Demographic and clinical features of patients with relapsed B‐cell precursor ALL harboring specific chromosomal abnormalities
| . | Total . | Clinical risk group . | Cytogenetic risk group . | Individual chromosomal abnormalities . | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| . | Standard . | High . | Good . | Intermediate . | High . | ETV6-RUNX1 . | High hyperdiploid . | t(1;19)(q21;p13) . | IGH translocation† . | B‐other . | KMT2A . | iAMP21 . | Haploidy . | Low hypodploidy . | t(17;19)(q23p13) . | t(9;22)(q34;q11) . | |
| Total, n (%) | 449 | 343 (76) | 106 (24) | 207 (48) | 163 (38) | 57 (13) | 83 (19) | 124 (29) | 9 (2) | 10 (3) | 144 (34) | 23 (5) | 19 (4) | 5 (1) | 5 (1) | 3 (1) | 2 (1) |
| Sex (male), % | 61 | 61 | 62 | 62 | 64 | 49 | 71 | 56 | 33 | 40 | 68 | 48 | 63 | 40 | 20 | 33 | 50 |
| Age at relapse, n (%) | |||||||||||||||||
| 1‐9 y | 259 (58) | 194 (57) | 65 (61)*** | 143 (69) | 74 (45) | 30 (53)*** | 58 (70)* | 85 (69)*** | 4 (44) | 1 (10)*** | 69 (48)** | 23 (100)*** | 0 (0)*** | 3 (60) | 2 (40) | 1 (33)* | 1 (50) |
| 10‐14 y | 123 (27) | 107 (31) | 16 (15) | 52 (25) | 51 (31) | 14 (25) | 20 (24) | 32 (26) | 4 (44) | 3 (30) | 44 (31) | 0 (0) | 11 (58) | 1 (20) | 1 (20) | 0 (0) | 1 (50) |
| 15‐18 y | 67 (15) | 42 (12) | 25 (24) | 12 (6) | 38 (23) | 13 (23) | 5 (6) | 7 (6) | 1 (11) | 6 (60) | 31 (22) | 0 (0) | 8 (42) | 1 (20) | 2 (40) | 2 (67) | 0 (0) |
| Time to first relapse, n (%)‡ | |||||||||||||||||
| Very early | 47 (10) | 0 (0) | 47 (44) | 2 (1) | 27 (17) | 17 (30)*** | 2 (2)*** | 0 (0)*** | 5 (56)*** | 1 (10) | 21 (15)* | 12 (52)*** | 0 (0) | 2 (40) | 2 (40) | 1 (33) | 0 (0) |
| Early | 144 (32) | 86 (25) | 58 (55) | 55 (27) | 57 (35) | 23 (40) | 18 (22) | 37 (30) | 3 (33) | 3 (30) | 51 (35) | 8 (35) | 8 (42) | 2 (40) | 2 (40) | 2 (67) | 1 (50) |
| Late | 258 (57) | 257 (75) | 1 (1) 7 | 150 (72) | 79 (48) | 17 (30) | 63(76) | 87(70) | 1(11) | 6(60) | 72 (50) | 3(13) | 11(58) | 1 (20) | 1 (20) | 0 (0) | 1 (50) |
| Site of first relapse, n (%)§ | |||||||||||||||||
| Isolated BM | 273 (61) | 188 (55) | 85 (80) | 126 (61) | 96 (59) | 42 (74) | 51 (61) | 75 (60) | 5 (56) | 9 (90) | 82 (57) | 16 (70) | 12 (63) | 5 (100) | 5 (100) | 3 (100) | 1 (50) |
| Isolated EM | 105 (23) | 93 (27) | 12 (11) | 48 (23) | 37 (23) | 9 (16) | 17(20) | 31(25) | 2(22) | 1(10) | 34 (24) | 5(22) | 4(21) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Combined | 71 (16) | 62 (18) | 9 (8) | 33 (16) | 30 (18) | 6 (11) | 15(18) | 18(15) | 2(22) | 0 (0) | 28 (19) | 2(9) | 3(16) | 0 (0) | 0 (0) | 0 (0) | 1 (50) |
| Clinical risk group, n (%)¶ | |||||||||||||||||
| Standard | 343 (76) | — | — | 186 (90) | 112 (69) | 25 (44)*** | 76 (92)*** | 110 (89)*** | 2 (22)*** | 6 (60) | 104 (72) | 6 (26)*** | 16 (84) | 4 (80)** | 4 (80)** | 0 (0) | 1 (50) |
| High | 106 (24) | — | — | 21 (10) | 51 (31) | 32 (56) | 7 (8) | 14 (11) | 7 (78) | 4 (40) | 40 (28) | 17 (74) | 3 (16) | 1 (20) | 1 (20) | 3 (100)** | 1 (50) |
| Minimal residual disease, n (%)‖ | |||||||||||||||||
| Positive | 144 (59) | 107 (57) | 37 (65) | 65 (57) | 55 (61) | 18 (62) | 26 (54) | 39 (58) | 3 (75) | 3 (100) | 49 (59) | 4 (44) | 8 (73) | 3 (100) | 3 (75) | 0 (0) | 0 (0) |
| Negative | 100 (41) | 80 (43) | 20 (35) | 50 (43) | 35 (39) | 11 (38) | 22 (46) | 28 (42) | 1 (25) | 0 (0) | 34 (41) | 5 (56) | 3 (27) | 0 (0) | 1 (25) | 1 (100) | 1 (100) |
| Unknown/not done | 205 | 156 | 49 | 92 | 73 | 28 | 35 | 57 | 5 | 7 | 61 | 14 | 8 | 2 | 1 | 2 | 0 |
| Outcome of induction therapy# | |||||||||||||||||
| Induction failure | 25 (6) | 6 (2) | 19 (18)*** | 3 (1) | 13 (8) | 9 (16)*** | 1(1)* | 2(2)* | 3(33)* | 1(10)* | 9 (6) | 3 (13) | 1(5) | 2 (40)** | 1 (20) | 2 (67)*** | 0 (0) |
| Induction death | 19 (4) | 11 (3) | 8 (8) | 4 (2) | 8 (5) | 6 (11) | 1 (1) | 3 (2) | 0 (0) | 2 (20) | 6 (4) | 2 (9) | 2 (11) | 0 (0) | 1 (20) | 0 (0) | 1 (50) |
| Second CR | 405 (90) | 326 (95) | 79 (75) | 200 (97) | 142 (87) | 42 (74) | 81 (98) | 119 (96) | 6 (67) | 7 (70) | 129 (90) | 18 (78) | 16 (84) | 3 (60) | 3 (60) | 1 (33) | 1 (50) |
| Outcome of patients achieving a second remission | |||||||||||||||||
| Relapsed | 108 (27) | 72 (22) | 36 (46)*** | 50 (25) | 38 (27) | 18 (43)*** | 21 (26) | 29 (24) | 3 (50) | 2 (29) | 33 (26) | 8 (44) | 5 (31)** | 3 (100)* | 2 (67) | 0 (0)* | 0 (0) |
| Died in CR | 54 (13) | 38 (12) | 16 (20) | 17 (9) | 24 (17) | 9 (21) | 6 (7) | 11 (9) | 1 (17) | 2 (29) | 21 (16) | 2 (11) | 6 (38) | 0 (0) | 0 (0) | 1 (100) | 0 (0) |
| Continuing second CR | 243 (60) | 216 (66) | 27 (34) | 133 (67) | 80 (56) | 15 (36) | 54 (67) | 79 (66) | 2 (33) | 3 (43) | 75 (58) | 8 (44) | 5 (31) | 0 (0) | 1 (33) | 0 (0) | 1 (100) |
| Survival at 5 y, % (95% CI) | |||||||||||||||||
| Progression-free | 48% (43‐53) | 56% (50‐62) | 24% (16‐33) | 58% (50‐65) | 43% (35‐52) | 20% (10‐33) | 57% (44‐68) | 58% (48‐67) | 22% (3‐51) | 17% (9‐50) | 47% (37‐55) | 31% (13‐52) | 16% (3‐37) | 0% | 20% (8‐58) | 0% | 50% (1‐91) |
| Overall | 55% (50‐60) | 65% (59‐70) | 26% (17‐35) | 68% (60‐75) | 47% (38‐56) | 26% (14‐40) | 67% (54‐77) | 68% (58‐77) | 22% (3‐51) | 16% (9‐49) | 52% (42‐60) | 42% (22‐61) | 16% (3‐39) | 0% | 40% (5‐75) | 0% | 50% (1‐91) |
| Hazard ratio (95% CI), P | |||||||||||||||||
| Progression-free | — | 1 | 3.45 (2.60‐4.60), <.001 | 0.58 (0.43‐0.80), .001 | 1 | 2.30 (1.59‐3.35), <.001 | 0.62 (0.42‐0.92), .017 | 0.57 (0.41‐0.80), .001 | 2.85 (1.34‐6.06), .007 | 2.05 (0.96‐4.35), .06 | 1.06 (0.79‐1.41),.7 | 2.15 (1.27‐3.81), .004 | 2.54 (1.47‐4.38), .001 | 6.67 (2.70‐16.47), <.001 | 3.11 (1.15‐8.37),.03 | 17.06 (5.28‐55.13), <.001 | 1.23 (0.17‐8.76),.8 |
| Overall | — | 1 | 4.15 (3.07‐5.61), <.001 | 0.48 (0.34‐0.67), <.001 | 1 | 2.17 (1.47‐3.20), <.001 | 0.51 (0.33‐0.81), .004 | 0.50 (0.34‐0.73), <.001 | 3.30 (1.55‐7.05), .002 | 2.48 (1.16‐5.29), .019 | 1.15 (0.84‐1.56),.4 | 2.20 (1.27‐3.81), .005 | 2.52 (1.43‐4.45), .001 | 6.85 (2.77‐16.91), <.001 | 2.71 (0.86‐8.50),.08 | 17.69 (5.49‐57.00), <.001 | 1.53 (0.21‐10.90),.7 |
| . | Total . | Clinical risk group . | Cytogenetic risk group . | Individual chromosomal abnormalities . | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| . | Standard . | High . | Good . | Intermediate . | High . | ETV6-RUNX1 . | High hyperdiploid . | t(1;19)(q21;p13) . | IGH translocation† . | B‐other . | KMT2A . | iAMP21 . | Haploidy . | Low hypodploidy . | t(17;19)(q23p13) . | t(9;22)(q34;q11) . | |
| Total, n (%) | 449 | 343 (76) | 106 (24) | 207 (48) | 163 (38) | 57 (13) | 83 (19) | 124 (29) | 9 (2) | 10 (3) | 144 (34) | 23 (5) | 19 (4) | 5 (1) | 5 (1) | 3 (1) | 2 (1) |
| Sex (male), % | 61 | 61 | 62 | 62 | 64 | 49 | 71 | 56 | 33 | 40 | 68 | 48 | 63 | 40 | 20 | 33 | 50 |
| Age at relapse, n (%) | |||||||||||||||||
| 1‐9 y | 259 (58) | 194 (57) | 65 (61)*** | 143 (69) | 74 (45) | 30 (53)*** | 58 (70)* | 85 (69)*** | 4 (44) | 1 (10)*** | 69 (48)** | 23 (100)*** | 0 (0)*** | 3 (60) | 2 (40) | 1 (33)* | 1 (50) |
| 10‐14 y | 123 (27) | 107 (31) | 16 (15) | 52 (25) | 51 (31) | 14 (25) | 20 (24) | 32 (26) | 4 (44) | 3 (30) | 44 (31) | 0 (0) | 11 (58) | 1 (20) | 1 (20) | 0 (0) | 1 (50) |
| 15‐18 y | 67 (15) | 42 (12) | 25 (24) | 12 (6) | 38 (23) | 13 (23) | 5 (6) | 7 (6) | 1 (11) | 6 (60) | 31 (22) | 0 (0) | 8 (42) | 1 (20) | 2 (40) | 2 (67) | 0 (0) |
| Time to first relapse, n (%)‡ | |||||||||||||||||
| Very early | 47 (10) | 0 (0) | 47 (44) | 2 (1) | 27 (17) | 17 (30)*** | 2 (2)*** | 0 (0)*** | 5 (56)*** | 1 (10) | 21 (15)* | 12 (52)*** | 0 (0) | 2 (40) | 2 (40) | 1 (33) | 0 (0) |
| Early | 144 (32) | 86 (25) | 58 (55) | 55 (27) | 57 (35) | 23 (40) | 18 (22) | 37 (30) | 3 (33) | 3 (30) | 51 (35) | 8 (35) | 8 (42) | 2 (40) | 2 (40) | 2 (67) | 1 (50) |
| Late | 258 (57) | 257 (75) | 1 (1) 7 | 150 (72) | 79 (48) | 17 (30) | 63(76) | 87(70) | 1(11) | 6(60) | 72 (50) | 3(13) | 11(58) | 1 (20) | 1 (20) | 0 (0) | 1 (50) |
| Site of first relapse, n (%)§ | |||||||||||||||||
| Isolated BM | 273 (61) | 188 (55) | 85 (80) | 126 (61) | 96 (59) | 42 (74) | 51 (61) | 75 (60) | 5 (56) | 9 (90) | 82 (57) | 16 (70) | 12 (63) | 5 (100) | 5 (100) | 3 (100) | 1 (50) |
| Isolated EM | 105 (23) | 93 (27) | 12 (11) | 48 (23) | 37 (23) | 9 (16) | 17(20) | 31(25) | 2(22) | 1(10) | 34 (24) | 5(22) | 4(21) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Combined | 71 (16) | 62 (18) | 9 (8) | 33 (16) | 30 (18) | 6 (11) | 15(18) | 18(15) | 2(22) | 0 (0) | 28 (19) | 2(9) | 3(16) | 0 (0) | 0 (0) | 0 (0) | 1 (50) |
| Clinical risk group, n (%)¶ | |||||||||||||||||
| Standard | 343 (76) | — | — | 186 (90) | 112 (69) | 25 (44)*** | 76 (92)*** | 110 (89)*** | 2 (22)*** | 6 (60) | 104 (72) | 6 (26)*** | 16 (84) | 4 (80)** | 4 (80)** | 0 (0) | 1 (50) |
| High | 106 (24) | — | — | 21 (10) | 51 (31) | 32 (56) | 7 (8) | 14 (11) | 7 (78) | 4 (40) | 40 (28) | 17 (74) | 3 (16) | 1 (20) | 1 (20) | 3 (100)** | 1 (50) |
| Minimal residual disease, n (%)‖ | |||||||||||||||||
| Positive | 144 (59) | 107 (57) | 37 (65) | 65 (57) | 55 (61) | 18 (62) | 26 (54) | 39 (58) | 3 (75) | 3 (100) | 49 (59) | 4 (44) | 8 (73) | 3 (100) | 3 (75) | 0 (0) | 0 (0) |
| Negative | 100 (41) | 80 (43) | 20 (35) | 50 (43) | 35 (39) | 11 (38) | 22 (46) | 28 (42) | 1 (25) | 0 (0) | 34 (41) | 5 (56) | 3 (27) | 0 (0) | 1 (25) | 1 (100) | 1 (100) |
| Unknown/not done | 205 | 156 | 49 | 92 | 73 | 28 | 35 | 57 | 5 | 7 | 61 | 14 | 8 | 2 | 1 | 2 | 0 |
| Outcome of induction therapy# | |||||||||||||||||
| Induction failure | 25 (6) | 6 (2) | 19 (18)*** | 3 (1) | 13 (8) | 9 (16)*** | 1(1)* | 2(2)* | 3(33)* | 1(10)* | 9 (6) | 3 (13) | 1(5) | 2 (40)** | 1 (20) | 2 (67)*** | 0 (0) |
| Induction death | 19 (4) | 11 (3) | 8 (8) | 4 (2) | 8 (5) | 6 (11) | 1 (1) | 3 (2) | 0 (0) | 2 (20) | 6 (4) | 2 (9) | 2 (11) | 0 (0) | 1 (20) | 0 (0) | 1 (50) |
| Second CR | 405 (90) | 326 (95) | 79 (75) | 200 (97) | 142 (87) | 42 (74) | 81 (98) | 119 (96) | 6 (67) | 7 (70) | 129 (90) | 18 (78) | 16 (84) | 3 (60) | 3 (60) | 1 (33) | 1 (50) |
| Outcome of patients achieving a second remission | |||||||||||||||||
| Relapsed | 108 (27) | 72 (22) | 36 (46)*** | 50 (25) | 38 (27) | 18 (43)*** | 21 (26) | 29 (24) | 3 (50) | 2 (29) | 33 (26) | 8 (44) | 5 (31)** | 3 (100)* | 2 (67) | 0 (0)* | 0 (0) |
| Died in CR | 54 (13) | 38 (12) | 16 (20) | 17 (9) | 24 (17) | 9 (21) | 6 (7) | 11 (9) | 1 (17) | 2 (29) | 21 (16) | 2 (11) | 6 (38) | 0 (0) | 0 (0) | 1 (100) | 0 (0) |
| Continuing second CR | 243 (60) | 216 (66) | 27 (34) | 133 (67) | 80 (56) | 15 (36) | 54 (67) | 79 (66) | 2 (33) | 3 (43) | 75 (58) | 8 (44) | 5 (31) | 0 (0) | 1 (33) | 0 (0) | 1 (100) |
| Survival at 5 y, % (95% CI) | |||||||||||||||||
| Progression-free | 48% (43‐53) | 56% (50‐62) | 24% (16‐33) | 58% (50‐65) | 43% (35‐52) | 20% (10‐33) | 57% (44‐68) | 58% (48‐67) | 22% (3‐51) | 17% (9‐50) | 47% (37‐55) | 31% (13‐52) | 16% (3‐37) | 0% | 20% (8‐58) | 0% | 50% (1‐91) |
| Overall | 55% (50‐60) | 65% (59‐70) | 26% (17‐35) | 68% (60‐75) | 47% (38‐56) | 26% (14‐40) | 67% (54‐77) | 68% (58‐77) | 22% (3‐51) | 16% (9‐49) | 52% (42‐60) | 42% (22‐61) | 16% (3‐39) | 0% | 40% (5‐75) | 0% | 50% (1‐91) |
| Hazard ratio (95% CI), P | |||||||||||||||||
| Progression-free | — | 1 | 3.45 (2.60‐4.60), <.001 | 0.58 (0.43‐0.80), .001 | 1 | 2.30 (1.59‐3.35), <.001 | 0.62 (0.42‐0.92), .017 | 0.57 (0.41‐0.80), .001 | 2.85 (1.34‐6.06), .007 | 2.05 (0.96‐4.35), .06 | 1.06 (0.79‐1.41),.7 | 2.15 (1.27‐3.81), .004 | 2.54 (1.47‐4.38), .001 | 6.67 (2.70‐16.47), <.001 | 3.11 (1.15‐8.37),.03 | 17.06 (5.28‐55.13), <.001 | 1.23 (0.17‐8.76),.8 |
| Overall | — | 1 | 4.15 (3.07‐5.61), <.001 | 0.48 (0.34‐0.67), <.001 | 1 | 2.17 (1.47‐3.20), <.001 | 0.51 (0.33‐0.81), .004 | 0.50 (0.34‐0.73), <.001 | 3.30 (1.55‐7.05), .002 | 2.48 (1.16‐5.29), .019 | 1.15 (0.84‐1.56),.4 | 2.20 (1.27‐3.81), .005 | 2.52 (1.43‐4.45), .001 | 6.85 (2.77‐16.91), <.001 | 2.71 (0.86‐8.50),.08 | 17.69 (5.49‐57.00), <.001 | 1.53 (0.21‐10.90),.7 |
P values from χ2 or log-rank tests as appropriate are represented as: *P < .05; **P < .01; ***P < .001.
Follow‐up was short for patients with IGH translocations. The PFS rate was quoted at 3.8 years and the OS rate at 4.8 years.
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 extramedullary (EM), or other, which included all combined relapses.
Patients with very early relapses or early isolated marrow relapses were classified as clinically high risk, whereas all other patients were classified as clinical intermediate/standard risk.
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 cerebrospinal fluid (CSF) blasts, or nonregression of testicular enlargement by day 35. Patients were defined as having achieved a second complete remission (CR) if they had <5% blasts in the marrow or no blasts in the CSF at the end of phase 1.