Background :

Allogeneic hematopoietic cell transplant (alloHCT) is the only potentially curative therapy for patients (pts) with relapsed or refractory (R/R) AML. Only a minority undergo alloHCT as they typically have dismal outcomes due to high relapse rates, especially those with TP53 mutations and active disease. Additionally, older pts cannot tolerate intensive treatment and hence are not eligible for alloHCT. 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can thus provide these pts access to alloHCT potentially leading to better disease control and outcomes even in pts with the TP53 mutation.

Methods:

The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting ≥6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy in the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. We report the characteristics and outcomes of all pts with TP53 mutation who were enrolled in the SIERRA trial.

Results:

In total, 153 pts were randomized (CC, n=77; 131I-apamistamab, n=76). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent HCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 months were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p<0.0001). A total of 37 pts with TP53 mutation were enrolled (CC=20; 131I-apamistamab =17) with a prevalence of 24.2%. Table 1 shows the baseline characteristics of these pts. Median overall survival (OS) for pts in the 131I-apamistamab group, who were TP53 negative was 6.37 mos compared to 5.72 mos for the TP53 mutation positive pts (HR=0.66; 95% CI [0.37, 1.18]; p=0.16). In the CC group (including CO pts), the median OS for TP53 positive pts was 2.96 mos. When the CC group without CO were analyzed, the median OS was 6.51 mos and 1.66 mos for the TP53 mutation negative and positive groups respectively (HR=0.28; 95% CI [0.12, 0.67]; p=0.0022). For TP53 mutation positive pts who received 131I-apamistamab ( 131I-apamistamab plus CO pts), the median OS was 5.49 mos compared to a median 1.66 mos in pts who did not receive 131I-apamistamab (CC pts without CO) [(HR=0.23; 95% CI [0.10, 0.52]; p=0.0002) (Figure 1)].

Conclusion:

Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.

Choe:Opna: Other: Receipt of equipment, materials, drugs to institution, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs to institution; MJH Life Sciences: Honoraria; Actinium Pharmaceuticals: Other: Support for attending meetings and/or travel; NIH National Cancer Institute: Research Funding. Gyurkocza:Actinium Pharmaceuticals, Inc: Research Funding. Nath:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria; Actinium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Pfizer: Current equity holder in publicly-traded company; AlloVir: Membership on an entity's Board of Directors or advisory committees. Stiff:Takeda: Research Funding; Macrogenics: Research Funding; Incyte Corp: Research Funding; Gamida Cell: Research Funding; Eisai: Research Funding; Amgen: Research Funding; AtaraBiotherapeutics: Research Funding; CRISPR: Consultancy. Foran:Sellas: Research Funding; Roivant: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Astellas: Research Funding; CTI: Membership on an entity's Board of Directors or advisory committees; NCI: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Actinium: Research Funding; Kura: Research Funding. Abedin:AltruBio: Research Funding; Incyte: Research Funding; Actinium Pharmaceutical: Research Funding; AbbVie: Consultancy, Honoraria; Daichii Sankyo: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Kebriaei:Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Sabloff:BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Orozco:Actinium Pharmaceuticals: Other: Site PI for clinical trials sponsored by Actinium, Research Funding. Jamieson:Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Research Funding. Van Besien:Intellia: Consultancy; Precision Biosciences: Research Funding; Orca: Research Funding; Avertix: Current equity holder in private company; Calibr: Research Funding; BMS: Research Funding; Actinium: Research Funding; Moprhosys: Consultancy; Hemogenyx: Consultancy, Current equity holder in publicly-traded company; SNIPR: Consultancy; Incyte: Consultancy. Schuster:Pfizer: Consultancy, Research Funding; Macrogenomics: Research Funding; Karyopharm: Research Funding, Speakers Bureau; CTI Biopharma Corp: Speakers Bureau; ADC Therapeutics: Other; Takeda: Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Rafael: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; MorphSys: Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Research Funding; GSK: Research Funding; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Celgene: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Beigene: Speakers Bureau; Astellas: Speakers Bureau; Amgen: Other: Stock, Speakers Bureau; AlloVir: Research Funding; Actinium: Research Funding; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau; Syndax Pharmaceuticals: Research Funding. Law:Actinium Pharmaceuticals: Research Funding. Mayer:Omeros: Consultancy. Lazarus:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Spross:Actinium Pharmaceuticals: Current Employment. Li:Actinium Pharmaceuticals: Current Employment. Haeuber:Actinium Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Vusirikala:Actinium Pharmaceuticals: Current Employment. Nahar:Actinium Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Sandmaier:Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Pagel:Loxo Oncology at Lilly: Current Employment. Giralt:Amgen, Actinuum, Celgene/BMS, Kite Pharma, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Spectrum Pharma, Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen, Actinuum, Celgene/BMS, Omeros, Johnson & Johnson, Miltenyi, Takeda: Research Funding. Desai:Actinium Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company.

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2023
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