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M. Burke et al.
(n=4) and multi-organ failure (n=2). Of the 14 deaths report- ed among patients on experimental arm 1, five occurred while on therapy and were attributed to infection (n=3), thrombosis (n=1) and multi-organ failure (n=1). A total of 235 subjects on the control arm and 477 on experimental arm 1 completed part 2 of consolidation and had toxicity data submitted. There were no significant differences in grade 3/4 adverse events or delays in starting the interim maintenance-1 phase of therapy after consolidation between the control arm and experimental arm 1 (Table 5A). In addition, a total of 193 subjects on the control arm and 389 on experimental arm 1 completed part 2 of delayed intensification and had toxicity data submitted. There were no significant differences in grade 3/4 adverse events or delays in starting the interim maintenance-1 phase of ther-
Table 3. Summary of disease-free survival events by randomization arm.
apy after delayed intensification between the control arm and experimental arm 1 (Table 5B).
One-hundred and seven patients went off therapy during consolidation or interim maintenance-1, with the reason stated being “physician determines it is in the best interest of the patient” (n=86; 32 in the control arm and 54 in exper- imental arm 1) or “refusal of further protocol therapy by patient/parent/guardian” (n=21; 3 in the control arm and 18 in experimental arm 1): Some of these patients may have proceeded to hematopoietic stem cell transplantation. Long-term study outcomes may be published in the future when follow-up data are more mature.
Discussion
The 5-year event-free survival rate for patients with high- risk B-ALL enrolled in the COG AALL0232 trial (2004 – 2011) randomized to high-dose methotrexate during inter- im maintenance-1 was 79.6% compared to 75.2% for the patients in the control arm (Capizzi methotrexate) (P=0.008) of that study.3 Patients identified as having VHR B-ALL are predicted to fare worse than high-risk patients overall and, depending on the specific VHR risk factors, their 4-year DFS rates can range anywhere from 40 to 80%.8,13-22 Based on the relatively poor outcomes for these VHR patients, they are candidates for investigation of novel, more intensive, yet potentially more toxic, therapeu- tic strategies designed to improve DFS. Based on this hypothesis, and without mature data from the AALL0232 study available at the time of study development, the COG high-risk B-ALL study AALL1131 was designed to further intensify cytotoxic chemotherapy during the consolidation
DFS event
None
Relapse
Isolated BM
Isolated CNS
Combined BM + CNS Combined BM + CNS + Other Other
Secondary malignancy
Death
Death on therapy Death in Follow-up
CA (N=240)
212 (88.3%)
16 (6.7%) 7
4
2
0
3
0 (0.0%)
12 (5.0%) 6
6
Exp 1 (N=483)
421 (87.2%)
47 (9.7%) 32
7
2
1
5
1 (0.2%)*
14 (2.9%) 5
9
CA: control arm; Exp 1: experimental arm 1; BM: bone marrow; CNS: central nervous system; *acute myeloid leukemia.
Table 4. Cumulative incidence rates for types of relapse by randomization arm.
Relapse type
Isolated BM
Isolated CNS
Combined BM + CNS
Other
VHR CA
4-year cumulative incidence
VHR Exp 1
4-year cumulative incidence
P-value
0.025
0.880
0.525
0.817
Rate ±SE
2.5±1.1%
2.3±1.2%
0.9±0.6%
1.5±0.9%
95% CI
(0.9%, 5.5%)
(0.7%, 5.6%)
(0.2%, 3.0%)
(0.4%, 4.1%)
Rate ±SE
14.5±3.3%
3.9±1.7%
2.8±2.2%
1.4±0.7%
95% CI
(8.8%, 21.6%)
(1.5%, 8.3%)
(0.4%, 9.6%)
(0.5%, 3.2%)
VHR: very high risk; CA: control arm; Exp 1: experimental arm 1; SE: standard error; 95% CI: 95% confidence interval; BM: bone marrow; CNS: central nervous system.
Table 5A. Toxicities in patients completing part 2 of consolidation.
Table 5B. Toxicities in patients completing part 2 of the delayed inten- sification.
Targeted toxicity Grade (Gr)
Gr 4 infection
Gr 3/4 AST/ALT*
Gr 4 lipase/amylase* Gr 3/4 bilirubin*
Gr 3/4 pancreatitis
Gr 3/4 acute kidney injury
Gr 3/4 non-hematologic*
Delays >14 days in
CA (N=235)
6 (2.6%)
5 (2.1%)
5 (2.1%) 0
5 (2.1%) 64 (27.2%)
P-value 12 (2.5%) 0.98
Exp 1 (N=477)
P-value 20 (5.1%) 0.98
4 (1.0%) 0.21
9 (2.3%) 0.23 1 (0.3%) 0.65 15 (3.9%) 0.40 84 (21.6%) 0.16
Grade 3 and 4 targeted toxicities (CTCAE v4.0). *Do not return to grade ≤2 by the time day 43 vincristine and asparaginase are scheduled to be administered during delayed intensification. CA, control arm; Exp 1, experimental arm 1.
Targeted toxicity Grade (Gr)
Gr 4 infection
Gr 3/4 AST/ALT*
Gr 4 lipase/amylase* Gr 3/4 bilirubin*
Gr 3/4 pancreatitis
Gr 3/4 acute kidney injury
Gr 3/4 non-hematologic*
Delays >14 days in
CA (N=193)
10 (5.2%)
5 (2.6%)
2 (1.0%)
1 (0.5%)
5 (2.6%)
49 (25.4%)
Exp 1 (N=389)
8 (1.7%)
0.68
6 (1.3%) 0.21 0 NA 20 (4.2%) 0.12
102 (21.4%) 0.09
starting interim maintenance
Grade 3 and 4 targeted toxicities (CTCAE v4.0).*Do not return to grade ≤2 by the time day 43 vincristine and asparaginase are scheduled to be administered during consol- idation. CA, control arm; Exp 1, experimental arm 1.
starting interim maintenance
990
haematologica | 2019; 104(5)