Prognostic significance and treatment strategies for IKZF1 deletion in pediatric B-cell precursor acute lymphoblastic leukemia

Abstract

Background: The predictive importance of IKZF1^del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1^del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1^del-based high-risk stratification versus a minimal residual disease (MRD)-guided protocol.

Methods: IKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1^del patients receiving a high-risk regimen. Conversely, in the Chinese Children's Cancer Group (CCCG)-ALL 2015 cohort, IKZF1^del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol.

Results: IKZF1^del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1-positive patients. Overall, IKZF1^del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1^del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1^wt. In the CCLG-ALL 2015 cohort, IKZF1^del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1^wt, but the differences were insignificant. The IKZF1^del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol.

Conclusions: The prognostic effect of IKZF1^del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1^del in children.

Keywords: IKZF1 deletion; Minimal residual disease-guided protocol; Pediatric B-cell precursor acute lymphoblastic leukemia.

Fig. 1

Outline of patient enrollment in this study. ALL, acute lymphoblastic leukemia; BCP-ALL, B-cell precursor acute lymphoblastic leukemia; MLPA, multiplex ligation-dependent probe amplification; CCLG, Chinese Children Leukemia Group; CCCG, Chinese Children’s Cancer Group; CR, complete remission

Fig. 2

Survival probability by IKZF1 status for patients overall and those with BCR::ABL1-negative disease in the CCLG-ALL 2008 cohort. According to IKZF1 status, patients were stratified into two groups: IKZF1^del and IKZF1^wt. EFS (a), OS (b), and CIR (c) according to IKZF1 status for patients overall. EFS (d), OS (e), and CIR (f) according to IKZF1 status for patients with BCR::ABL1-negative disease. EFS, event-free survival; OS, overall survival; CIR, cumulative incidence of relapse

Fig. 3

Survival probability by IKZF1 status for patients overall and those with BCR::ABL1-negative disease in the CCLG-ALL 2015 cohort. According to IKZF1 status, patients were stratified into two groups: IKZF1^del and IKZF1^wt. EFS (a), OS (b), and CIR (c) according to IKZF1 status for patients overall. EFS (d), OS (e), and CIR (f) according to IKZF1 status for patients with BCR::ABL1-negative disease. EFS, event-free survival; OS, overall survival; CIR, cumulative incidence of relapse

Fig. 4

Survival probability by IKZF1 status for low-risk and intermediate-risk patients in the CCLG-ALL 2015 cohort. According to IKZF1 status, patients were stratified into two groups: IKZF1^del and IKZF1^wt. EFS (a), OS (b), and CIR (c) according to IKZF1 status for low-risk patients. EFS (d), OS (e), and CIR (f) according to IKZF1 status for intermediate-risk patients. EFS, event-free survival; OS, overall survival; CIR, cumulative incidence of relapse

Fig. 5

Survival probability by treatment strategy in IKZF1^del patients. EFS (a), OS (b), CIR (c), and CID_TRM (d) according to treatment strategy. Patients were stratified into two groups: IKZF1^del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) and those treated with the CCCG-ALL 2015 MRD-guided protocol. EFS, event-free survival; OS, overall survival; CIR, cumulative incidence of relapse; CID_TRM, cumulative incidence of treatment-related mortality

Fig. 6

Survival probability by treatment strategy in IKZF1^del patients without conventional high-risk features, including BCR::ABL1-positive, KMT2A-rearrangements, and MRD ≥ 1% detected by MFC at TP2. EFS (a), OS (b), CIR (c), and CID_TRM (d) according to treatment strategy. Patients were stratified into two groups: IKZF1^del patients without conventional high-risk features treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) and those treated with the CCCG-ALL 2015 MRD-guided protocol. EFS, event-free survival; OS, overall survival; CIR, cumulative incidence of relapse; CID_TRM, cumulative incidence of treatment-related mortality