Inotuzumab ozogamicin as a bridging therapy to allogeneic hematopoietic stem cell transplantation in children with refractory/relapsed B-cell acute lymphoblastic leukemia

Abstract

In children with acute lymphoblastic leukemia (ALL), relapse is still the leading cause of treatment failure occurring in 10–15% of cases. Overall survival after relapse plateaus at 50–60%, whereas event-free survival after second and third relapse is approximately 25% and 15%, respectively. The introduction of new immunotherapeutic agents such as blinatumomab (a bispecific T-cell engager), inotuzumab ozogamicin (InO; a CD22+ monoclonal antibody) and a chimeric antigen T-cell receptor targeted to CD19+ can significantly increase the effectiveness of treatment for relapsed ALL and help patients achieve remission faster and thus shorten the time to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the toxicity of these novel agents and their impact on the results of allo-HSCT are still to be investigated. Our study included 55 patients with refractory B-cell ALL aged from 3 to 17 years (the median age was 10 years). The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. The patients were divided into two groups based on whether they received inotuzumab ozogamicin or not: InO+ group (n = 24; 43.6%) and InO– group (n = 31; 56.4%). The majority of the patients underwent haploidentical HSCT (n = 53; 96.4%); 1 (1.8%) patient received HSCT from a matched related donor, and 1 (1.8%) from a matched unrelated donor. Conditioning regimens before allo-HSCT included: myeloablative conditioning (n = 20; 36.4%), reduced toxicity myeloablative conditioning (n = 5; 9.1%), and reduced intensity conditioning (n = 30; 54.5%). Acute graft-versus-host disease prophylaxis with post-transplant cyclophosphamide was given to 49 (87.7%) recipients; 6 (12.3%) patients received seroprophylaxis. Basic combined immunosuppressive therapy consisting of a calcineurin inhibitor and an mTOR inhibitor was used in 35 (63.6%) cases, and single m-TOR inhibitor treatment was administered to 20 (36.4%) patients. In the InO+ group, 21 (87.5%) patients achieved complete remission with incomplete hematologic recovery before allo-HSCT: 5 (23.8%) patients had minimal residual disease (MRD), and 16 (76.2%) patients were MRD negative. In the InO– group, remission with incomplete hematologic recovery before allo-HSCT was achieved in 15 (48.4%) patients: 3 (9.7%) cases were MRD positive and 12 (38.7%) were MRD negative (p = 0.003). All the patients underwent allo-HSCT, regardless of response to prior therapy. Engraftment was achieved in the InO+ group in 20 (83.3%) children in a median of 22 days (D+22) and in the InO– group in 25 (80.6%) children in a median of 19 days (D+19). Relapse was observed in 11 (55%) patients in the InO+ group and in 15 (60%) patients in the InO– group at a median of 164 days and 203 days post-transplant, respectively (p = n. s.). In the InO+ group, 5 (31.25%) out of 16 patients in complete remission with incomplete hematologic recovery and negative MRD status relapsed after allo-HSCT within a median of 105 days (D+58 – D+169). In the InO–, 6 (50%) out of 12 patients in complete remission with incomplete hematologic recovery and negative MRD status relapsed within a median of 296 days (D+108 – D+929). Due to the small number of patients in the groups, a correlation and regression analysis showed a weak correlation between the use of InO before allo-HSCT and the occurrence of post-transplant relapse (Pearson's contingency coefficient was 0.178). Loss of the HLA haplotype at relapse was found in 1 (4.2%) patient from the InO+ group and in 2 (6.5%) patients from the InO– group (p = n. s.). Transplant-associated thrombotic microangiopathy was diagnosed in 6 (25%) recipients in the InO+ group and in 3 (9.7%) recipients in the InO– group. Eight (32%) patients in the InO+ group and 3 (9.7%) patients in the InO– group had clinical manifestations of sinusoidal obstruction syndrome. Our study suggests the effectiveness of inotuzumab ozogamicin for the treatment of relapsed B-ALL in children before allo-HSCT. Patients with large tumor burden and high expression of CD22+ would benefit the most from therapy with InO. The application of reduced intensity conditioning regimen after CD22+ directed monoclonal antibody therapy significantly improves the overall survival rates by reducing early transplant-related mortality and makes it possible to use adoptive immunotherapy as a next line of treatment. Current allo-HSCT protocols and approaches to acute graft-versus-host disease prevention help control the development of severe complications in the early post-transplant period. Our study showed that adoptive immunotherapy via donor lymphocyte infusions can be applied in patients treated with InO who experience loss of the HLA haplotype at relapse after allo-HSCT.