Abstract
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Background: Patients ≥ 55 years of age with high-risk acute myeloid leukemia (AML) may benefit from an allogeneic hematopoietic stem cell transplantation (HSCT), which is often the only potentially curative therapy available. However, complete remission (CR) is usually a prerequisite for most centers to perform HSCT, as CR predicts an optimal outcome. Many older patients with relapsed/refractory (R/R) AML do not receive HSCT, as they do not achieve the required CR. Additionally, many are unable to tolerate the myeloablative conditioning required for eradication of disease. While the reduced intensity conditioning is better tolerated, it often exhibits high rates of relapse. SIERRA trial is a prospective, randomized, phase 3 trial for older patients with R/R AML to address this unmet need. Iomab-B (131I labeled apamistamab) targets CD45, which is highly expressed in leukemia cells. We hypothesized that the targeted delivery of therapeutic Iomab-B with an imaging-based dosimetry enables successful engraftment despite active disease in the marrow. Methods: Eligible patients with active R/R AML, adequate organ function, and related/unrelated 8/8 HLA-matched donors were randomized (1:1) to the Iomab-B or Conventional Care (CC) arm. Patients randomized to Iomab-B received a low dose of Iomab-B, followed by 3 sequential gamma camera images (Fig 1) to determine the personalized therapeutic dose that would deliver maximal radiation to the marrow while limiting the liver dose to 24 Gy. Dosimetry was performed using serial imaging data and Olinda program (V2.1, Hermes Medical). Following a therapeutic infusion of Iomab-B and a non-myeloablative conditioning backbone of fludarabine (30 mg/m2 x 3) and 2 Gy Total Body Irradiation, HSCT was performed 12-14 days later. Each patient on the CC arm received the investigator’s choice of non-radioactive salvage therapy and could proceed to HSCT if they achieved CR. If no CR, the study allowed patients to cross over and receive Iomab-B-based conditioning followed by allogeneic HSCT. Patient age, donor type, bone marrow cellularity, blast percentage, type of donor, stem cell dose, administered Iomab-B activity (mCi), and radiation dose to marrow (Gy), were analyzed for a relationship to days to engraftment among each group.
Results: Preliminary data were available from 113 patients (Table 1). 56 patients were randomized to Iomab-B for which 49 patients received allogeneic transplant. In the CC arm, 82% (47/57) of patients failed salvage therapy. 30 of the 47 (64%) CC patients crossed over and received Iomab-B followed by allogeneic HSCT. Median time to neutrophil and platelet engraftment were 14 days (range 9-22) and 18 days (range 4-39), respectively, in Iomab-B group, with 89% of evaluable patients achieving full donor chimerism (> 95% by day 100). All patients who received Iomab-B treatment achieved engraftment, including the Iomab-B group and the cross-over patients. Neither the radiation dose delivered to marrow (median 14.7 Gy; range 4.6-32 Gy) nor the administered activity (median 646 mCi; range 354-1027 mCi) showed correlation with the time to either neutrophil (p = 0.525) or platelet engraftment (p = 0.952). Regression analyses, considering all the variables individually, did not indicate a statistically significant correlation (p > 0.1) between days to engraftment and marrow dose. These results were consistent for the cross-over group. Furthermore, the marrow radiation dose did not show a significant correlation with % chimerism at day 28 in patients on the Iomab-B arm or in cross-over patients. Conclusion: No significant relationship between total administered activity or radiation dose to marrow with the speed of engraftment was found, indicating the dosimetry estimates for ablative doses appear to be adequate and successful in ablation, despite a heavy leukemia burden prior to HSCT.
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