Long-Term Follow-up of the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed-Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Trial

Background:

The outcome of patients with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin and blinatumomab are highly active single agents in R-R ALL. The combination of inotuzumab with low-intensity mini-hyper-CVD chemotherapy showed encouraging results in this patient population. The sequential addition of blinatumomab might optimize the efficacy of the regimen, reduce its toxicities, and further improve outcomes in R-R ALL. The aim of the analysis is to evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy with or without blinatumomab in R-R ALL.

Methods:

Patients with relapsed-refractory Philadelphia chromosome-negative ALL were eligible. The mini-hyper-CVD (cycles 1, 3, 5, 7) were comprised of cyclophosphamide (150 mg/m² every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. Even cycles (cycles 2, 4, 6, 8) were comprised of methotrexate (250 mg/m² on day 1) and cytarabine (0.5 g/m² given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for the first 4 courses. Inotuzumab ozogamicin was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m² at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 67 pts were treated, an amendment was made to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + inotuzumab ozogamicin. Inotuzumab ozogamicin was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m² at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m² at subsequent cycles; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with allogeneic hematopoietic cell transplantation (HCT) was based on the discretion of the treating physician after discussion with the patient.

Results:

From 2/2013 to 9/2019, 96 patients were enrolled and treated including 29 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 36 months (range, 0.1-87.5). Patient characteristics and outcome are summarized in Table 1. The median age was 37 years (range, 17-87), and 20% of patients had received prior HCT. The overall response rate was 80% (CR, 57%, CRp/CRi, 20%). These rates were 91% in salvage(S) 1 (primary refractory, 100%; CR1 duration <12 months, 84%; CR1 duration >12 months, 94%) 61% inS2, and 57% in S3 or higher. Among 75 evaluable patients for minimal residual disease (MRD) assessment, 62 patients (83%) achieved negative MRD by multi-color flow cytometry with higher rates of MRD negativity in S1 (89%). Forty four patients (46%) received HCT. Three-year CR duration and overall survival (OS) rates were 32% and 33%, respectively (Figure 1). The 3-year OS rates for patients treated in S 1 and S 2+ were 42% and 13%, respectively (p=0.002). Historical comparison showed median OS of 13 months versus 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab versus inotuzumab ozogamicin single agent, respectively (p<0.001) (Figure 2). Among the 96 evaluable patients, VOD was observed in 10 (10%). The incidence of VOD was reduced from 9/67 (13%) with single dose of inotuzumab ozogamicin to 1/29 (3%) with fractionated dose schedule. Of the 17 patients treated with mini-hyper-CVD + inotuzumab ozogamicin + blinatumomab, 15 patients underwent HCT; among 15 patients, 1 patient developed VOD.

Conclusion: The long-term follow-up of the combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy continues to show promising results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with a fractionated inotuzumab ozogamicin followed by blinatumomab schedule.