TRK Protein Expression in TP53 Altered Acute Erythroid Leukemia

Introduction: Acute erythroid leukemia (AEL; also called pure erythroid leukemia or PEL) is characterized by a neoplastic proliferation of erythroid elements with maturation arrest and 30% or greater proerythroblasts. AEL is associated with multi-hit alterations in TP53 and complex cytogenetics. Outcomes are poor and the median overall survival for adult patients with AEL is typically 6 months or less. Novel treatment approaches targeting AEL are needed. The neurotrophic receptor tyrosine kinase (NTRK) family encompasses various TRK receptors that can be affected by mutations and gene arrangements in both solid and hematological malignancies. NTRK1 mutations have been rarely identified in patients with AEL (Iacobucci et al. Nat Genetics 2019). Recent studies have suggested that TRK signaling in leukemic cells with TP53 inactivation may result in sensitivity to TRK inhibitors (Nechiporuk et al. Cancer Discov 2019) and a clinical trial is currently evaluating the combination of the NTRK inhibitor, entrectinib, with ASTX727 in patients with relapsed refractory TP53 mutated acute myeloid leukemia (AML) (NCT05396859). Given the association of TP53 alterations with AEL, we sought to retrospectively evaluate the expression of TRK proteins in AEL using immunohistochemistry (IHC).

Methods: We retrospectively reviewed samples from adult patients diagnosed with AEL between 2019-2024. Lesional bone marrow or extramedullary biopsy samples were investigated for expression of TRK-family proteins using IHC using a pan-anti-TRK antibody. Two hematopathologists scored samples together to determine TRK expression by consensus on a scale ranging between 0 (no expression) to 3+ (strong expression) amongst leukemic blasts and quantified the percentage of TRK+ blasts.

Results: Eleven patients with AEL and sufficient diagnostic material were identified; the median age of the cohort was 74 (range 43-87) and 36% of patients were females. At the time of AEL diagnosis, 4 patients had secondary leukemia progressing from prior myelodysplastic syndrome/neoplasm (MDS), 5 patients had post-cytotoxic therapy associated AEL after prior cancer diagnoses, 1 patient had progression from AML with myelodysplasia related changes, and 1 patient had de novo AEL. The median pronormoblast% by morphology on core biopsy was 80% (range 70% to >90%). Nine of 11 (82%) patients had both a complex and monosomal karyotype, 1 patient had a normal karyotype, and 1 patient had unknown cytogenetics. All 11 patients (100%) had mutations in TP53, including 6 patients (55%) with 2 or more TP53 mutations and 3 patients (27%) with TP53 mutations with variable allele fractions (VAF) above 50%. Seven of 11 patients (64%) had copy number losses of TP53 on cytogenetics. Overall, 10 of 11 patients had multi-hit TP53 alterations, while 1 patient had a normal karyotype with a TP53 mutation with <10% VAF. Eight of 11 patients (73%) had TRK family protein expression by IHC (1 patient with 1-2+, 6 patients with 2+, and 1 patient with 2-3+ expression). The median percentage of pronormoblasts staining TRK positive among positive cases was 65% (range 5% - 100%). Significant TRK expression was not seen among background maturing hematopoietic elements.

Conclusions and future directions: In this small cohort of patients with AEL with TP53 alterations, a majority of patients had TRK family protein expression of varying degrees by IHC in the blast population. We will be next evaluating TRK expression in non-AEL acute leukemias both with TP53 alterations and without TP53 alterations as well non-leukemic marrow samples for comparison. Further functional evaluation is needed to elucidate the role of TRK family proteins in erythroblasts in malignant and non-malignant states. Additionally, investigation of potential susceptibility of AEL to NTRK inhibitors and any correlation to the level of TRK expression would be of clinical interest given the poor outcomes of this subtype.

Narayan:Novartis: Other: Research funding to the institution; Sanofi: Other: Spouse employment. Swords:Disc Medicine: Consultancy. Brunner:Agios: Consultancy; BMS: Consultancy, Research Funding; i-Mab Biopharma: Consultancy; Keros Therapeutics: Consultancy; Lava Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Rigel Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Research Funding; Geron: Consultancy; AstraZeneca: Research Funding; Servier: Consultancy. Hobbs:Abbvie: Honoraria; BMS: Honoraria; Incyte: Honoraria, Research Funding; GSK: Honoraria; Pharmaessentia: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Sobi: Honoraria; Cogent: Honoraria; Regeneron: Other: spouse employment. Lee:Morphosys: Membership on an entity's Board of Directors or advisory committees. Fathi:Autolus: Consultancy; Daiichi Sankyo: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Astellas: Consultancy; Mablytics: Consultancy; Ipsen: Consultancy; ImmunoGen: Consultancy; Orum: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Agios: Ended employment in the past 24 months; AbbVie, BMS/Celgene, and Agios/Servier: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Menarini Group: Consultancy; Amgen: Consultancy; Servier: Consultancy, Research Funding; Takeda: Consultancy; EnClear: Consultancy; Rigel: Consultancy; Pfizer: Consultancy; Remix: Consultancy; Kite: Consultancy; Foghorn, Blueprint Medicines, Kura, Trillium: Honoraria; Forma: Consultancy; PureTech: Consultancy; Ispen: Consultancy; MorphoSys: Consultancy; AstraZeneca: Honoraria; BMS/Celgene: Consultancy. Hasserjian:Bluebird Bio: Consultancy.