T-cell Kinetics during First-Line Blinatumomab Therapy in Patients with BCP-ALL
Adult patients with B-cell precursors acute lymphoblastic leukemia (BCP-ALL), specifically those aged 40 years and above, have a discouraging prognosis with only 25-57% achieving long-term survival with standard treatment regimens. Blinatumomab, a bispecific T-cell engager targeting CD19+ (malignant) B-cells, has improved patient outcomes by promoting T-cell-mediated cytotoxicity. However, the extent to which the various subsets within T-cell compartment shape the response to first-line blinatumomab treatment is not fully understood. Therefore, flow cytometric immunophenotyping analysis was performed to investigate immune cell dynamics following blinatumomab treatment and its relationship with treatment response.
For the HOVON146 (NCT03541083), a single-arm phase II trial for newly diagnosed BCP-ALL patients between the age of 18-70 years old, leukocyte populations were analyzed following the first cycle of frontline blinatumomab treatment. Patients received 10 days of steroid pre-treatment, with blinatumomab starting on day 5. The leukocyte populations, with a specific focus on T-cell subsets, were characterized using four 8-color flow cytometry panels. FlowSOM, an unsupervised clustering technique for flow cytometry data, was used to identify and visualize the difference in immune cell populations between patients. Treatment response was assessed using cytological assessment of the bone marrow, and minimal residual disease (MRD) monitoring using RQ-PCR analysis of patients-specific IG/TR gene rearrangements and next generation flow cytometry.
A total of 71 patients were included (median age, 53 years; range: 18-70). High-risk factors, such as high white blood cell count at diagnosis and unfavorable cytogenetic abnormalities, were present in 55/71 (77%) patients. In total, 70/71 patients received the full first cycle of blinatumomab treatment (8 with interruption due to toxicity). Non-responders, defined as patients who remained MRD+ and failed to achieve a complete response, had significantly higher bone marrow blast percentages before the start of the treatment. Preliminary analyses showed no baseline difference in the total number of CD3+ T-cells, CD4+ T-cells or CD8+ T-cells, nor in any of the subsets, between responders and non-responders. Likewise, the kinetics of T-cell subsets throughout the first blinatumomab cycle revealed no significant differences in the number of CD25+FoxP3+ T-regulatory cells, and central memory, effector memory, and effector CD4+ T-cells or CD8+ T-cells. Notably, however, at the end of the first blinatumomab cycle, non-responders exhibited higher numbers of naïve CD4+ T-cells and naïve CD8+ T-cells.
In this cohort of newly diagnosed adult BCP-ALL patients, we characterized early immunological dynamics following first-line blinatumomab treatment. A higher bone marrow blast percentage prior to treatment and the expansion of naïve T-cells during treatment was more frequently observed in non-responders than responders. However, further studies are warranted to identify predictive immune biomarkers to guide patient stratification and optimize treatment outcomes.