Discussion
leukemia, death, R-R ALL, ALL
LEUKEMIA, DISEASE
The combination of mini-Hyper-CVD-inotuzumab ± blinatumomab was effective and safe in patients with R-R ALL. The overall response rate was 83%, and the 3 year OS rate was 40%. In Salvage 1, the overall response rate was 92% and the 3 year OS rate was 49%. These figures emphasize the potential transition of R-R ALL, particularly in Salvage 1, from a disease that carried a death sentence (historical 3 year OS rates < 10%) [The longer follow-up of this study in a larger number of patients highlighted two novel important findings. The first is the benefits noted after the addition of sequential blinatumomab and the use of lower and fractionated inotuzumab doses. The 3 year survival rate was 52% (95% CI 36–66%) with the modified regimen versus 34% (95% CI 23–45%) in the original regimen (In this study, the best results were obtained in Salvage 1 with achievement of MRD-negative status. This indicates the importance of considering such combinations of all effective therapies in the form of a “total chemo-immunotherapy regimen” rather than losing the opportunity of a high “treatment value” and using single-agent antibody therapy, as is currently often practiced in the oncology community and in many referral leukemia centers. Rather than conducting randomized trials to evaluate the individual components incorporated into this regimen, we suggest this mini-Hyper-CVD-inotuzumab-blinatumomab total therapy be investigated in a single arm multi-institutional trial. Once confirmed, the regimen can be modified into a dose-dense regimen with the potential addition of CAR T-cell therapy, if our pilot trials with these 2 modifications are shown to be safe and more effective. In older patients above the age of 70 years, the combination of inotuzumab and blinatumomab is currently being evaluated as an effective chemotherapy-free alternative with a better safety profile.With the modifications implemented in the latter part of the study (lower and fractionated inotuzumab, ursodiol prophylaxis, distancing the last inotuzumab dose from the allogeneic SCT time, and perhaps more experience), the incidence of SOS was reduced from 13 to 2%, even after allogeneic SCT (SOS 24% vs. later 4%). We suggest incorporating these strategies into future ALL trials evaluating inotuzumab and later allogeneic SCT. The amendments reduced the total inotuzumab dose to a maximum of 2.7 mg/mOur analysis identified interesting adverse factors which should be further evaluated in all patients in ongoing trials. These include cytogenetic abnormalities like In summary, the long-term follow-up of the mini-Hyper-CVD-inotuzumab ± blinatumomab confirmed the efficacy and safety of this regimen and showed that the addition of blinatumomab may further improve outcomes. Confirmation in a large multi-institutional trial is needed in order to establish it as a new form of standard of care therapy in adult R-R ALL.