A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

Pratz, Keith W.; Cherry, Mohamad; Altman, Jessica K.; Cooper, Brenda; Cruz, José C.; Jurcic, Joseph G.; Levis, Mark J.; Lin, Tara L.; Perl, Alexander E.; Podoltsev, Nikolai A.; Schiller, Gary J.; Hill, Jason E.; James, Angela; Lu, Qiaoyang; Tiu, Ramon V.

doi:10.1182/blood-2020-137685

Cited by 27 publications

(32 citation statements)

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“…In a study of 79 patients with newly diagnosed AML (56% had FLT3mutated AML) treated with 3+7 plus gilteritinib, the overall response rate was 82%, and the estimated 2-year survival was 72%. 146 Sorafenib added as maintenance therapy after allogeneic SCT in patients with FLT3mutated AML improved survival and/or relapse-free survival. 147,148 The combination of azacitidine and sorafenib in older patients with FLT3-ITD AML resulted in a CR-CRi rate of 78%.…”

Section: Frontline Therapy With Flt3 Inhibitorsmentioning

confidence: 99%

“…Several trials are evaluating newer‐generation FLT3 inhibitors with intensive chemotherapy. In a study of 79 patients with newly diagnosed AML (56% had FLT3‐ mutated AML) treated with 3+7 plus gilteritinib, the overall response rate was 82%, and the estimated 2‐year survival was 72% 146 . Sorafenib added as maintenance therapy after allogeneic SCT in patients with FLT3 ‐mutated AML improved survival and/or relapse‐free survival 147,148 .…”

Section: Exciting Discoveries In Aml Present and Futurementioning

confidence: 99%

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Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach

Kantarjian

Kadia

DiNardo

et al. 2021

Cancer

109

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The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy.

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Section: Frontline Therapy With Flt3 Inhibitorsmentioning

confidence: 99%

Section: Exciting Discoveries In Aml Present and Futurementioning

confidence: 99%

Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach

Kantarjian

Kadia

DiNardo

et al. 2021

Cancer

109

View full text Add to dashboard Cite

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“…The maximum tolerated dose of gilteritinib was 120 mg daily. CRc was achieved by 81.8% of patients across all dose groups with mutational clearance (FLT3 ITD signal ratio of ≤ 10 –4 after induction or consolidation) was achieved by 70% of patients with FLT-ITD mutation receiving a gilteritinib dose of ≥ 120 mg [ 54 ]. Two large randomized clinical trials of induction and consolidation chemotherapy plus gilteritinib vs midostaurin in FLT3 mutated AML patients are ongoing in the US (PrECOG trial) (NCT03836209)) and in Europe (HOVON 156 AML / AMLSG 28–18 trial (NCT04027309)).…”

Section: Targeted Therapies: Alone or Combinationmentioning

confidence: 99%

Emerging agents and regimens for AML

Liu

2021

J Hematol Oncol

156

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Until recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML.

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“…Among 38 patients with FLT3 mut AML who received gilteritinib 120 mg daily, the CRc rate was 81.6% ( n = 31) including 39.5% CR and median OS was not reached at a median follow-up of 35.8 months. Two randomized trials are evaluating the addition of gilteritinib vs midostaurin to induction and consolidation therapy in patients with newly diagnosed FLT3 mut AML 44 (NCT04027309, NCT03836209).…”

Section: Moving Forward To Maximize Benefit: Flt3 Inhibitors Combination Therapymentioning

confidence: 99%

“…The choice of treatment backbone depends on the patient’s ability to successfully tolerate intensive chemotherapy. Accumulating evidence have shown improved outcomes in FLT3 -ITD mut patients receiving induction with higher dose anthracyclines 57 , cladribine 58 , or fludarabine added to induction backbone 21 , and incorporating FLT3i with induction (either first or second generation) in FLT3 mut AML 24 , 44 , 59 , 60 (Fig. 1A ).…”

Section: Moving Forward To Maximize Benefit: Flt3 Inhibitors Combination Therapymentioning

confidence: 99%

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021

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Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

Cited by 27 publications

References 0 publications

Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach

Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach

Emerging agents and regimens for AML

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

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