Xospata (gilteritinib)

Oral azacitidine (CC-486) demonstrated overall survival benefit in older patients in first complete remission who were not transplant candidates, establishing a standard of care in this population. In FLT3-mutated AML, post-transplant maintenance with sorafenib and gilteritinib reduces relapse risk, with emerging evidence supporting MRD as a predictive biomarker for benefit. Other targeted agents and immunotherapies have shown promising early-phase results, although confirmatory data are limited. Ongoing phase III studies will clarify optimal patient selection, treatment duration, and integration with transplantation, aiming to transform post-remission management from passive surveillance to precision-based relapse prevention.

P2, N=181, Active, not recruiting, PrECOG, LLC. | Trial completion date: Dec 2026 --> Jul 2026

Second-generation FLT3 inhibitors significantly improve survival outcomes in FLT3-mutated AML, particularly for gilteritinib and in relapsed/refractory disease. Further studies are needed to clarify mutation subtype-specific and dose-specific effects.

P1/2, N=20, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1/2, N=58, Recruiting, Hellenic Society Of Hematology | Not yet recruiting --> Recruiting

Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.

Gilteritinib was generally well-tolerated, with no observed increase in cytomegalovirus (CMV)-related or graft-versus-host complications. This study provides real-world evidence in a clinically relevant scenario and supports the use of gilteritinib maintenance in patients with FLT3-mutated AML who undergo transplantation during R/R disease.

We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of a clinical trial cohort of acute myeloid leukemia (AML) patients treated on the Phase 1b clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Gilt) to characterize immunophenotypic, transcriptional, and genetic clonal evolution driving resistance. These results underscore that RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to AML monocytic differentiation and highlight RAS pathway inhibition as a viable clinical strategy to combat resistance. CT# NCT03625505.

Randomized studies comparing this regimen to standard of care approaches are warranted. This trial is registered at www.clinicaltrials.gov #NCT04140487.

Timely identification of this fusion gene led to targeted management of our patient, who achieved complete resolution of his FDG-avid lymphadenopathy only after the addition of gilteritinib. Two years after successful bone marrow transplant, the patient remains in complete remission. Clinicians and pathologists should have a low index of suspicion for a M/LN-eo-TK when evaluating patients with and without unexplained eosinophilia in the context of extramedullary lymphoid or myeloid disease or unusual myeloproliferative disorders.

We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of DNMT3A/FLT3-mutant AML by impairing pro-oncogenic survival and proliferation factors to effectively block leukemogenesis. This work identifies potential clinical utility of a targeted, triplet combination therapy for treatment of AML.

Functional studies using EML4::ALK-dependent Ba/F3 cells demonstrated that ALK K1150dup confers resistance to lorlatinib and other ALK-TKIs including NVL-655 (neladalkib), with sustained ALK phosphorylation and downstream signaling. These findings reveal K1150dup as a previously unidentified mechanism of resistance to first-line lorlatinib, and highlight gilteritinib as a potential therapeutic option for patients harboring this mutation. Notably, they also challenge the prevailing assumption that first-line lorlatinib precludes the emergence of single on-target ALK resistance mutations.