S1628 Targeting the Immunophilin Fkbp12 by Drug Repurposing or Rnase‐based Approaches for Bmp‐smad Pathway and Hepcidin Upregulation in Hereditary Hemochromatosis

Abstract

Results: 155 patients underwent allogeneic HCT for AML at our institution during the study period. Disease status was defined as CR in 80 (52%), CRi in 55 (35%) and AD in 20 (13%). There were no significant demographic or transplant characteristics between the groups. The 5-year probability of survival for CR patients was 51.3% (95%CI 40.2-65.4), compared to 24.4% (95%CI 14.1-42.4) for CRi and 12.7% (95%CI 3.6-45.2) for AD (p<0.001) (adjusted HR 1.92 (95% CI 1.20-3.06, p = 0.006) for CRi and 2.82 (95% CI 1.39-5.72, p < 0.001) for AD). 100 day NRM was 6.3%, 23.6% and 35.0% for CR, CRi and AD groups respectively (p < 0.001), with 5-year with cumulative incidence of NRM of 26.8%, 46.8% and 48.1% (p < 0.001). The cumulative incidence of relapse at two years was higher for the AD group (36.9%), but did not differ significantly between the CR and CRi groups (19.3% vs 20.6%, p = 0.86). These finding persistent in MRD negative patients (n = 107), with 5 year OS 37.5% vs 56.7% (p = 0.006) and NRM of 46.4% vs 30.4% (p = 0.003) for CR and CRi groups respectively, with no difference in the probability of relapse. Summary/Conclusion: Our data shows that patients undergoing HCT in CRi have a poorer survival and higher NRM without increased relapse risk compared to those transplanted in CR. The persistently increased NRM in CRi patients without MRD supports the notion that the poorer survival may result from poor fitness for transplant and increased susceptibility to transplant related complications rather than an imminent relapse. With the advent of increasingly sensitive MRD technologies, these data may suggest that further pre-transplant optimization to promote marrow recovery may be permissible in order to minimize NRM without risking increased relapses in CRi patients. The high NRM may also caution against pursuing MRD negativity at all cost, particularly if that risks incomplete count recovery.

Flavor of Iron at EHA2023: Novel Regulatory Mechanisms and Therapeutic Options for the Correction of Anemia

“…Dr Silvestri recently investigated the molecular mechanism underlying FKBP12 regulation of BMP-SMAD pathway activation and hepcidin expression. 9 Through pharmacologic and genetic studies, FKBP12 was shown to modulate BMP-receptor interactions and ligand sensitivity. Mechanistically, BMP6 and TAC increase ALK2 homo- and ALK2-ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors.…”

“…Both the physiological ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate signal transduction. Dr Silvestri recently investigated the molecular mechanism underlying FKBP12 regulation of BMP‐SMAD pathway activation and hepcidin expression 9 . Through pharmacologic and genetic studies, FKBP12 was shown to modulate BMP‐receptor interactions and ligand sensitivity.…”