The Efficacy and Toxicity of Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia: Russian Multicenter Experience

Introduction. The prognosis of patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), especially after allogeneic hematopoietic stem cell transplantation (allo-HSCT), is very poor. Therapeutic options for these pts are limited. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3. BiTE® therapy may help to overcome the resistance to chemotherapy (CT) with minimal toxicity, and may be a bridge to allo-HSCT.

Patients and Methods. We analyzed data of 52 pts from 7 hematologic centers in Russian Federation with CD19 positive R/R ALL, who received BiTE®. The median age was 21 (range 1-53) years, 18 (35%) pts <18 yrs, 34 (65%) pts ≥18 yrs. The diagnosis was ALL B-I (EGIL) subtype in 15 pts, B-II - in 29, B-III - in 5 pts, B-IV - in 2 pts, and 1 patient had mixed phenotype leukemia (M5 (FAB) and B-ALL). Five (10%) pts had Philadelphia positive (Ph+) ALL. Primary refractory in 1 pts. In 19 pts it was the 1st relapse of ALL, in 17 - 2nd, in 15 - 3rd. In 47 pts it was isolated bone marrow relapse, in 5 pts - combined relapse (bone marrow and extramedullary sites). The bone marrow blast infiltration was <50% in 27 pts, >50% in 25 pts. Disease relapse was revealed after CT in 31 pts. Allo-HSCT after BiTE® therapy was performed 12 (39%) pts (4 - from related, 5 - from unrelated, 3 - from haploidentical donors). Twenty one pts received BiTE® due to relapse after allo-HSCT (6 - from related, 12 - from unrelated, 3 - from haploidentical donors). Six pts received 2nd allo-HSCT after BiTE® therapy. In 10 pts with posttransplant relapse donor lymphocyte infusion (DLI) was used in combination with BiTE®. Every patient received from 1 to 7 cycles (median 2) of BiTE®.

Results. Complete remission (CR) was achieved in 31/52 (60%) pts: in 18/31 (58%) pts with ALL relapse after CT, in 13/21 (62%) pts - after allo-HSCT. In 22/31 (71%) pts with CR after BiTE® therapy minimal residual disease was negative. Pts with less than 50% blasts in bone-marrow at baseline experienced substantially higher response rates compared with patients with 50% blasts or higher (70% (19/27) vs 48% (12/25)). Response rates were similar although the number of relapse - 58% (11/19) in 1^st relapse, 59% (10/17) in 2^ndrelapse and 60% (9/15) in 3^drelapse. Pts with posttransplant ALL relapse who received BiTE® in combination with DLI had higher response rate than pts, who received BiTE® as monotherapy: 70% (7/10) vs 54% (6/11) respectively. One-year OS was 50% (95% CI 25-75%). One-year DFS was 42% (95% CI 18-66%). Grade ≥3 hematological toxicity (neutropenia, thrombocytopenia) was observed in 14 (27%) pts, grade ≥3 liver toxicity - in 6 (12%) pts. Ten pts (19%) developed toxic neuropathy during the therapy. Cytokine release syndrome occurred in 5 (9%) pts. One pts after allo-HSCT (but not after DLI) developed grade I aGVHD. One pts after allo-HSCT developed grade II aGVHD after BiTE® in combination with DLI. There were no fatal treatment related toxicity. Nine (29%) pts who responded to BiTE® had relapse, 6 of them bone marrow and 3 extramedullary sites. Nine (29%) pts died: 5 pts - due to R/R ALL, 2 pts due to infection, 1 case of transplant related mortality and 1 pts due to second solid tumor (synovial sarcoma).

Conclusion. The treatment of R/R ALL with BiTE® is effective and has acceptable toxicity. We demonstrated high efficacy in therapy of posttransplant ALL relapses, especially when BiTE® was combined with DLI, perhaps, due to additional immunological effect of the transplant.