Background: Despite recent advances in the treatment of acute myeloid leukemia (AML), prognosis for patients with relapsed, refractory (R/R) disease remains poor. The only potentially curative option for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). However, only a minority reach complete remission (CR) or sufficient disease control to allow for HSCT, and moreover induction and conditioning regimens are poorly tolerated in the older population. Iomab-B (131I-apamistamab) is an anti-CD45 radioimmunoconjugate delivering targeted myeloablative radioactivity to stem cells and leukemic blasts with reduced intensity tolerability.
Aims: SIERRA (NCT02665065) is a multi-centre, randomized, controlled phase 3 study comparing the efficacy of Iomab-B based conditioning versus physician’s choice of conventional care (CC) in older, R/R AML with active disease routinely ineligible for HSCT. Primary endpoint was durable CR (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp).
Methods: Pts ≥55 years of age with active R/R AML were randomized (1:1) to CC or Iomab-B with fludarabine and total body irradiation (2 Gy) followed by HSCT. CC pts achieving CR received physician’s choice conditioning and HSCT. Pts not achieving CR could crossover (CO) to Iomab-B-based conditioning followed by HSCT. Assessment for CR/CRp occurred between days 28-56 post HSCT or initiation of therapy on the CC arm. Pts in CR/CRp were evaluated for the primary endpoint of dCR 6 mos after achieving initial CR/CRp.
Results: Baseline pt characteristics were balanced between both arms. 61% pts failed targeted therapies prior to enrolment, of whom 66% received venetoclax-based therapy. Median time to HSCT was 29 and 66.5 days on Iomab-B and CC arms (CC pts who had CR/CRp), respectively. The median infused activity of Iomab-B was 664.4 and 613.3 mCi in Iomab-B and CO arms respectively with median dose to marrow of 16 Gy in both arms. All pts who received the therapeutic dose of Iomab-B (n=66) underwent HSCT vs 14 (18.2%) on CC arm. Of evaluable pts (Iomab: 59; CC: 64), 44 (74.6%) pts on the Iomab-B arm achieved initial CR/CRp compared to 4 (6.3%) on CC. Durable CR rates were 22% vs 0% (95% CI; 12.29, 34.73; p<0.0001). The median overall survival (OS) was 6.4 vs 3.2 mos for pts receiving Iomab-B-based conditioning followed by HSCT vs non-CO pts on CC arm, respectively. Median OS in the CO vs non-CO cohorts on the CC arm was 7.1 vs 3.2 mos (HR=0.51; 95% CI [0.31, 0.85]; p=0.0078). OS in pts receiving Iomab-B and HSCT achieving dCR (n=13) was 92% and 60% at 1 and 2 yrs respectively (Figure 1). Event-free survival (EFS) at 6 mos on Iomab-B vs CC was 26% vs 0.2% (HR=0.22; 95% CI [0.15, 0.34]; p<0.0001). Iomab-B-based conditioning followed by HSCT was well tolerated with a favourable safety profile, with lower rates of sepsis in pts receiving Iomab-B based conditioning vs pts undergoing standard of care HSCT.
Summary/Conclusion: In pts ≥55 yrs with active R/R AML, Iomab-B was able to safely deliver myeloablative doses of targeted radiation to bone marrow. Iomab-B based conditioning with HSCT resulted in rapid engraftment and high initial CR/CRp rates, a favourable toxicity profile and resulted in statistically significant improvement in the pre-specified primary endpoint of dCR. The majority of pts who achieved dCR are long term survivors, in whom OS and EFS was significant. Iomab-B based conditioning was well-tolerated and provided access to HSCT with curative potential in a vulnerable pt population traditionally not considered eligible for HSCT.
Keywords: Radioimmunotherapy, Acute myeloid leukemia, Conditioning, Allogeneic hematopoietic stem cell transplant