Therapeutic Targets in Childhood B-Acute Lymphoblastic Leukemia : What about HER2/Neu?

Relapsed B-lineage acute lymphoblastic leukemia (ALL) in children is associated with poor prognosis. Therefore, it seems essential to stratify patients according to prognostic factors in order to adapt therapies. The evaluation of minimal/measurable residual disease (MRD) during chemotherapy constitutes the most powerful prognostic factor in all age groups, indeed, patients with early low MRD having better outcomes.

New immunotherapies based on monoclonal antibodies have recently been developed and are giving promising results in chemoresistant forms with limited toxicities. Indeed, CD20, CD38, CD22 and, less developed, HER2/neu constitute therapeutic targets. However, few studies have reported on the expression level of these markers and compared it to the normal counterpart, precursor B-cells or hematogones. Such investigations would be useful to appreciate the potential efficacy of immunotherapies targeting these markers. Moreover, it could help for the detection of minimal/measurable residual disease during follow-up.

A cohort of 125 B-ALL patients (1-25 years old) was retrospectively enrolled in this study, treated between January 2011 and February 2020. Samples collected from bone marrow or peripheral blood were studied in multiparameter flow cytometry (MFC). Cells were analyzed with a Canto II flow cytometer (BD Biosciences), and Diva (BD Biosciences) software was used to assess the expression of the antigenic markers. The same MFC assay had been performed over the whole period, allowing for fluorescence intensities comparison. Additionally, results from 36 normal bone marrow samples were examined, to compare the level of antigen expression by hematogones.

CD20, CD38 and CD22 were expressed in respectively 53.6%, 99.2% 98.4% of the cases, rather homogeneously and at intermediate levels. The mean fluorescence intensity of CD38 was much higher on hematogones than blasts, which made it a leukemia-associated immunophenotype (LAIP) for 101 patients (81.4%). HER2/neu, a marker of breast cancer also expressed in a subset of ALL, was present in 16 samples (13.4%), but not detectable on hematogones, and can thus always be considered a LAIP. Interestingly, in this subgroup, patients had a significantly lower 5-year EFS compared to patients without expression of HER2/neu (63% versus 80.5%, p=0.02) (Figure 1). No significant difference in the expression of tested potential therapeutic markers was found between age groups.

In conclusion, these 4 antigens have sufficient expression intensities to make them potential therapeutic targets, which could be an interesting alternative for the treatment of refractory/relapsed childhood B-ALL. For example, trastuzumab could be a potential immunotherapy in the HER2/neu expressing group, especially regarding their poorer prognosis. Moreover, CD38 and HER2/neu are good candidates for monitoring MRD. These results are of interest as it has been shown that monitoring MRD early was prognostic on patients’ outcome.