TABLE 3.
Event Rates and Randomized Comparisons by Arm and in the Trial Overall
| Event | Standard | Short | SIM | HDM | Pulses | No Pulses | All Patients |
|---|---|---|---|---|---|---|---|
| Induction failure,a No. (%) | 34 (3.6) | 42 (4.4) | 4 (0.5) | 10 (1.3) | 6 (0.8) | 8 (1.0) | 114 (4.2) |
| P = .41 | |||||||
| Induction TRM, No. (%) | 6 (0.6) | 10 (1.1) | — | — | — | — | 17 (0.6) |
| P = .45 | |||||||
| High-risk MRD at week 14 (TP2), No. (%) | 5 (0.5) | 8 (0.8) | — | — | — | — | 15 (0.6) |
| P = .58 | |||||||
| EFS | |||||||
| Events, No./n | 165/950 | 196/952 | 137/783 | 133/787 | 117/784 | 153/786 | 481/2,750 |
| 5-year EFS rate, % (range) | 83.9 (81.4-86.1) | 81.7 (78.1-84.0) | 84.0 (81.2-86.4) | 84.8 (82.1-87.2) | 86.7 (84.1-88.9) | 82.1 (79.2-84.7) | 83.9 (82.5-85.3) |
| HR (95% CI) | 1.21 (0.98 to 1.49) P = .069 |
0.97 (0.77 to 1.24) P = .83 |
1.34 (1.06 to 1.71) P = .016 |
— | |||
| OS | |||||||
| Deaths, No./n | 100/950 | 103/952 | 66/783 | 59/787 | 52/784 | 73/786 | 251/2,750 |
| 5-year OS rate, % (range) | 91.5 (89.5-93.1) | 90.8 (88.7-92.5) | 93.3 (91.3-94.9) | 93.4 (91.4-94.9) | 94.7 (92.9-96.1) | 91.9 (89.8-93.7) | 92.2 (91.1-93.1) |
| HR (95% CI) | 1.04 (0.79 to 1.37) P = .78 |
0.89 (0.63 to 1.27) P = .53 |
1.42 (1.00 to 2.03) P = .050 |
— | |||
| Relapse | |||||||
| Relapse, No./n | 129/950 | 169/952 | 125/783 | 122/787 | 110/784 | 137/786 | 403/2,750 |
| 5-year cumulative incidence, % (range) | 12.6 (10.6-14.9) | 15.7 (13.5-18.2) | 14.5 (12.2-17.2) | 14.3 (12.0-16.9) | 12.7 (10.5-15.2) | 16.1 (13.7-18.9) | 13.4 (12.2-14.8) |
| HR (95% CI) | 1.34 (1.07 to 1.69) P = .012 |
0.98 (0.77 to 1.26) P = .89 |
1.27 (0.99 to 1.63) P = .062 |
— | |||
| BM relapse (ALL only)b | |||||||
| BM relapse, No./n | 97/901 | 121/904 | 92/783 | 83/787 | 76/729 | 86/701 | 291/2,601 |
| 5-year cumulative incidence, % (range) | 9.8 (8.0-11.9) | 11.4 (9.5-13.7) | 11.2 (9.1-13.8) | 9.6 (7.7-12.0) | 9.0 (7.1-11.4) | 11.1 (9.0-13.7) | 10.0 (8.9-11.2) |
| HR (95% CI) | 1.26 (0.96 to 1.65) P = .089 |
0.89 (0.66 to 1.19) P = .42 |
1.19 (0.87 to 1.62) P = .27 |
— | |||
| 5-year difference | +1.7% (–1.5% to 4.1%) | ||||||
| CNS relapse | |||||||
| CNS relapse, No./n | 44/950 | 65/952 | 46/783 | 45/787 | 39/784 | 52/786 | 148/2,750 |
| 5-year cumulative incidence, % (range) | 4.4 (3.3-5.9) | 6.3 (4.9-8.1) | 5.3 (3.9-7.2) | 5.5 (4.1-7.4) | 4.7 (3.4-6.4) | 6.2 (4.7-8.1) | 5.1 (4.3-6.0) |
| HR (95% CI) | 1.50 (1.02 to 2.19) P = .038 |
0.98 (0.65 to 1.49) P = .94 |
1.35 (0.89 to 2.04) P = .16 |
— | |||
| Isolated CNS relapse | |||||||
| Isolated CNS relapse, No./n | 22/950 | 41/952 | 26/783 | 32/787 | 23/784 | 35/786 | 90/2,750 |
| 5-year cumulative incidence, % (range) | 2.3 (1.5-3.4) | 4.2 (3.1-5.6) | 3.1 (2.1-4.6) | 4.1 (2.9-5.8) | 3.0 (2.0-4.4) | 4.2 (3.0-5.9) | 3.2 (2.6-4.0) |
| HR (95% CI) | 1.88 (1.12 to 3.16) P = .015 |
1.24 (0.74 to 2.08) P = .42 |
1.53 (0.90 to 2.59) P = .11 |
— | |||
| Non-BM relapse | |||||||
| Non-BM relapse, No./n | 33/950 | 47/952 | 32/783 | 39/787 | 30/784 | 41/786 | 110/2,750 |
| 5-year cumulative incidence, % (range) | 3.4 (2.4-4.8) | 4.7 (3.5-6.3) | 3.7 (2.6-5.3) | 5.0 (3.7-6.8) | 3.7 (2.6-5.3) | 5.0 (3.7-6.8) | 3.9 (3.3-4.7) |
| HR (95% CI) | 1.43 (0.92 to 2.24) P = .11 |
1.23 (0.77 to 1.96) P = .39 |
1.38 (0.86 to 2.20) P = .18 |
— | |||
| Second cancer (as first event) | |||||||
| SMN, No./n | 18/950 | 4/952 | 10/783 | 8/787 | 3/784 | 15/786 | 26/2,750 |
| 5-year cumulative incidence, % (range) | 1.6 (1.0-2.7) | 0.4 (0.2-1.1) | 1.3 (0.7-2.4) | 0.8 (0.4-1.7) | 0.3 (0.1-1.0) | 1.8 (1.1-3.0) | 0.8 (0.5-1.2) |
| HR (95% CI) | 0.22 (0.07 to 0.65) P = .0027 |
0.80 (0.32 to 2.02) P = .63 |
5.02 (1.45 to 17.35) P = .0045 |
— | |||
| Death in CR | |||||||
| Deaths, No./n | 22/942 | 16/940 | 9/783 | 5/787 | 4/784 | 10/786 | 47/2,728 |
| 5-year cumulative incidence, % (range) | 2.1 (1.3-3.2) | 1.4 (0.8-2.4) | 0.9 (0.4-1.9) | 0.4 (0.1-1.2) | 0.4 (0.1-1.2) | 0.9 (0.4-1.9) | 1.5 (1.1-2.1) |
| HR (95% CI) | 0.73 (0.38 to 1.39) P = .34 |
0.56 (0.19 to 1.67) P = .29 |
2.49 (0.78 to 7.95) P = .11 |
— | |||
| Trial treatment-related deathc | |||||||
| Deaths, No./n | 16/942 | 11/940 | 9/783 | 5/787 | 4/784 | 10/786 | 31/2,728 |
| 5-year cumulative incidence, % (range) | 1.4 (0.8-2.4) | 0.9 (0.4-1.7) | 0.9 (0.4-1.9) | 0.4 (0.1-1.2) | 0.4 (0.1-1.2) | 0.9 (0.4-1.9) | 0.9 (0.6-1.4) |
| HR (95% CI) | 0.69 (0.32 to 1.49) P = .35 |
0.56 (0.20 to 1.66) P = .30 |
2.49 (0.78 to 7.95) P = .11 |
— | |||
NOTE. All results given in the table are ITT except for the BM relapse pulse random assignment. Rates of induction failure, TRM, and high-risk MRD were compared using Fisher's exact tests; EFS and OS were analyzed using Kaplan-Meier survival analysis with treatment arms compared using Cox regression and the log-rank test. Time to relapse (including site-specific relapse), incidence of second cancer, and trial treatment-related deaths/death in CR were analyzed using competing risks survival analysis by the method of Fine and Grey. For R1 and whole-cohort analyses, times are measured from the date of R1 random assignment/registration and for R2 from the date of R2 random assignment with patients not experiencing an event censored at the date last seen.
Abbreviations: BM, bone marrow; CR, complete remission; EFS, event-free survival; EOI, end of induction; HDM, high-dose methotrexate; HR, hazard ratio; ITT, intention-to-treat; MRD, minimal residual disease; OS, overall survival; R1, randomization 1; R2, randomization 2; SCT, stem cell transplant; SIM, standard interim maintenance; SMN, secondary malignancy; TRM, treatment-related mortality.
M2 or M3 marrow at EOI, ≥5% MRD at EOI or ≥0.5% at end of consolidation, death from ALL in induction, or trial termination for failure to achieve remission without BM blasts of MRD available. All patients who remained on protocol and were randomly assigned at R2 were induction failures on the basis of MRD (>5%) and all achieved MRD <0.5% by end of consolidation.
ALL patients only, patients who died of ALL during induction (N = 2) are included as events.
SCT (in first CR) also treated as a competing risk.