Mini-Dosed Blinatumomab Maintenance Therapy Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute B-Cell Lymphoblastic Leukemia

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improves patient outcomes, yet post-transplant relapse remains a major cause of mortality. Currently, there is no widely accepted maintenance therapy for B-cell acute lymphoblastic leukemia (B-ALL) patients following transplantation. Blinatumomab, the first bispecific T-cell engager targeting CD19 and CD3, has demonstrated significant efficacy in relapsed B-ALL and minimal residual disease (MRD) clearance. This study explores the efficacy of blinatumomab as maintenance therapy post-allo-HSCT in B-ALL.

Methods

This prospective, single-arm clinical trial includes B-ALL patients scheduled to allo-HSCT. All patients underwent myeloablative conditioning. Peripheral stem-cell grafts were obtained from HLA-matched sibling donors (MSD), matched unrelated donors (MUD), or haploidentical donors (HID). Post-transplantation acute graft versus host disease (GvHD) prophylaxis included cyclophosphamide and cyclosporine, with mycophenolate mofetil added from day +5 to day +35 for HID transplant recipients. Patients without active GvHD were enrolled in this trial. The first cycle of blinatumomab maintenance started between 75-90 days post-transplant and was administered every three months up to one year. Blinatumomab was continuously administered with an initial dosage of 8 μg/day for the first two days, followed by 16 μg/day for days 3-7, 3 vials per cycle. Follow-up examinations were scheduled at +1, +2, +3, +4, +6, +9, +12, +18-, and +24-months post-transplant.

Results

Nineteen patients (7 males, 12 females) with a median age of 34 years (range 16-58) were enrolled. Ten patients were diagnosed with Philadelphia chromosome-positive ALL. All patients achieved complete remission (CR) before transplantation (13 of CR1, 5 of CR2, and 1 of CR3), and 17 achieved MRD clearance. The other two patients exhibited MRD levels between 10^-5 and 10^-3. Allo-HSCT was performed using MSD in 1 patient, MUD in 1 patient, and HID in 17 patients. By day +30 post-ASCT, all patients achieved CR with negtive MRD.

During maintenance therapy, two patients discontinued treatment due to drug-related seizures. Among the remaining 17 patients, 10 completed four cycles of blinatumomab, 2 completed three cycles, 1 completed two cycles, and 4 completed one cycle. In the first cycle, five patients experienced drug-related adverse events (5/17, 29.4%), including 2 with grade I cytokine release syndrome (CRS) (11.8%), 1 with grade I immune effector cell-associated neurotoxicity syndrome (ICANS) (5.9%), 1 with grade I headache (5.9%), 2 with grade I nausea (11.8%), and 1 with grade I rash (5.9%). In the following cycles, the adverse reaction gradually decreases. No patient developed a new onset or progression of GvHD after maintenance therapy. No patient died of the adverse event of blinatumomab maintenance.

We paired another 39 B-ALL patients who underwent allo-SCT in the same period of time without post-transplant maintenance therapy as a control group. We compared the incidence of relapse, GvHD, and survival of both groups. No relapse occurred in the blinatumomab group, but 15 in the control group. The 1-year cumulative relapse rates were 0.0% and 39.5%, respectively, with a significant difference (P=0.009). One patient died of septicemia in the blinatumomab group at 19.3 months post-transplant, and 14 died of relapse in the control group. The 18-month leukemia-free survival rates were 100% and 60.5%, respectively, with a significant difference (P=0.037). The 18-month overall survival rates were 100% and 73.4%, respectively. The grade II-IV acute GvHD incidences were 25.3% and 15.9%, respectively. Grade III-IV acute GVHD incidences were 7.6% and 5.3%, respectively. No significant differences were observed between the two groups.

Conclusion

Blinatumomab maintenance therapy following allo-HSCT is safe. Although the dosage of blinatumomab was markedly lower than recommended, it significantly reduced post-transplant relapse and improved leukemia-free survival for B-ALL patients. Further research is needed to confirm its long-term efficacy and safety.