Page 278 - Haematologica - Vol. 105 n. 6 - June 2020

P. Vo et al.
outcomes even with myeloablative HCT, with 3-year esti- mates of relapse of 65%.3,16 Our study establishes proof of principle that radioimmunoconjugates can deliver supple- mental doses of radiation to sites of leukemic involvement and have the potential to improve the cure rate by decreasing the risk of relapse in these high-risk patients.
More importantly, the results presented here show the feasibility of using 90Y-DOTA-BC8 combined with reduced-intensity allogeneic HCT for patients with high- risk MDS and AML. Engraftment was not delayed after delivery of 90Y-DOTA-BC8, and infusion-related toxicities were mild and manageable. Intensified conditioning with 90Y-DOTA-BC8 resulted in few toxicities beyond those expected with FLU and TBI alone with no grade 4 adverse events reported. Most commonly seen grade 3 adverse events were neutropenic fever with or without identified sources of infection and constitutional symptoms. There was one case of NRM in the first 100 days after transplan- tation that was not attributed to the investigational thera- py among the 15 patients treated. Taken altogether, these findings suggest that this transplantation-conditioning strategy has acceptable toxicity profiles while comple- menting the efficacy of reduced-intensity conditioning, and demonstrates the potential exportability of this approach to other patient populations with hematologic malignancies.
The overall incidence of grades II to IV acute GvHD in this study was 67%. This incidence is similar to that seen with FLU or TBI alone at our center.17 The incidence of chronic GvHD (33%) in the current study is comparable to that among patients who received reduced intensity conditioning without targeted radiotherapy, suggesting that the radiolabeled antibody has no demonstrative effect on the risk of chronic GvHD.18,19
Although we previously estimated an MTD of 24 Gy in our study using 131I-BC8,2 no grade III or IV DLT were observed when the same antibody was conjugated to 90Y, despite targeted doses of up to 30 Gy to the liver (median dose 19 Gy), suggesting that higher doses of radiation may be tolerated in the marrow or spleen. Nonetheless, theoret- ical concerns persist about both the short- and long-term consequences of 90Y at higher doses due to its long path-
length. After treating these 15 patients, grant funding was exhausted, and in seeking renewed funding, we chose instead to pursue α emitters for two reasons. First, given the lack of DLT even after reaching 30 Gy to liver, it seemed unlikely that we would be able to load enough 90Y onto the amount of antibody that provides optimal biodis- tribution without damaging the antibody itself.20 Secondly, α-emitting radionuclides have a higher linear energy trans- fer that is coupled with a short path length capable of killing the target cells with only a few cell traversals, there- by potentially providing even greater specificity at high radiation doses.21 Ongoing studies are evaluating the use of an α emitter, astatine-211, conjugated to anti-CD45 anti- body BC8 as part of an HCT conditioning regimen for patients with advanced leukemia or high-risk MDS.
In summary, the delivery of supplemental radiation to bone marrow and spleen by 90Y-DOTA-BC8 was well tol- erated when combined with FLU/TBI in patients undergo- ing HCT for advanced AML and high-risk MDS who were not candidates for myeloablative HCT. The encouraging results from this study support more clinical trials using radioimmunotherapy as part of the conditioning regimen for allo-HCT. The antileukemic potential of this approach, combined with the promise of reduced toxicity, may improve outcomes after allogeneic HCT for patients with advanced hematologic malignancies.
Acknowledgments
The authors thank the patients who participated in the clinical trial. They also thank their colleagues in the transplant services, the research staff, and clinical staff. We greatly appreciate Monina Almeda’s assistance in data management and regulato- ry support, and Helen Crawford’s assistance with manuscript preparation.
Funding
Research funding was provided by the National Institutes of Health, Bethesda, MD, grants, P01 CA044991, P01 CA078902, and P30 CA015704 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health nor its subsidiary Institutes and Centers.
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Figure 2. Estimates of the probability of overall survival, relapse-free survival, and relapse among all patients who received a therapeutic dose of 90Y-DOTA-BC8 fol- lowed by total body irradiation/fludarabine. HCT: allo- geneic hematopoietic cell transplantation.