Nature of Clinical Response and Depth of Molecular Response in Patients with TP53 Mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) Treated with Magrolimab with Azacitidine

Background

Magrolimab is a monoclonal anti-CD47 antibody that blocks the antiphagocytic signal widely expressed on tumor cells, including myeloid blasts. The hypomethylating agent (HMA) azacitidine increases expression of prophagocytic signals such as calreticulin on the surface of tumor cells, synergizing with magrolimab to facilitate tumor cell phagocytosis by macrophages.

In patients with AML or MDS, response to therapy and overall survival (OS) are heavily influenced by the underlying molecular architecture and loss of detection of mutations with treatment (i.e. molecular negativity), particularly in TP53 MDS/AML, has been associated with improved OS. Here, we report the somatic mutational landscape of a subset of patients with AML (n=23) or MDS (n=56) receiving magrolimab + azacitidine in a Phase 1 trial to identify genetic mutations prognostic of response and OS (NCT03248479). Longitudinal analysis during treatment of the most frequent mutations was also performed.

Methods

Magrolimab was administered in an escalating dose from 1 to 30 mg/kg for the first 2 weeks, then at a maintenance dose of 30 mg/kg weekly or once every 2 weeks from cycle 3 onward. Azacitidine (75 mg/m²) was given on days 1-7 of each 28-day cycle. Whole-exome sequencing (WES) was performed on available samples from screening and posttreatment bone marrow aspirates from treatment-naive patients with IPSS-R higher-risk MDS and patients with AML ineligible for induction therapy. Customized WES processing pipelines combining published algorithms with novel filtering, curation, and quality-control steps were developed using a variant allele frequency (VAF) cutoff of 0.07.

Results

At screening, TP53 was the most common variant observed in patients with MDS (8/51 [16%]; median VAF, 0.38 [range, 0.14-0.86]) and AML (22/35 [63%]; median VAF, 0.37 [range, <0.07-0.88]); 63% of patients with MDS (5/8) and 59% of patients with AML (13/22) had complex cytogenetics. TP53 biallelic loss (2 mutations, mutation + alt 17, or VAF >0.5) was observed in 5 patients with MDS and 17 with AML.

In patients with TP53-mutated MDS, 3 of 8 (38%) achieved complete remission (CR), and 1 of 8 (13%) had a marrow CR (mCR). In comparison, 13 of 43 (30%) patients with wild-type TP53 MDS achieved CR, and 15 of 43 (35%) had a mCR. All 3 patients achieving a CR had a TP53 VAF <0.07 by cycle 5 day 1.

In patients with TP53-mutated AML, 13 of 22 (59%) achieved CR, 2 of 22 (9%) had CRi or CRh, and 1 of 22 (5%) had MLFS. Among patients with CR, TP53 VAF <0.07 was observed in 7 of 13 (54%) patients at cycle 3 day 1, 9 of 12 (75%) at cycle 5 day 1, and 3 of 5 (60%) at cycle 7 day 1. In patients with TP53 wild-type AML, 6 of 13 (46%) achieved CR.

Similar response rates (CR range, 20%-50% in MDS and 33%-100% in AML) were observed in patients with mutations other than TP53. However, decreases in VAF were not as great. Longitudinal assessment of ASXL1, TET2, EZH2, and RUNX1 did not demonstrate decreases <0.07 over time in MDS. In AML, VAF <0.07 was observed in patients with NRAS (2/3 [66%]) and RUNX1 (2/2 [100%]) mutations, but patients with DNMT3A or EZH2 mutations had VAF >0.10 at all timepoints.

Conclusions

In this phase 1b study, magrolimab demonstrated a reduction in the allele frequency of TP53 mutations as early as cycle 3 in patients with MDS or AML treated with magrolimab + azacitidine, potentially altering the course of disease in patients with TP53-mutated malignancies.

Johnson:Gilead Sciences: Current Employment, Current holder of stock options in a privately-held company; Trillium Therapeutics (acquired by Pfizer): Current equity holder in private company, Patents & Royalties; Takeda: Current holder of stock options in a privately-held company. Zhang:Gilead Sciences: Current Employment, Current holder of stock options in a privately-held company. Li:Gilead Sciences: Current Employment, Current holder of stock options in a privately-held company. Aviles:Gilead Sciences: Current Employment. Lal:Gilead Sciences: Current Employment. Ramsingh:Gilead Sciences: Current Employment, Current holder of stock options in a privately-held company. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Vyas:JAZZ: Honoraria; Daiichi Sankyo: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Pfizer: Honoraria; Astellas: Honoraria; Bristol Myers Squibb: Research Funding. Sallman:Intellia: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Nemucore: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Lixte: Patents & Royalties: LB-100; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syntrix Pharmaceuticals: Research Funding; Magenta: Consultancy; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees.