CD58 Could be As a Leukemic Marker in Relapsed/Refractory B-ALL Patients after Multiline Therapies

Abstract

It has been verified that CD58, a member of the immunoglobulin superfamily, is expressed in B-cell lymphoblastic leukemia (B-ALL) at a higher level and is a marker of minimal residual disease in B-ALL. A study reported that CD58 was expressed in 99.4% of B-ALL cases at diagnosis. Nevertheless, little is known regarding CD58 expression in relapsed/refractory (r/r) B-ALL patients having received multiline therapies especially chimeric antigen receptor (CAR) T-cells. Although CD19-specific CAR-T therapy resulted in high complete remission (CR) rates, some patients relapsed after CAR-T and part of them showed CD19 loss, under this circumstance, additional B-cell antigen specifically expressed on the B-ALL cells could help us to identify the leukemia cells. In this study, we investigated the CD58 expression in r/r B-ALL patients before CAR-T, and the influence of CAR-T cells on CD58 antigen of lymphoblasts in patients failed or relapsed after CAR-T. CD58 on leukemic cells of r/r B-ALL patients has been routinely detected by flow cytometry in our center. Data of r/r B-ALL patients were collected from May 2019 through May 31, 2022. Samples were detected on an 8-color BD FACSCanto II flow cytometer, and analyzed by FACS Diva software from BD or Kaluza software from Beckman Coulter. Antigen full expression, partial expression and no expression were defined as >80%, 20%-80% and <20% of gated cells displaying the antigen of interest, respectively. A total of 274 r/r B-ALL patients planned to be administered CD19 CAR-T cells were assayed CD58 antigen before CAR-T, all of them had received multiline chemotherapies, 61 (22.3%) underwent allogeneic hematopoietic cell transplant (allo-HCT) and 6 cases had a history of antibody (CD20, CD19 or CD22) treatment. The median age was 12 years (range, 1-75 years), including 97 adults and 177 children younger than 18 years. Among all 274 patients, 228 (83.2%, 228/274) showed CD58 expression, consisting of 180 (78.9%, 180/228) cases with full expression and 48 (21.1%, 48/228) with partial expression; whereas 46 (16.8%, 46/274) patients were CD58-negative, demonstrating that CD58 was expressed on the majority (83.3%) of r/r B-ALL patients after treated by multiple intensive chemo drugs and even allo-HCT. Then, we observed the influence of CAR-T cells on the expression of CD58 antigen of lymphoblasts. We followed-up 57 patients who had CD58 expression before CD19 CAR-T but failed or relapsed after CAR-T. Of them, 45.6% (26/57) cases received the further treatment as a consolidation following CD19 CAR-T (CD22 CAR-T, 14; allo-HCT, 12). Among 57 patients, 10 were CD58-negative while 47 cases still showed CD58-positive, the frequency of CD58 expression was 82.5% (47/57) after treated by CAR-T cells and allo-HCT. When we excluded the 26 patients who received following CD22 CAR-T or allo-HCT, and only considered the 31 patients exposed to one-time CD19 CAR-T cells, the CD58 expression rate was 87.1% (27/31). It was reported that CD58 loss in tumor cells induced resistance to CAR-T therapy in cell lines and mouse models. We therefore analyzed the influence of CD58 expression on the treatment response of CAR-T cells. Among 274 r/r B-ALL patients received CD19 CAR-T, 6 were unable to evaluate the treatment response due to death or hospital discharge within 15 days after cell infusion, the remaining 268 patients had evaluation data including 223 cases with CD58 expression (full or partial expression) and 45 without CD58 expression. After CD19 CAR-T therapy, the CR (including MRD+CR) rate in patients with CD58 expression was 91.9% (205/223) while it was 95.6% (43/45) in patients without CD58 expression, indicating that CD58 negativity was irrelevant to CAR-T treatment failure in r/r B-ALL. In conclusion, CD58 antigen was expressed in the majority (83.2%) of r/r B-ALL cells without exposing to CAR-T treatment, and still expressed on the lymphoblasts of most patients (>80%) failed or relapsed after CAR-T, therefore, it could be as a leukemic marker for identifying tumor cells in r/r B-ALL patients who have received multiline therapies including allo-HCT and CAR-T. Additionally, CD58-negative patients achieved a similar high CR rate as CD58-positive patients did after CD19 CAR-T.