Rydapt (midostaurin)

Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I's activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients' mutational status in terms of FLT3 and DNA methlome regulators.

Drug sensitivity of MV411 cells to doxorubicin, quizartinib and midostaurin can be enhanced significantly after miR-155 knockout, which is related to the inhibition of multiple signaling pathways including mTOR and Wnt signaling pathways.

No abstract available

Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.

P2, N=107, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting

Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163+ protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes.

P1, N=22, Not yet recruiting, Maximilian Stahl, MD

P1, N=18, Recruiting, Uma Borate | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=20, Not yet recruiting, University Hospital Tuebingen

Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.

Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

P1, N=29, Active, not recruiting, Richard Stone, MD | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

Avapritinib and midostaurin can also temper IgE-mediated degranulation...Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM...Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

No abstract available

Most importantly, the drug sensitivity analysis revealed a positive correlation between ARL4C expression and the heightened sensitivity of tumors to Staurosporine, Midostaurin, and Nelarabine. The findings from our study indicate that the expression level of ARL4C may exert an influence on cancer development, prognosis, and susceptibility to immunotherapy drugs. In addition, the involvement of ARL4C in the tumor immune microenvironment has expanded the concept of ARL4C-targeted immunotherapy.

Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.

Since 2020, FLT3 testing protocols have been further optimized to meet a 7-day turnaround time; additionally, almost all chemotherapy-fit patients with FLT3 mutation receive midostaurin in combination with 3+7 chemotherapy after reimbursement of midostaurin was implemented in Taiwan in February 2020... This study provided information on the real-world landscape of FLT3 testing among patients with AML in Taiwan. The turnaround time of FLT3 testing in the current study was longer than the time reported in clinical trials, likely owing to different procedures in sampling arrangement and report delivery between real world and clinical trial settings. The distribution of FLT3 mutation and pattern of clonal evolution were largely consistent with previously published clinical studies.

In the context of acute myeloid leukemia (AML) specifically, several efficacious combination therapies have been approved for specific patient subsets, such as all-trans retinoic acid (ATRA) plus arsenic trioxide in the PML-RARA fusion acute promyelocytic subtype and Midostaurin plus Cytarabine and Daunorubicin in FLT3-mutant AML. Strong established hits in our screen include ATR inhibition plus Gemcitabine treatment as well as several combinations involving the BCL-2 inhibitor Venetoclax with chemotherapies (Decitabine and Daunorubicin), Quizartinib, Idasanutlin, and mTOR inhibitors. Thus, we have developed an efficient and cost-effective high throughput drug combinations profiling system that has uncovered candidate therapies that may expand treatment options for patients afflicted by AML.

9%) use hypomethylating agents (HMA) (azacitidine N=51 (82. 3%), decitabine N=6 (9. 6%), HMA with venetoclax N=23 (37%), HMA with donor lymphocyte infusion (DLI) N=38 (61%), or a combination of modalities in 42 (67...The most common choice was sorafenib in 82/93 (88. 2%) centers, midostaurin in 28 (30%), and gilteritinib in 30 (32...2%) use enasidenib... In this survey, the majority of responding EBMT-affiliated transplant centers is implementing post-transplant AML maintenance treatment, predominantly HMA and FLT3 inhibitors. Further studies are needed to clarify the appropriate strategy and duration of maintenance therapy. The study will help the EBMT to incorporate post-transplant strategies as a routine registry capture parameter.

In the Phase II Trial REL AML 001 (EudraCT Number 2017-002094-18; ClinicalTrials ID: NCT 03686345) adult CBF leukemia patients treated with a continuation therapy with Midostaurin were included, and the measurable residual disease (MRD) was performed by molecular MRD assessment (qPCR) and multiparametric flow cytometric-MRD (MCF-MRD) assay... Although MCF-MRD assay showed lower sensitivity than CBF qPCR, MCF offered interesting informations about the dynamics of the abnormal clone size with time, evaluated as the increasing number of MRD clustering events, which may predict an impending relapse.

Initial induction therapy with cytarabine/daunorubicin (standard 7+3) with or without midostaurin (in patients with FLT3 mutations) was done in 12 (67%) patients and hypomethylating agent/venetoclax was used in 5 (28%) patients. One patient was managed with azacitidine only... While Fractional OXPHOS and basal respiration were lower in the patients who had remission after induction therapy, this difference was not statistically significant. We did not find a clinically significant correlation in the bioenergetic profile of AML cells; however, our study is limited by small sample size. Further research is warranted to investigate the role of OXPHOS kinetics in patients of AML that can translate into clinically meaningful outcomes.

Concomitant midostaurin (days 8-21) was allowed for patients with FLT3 mutations (Patients #1 and #8)...ConclusionThis ongoing phase 1b/2 trial of CPX-351 (liposomal cytarabine and daunorubicin) as re-induction treatment for intermediate and high-risk AML has been safe and tolerable with early treatment outcomes that appear to be much better than reported historical controls. Correlative studies by mass cytometry will further establish the mechanistic reasons for the observed responses.

We separated patients that underwent treatment with FLAG-IDA and a FLT3 inhibitor (gilteritinib, midostaurin, or sorafenib), venetoclax, or FLAG-IDA alone. The limitations of our study include its retrospective nature; subsequent FLT3 inhibitor combinations or maintenance strategies may have provided a survival benefit the FLT3i cohort. Therefore, prospective clinical trial designs are needed to further confirm these findings.

Quizartinib recently demonstrated improved overall survival (OS) compared to placebo when combined with standard 7+3 induction in patients up to 75 years of age, although the benefit in patients 60 and above was less clear (Erba et al; Lancet Oncol 2023)...The most common consolidation regimen was high dose cytarabine (HiDAC) in combination with midostaurin (n=5, 25%)...Reduced intensity conditioning (n=12/14; 86%) and GVHD prophylaxis with tacrolimus/ sirolimus prophylaxis (n=8; 57%) was commonly used in patients undergoing alloHCT...Five patients (36%) patients received post-transplant FLT3 maintenance with the most common agents being midostaurin (n=2) and gilteritinib (n=2). The addition of midostaurin to intensive 7+3 chemotherapy induction for ND FLT3m AML is feasible and well tolerated in older AML patients. The combination results in high remission rates and the majority of patients are able to proceed to alloHCT.

From January 1, 2017, to January 30, 2023, we retrospectively reviewed all adult patients (18 or older) with newly diagnosed AML who received midostaurin in combination with cytarabine and an anthracycline (7+3)...There were no significant differences in baseline characteristics (Table 1) except for more patients receiving isavuconazole (moderate CYP 3A4 inhibitor) in the concurrent group (50% vs 0%; p<0. 01) and more micafungin in the sequential or no azole group (0% vs 72%; p<0... In conclusion, the addition of azole antifungal was found to be equally safe and effective in the treatment of newly diagnosed FTL3 AML. Dose modifications in midostaurin appeared not to be necessary with concurrent azole antifungal therapy. Further analysis based on a larger cohort is needed to confirm the outcomes and safety endpoints reported in the current study.

In FLT3 mutated pts standard induction/consolidation therapy was enriched with midostaurin. Low intensity treatment consisted of azacitidine (1 pts), low dose Ara-C (LDAra-C, 2 pts) and LDAra-C + cladribine (1 pts)...ConclusionsOur preliminary results indicate the signaling pathways disturbed in high-risk AML patients. The miR-125b-5p, miR-15a-5p as well as the TEK and SPP1 gene expression may possibly act as biomarkers in patients with de novo AML.

Introduction Induction chemotherapy (IC) in acute myeloid leukemia (AML) in younger and fit patients has historically combined an anthracycline (ie, daunorubicin or idarubicin) with the antimetabolite cytarabine, which has been termed the 7 + 3 regimen...Patients either received 7+3 or 7+3 plus midostaurin if they were FLT3+ in one arm or FLAG-IDA/Venetoclax...Our results are similar to previously published reports in patents with ND-AML. Toxicity profiles were similar with the clear benefit of decreased early morality are increased response rates.

85) significantly in favor of quizartinib (Qui) + low dose cytarabine (LDAC) vs. LDAC alone. In two nRCTs (N=63) on unfit patients, Qui + venetoclax (Ven) +Aza/LDAC showed complete response (CR)/overall response (ORR) of 42%/72% and Qui+Aza/LDAC showed CR/ORR of 44%/56%...5% with midostaurin (Mid)+ chemotherapy and chemotherapy, respectively...9% and 73% with Gil+chemotherapy and crenolanib (Cren) + chemotherapy, respectively... Addition of Gil, Qui, Lus, Mid, or Cren to standard therapy was well tolerated by most of the patients with FLT-3 mutation. Addition of Mid or Qui to chemotherapy significantly improved survival and response rates as compared to chemotherapy alone in fit patients with FLT-3 mutation and the results were consistent in both young and old fit patients. In early phase trials, Gil and Cren were effective in combination with chemotherapy in fit patients.

No abstract available

Despite the approval of several FLT3 inhibitors over the last couple of years, the treatment of patients with FLT3-mutated AML remains challenging and many questions still need to be addressed. This review will provide an up-to-date overview of our current understanding of FLT3-mutated AML and discuss what the current status is of the available FLT3 inhibitors for the day-to-day management of this aggressive disease.

Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.

The patient started hematological follow up, treatment with hydroxyurea and transfusion support for LMMC diagnosis. Midostaurin is a TKI effective against KITD816V with an ORR of 60% in aggressive SM. Although midostaurin represents the most potent agent available for SM patients, other medications are under investigation to overcome resistance due to D816V-mutated variant of KIT.

Two cohorts of FLT3-mut AML patients treated either with Midostaurin in combination with intensive chemotherapy (M cohort) as induction or Gilteritinib (G cohort) as salvage at Seràgnoli Hematology Institute of Bologna were enrolled. Conclusions. This study portrays evolutionary trajectories under FLT3i-containing regimens pressure and highlights novel preliminary differences in immune transcriptomic profile associated with FLT3i effectiveness.

To evaluate the effect of FLT3 inhibitors in ALL, we treated ex vivo primary leukemic cells of 6 adult ALL patients (FLT3 mut n=4; FLT3 wt n=2) with increasing concentrations of Gilteritinib, Midostaurin, Crenolanib, Sorafenib and Quizartibin for 24, 48 and 72h. AIRC IG 2019 (Project Code: 23810). Figure 1.

The introduction of midostaurin and gentuzumab ozogamicin (GO) changed therapeutic strategies...Finally, int risk patients fared better when referred to HSCT, especially in presence of clinical high-risk features. Prospective studies are needed to determine if MRD monitoring is sufficient to guide therapeutic decisions in this risk category.

We observed three cases of invasive fungal infections (8.5%), once again with no differences between the two groups. Our study suggest that the concomitant administration of PCZ and midostaurin results effective and safe for FLT3-mut AML patients.

First line therapy was 3+7 or analogues in 81,3% of patients, CPX-351 in one patient, HMA plus venetoclax in one patient...In patients treated with midostaurin as a part of their induction regimen CR rate was 60%, median OS was 18.5 months, and median EFS was 16.7 months...The prognosis of FLT3 mutated AML with associated myeloid sarcoma remains dismal. Gilteritinib could play a role in relapsed setting, and in our series demonstrated activity in CNS disease; this positive effect needs to be validated in a larger series of patients.