) | 9 (56) | 44 (66) | 35 (90) | 22 (67) | 21 (66) | 15 (79) | 12 (75) | 14 (88) | 9 (60) | 9 (69) | 9 (82) | 6 (60) | 12 (71) |
| Isolated EM | 93 (27) | 47 (25) | 30 (27) | 6 (24) | 16 (21) | 31 (28) | 29 (28) | 4 (25) | — | — | — | — | — | — | — | — | — | — | — | — |
| Combined | 62 (18) | 32 (17) | 23 (21) | 5 (20) | 15 (20) | 17 (15) | 22 (21) | 3 (19) | 23 (34)* | 4 (10)* | 11 (33) | 11 (34) | 4 (21) | 4 (25) | 2 (13) | 6 (40) | 4 (31) | 2 (18) | 4 (40) | 5 (29) |
| Minimal residual disease, n (%)¶ | ||||||||||||||||||||
| Positive | 107 (57) | 56 (55) | 35 (56) | 10 (77) | 22 (50) | 34 (59) | 33 (56) | 5 (63) | 29 (62) | 22 (69) | 19 (67) | 12 (50) | 7 (46) | 7 (70) | 9 (69) | 4 (44) | 6 (60) | 7 (78) | 7 (88) | 9 (69) |
| Negative | 80 (43) | 46 (45) | 27 (44) | 3 (23) | 22 (50) | 24 (41) | 26 (44) | 3 (38) | 18 (38) | 10 (31) | 9 (32) | 12 (50) | 6 (46) | 3 (30) | 4 (31) | 5 (55) | 4 (40) | 2 (22) | 1 (13) | 4 (31) |
| Unknown/not done | 156 | 84 | 50 | 12 | 32 | 52 | 45 | 8 | 20 | 7 | 5 | 8 | 6 | 6 | 3 | 6 | 3 | 2 | 2 | |
| Outcome of induction therapy‖ | ||||||||||||||||||||
| Induction failure | 6 (2) | 2 (1) | 3 (3) | 1 (4) | 1 (1) | 1 (1) | 3 (3) | 1 (6) | 2 (3) | 2 (5) | 3 (9) | 2 (6) | 0 (0) | 1 (6) | 0 (0) | 0 (0) | 1 (8) | 0 (0) | 0 (0) | 0 (0) |
| Induction death | 11 (3) | 2 (1) | 5 (4) | 3 (12) | 0 (0) | 2 (2) | 3 (3) | 2 (13) | 4 (6) | 4 (10) | 1 (3) | 1 (3) | 3 (16) | 1 (6) | 0 (0) | 2 (13) | 0 (0) | 0 (0) | 0 (0) | 1 (6) |
| Second CR | 326 (95) | 182 (98) | 104 (93) | 21 (84)* | 75 (99) | 107 (97) | 98 (94) | 13 (81)* | 61 (91) | 33 (85) | 29 (88) | 29 (91) | 16 (84) | 14 (88) | 16 (100) | 13 (87) | 12 (92) | 11 (100) | 10 (100) | 16 (94) |
| Outcome of patients achieving a second CR | ||||||||||||||||||||
| Relapsed | 72 (22) | 41 (23) | 22 (21) | 7 (33) | 18 (24) | 23 (22) | 20 (16) | 3 (23) | 12 (20) | 8 (24) | 8 (28) | 6 (21) | 2 (13) | 6 (43) | 2 (13) | 2 (15) | 4 (33) | 4 (36) | 5 (50) | 7 (44) |
| Died in CR | 38 (12) | 13 (7) | 17 (16) | 5 (24) | 5 (7) | 8 (7) | 16 (16) | 5 (38) | 7 (11) | 5 (15) | 1 (3) | 4 (14) | 2 (13) | 2 (14) | 2 (13) | 2 (15) | 2 (17) | 0 (0) | 1 (10) | 1 (6) |
| Continuing second CR | 216 (66) | 128 (70) | 65 (63) | 9 (43)* | 52 (69) | 76 (71) | 62 (63) | 5 (38)** | 42 (69) | 20 (61) | 20 (69) | 19 (66) | 12 (75) | 6 (43) | 12 (75) | 9 (69) | 6 (50) | 7 (64) | 4 (40) | 8 (50) |
| Survival at 5 y, % (95% CI) | ||||||||||||||||||||
| Progression-free | 56% (50-62) | 62% (54-70) | 50% (39-60) | 25% (8-46) | 60% (45-61) | 64% (52-73) | 53% (42-63) | 19% (4-44) | 60% (46-71) | 50% (33-64) | 56% (36-72) | 56% (36-72) | 61% (34-79) | 32% (10-56) | 74% (45-89) | 56% (25-78) | 43% (16-68) | 55% (18-80) | 35% (8-64) | 37% (12-62) |
| Overall | 65% (59-70) | 73% (65-80) | 57% (46-67) | 29% (9-52) | 71% (57-82) | 74% (63-82) | 61% (49-71) | 20% (3-46) | 65% (51-76) | 57% (39-71) | 68% (48-81) | 66% (45-80) | 67% (40-84) | 43% (15-69) | 73% (43-89) | 50% (16-77) | 43% (16-68) | 91% (51-99) | 53% (17-80) | 48% (19-72) |
| Hazard ratio (95% CI) from Cox model, P | ||||||||||||||||||||
| Progression-free | 0.66 (0.45-0.97), .034 | 1 | 2.49 (1.41-4.39), .002 | 0.77 (0.50-1.22), .3 | 0.64 (0.43-0.95), .026 | 1.15 (0.80-1.68), .4 | 3.62 (1.95-6.74), <.001 | 0.96 (0.58-1.59), .9 | 1.38 (0.81-2.36), .2 | 1.07 (0.58-1.96), .8 | 1.25 (0.68-2.31), .5 | 1.05 (0.48-2.30), .9 | 1.90 (0.96-3.74), .07 | 0.55 (0.20-1.51), .2 | 1.51 (0.65-3.50), .3 | 1.54 (0.71-3.35), .3 | 0.95 (0.35-2.62), .9 | 1.69 (0.72-3.95), .2 | 1.72 (0.85-3.47), .1 | |
| Overall | 0.54 (0.35-0.83), .005 | 1 | 2.30 (1.25-4.23), .008 | 0.64 (0.37-1.10), .1 | 0.57 (0.36-0.91), .018 | 1.29 (0.85-1.96), .2 | 3.75 (1.94-7.24), <.001 | 1.09 (0.72-1.64), .7 | 1.28 (0.82-2.02), .3 | 0.83 (0.49-1.41), .5 | 0.91 (0.52-1.61), .7 | 1.32 (0.72-2.41), .4 | 1.43 (0.82-2.48), .2 | 0.54 (0.22-1.33), .2 | 1.75 (0.93-3.30), .08 | 2.56 (1.61-4.06), <.001 | 0.17 (0.02-1.24), .08 | 1.71 (0.91-3.22), .098 | 1.91 (1.13-3.22), .015 | |
| . | Total . | Cytogenetic goodrisk . | Cytogenetic intermediate risk . | Cytogenetic high risk . | ETV6-RUNX1 . | High hyperdiploidy . | B-other . | iAMP21 . | CDKN2A/B deletion . | IKZF1 deletion . | PAX5 alteration . | ETV6 deletion . | KRAS mutation . | NRAS mutation . | PTPN11 mutation . | P2RY8-CRLF2 . | TP53 alteration . | RB1 deletion . | NR3C1 deletion . | NR3C1/BTG1 deletion . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total, n (%)† | 343 | 186 | 112 | 25 | 76 | 110 | 104 | 16 | 67 | 39 | 33 | 32 | 19 | 16 | 16 | 15 | 13 | 11 | 10 | 17 |
| Sex ratio (% males) | 61% | 60% | 66% | 48% | 71%* | 53%* | 68% | 56% | 61% | 46% | 58% | 53% | 42% | 63% | 31%* | 60% | 38% | 73% | 50% | 59% |
| Age at relapse, n (%) | ||||||||||||||||||||
| 1-9 y | 194 (57) | 127 (68) | 46 (41) | 9 (36) | 52 (68)* | 75 (68)** | 46 (44)** | 0 (0) | 31 (46) | 11 (28) | 18 (55) | 15 (47) | 12 (63) | 12 (75) | 5 (31) | 9 (60) | 5 (38) | 4 (36) | 6 (60) | 7 (41) |
| 10-14 y | 107 (31) | 49 (26) | 42 (38) | 10 (40) | 20 (26) | 29 (26) | 38 (37) | 10 (63) | 26 (39) | 18 (46) | 11 (33) | 12 (38) | 4 (21) | 3 (19) | 8 (50) | 3 (20) | 4 (31) | 4 (36) | 2 (20) | 5 (29) |
| 15-18 y | 42 (12) | 10 (5) | 24 (21) | 6 (24) | 4 (5) | 6 (5) | 20 (19) | 6 (38)*** | 10 (15) | 10 (26) | 4 (12) | 5 (16) | 3 (16) | 1 (6) | 3 (19) | 3 (20) | 4 (31) | 3 (27) | 2 (20) | 5 (29) |
| Time to first relapse, n (%)‡ | ||||||||||||||||||||
| Very early | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Early | 86 (25) | 36 (19) | 34 (30) | 8 (32) | 13 (17) | 23 (21) | 33 (32) | 5 (31) | 10 (15) | 2 (5) | 6 (18) | 4 (13) | 1 (5) | 0 (0) | 1 (6) | 3 (20) | 2 (15) | 0 (0) | 1 (10) | 1 (6) |
| Late | 257 (75) | 150 (81) | 78 (70) | 17 (68) | 63 (82) | 87 (79) | 71 (68)* | 11 (69) | 57 (85)** | 37 (95) | 27 (82) | 28 (88) | 18 (95) | 16 (100) | 15 (94) | 12 (80)* | 11 (85) | 11 (100) | 9 (90) | 16 (94) |
| Site of first relapse, n (%)§ | ||||||||||||||||||||
| Isolated BM | 188 (55) | 107 (58) | 59 (53) | 14 (56) | 45 (59) | 62 (56) | 53 (51) | 9 (56) | 44 (66) | 35 (90) | 22 (67) | 21 (66) | 15 (79) | 12 (75) | 14 (88) | 9 (60) | 9 (69) | 9 (82) | 6 (60) | 12 (71) |
| Isolated EM | 93 (27) | 47 (25) | 30 (27) | 6 (24) | 16 (21) | 31 (28) | 29 (28) | 4 (25) | — | — | — | — | — | — | — | — | — | — | — | — |
| Combined | 62 (18) | 32 (17) | 23 (21) | 5 (20) | 15 (20) | 17 (15) | 22 (21) | 3 (19) | 23 (34)* | 4 (10)* | 11 (33) | 11 (34) | 4 (21) | 4 (25) | 2 (13) | 6 (40) | 4 (31) | 2 (18) | 4 (40) | 5 (29) |
| Minimal residual disease, n (%)¶ | ||||||||||||||||||||
| Positive | 107 (57) | 56 (55) | 35 (56) | 10 (77) | 22 (50) | 34 (59) | 33 (56) | 5 (63) | 29 (62) | 22 (69) | 19 (67) | 12 (50) | 7 (46) | 7 (70) | 9 (69) | 4 (44) | 6 (60) | 7 (78) | 7 (88) | 9 (69) |
| Negative | 80 (43) | 46 (45) | 27 (44) | 3 (23) | 22 (50) | 24 (41) | 26 (44) | 3 (38) | 18 (38) | 10 (31) | 9 (32) | 12 (50) | 6 (46) | 3 (30) | 4 (31) | 5 (55) | 4 (40) | 2 (22) | 1 (13) | 4 (31) |
| Unknown/not done | 156 | 84 | 50 | 12 | 32 | 52 | 45 | 8 | 20 | 7 | 5 | 8 | 6 | 6 | 3 | 6 | 3 | 2 | 2 | |
| Outcome of induction therapy‖ | ||||||||||||||||||||
| Induction failure | 6 (2) | 2 (1) | 3 (3) | 1 (4) | 1 (1) | 1 (1) | 3 (3) | 1 (6) | 2 (3) | 2 (5) | 3 (9) | 2 (6) | 0 (0) | 1 (6) | 0 (0) | 0 (0) | 1 (8) | 0 (0) | 0 (0) | 0 (0) |
| Induction death | 11 (3) | 2 (1) | 5 (4) | 3 (12) | 0 (0) | 2 (2) | 3 (3) | 2 (13) | 4 (6) | 4 (10) | 1 (3) | 1 (3) | 3 (16) | 1 (6) | 0 (0) | 2 (13) | 0 (0) | 0 (0) | 0 (0) | 1 (6) |
| Second CR | 326 (95) | 182 (98) | 104 (93) | 21 (84)* | 75 (99) | 107 (97) | 98 (94) | 13 (81)* | 61 (91) | 33 (85) | 29 (88) | 29 (91) | 16 (84) | 14 (88) | 16 (100) | 13 (87) | 12 (92) | 11 (100) | 10 (100) | 16 (94) |
| Outcome of patients achieving a second CR | ||||||||||||||||||||
| Relapsed | 72 (22) | 41 (23) | 22 (21) | 7 (33) | 18 (24) | 23 (22) | 20 (16) | 3 (23) | 12 (20) | 8 (24) | 8 (28) | 6 (21) | 2 (13) | 6 (43) | 2 (13) | 2 (15) | 4 (33) | 4 (36) | 5 (50) | 7 (44) |
| Died in CR | 38 (12) | 13 (7) | 17 (16) | 5 (24) | 5 (7) | 8 (7) | 16 (16) | 5 (38) | 7 (11) | 5 (15) | 1 (3) | 4 (14) | 2 (13) | 2 (14) | 2 (13) | 2 (15) | 2 (17) | 0 (0) | 1 (10) | 1 (6) |
| Continuing second CR | 216 (66) | 128 (70) | 65 (63) | 9 (43)* | 52 (69) | 76 (71) | 62 (63) | 5 (38)** | 42 (69) | 20 (61) | 20 (69) | 19 (66) | 12 (75) | 6 (43) | 12 (75) | 9 (69) | 6 (50) | 7 (64) | 4 (40) | 8 (50) |
| Survival at 5 y, % (95% CI) | ||||||||||||||||||||
| Progression-free | 56% (50-62) | 62% (54-70) | 50% (39-60) | 25% (8-46) | 60% (45-61) | 64% (52-73) | 53% (42-63) | 19% (4-44) | 60% (46-71) | 50% (33-64) | 56% (36-72) | 56% (36-72) | 61% (34-79) | 32% (10-56) | 74% (45-89) | 56% (25-78) | 43% (16-68) | 55% (18-80) | 35% (8-64) | 37% (12-62) |
| Overall | 65% (59-70) | 73% (65-80) | 57% (46-67) | 29% (9-52) | 71% (57-82) | 74% (63-82) | 61% (49-71) | 20% (3-46) | 65% (51-76) | 57% (39-71) | 68% (48-81) | 66% (45-80) | 67% (40-84) | 43% (15-69) | 73% (43-89) | 50% (16-77) | 43% (16-68) | 91% (51-99) | 53% (17-80) | 48% (19-72) |
| Hazard ratio (95% CI) from Cox model, P | ||||||||||||||||||||
| Progression-free | 0.66 (0.45-0.97), .034 | 1 | 2.49 (1.41-4.39), .002 | 0.77 (0.50-1.22), .3 | 0.64 (0.43-0.95), .026 | 1.15 (0.80-1.68), .4 | 3.62 (1.95-6.74), <.001 | 0.96 (0.58-1.59), .9 | 1.38 (0.81-2.36), .2 | 1.07 (0.58-1.96), .8 | 1.25 (0.68-2.31), .5 | 1.05 (0.48-2.30), .9 | 1.90 (0.96-3.74), .07 | 0.55 (0.20-1.51), .2 | 1.51 (0.65-3.50), .3 | 1.54 (0.71-3.35), .3 | 0.95 (0.35-2.62), .9 | 1.69 (0.72-3.95), .2 | 1.72 (0.85-3.47), .1 | |
| Overall | 0.54 (0.35-0.83), .005 | 1 | 2.30 (1.25-4.23), .008 | 0.64 (0.37-1.10), .1 | 0.57 (0.36-0.91), .018 | 1.29 (0.85-1.96), .2 | 3.75 (1.94-7.24), <.001 | 1.09 (0.72-1.64), .7 | 1.28 (0.82-2.02), .3 | 0.83 (0.49-1.41), .5 | 0.91 (0.52-1.61), .7 | 1.32 (0.72-2.41), .4 | 1.43 (0.82-2.48), .2 | 0.54 (0.22-1.33), .2 | 1.75 (0.93-3.30), .08 | 2.56 (1.61-4.06), <.001 | 0.17 (0.02-1.24), .08 | 1.71 (0.91-3.22), .098 | 1.91 (1.13-3.22), .015 | |
Only abnormalities present in 10 or more patients were considered
P values from χ2 or log-rank tests as appropriate: *P < .05; **P < .01; ***P < .001.
Not all patients were successfully tested for all abnormalities.
Time to first relapse was defined as very early (<18 months after initial diagnosis), early (<6 months after the end of treatment), or late (>6 months after the end of treatment).
Site of relapse was defined as isolated marrow, isolated CNS, or other, which included all combined relapses as well as other isolated extramedullary relapses (eg, testes).
Minimal residual disease (MRD) was evaluated by real-time qPCR analysis of immunoglobulin and T-cell receptor gene rearrangements on marrow samples obtained at relapse and day 35 of induction, and classified as positive (>1 × 10−4) or negative (<1 × 10−4).
Induction failure was defined as ≥5% blasts, persistence of CSF blasts, or nonregression of testicular enlargement by day 35. Patients were defined as having achieved a second CR if they had <5% blasts in the marrow or no blasts in the CSF at the end of phase 1.