Blinatumomab: a new standard in the consolidation therapy for children with high-risk acute lymphoblastic leukaemia patients in first relapse
The current standard therapy for children with high-risk relapsed Philadelphia chromosome negative (Ph-) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) consists of induction chemotherapy followed by three courses of consolidation chemotherapy and a haematopoietic stem cell transplantation (HSCT). Data presented at ASH 2020 now demonstrate that consolidation therapy with the bispecific T-cell engager blinatumomab before HSCT is superior to a third consolidation course of chemotherapy. With blinatumomab, patients obtained a superior event-free survival, with a superior rate of minimal residual disease negativity prior to HSCT. Moreover, the blinatumomab-containing regimen also proved to be less toxic than the standard three cycles of consolidation chemotherapy.
Background
With the currently available chemotherapy regimens, roughly 15% of children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) will relapse after standard treatment. The prognosis of these children largely depends on the timing of this relapse as well as on the site of relapse. Importantly, most children with relapsed BCP-ALL are candidates for allogeneic haematopoietic stem cell transplantation (allo-HSCT) after a second morphological complete remission is achieved. Usually, the standard treatment approach for high-risk relapsed Philadelphia chromosome negative (Ph-) BCP-ALL patients consists of induction chemotherapy followed by three courses of consolidation chemotherapy. The ultimate goal of this therapy is to obtain minimal residual disease (MRD) negativity before the transplantation. At ASH 2020, results of an open-label randomised, controlled phase III trial comparing blinatumomab with high-risk consolidation (HC) chemotherapy as pre-transplant consolidation therapy for children with high-risk first relapse BCP-ALL were presented. Blinatumomab is a bispecific T-cell engager creating an immunological synapsis between CD3-positive lymphocytes and CD19-positive B-cells, eventually leading to apoptosis of leukaemia cells. In the study at hand, children with M1 (< 5% blasts) or M2 (< 25% and ≥ 5% blasts) ALL were randomised (1:1) after induction therapy and cycles of HC1 and HC2 chemotherapy, to receive a third consolidation course with either blinatumomab (15 µg/m2/day for four weeks) or HC3 (dexamethasone, vincristine, daunorubicin, methotrexate, ifosfamide, PEG-asparaginase). The study initially planned to enrol 202 patients, however after 50% of the expected event-free survival events were reported, the data monitoring committee recommended early termination of enrolment because of the benefit observed with blinatumomab.
Results
The primary endpoint of superior event-free survival (EFS) in the blinatumomab arm was clearly met, with a 67% risk reduction in favour of blinatumomab (HR [95%CI]: 0.33 [0.18-0.61], p<0.001). The benefit of blinatumomab was most pronounced in patients with an early relapse, (<18 months; HR [95%CI]: 0.21 [0.07-0.59]), but was also observed in patients with a disease relapse between 18 and 30 months (HR [95%CI]: 0.43 [0.20-0.95]). Patients receiving blinatumomab also benefitted from a longer overall survival (OS) compared to patients receiving HC3 (HR [95%CI]:0.43 [0.18-1.01]), although this difference did not prove to be statistically significant. A significantly lower cumulative incidence of relapse (CIR) after CR2 was observed in the blinatumomab arm compared to HC3 (CIR at 24 months; 24.9% vs. 70.8%). Finally, patients in the blinatumomab arm were more likely to have an MRD remission at the end of treatment compared to patients in the HC3 arm (90% vs. 54%). With respect to safety, grade ≥3 adverse events (AEs) were reported by 57% and 82% of patients in the blinatumomab and HC3 groups, respectively, with lower incidences of febrile neutropenia (4% vs. 26%), aplasia (4% vs. 8%) and anaemia (15% vs. 41%) among patients treated with blinatumomab. No fatal AEs occurred in either group. As expected, neurologic events of any grade occurred more frequently with blinatumomab than with HC3 (48% vs. 29%) with grade 3 and grade 4 neurologic events occurring in 4% vs. 2% and 2% vs. 0% of patients, respectively. No grade ≥ 3 cytokine release syndrome events were reported in either arm. This is likely due to the very low tumour mutational burden at time of randomisation in both arms.
Conclusions
Blinatumomab monotherapy as consolidation therapy before allo-HSCT in children with high-risk first-relapse BCP-ALL leads to significantly better EFS, lower risk of recurrence, and fewer grade ≥3 treatment-emergent AEs as compared to HC3. These findings support blinatumomab as a new standard of care in this setting.
Reference
Locatelli F, Zugmaier G, Rizzari C, et al. Superior Event-Free Survival with Blinatumomab Versus Chemotherapy in Children with High-Risk First Relapse of B-Cell Precursor Acute Lymphoblastic Leukemia: A Randomized, Controlled Phase 3 Trial. Presented at ASH 2020; Abstract 268.
