The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Swaminathan, Mahesh; Kantarjian, Hagop; Daver, Naval; Borthakur, Gautam; Ohanian, Maro; Kadia, Tapan M.; DiNardo, Courtney D.; Jain, Nitin; Estrov, Zeev; Ferrajoli, Alessandra; Konopleva, Marina; Andreeff, Michael; Pemmaraju, Naveen; Jabbour, Elias; Alvarado, Yesid; Wierda, William G.; Pinsoy, Maria Rhona; Ravandi, Farhad; Cortés, Jorge E.

doi:10.1016/j.clml.2017.09.027

Cited by 24 publications

(21 citation statements)

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“…These findings are consistent with a post hoc analysis of two phase II trials of quizartinib monotherapy (NCT01565668 and NCT00989261), wherein single-agent quizartinib CRc rates were 48-53% in prior FLT3 TKI naïve compared with 33-36% in prior FLT3 TKI-exposed patients [17]. LIT combinations with quizartinib showed high efficacy with CRc rates of 64% and 33% and median OS of 10.7 and 6.1 in prior FLT3i naïve and prior FLT3i-exposed R/R patients, respectively, consistent with previous data [21].…”

Section: Discussionmentioning

confidence: 99%

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

et al. 2020

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Background Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45–55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. Methods We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019. Results In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. Conclusion CRc rates drop progressively with sequential exposure to FLT3i’s in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.

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Section: Discussionmentioning

confidence: 99%

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

et al. 2020

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“…In a phase I/II study of 37 patients with both newly diagnosed and previously treated AML, MDS or chronic myelomonocytic leukemia with FLT3-ITD mutation the combination of 5-AZA and quizartinib showed an overall response (CR, CRi, CRp, partial remission (PR)) rate of 76% with a median OS of 13.4 months. 131 An overview of selected completed studies of HMAs in combination with several forms of targeted therapies is provided in Table 3.…”

Section: Combination Of Epigenetic Therapy With Targeted Therapymentioning

confidence: 99%

Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

Bewersdorf

Shallis

Stahl

2019

Therapeutic Advances in Hematology

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Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.

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“…Furthermore, combination of FLT3 inhibitors including sorafenib, quizartinib and gilteritinib with other low intensity treatment including azacytidine or decitabine, the hypomethylating agents, have been shown to be synergistic in laboratories [68][69][70] and appeared to be effective in Phase II clinical trials [19,71,72].…”

Section: Combination Of Flt3 Inhibitors With Low Intensity Regimenmentioning

confidence: 99%

Overcoming Resistance to FLT3 Inhibitors in the Treatment of FLT3-Mutated AML

Lam

Leung

2020

IJMS

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Acute myeloid leukaemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine kinase 3 (FLT3) gene is associated with high risk of relapse and poor clinical outcome upon treatment with conventional chemotherapy. FLT3 inhibitors have been approved for the treatment of this AML subtype but leukaemia relapse remains to be a major cause of treatment failure. Mechanisms of drug resistance have been proposed, including evolution of resistant leukaemic clones; adaptive cellular mechanisms and a protective leukaemic microenvironment. These models have provided important leads that may inform design of clinical trials. Clinically, FLT3 inhibitors in combination with conventional chemotherapy as induction treatment for fit patients; with low-intensity treatment as salvage treatment or induction for unfit patients as well as maintenance treatment with FLT3 inhibitors post HSCT hold promise to improve survival in this AML subtype.

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The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Cited by 24 publications

References 0 publications

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

Overcoming Resistance to FLT3 Inhibitors in the Treatment of FLT3-Mutated AML

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