Paper Details

ABSTRACT

Introduction: Pediatric hypodiploid B cell Acute Lymphoblastic Leukemia (B-ALL) is rare (1-2% of pediatric B-ALL) and difficult to cure. The last large studies (McNeer et al, JCO 2019, N=131; and Pui et al, JCO 2019, N=232 for <44 chromosomes) included patients treated up to 2013: 5-year event free survival (EFS) was only 50-60%. Patients who were measurable residual disease (MRD) negative (neg, <0.01%) at the end of induction (EOI) had a 5-year EFS of 63%-75%. Approximately one third of patients were EOI MRD positive (pos, ≥0.01%) and had 5-year EFS of 26%-55%. There was not a clear benefit for hematopoietic cell transplant (HCT) in first clinical remission (CR1) leading to a hypothesis that hypodiploid B-ALL may be resistant to immunotherapy. Recent small studies suggest that hypodiploid B-ALL has a propensity to lose CD19 expression after CD19-targeted immunotherapy, as chromosome 16, which contains the CD19 gene, is often absent in blasts. The impact of immunotherapies such as blinatumomab (blina), CART, and inotuzumab (ino), all introduced after 2013, on hypodiploid B-ALL are unknown.

To investigate the efficacy of immunotherapies in children with hypodiploid B-ALL, we recruited pediatric cancer centers globally and collected patient-level treatment data, with a focus on immunotherapy, HCT, and survival outcomes, including MRD and HCT details not included in prior studies.

Methods: IRB approval was obtained from over 50 centers in North America, Europe, Japan and Australia. Eligibility criteria: 1) hypodiploid (<44 chromosomes) or masked hypodiploid B-ALL, 2) diagnosis from 2003 to 2023, and 3) age <30 at diagnosis. Kaplan–Meier analyses with log-rank tests and Cox proportional hazards regression (including multivariable regression) were performed to evaluate OS and EFS from EOI or end of consolidation (EOC), as appropriate, with EFS events defined by relapse, death, or second malignancy.

Results: 302 eligible patients were included in this analysis. The large majority were diagnosed after 2012 (72%) with a mean age of 10.3 years.

Both EOI and EOC MRD pos was significantly associated with worse outcomes in univariate analysis (UVA) (EFS Hazard Ratio [HR] 1.94 [95% CI 1.34–2.83] and 2.32 [1.29-4.15] respectively; Overall survival [OS] HR 1.7 [1.11-2.6] and 2.34 [1.24-4.41]). In multivariable analysis (MVA) adjusting for immunotherapy and HCT before relapse, EOI and EOC MRD pos remained associated with inferior EFS (HR 2.15 [1.44-3.2] and 2.73 [1.26-5.89]), but not OS (HR 1.01[0.62-1.59] and 0.96 [0.49-1.9]), suggesting these treatments mitigated the impact of early MRD on OS. Detailed analyses of treatment decisions based on EOI vs. EOC MRD are underway.

The use of blina for consolidation in CR1 was strongly beneficial. In UVA, CR1 blina significantly improved EFS for EOI MRD pos patients (HR 0.16 [0.04-0.7]; n=48, 19 received blina) which corresponds to a 5-year EFS of 89.5% vs 48.3%, p<0.01. Blina consolidation also yielded favorable HR for OS in EOI MRD pos patients (HR 0.23 [0.05-1.02]) and in MRD neg patients for both EFS and OS (HR 0.4 [0.12-1.29] and 0.55 [0.16-1.73]; n=175, 31 received blina) but did not reach statistical significance. In MVA, blina consolidation in CR1 resulted in significant survival benefit in EOI MRD pos patients for EFS (HR 0.17 [0.04-0.75]). EOI MRD neg patients had a favorable HR for EFS, suggesting benefit from blina, but significance was not achieved (HR 0.6 [0.17-2.04]).

While no clear benefit for CR1 CART or ino was noted, the number of patients receiving these therapies was lower than blina and they were often given as second line therapies. HCT also did not show a clear benefit in CR1, but if HCT was performed, outcomes were improved with TBI vs. non-TBI conditioning (HR for RFS was 0.44 [0.26-0.75]), a challenging finding in a population with a high rate of constitutional TP53 mutations. Data from an additional 130+ patients with this rare form of B-ALL are being validated or have been committed and will be used to increase power to assess the impact of these therapeutic strategies, hypodiploid subtypes, and constitutional and/or somatic TP53 mutations on outcomes.

Conclusions: Despite emerging concerns regarding decreased efficacy of CD19-targeted therapy in hypodiploid B-ALL, the use of blina consolidation in CR1 in this large, international study was highly beneficial, particularly for EOI MRD pos patients who in previous studies had dismal outcomes with chemotherapy +/- HCT.