Table 3.
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 | |
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.