FLT3 positive

P1/2, N=74, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Study findings showed that there was a lack of routine testing for FLT3 mutations at first diagnosis of R/R AML, and initial treatment decisions did not differ by FLT3 mutation status. Given the clinical burden of FLT3MUT, likelihood of FLT3 status changes, and emerging FLT3 inhibitors, further routine FLT3 screening is needed to optimize treatment of R/R AML.

P2, N=22, Completed, Randy Windreich | Active, not recruiting --> Completed | Trial completion date: Nov 2023 --> Apr 2023 | Trial primary completion date: Nov 2023 --> Apr 2023

P1/2, N=74, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2023 --> Dec 2024

Novel drug combinations and strategies against FLT3 mutated AML are currently under investigation and will be the focus of future studies. The development of more selective and potent FLT3 inhibitors may further improve outcomes for patients with FLT3-positive AML. Monitoring minimal residual disease and overcoming resistance are key issues for the future.

This phase 1 study has demonstrated an acceptable safety profile and a significant anti-leukaemic activity of clifutinib in FLT3 mutant R/R AML, with the best response at the dose of 40 mg/day in FLT3-ITD(+)/TKD(-) AML. A confirmatory phase 3 study is currently ongoing to further evaluate the efficacy and safety of clifutinib dosed at 40 mg/day in R/R AML pts after first-line therapy with FLT3-ITD(+)/TKD(-) (NCT05586074).

XY0206 is a novel FLT3 inhibitor that showed a good safety profile, a potent anti-leukemic activity and improved efficacy in patients with FLT3mut+ R/R AML.

FLT3 mutations occur predominantly in AML and less frequently in other myeloid neoplasms. Progress in mutational signature analysis has provided insights into cancer biology and allows opportunities for prevention, risk management, and therapeutic management. Early studies of ID signatures in subsets of AML suggest the most common may include ID9, ID1, ID2, and ID23.

The study results suggest that cytarabine + anthracyclines was the most common first-line (1L) treatment, accounting for 41.3% of the patients...FLT3i was the most prescribed treatment across the study period and the overall median OS after initiating FLT3i treatment was over 1 year. The findings of this study could be helpful for clinicians to optimize treatment strategies for FLT3m + AML in Japan.

Almost half (n=30; 55%) of the included cases treated with 3&7 protocol as induction chemotherapy, (n=15; 27%) received high dose Ara-c (HIDAC) as consolidation, (n=10; 18%) received HYPER-CVAD protocol as induction chemotherapy and (n=5; 9%) received tyrosine kinase- based regimen (BCR-ABL positive ALL)...Professionally planned oral hygiene protocols, regular follow-ups, and oral microbial surveillance are highly recommended to avoid complications. We plan to evaluate a larger population to establish a correlation between various hematological malignancies and oral complications.

The overall median survival time for the cohort and FLT3+ group was 1467 days, while that of the FLT3-group could not be estimated due to the very high survival rate. No significant differences in outcomes were observed in patients who were FLT3 positive compared to those who were FLT3 negative.

Patients with peripheral edema had a 10.47 (95% CI: 1.64-66.82) times higher risk of death than those without peripheral edema (p<0.05). This research showed that patients with febrile neutropenia and peripheral edema were at a high risk of death when compared to patients without febrile neutropenia and peripheral edema.

NPM1 mut-MRD has prognostic role in chemotherapy and venetoclax-based regimes and correlates with disease burden. NPM1 mut transcript monitoring in Gilt sensitive pts may follow different dynamical patterns, possibly reflecting drug-induced differentiation and not necessarily correlating with disease burden. FLT3, Acute myeloid leukemia, Minimal residual disease (MRD), flt3 inhibitor

Aims: The primary outcome measures of AML1819 are to determine (1) the percentage of MRD negativity after consolidation in patients treated in induction and consolidation with GO; (2) the efficacy of a post-transplant maintenance with glasdegib vs clinical observation in terms of disease free survival improvement. I n the AML1819 trial, the preliminary analysis of the MRD status after consolidation indicates that a remarkable proportion of patients become negative when GO is added to intensive chemotherapy. With all the limits of such a comparison, we also found that the proportion of patients being MRD negative after consolidation was higher inAML1819 trial than in AML1310 one, in which no GO was added to chemotherapy. Such a finding has practical implications since, in AML1819 trial, a lower fraction of patients is submitted to ASCT.

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody approved by EMA in 2018 for the treatment of patients aged 15 years and above with previously untreated de novo CD33-positive AML, in combination with daunorubicin and cytarabine...Two additional cycles (Clofarabin-daunorubicin-Cytarabin and high dose Etoposide) were administered, without response. The patient then received additional treatment based on the association of GO, Doxorubicin, Aracytin and Midostaurin. Haploidentical HSCT with peripheral TCRalpha/beta-CD19 depleted cells from father was then performed in aplasia, preceded by a myeloablative conditioning regimen based on TBI-Melphalan...Additional treatment with Fludarabin-Aracytin-Myocet-G CSF could not prevent disease progression... GO integration into the FLT3-AML therapy before HSCT resulted in improved outcomes for pediatric patients with refractory AML. Combination of targeted inhibition of FLT3 and CD33 followed by allogeneic HSCT could be a promising therapeutic opportunity for refractory/relapsed pediatric AML.

Efficient anti-FLT3 CAR T-cells can be generated using CRISPR/Cas9.

P2, N=22, Active, not recruiting, Randy Windreich | Recruiting --> Active, not recruiting | N=16 --> 22 | Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2022 --> Nov 2023

Limited evaluation of FLT3-targeted TKIs as post-alloHCT maintenance therapy in FLT3-positive patients suggest improved outcomes and tolerable safety profiles, with ongoing studies further investigating second-generation agents. Thus, this commentary aims to review the role of post-alloHCT FLT3-targeted maintenance therapy and considerations for clinical practice.

Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.

CONCLUSIONS This study showed for the first time that FLT3-TKD mutation is common among northeast Thai AML patients. The data should prove useful for selecting efficacious targeted treatment plans for the patients.

Conclusion This is the first study clarifying the clonal dynamics of minute FLT3-ITD in clinically FLT3-ITD-negative AML. The clinical significance of an FLT3 inhibitor for patients with minute FLT3-ITD needs to be clarified in the future.

The combination of azacitidine, venetoclax and gilteritinib is effective in pts with FLT3-mutated AML. OS in the ND cohort compares favorably with historical expectations of FLT3-mutated AML treated with HMA plus venetoclax without a FLT3 inhibitor.

Majority of pts were treated with "7+3" (44%) and "7+3+ gemtuzumab ozagamicin (GO)" (40%) as induction regimens (Table 1). Daunorubicin was the predominant anthracycline, used in 80% of pts treated with "7+3" and 48% received dose of 90 mg/m2...Median number of consolidation cycles was 3, and GO was incorporated in consolidation (commonly with high dose cytarabine) for 29 (43%) pts... CBF-AML continues to be a favorable risk disease, with a median OS >7 years in our study population. Post-treatment CBF-MRD negativity rate was 73% and was predicted by the incorporation of GO in induction or consolidation. Rate of relapse rate was low at 15%, and all occurred in pts who did not receive GO during induction or consolidation.

Our data suggest that FLT3m are more likely to emerge at AML relapse with concomitant NRAS mutations and indicate that FLT3m testing should be performed at relapse, irrespective of FLT3status at diagnosis. It is common for the FLT3 status to change, either from mutant to WT or vice versa. FLT3 status has immediate and clinically important implications for selection of appropriate therapeutic agents in the setting of salvage therapy.