Exploring the role of bortezomib in newly diagnosed T-ALL/T-LL patients: a phase III COG AALL1231 clinical trial

Currently, children with relapsed T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL) have a poor prognosis (5-year overall survival [OS] rate <35%)
.

Therefore, the Children's Oncology Group (COG) research focuses on preventing recurrence in newly diagnosed patients through improved risk stratification, introduction of new drugs, and intensive chemotherapy
.

The COG AALL0434 trial reported excellent outcomes in children and young adults with T-ALL and T-LL, superior to high-dose methotrexate (HDMTX) in addition to an enhanced aBFM regimen with dose-escalating methotrexate (C-MTX) ) combined with aBFM, and the addition of six 5-day courses of nerabine improved disease-free survival (DFS)
.

Although DFS and OS are good, recurrence is still the main cause of treatment failure
.

Furthermore, 90% of patients with AALL0434 T-ALL received cranial radiotherapy (CRT)
.

Encouraged by the compelling biological rationale and favorable preclinical data of the proteasome inhibitor bortezomib, safety and efficacy in patients with relapsed T-ALL/T-LL in the COG AALL07P1 trial
.

The investigators conducted a follow-up phase III trial (COG AALL1231 trial) with the primary objective of comparing random assignment to modified aBFM with/without bortezomib in T-ALL/ Event-free survival (EFS) in children and young adults with T-LL
.

A secondary objective was to determine whether prophylactic CRT could be safely withdrawn in 85%-90% of patients with standard-risk (SR) or intermediate-risk (IR) T-ALL
.

Study Methods Newly diagnosed T-ALL or T-LL patients aged 1-30 years were eligible for enrollment
.

Patients were randomized 1:1 at enrollment to receive a modified aBFM regimen with or without bortezomib during induction and DI
.

Four doses of bortezomib were given at a dose of 1.
3 mg/m2
.

During induction therapy, bortezomib was administered on days 1, 4, 8, and 11; during DI therapy, bortezomib was administered on days 1, 4, 15, and 18
.

T-ALL and T-LL patients were classified as SR, IR, and very high risk (VHR) based on disease characteristics and treatment response, respectively, for treatment allocation
.

Modifications of the aBFM regimen in AALL0434 (including the use of dexamethasone instead of prednisone and the addition of 2 additional doses of pegaspargase) were made to enhance CNS-directed systemic therapy and limit the use of CRT
.

Results 01 Patient Characteristics The COG AALL1231 study enrolled 847 patients between September 2014 and December 2017
.

Of these, 824 were eligible and evaluable
.

There were 615 T-LL patients; 209 B-LL patients (Table 1), of which 416 were randomly assigned to arm A (without bortezomib) and 408 to arm B (bortezomib; Figure 1)
.

Except for a slightly higher proportion of males in group A, patient characteristics were similar between groups (Table 1)
.

Overall, 35.
6% of patients had SR, 53.
8% had IR, and 4.
1% had VHR, with a similar distribution between T-ALL and T-LL
.

Risk stratification could not be performed in 54 patients (6.
6%)
.

Table 1 Figure 102 Remission and survival ①Remission and survival of the overall patients: The 4-year EFS rate and OS rate were 81.
9%±1.
5% and 87.
0±1.
3%, respectively (Figure 2A), similar to T-ALL and T-LL patients (Figures 2B and 2C)
.

There were no differences in outcomes by race, ethnicity, or gender
.

The 4-year EFS rates of patients in group A and group B were 80.
1%±2.
3% and 83.
8%±2.
1%, respectively; HR: 0.
833; P=0.
131 (Fig.
3A)
.

The 4-year OS rates of group A and group B were 85.
7%±2.
0% and 88.
3%±1.
8%, respectively; HR: 0.
772; P=0.
085 (Fig.
3B)
.

Ninety-five percent of risk-stratified patients had SR or IR, and arm B had significantly improved EFS compared with arm A (Table 2)
.

VHR patients had poor survival, but group A had better survival (Table 2)
.

Figure 2 Figure 3 Table 2 ② Remission and survival of T-ALL patients: At EOI (day 29), 94.
3% (563/597) of T-ALL patients achieved complete remission (M1); ratios between groups similar
.

EOI MRD using a 0.
01% threshold and EOC MRD using a 0.
1% threshold were used for T-ALL risk stratification
.

Among T-ALL patients using EOI MRD, 38.
8% (115/296) and 34.
9% (104/298) of patients in groups A and B had an MRD ≥ 0.
01% (P=0.
318)
.

EOC MRD is only used in patients with EOI MRD ≥ 0.
01%
.

There were 12 and 13 patients with EOC MRD≥0.
1% in group A and group B, respectively (P=0.
931)
.

Compared with AALL0434, modified induction improved EOI MRD <0.
1% (AALL1231 group A: 69.
6%; group B: 72.
2%; AALL0434: 64.
6%; P<0.
02)
.

EFS and OS were similar in T-ALL patients in the bortezomib-free or bortezomib groups (Figures 3C and 3D)
.

③Patients and survival of T-LL patients: Except for 2 T-LL patients, other patients (196/198; 99.
9%) were in CR/PR at EOI
.

Four-year EFS rate (86.
4%±4.
0% vs 76.
5%±5.
1%; HR: 0.
563; P=0.
041) and OS rate (89.
5%±3.
6% vs 78.
3%±4.
9) of T-LL patients treated with bortezomib %; HR: 0.
421; P=0.
009; Figures 3E and 3F) were significantly better
.

03 Adverse Events The incidence of overall grade ≥ 3 toxicity was similar between the two groups (Group A: 76.
5%, Group B: 80.
0%; P=0.
234)
.

Twenty infection-related deaths occurred (induction: 5, consolidation: 4, DI: 8, maintenance: 3), 10 in each group
.

Eleven died from invasive fungal disease (nine: group A)
.

Bortezomib can cause peripheral neuropathy and rarely short-term severe pulmonary toxicity
.

The overall incidence of peripheral neuropathy was as expected and similar between groups
.

During induction and DI, the number of patients with grade ≥4 pulmonary toxicity in group A and B patients was 11 and 15, respectively (P=0.
393)
.

04 Comparison with AALL0434, including cancellation of prophylactic CRT Although AALL1231 had a better EOI MRD response than AALL0434, the overall 4-year EFS rate was similar in both studies (AALL1231: 81.
9% ± 1.
5%; AALL0434: 84.
4% ± 0.
9%; P = 0.
131; Figure 4A), the 4-year OS rate of AALL1231 (87.
0% ± 1.
3%) was lower than that of AALL0434 (90.
0% ± 0.
7%; P = 0.
006; Figure 4B)
.

Comparing events between trials in Figure 4, poorer OS was primarily due to increased death from toxicity, which was similar in patients with T-ALL and T-LL
.

In the AALL0434 trial, the first event in 37/1844 (2.
0%) evaluable patients was death (7: induction; 30: remission), while in the AALL1231 trial, 50/824 (6.
1%) patients had the first event in death (12: induction; 38: remission)
.

The induced mortality of AALL1231 and AALL0434 were 1.
5% and 0.
4%, respectively (P=0.
002)
.

A subgroup analysis was performed in the AALL0434 study comparing similar patients planning to receive CRT, but not in AALL1231, with only 9.
5% of patients planning to receive CRT (CNS3 T-ALL/T-LL: 5.
7 %; VHR T-ALL: 4.
1%)
.

Excluding patients receiving nerabine (AALL0434) or bortezomib (AALL1231), 4-year EFS rate (P=0.
412), OS rate (P=0.
600), CI for CNS recurrence (P=0.
456) and overall recurrence (P=0.
456) =0.
836) There was no significant between-study difference
.

A pure comparison was not possible due to different risk stratification and the fact that many AALL0434 patients were not assessed for EOC MRD
.

Conclusions In the AALL1231 study, the addition of bortezomib significantly improved EFS and OS in T-LL patients
.

Systemic intensive therapy enables over 90% of T-ALL patients to cancel CRT without excessive relapse
.

Reference source: David T Teachey, Meenakshi Devidas, Brent L Wood, et al.
Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.
J Clin Oncol.
2022 Mar 10; JCO2102678.
doi: 10.
1200/JCO.
21.
02678.
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