Chemo-free regimen of inotuzumab ozogamicin and blinatumomab shows promising results in older patients with newly-diagnosed Ph-negative CD22+ B-cell ALL
Older adult patients with newly diagnosed Philadelphia chromosome (Ph)-negative acute lymphoblastic leukaemia (ALL) have poor survival with conventional chemotherapy. In this study, the chemotherapy-free regimen of inotuzumab ozogamicin induction and blinatumomab consolidation showed to be highly effective and safe in this patient population. These findings justify further study of this combination and its consideration as a standard of care regimen for this patient population that had, up to now, a poor prognosis.
Older adult patients with newly diagnosed Philadelphia chromosome (Ph)- negative acute lymphoblastic leukaemia (ALL) have poor survival with conventional chemotherapy, with 3-5 year overall survival rates of about 20%. The anti-CD22 antibody-drug conjugate inotuzumab ozogamicin (InO) and the anti-CD19/CD3 T-engager blinatumomab were each superior to conventional chemotherapy in phase III studies in relapsed/refractory (R/R) B-ALL patients. However, little is known about the efficacy and safety of these agents combined in front-line therapy for B-ALL, and there are no reported multicentric studies. This study hypothesised that induction with InO followed by consolidation with blinatumomab would improve 1-year event-free survival (EFS) compared to historical conventional chemotherapy (1-year EFS = 10%) in this patient population.
Study design
This study enrolled elderly patients (age ≥ 60 years) with Ph-negative, CD22+ precursor B-cell acute ALL, for whom allogenic or autologous haematopoietic cell transplantation was not planned. Patients received induction therapy (course I) with InO on days 1, 8 and 15 (0.8, 0.5 and 0.5 mg/m3, respectively), followed by response assessment on days 18-21. If an adequate ALL cytoreduction was observed, this was followed by a second induction course and a consolidation course (course II) with blinatumomab (28 mcg/day). Instead, patients who failed to achieve ALL cytoreduction were directly assigned to receive blinatumomab consolidation. After the response assessment on days 81-84, the treatment was terminated for patients with R/R disease, while patients with a complete response (CR)/CR with incomplete count recovery (CRi) received a second consolidation course. The primary endpoint was the 1-year EFS, estimated using a Kaplan-Meier curve and a two-sided 90% confidence interval. The definition of event included the progression of disease prior to the end of two consolidation cycles of blinatumomab, relapse, or death from any cause. Secondary endpoints included, among others, overall survival (OS), relapse-free survival (RFS) and complete remission (CR) rates.
Results
In total, 33 patients participated in this study, of whom 52% were older than 70 years. Of those, 32 patients had a composite CR (CR, CRi and CR with partial hematologic recovery [CRh]) as best cumulative response, with 20 patients having a CR. After a median follow-up of 22 months, the estimated 1-year EFS was 75% (90%CI: 63-89%). In total, twelve patients (36%) had an event, of which nine were relapses (27%) and three were deaths. EFS did not seem to be affected by age (< or ≥ 70 years) or prior malignancy/chemotherapy. The 1-year OS rate was estimated at 84% (95%CI: 72-98%), and the median OS was not reached. Nine patients have died, the cause of death was relapsed ALL in six patients, while it was associated with adverse events (AEs) in three patients (two with refractory ALL and one in remission). Grade ≥3 AEs (evaluable in ≥10% of patients) included decreased neutrophil (87.9%), platelet (72.7%), white blood cells (39.4%) and lymphocyte (27.3%) counts, anaemia (42.4%), febrile neutropenia (21.2%) and encephalopathy (12.1%). The most common grade 4 AEs were decreased neutrophil (69.7%), platelet (57.6%) and while blood cell counts (24.2%). Only two patients had grade 5 AEs/deaths on treatment (one encephalopathy and one respiratory failure).
Conclusions
This study showed that the chemotherapy-free regimen of InO induction and blinatumomab consolidation is highly effective and safe in older patients with newly-diagnosed Ph-negative CD22+ B-cell ALL. These outcomes appeared to be superior to approaches using conventional chemotherapy in this population, with a low rate of death in remission. These findings justify further study of this combination and its consideration as a standard of care regimen for this patient population.
Reference
Wieduwilt M, Yin J, Oudom Kour, et al. Chemotherapy-free treatment with inotuzumab ozogamicin and blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B- cell acute lymphoblastic leukemia: Alliance A041703. Presented at EHA 2023; Abstract S117.
