FLT3-TKD mutation

Only two patients in the MRD negative group received the FLT3 inhibitor midostaurin combined with chemotherapy...NGS-MRD was not prognostic in this cohort of FLT3-TKD mutated AML patients. Shared first authors: Isabell Arnhardt, Christian M Vonk Shared senior authorship: Michael Heuser, Peter J.M. Valk

This review also discusses the development of molecular treatments targeting FLT3, including first-generation and next-generation tyrosine kinase inhibitors, highlighting the challenges of resistance that often arise during therapy. The final chapter describes FLT3 protein domain rearrangements and their relevance to AML pathogenesis.

An 80-year-old man with FLT3-TKD mutation-positive acute myeloid leukemia (AML) relapsed during consolidation therapy with venetoclax/azacitidine and was started on gilteritinib as salvage therapy. The patient was discharged from the intensive care unit on the 18th day after the onset of CDI. We report this case not only due to the rarity of fulminant CDI during AML treatment, but also because it is a valuable example of effective treatment of fulminant CDI with fidaxomicin.

P2, N=153, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

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 vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

P1, N=65, Not yet recruiting, The Second Affiliated Hospital of Dalian Medical University; The Second Affiliated Hospital of Dalian Medical University

our results show that the frequency of FLT3-ITD mutations and their association with worse prognosis was similar to those described in high-income countries previously to the Introduction of TKI as the standard of care. Therefore, allogeneic HSCT remains a valid consolidation strategy for FLT3-mutated patients. However, less than half of the patients for whom HSCT was indicated were actually transplanted.

P2, N=50, Recruiting, Centre Antoine Lacassagne | Not yet recruiting --> Recruiting

Regarding the intensive chemotherapy schedule in induction, 162 (84.8%) patients were treated with idarubicin-based regimens, 18 (9.4%) with daunorubicin-based regimens, and 8 (4.2%) with CPX-351... This real-life study suggests that the addition of midostaurine to intensive chemotherapy regimens in elderly patients could result in acceptable CRc, OS and EFS. In order to establish the benefit of midostaurin, we will compare these results with a historical control cohort.

However, 80mg of GILT was selected for the phase II portion of this study based on the more favorable safety/efficacy profile and better count recovery observed in a parallel study of azacitidine combined with VEN and GILT in AML. Conclusion In this poor-risk population of pts with R/R FLT3-mutated AML or MDS/CMML, many of whom received prior HMA + VEN, the combination of ASTX727, VEN, and GILT was active, with an ORR of 53%. The trial continues to enroll to the R/R cohort, and is now open for patients with newly diagnosed FLT3-mutated AML who are unsuitable for intensive chemotherapy.

During the first induction treatment, most patients (98.1%; n=105/107) received GO in association with other agents, most commonly cytarabine and daunorubicin (60.0%; n=63/105)... GO was predominantly administered according to its indication. Response rates were similar to those reported in the pivotal ALFA-0701 study. Median OS was longer in this study than in ALFA-0701 (49.8 vs 27.5 months), although median RFS and EFS were reduced.

Taken together, we present novel neoantigens with promise as immunotherapy targets for AML and other hematologic malignancies with FLT3-D835 mutations. Future studies will evaluate the efficacy of Neo-D835H-specific TCR-engineered T-cell-based immunotherapy in vivo in patient-derived xenograft murine model and TCR-based therapeutic approaches targeting other FLT3-TKD mutations.

The higher CR/CRi rate will give a clue to determine a potentialeffectiveness of BHA for AML patients carrying FLT3 mutation in a further investigation. https://www.chictr.org.cn/, identifier ChiCTR2000029841.

Patients treated with midostaurin faced a lower mortality risk than those administered sorafenib. This study underscores the significance of FLT3 mutations in AML, their influence on clinical outcomes, and the advantages of targeted therapies. Our findings stress the urgency for further investigation aimed at enhancing the prognosis for AML patients with FLT3 mutations.

P3, N=777, Active, not recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Recruiting --> Active, not recruiting

BHA chemotherapy was safe and can serve as a reinduction therapy for R/R AML, particularly with FLT3 mutation. The higher response rate will pave a way for potential long-term survival in patients with R/R-AML, especially for those with FLT3 mutation. Clinical Trial registration: https://www.chictr.org.cn/ , identifier [ChiCTR2000029841].

Of the 42 pts with FLT3 mutated AML, 34 pts (82%) received a FLT3i at some time during their treatment: 27 pts (79.4%) received mido, 24 pts (70.6%) another FLT3i (mainly sorafenib) and in 17 pts (50%) mido was followed by another FLT3i...Other known risk factors (i.e. age≥60 years, adverse or intermediate risk cytogenetics, obesity, preexisting cardiac comorbidity, female sex or cumulative daunorubicin equivalence dose) were not associated with a significantly higher number of CAEs... We here identified mido and/or FLT3i treatment as an independent risk factor for CAEs inpts undergoing HCT without higher NRM or impaired OS. The higher risk of rarely life-threatening CAE should not preclude administration of mido and/or FLT3i, even in pts with preexisting cardiac comorbidities, but close monitoring is warranted.

P1, N=0, Withdrawn, Ayman H Qasrawi | N=15 --> 0 | Not yet recruiting --> Withdrawn

P1, N=22, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Suspended --> Recruiting

For patients with isolated MS, treatment by chemotherapy and surgery are radical procedure, and initial treatment using chemotherapy alone should be considered for MS with synchronous intramedullary AML. Poor response to chemotherapy, short interval to leukemia occurrence, and heavy tumor burden (> 10 cm) could indicate a poor prognosis for patients with MS.

Our patient died in 6 months from the date of diagnosis. Although a rare occurrence, it has been discussed in literature to identify t(8;16) as a separate subtype of AML due to unique characteristics.

P3, N=768, Recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Suspended --> Recruiting

P3, N=768, Suspended, Stichting Hemato-Oncologie voor Volwassenen Nederland | Trial completion date: Mar 2033 --> Jun 2033 | Trial primary completion date: Mar 2023 --> Dec 2024

While co-mutated FLT3-TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high FLT3-ITD allelic ratio, comparative studies are needed to evaluate which FLT3-ITD mutated patients benefit from which consolidation strategy.

P3, N=768, Suspended, Stichting Hemato-Oncologie voor Volwassenen Nederland | Trial completion date: Sep 2032 --> Mar 2033 | Recruiting --> Suspended

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.

Of the 29 patients who used maintenance therapy after HSCT, 18 (62%) received gilteritinib while 11 (38%) received midostaurin. Amongst our patients receiving FLT3 inhibitors for maintenance, OS at 24 months was 96.2% and RFS was 89.7%. OS and RFS for this group remained high at 36 months.

Also, the frequency of FLT3-TKD mutation was low 2% and no compound between the two mutations was found, as individuals showed to carry the two mutations were not detected. These findings are likely useful for a better understanding of molecular leukemogenetic steps in AML-NK patients and may be beneficial for clinical relevance for risk grouping, study design and choice of therapy in Syrian population.

Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.

P1, N=22, Suspended, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Suspended

P2, N=153, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Oct 2022 --> Feb 2023

Hydroxyurea or 1 dose of cytarabine up to 1000 mg was allowed in pts with proliferative disease to lower white blood count to ≤ 25 x 109/L before initiation of study therapy. The combination therapy with ASTX727, VEN, and gilteritinib appears to be effective and safe in R/R FLT3 mutated AML and HR-MDS. Myelosuppression was frequent but manageable. Continued accrual is anticipated to define the optimal triplet regimen in both R/R and newly diagnosed FLT3-mutated AML.

Multivariate analyses disclosed female gender (HR 1.61, 95%CI 1.07-2.42, p=0.02), adverse cytogenetic risk (HR 2.52, 95%CI 1.24-5.13, p=0.01) and allo-HSCT after gilteritinib (HR 0.13, 95%CI 0.05-0.37, p<0.0001) as factors significantly and independently associated with OS. Conclusion Although patients in this study were more heavily pretreated, these real-world data reproduce ADMIRAL results and provide new insights in the outcome of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment.

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.

We included patients from January 2013 to August 19, 2021 from 7 centers with NPM1+ AML who received induction chemotherapy with an anthracycline and cytarabine... In our multicenter cohort of pts with NPM1+ AML, OS was significantly inferior in pts with ITDhigh v. FLT3neg, but not in ITDlow and TKD. Co-mutations in DNMT3A and TET2 adversely affected overall survival. Our data did not find a significant difference in OS in pts >60 with NPM1+/FLT3-ITDneg who were consolidated with chemotherapy versus SCT, though larger follow up studies are needed.

Induction chemotherapy regimen consisted in one cycle of idarubicin 8 mg/m²/day, D1 to D5, cytarabine 100 mg/m²/d, CIV D1 to D7, lomustine 200 mg/m²/d, orally at D1 and dexamethasone 10 mg/12h, IV, D1 to D3...The addition of midostaurin in patients with FLT3-ITD or FLT3-TKD mutations was allowed during induction, consolidation and maintenance...Conclusion In older AML patients who are eligible for intensive treatment, adding dexamethasone to induction and consolidation chemotherapy is feasible and associated with a high response rate after a single induction cycle and encouraging overall survival. A historical comparison with the patient population of the LAM-SA 2007 trial (Pigneux A, JCO 2018) will be presented during the meeting to highlight a potential signal of activity.

The induction chemotherapy regimen consisted of one cycle of daunorubicin 60 mg/m²/day (d), d1 to d3, cytarabine 100 mg/m²/d, CIV d1 to d7, lomustine 200 mg/m², orally d1...Pts then received 6 months of maintenance therapy alternating mercaptopurin and methotrexate. The addition of midostaurin in patients with FLT3-ITD or FLT3-TKD mutations was not allowed during induction...These differences are not statistically significant. Conclusion In older AML pts eligible for intensive treatment, adding eltrombopag to induction is feasible and safe, reduces significantly the need of platelet transfusions, yet did not impact survival in this study.