Randomized Phase III SIERRA Trial of I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.

Purpose: Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate I-apamistamab with conventional care.

Methods: SIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population.

Results: The ITT population included 153 patients (I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the I-apamistamab and conventional care groups, respectively.

Conclusion: The I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. I-apamistamab was well tolerated and could address an unmet need in this population.