Physician University Hospital Würzburg, United States
Introduction: The majority of patients treated with CAR-T-cell display unexplained prolonged cytopenia. Our study aimed to explore biomarkers that correlate with cytopenia post CAR-T in multiple myeloma (MM).
Methods: We prospectively analyzed peripheral blood (PB) of MM patients treated with idecabtagen-vicleucel at these time points: before lymphodepleting (baseline), after CAR-T on d4, 7, 14, 28, and monthly thereafter. Flow cytometry was performed with following markers: CD45, CD3, CD4, CD8, CD62L, CD45RA, CD19, CD14, CD138, CD38 and a BCMA-CAR-detection marker.
Results: We included a total of 191 sequential PB samples of 32 MM patients. The patients were pretreated with a median of 5 therapy lines (range 2-10). 31 (97%) and 8 (25%) patients underwent autologous and allogeneic stem cell transplant, respectively. Of note, patients with allogeneic stem cell transplant or ≥5 prior therapy lines did not show longer duration of grade ≥3 cytopenia than the remaining patients. However, baseline hemoglobin and platelet count correlated with the duration of grade ≥3 anemia (r=-0.63, P< 0.001) and thrombocytopenia (r=-0.44, P=0.01), respectively. Moreover, the ferritin peak post CAR-T significantly correlated with the duration of grade ≥3 anemia (r=0.65, P< 0.001) and thrombocytopenia (r=0.69, P< 0.001), and the baseline ferritin showed a correlation with the duration of grade ≥3 anemia (r=0.54, P=0.001) and thrombocytopenia (r=0.54, P=0.001). Interestingly, the duration of grade ≥3 lymphopenia significantly correlated with CD4+ (r=0.55, P=0.004), CD8+ T-cell (r=-0.59, P=0.002) frequencies and the CD4+/CD8+ ratio (r=0.55, P=0.004) at baseline. We then divided the patients into two groups: early (< d60) vs prolonged (≥d60) cytopenia. In both groups, high baseline ferritin level indicated severe anemia (< d60: r=-0.50, P< 0.001; ≥d60: r=-0.64, P< 0.001) and thrombocytopenia (< d60: r=-0.61, P< 0.001; ≥d60: r=-0.74, P< 0.001). In the ≥d60 group, the frequency of T-cells showed a negative correlation with hemoglobin (r=-0.52, P=0.001) but a positive correlation with lymphocyte count (r=0.62, P< 0.001), suggesting that prolonged lymphopenia post CAR-T was mainly attributed to the lack of T-cell. The frequency of naïve CD4+ T-cells correlated with neutrophil count (r=0.57, P< 0.001), hemoglobin (r=0.44, P=0.009) and leukocyte count (r=0.48, P=0.004). In prolonged lymphopenia, we found a significant correlation between lymphocyte count and the frequencies of CAR+CD4+ (r=-0.52, P=0.002), CAR+CD8+ (r=0.53, P< 0.001), CAR-CD4+ (r=-0.63, P< 0.001), CAR-CD8+ (r=0.73, P< 0.001) T-cells as well as the ratio of CAR+CD4+/CAR+CD8+ (r=-0.54, P=0.001) and CAR-CD4+/CAR-CD8+ (r=-0.69, P< 0.001).
Conclusions: Together, high ferritin level and preexisting cytopenia were associated with prolonged cytopenia post CAR-T in MM. Patients with high CD4+/CD8+ ratio, e.g. newly diagnosed MM, are at risk of prolonged T-cell lymphopenia, which may be an issue for infectious complications and later T-cell based immunotherapies.
