Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group

Abstract

While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0-3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58-65% vs. MRDpos 10-19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.

Keywords: acute lymphoblastic leukaemia; acute lymphocytic leukaemia; minimal residual disease; paediatric leukaemia; proteasome inhibition.

Figure 1 Legend:

Consort diagram for the Children’s Oncology Group (COG) AALL07P1 clinical trial. ALL: acute lymphoblastic leukaemia; CR: complete remission; ER: early relapse; LL: lymphoblastic lymphoma; VER: very early relapse.

Figure 2 Legend:

Percentage of patients in complete remission with an MRD from bone marrow below either 0.01% (white bars) or 0.1% (black bars) at the end of reinduction (cycle 1), cycle 2 and cycle 3 of chemo-therapy. Patient number for MRD assessment varied by therapy block (n=88 cycle 1, n-49 cycle 2, n=31 cycle 3). MRD: minimal residual disease

Figure 3 Legend:

Survival as a function of MRD in pre-B ALL patients less than 21 years of age in early relapse. A: Three-year EFS for patients relapsing <18 months from diagnosis (very early relapse) stratified by MRD status at the end of the first cycle of therapy (reinduction). B: 3-year EFS for patients relapsing 18–36 months from diagnosis (early relapse) stratified by MRD status. C: Three-year overall survival for very early relapse patients stratified by MRD status. D: 3-year EFS for early relapse patients stratified by MRD status. EFS: event-free survival; MRD: minimal residual disease; MRDneg: minimal residual disease negative; MRDpos: minimal residual disease positive.

Figure 3 Legend:

Survival as a function of MRD in pre-B ALL patients less than 21 years of age in early relapse. A: Three-year EFS for patients relapsing <18 months from diagnosis (very early relapse) stratified by MRD status at the end of the first cycle of therapy (reinduction). B: 3-year EFS for patients relapsing 18–36 months from diagnosis (early relapse) stratified by MRD status. C: Three-year overall survival for very early relapse patients stratified by MRD status. D: 3-year EFS for early relapse patients stratified by MRD status. EFS: event-free survival; MRD: minimal residual disease; MRDneg: minimal residual disease negative; MRDpos: minimal residual disease positive.

Figure 3 Legend:

Survival as a function of MRD in pre-B ALL patients less than 21 years of age in early relapse. A: Three-year EFS for patients relapsing <18 months from diagnosis (very early relapse) stratified by MRD status at the end of the first cycle of therapy (reinduction). B: 3-year EFS for patients relapsing 18–36 months from diagnosis (early relapse) stratified by MRD status. C: Three-year overall survival for very early relapse patients stratified by MRD status. D: 3-year EFS for early relapse patients stratified by MRD status. EFS: event-free survival; MRD: minimal residual disease; MRDneg: minimal residual disease negative; MRDpos: minimal residual disease positive.

Figure 3 Legend:

Survival as a function of MRD in pre-B ALL patients less than 21 years of age in early relapse. A: Three-year EFS for patients relapsing <18 months from diagnosis (very early relapse) stratified by MRD status at the end of the first cycle of therapy (reinduction). B: 3-year EFS for patients relapsing 18–36 months from diagnosis (early relapse) stratified by MRD status. C: Three-year overall survival for very early relapse patients stratified by MRD status. D: 3-year EFS for early relapse patients stratified by MRD status. EFS: event-free survival; MRD: minimal residual disease; MRDneg: minimal residual disease negative; MRDpos: minimal residual disease positive.

Figure 4 Legend:

Outcome by MRD status (cut-off 0.01%) in patients with T-ALL. A: Event free survival in MRD negative patients (EFS 75%) and in MRD positive patients (43% until censored). B: Overall survival in MRD negative patients (EFS 67%) vs. MRD positive patients (EFS 43%). ALL: acute lymphoblastic leukaemia; EFS: event-free survival; MRD: minimal residual disease; MRDneg: minimal residual disease negative; MRDpos: minimal residual disease positive.

Figure 4 Legend:

Outcome by MRD status (cut-off 0.01%) in patients with T-ALL. A: Event free survival in MRD negative patients (EFS 75%) and in MRD positive patients (43% until censored). B: Overall survival in MRD negative patients (EFS 67%) vs. MRD positive patients (EFS 43%). ALL: acute lymphoblastic leukaemia; EFS: event-free survival; MRD: minimal residual disease; MRDneg: minimal residual disease negative; MRDpos: minimal residual disease positive.