Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML

Abstract

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 ¹³¹I-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 ¹³¹I-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 ¹³¹I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive ¹³¹I-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 (¹³¹I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received ¹³¹I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with ¹³¹I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring ¹³¹I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the ¹³¹I-apamistamab and conventional care groups, respectively.

Conclusion: The ¹³¹I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. ¹³¹I-apamistamab was well tolerated and could address an unmet need in this population.

FIG 1.

Trial profile. ^aDue to death (n = 1), investigator decision (n = 1), insurance (n = 1), did not meet eligibility criteria (n = 1). ^bPatient withdrew consent. ^cDue to investigator decision (n = 3), grade 3 infusion reaction (n = 1), rapid disease progression (n = 1), unfavorable biodistribution (n = 1). ^dDefined as <5% blasts in bone marrow within 28 to 42 days. ^eDue to decline in Karnofsky performance status (n = 2), investigator decision (n = 1), patient withdrew consent (n = 1). ^fPatients listed as relapsed had disease relapse but were alive at the time of last contact/data cutoff. ^gInvestigator decision (n = 1), insurance (n = 1), did not meet eligibility criteria (n = 1). ^hAt the primary cutoff (June 30, 2022). At the subsequent cutoff on January 22, 2024, eight patients were ongoing, with one having discontinued because of relapse. ⁱAt the primary cutoff (June 30, 2022). At the subsequent cutoff on January 22, 2024, four patients were ongoing, with two patients in the crossover group having died and one having completed 5-year survival follow-up. alloHCT, allogeneic hematopoietic cell transplantation; CR, complete remission; CRp, complete remission with incomplete platelet recovery; ITT, intention-to-treat; MLFS, morphologic leukemia-free state.

FIG 2.

OS and EFS. (A) OS in the ITT population. (B) OS in patients who achieved dCR. (C) EFS in the ITT population assessed by actual time. The initial decreases in the Kaplan-Meier curves are due to the patients who failed to achieve initial CR/CRp within the protocol-specified timeframe or those who had induction treatment failure on the day of random assignment. (D) Prespecified exploratory subgroup analyses of EFS assessed by grouped survival analysis in the ITT population. Data are from the January 22, 2024 cutoff. CR, complete remission; CRp, CR with incomplete platelet recovery; dCR, durable complete remission; EFS, event-free survival; HR, hazard ratio; ITT, intention-to-treat; NE, not evaluable; OS, overall survival.