Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia

McMahon, Christine M.; Ferng, Timothy; Canaani, Jonathan; Wang, Eunice S.; Morrissette, Jennifer J.D.; Eastburn, Dennis J.; Pellegrino, Maurizio; Durruthy-Durruthy, Robert; Watt, Christopher D.; Asthana, Saurabh; Lasater, Elisabeth A.; DeFilippis, RosaAnna; Peretz, Cheryl A.C.; McGary, Lisa H.F.; Deihimi, Safoora; Logan, Aaron C.; Luger, Selina M.; Shah, Neil P.; Carroll, Martin; Smith, Catherine C.; Perl, Alexander E.

doi:10.1158/2159-8290.cd-18-1453

Cited by 337 publications

(362 citation statements)

References 35 publications

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“…In a recent report from our group, treatment-emergent Ras/MAPK pathway mutations were acquired in 15 of 41 (36.6%) patients treated with gilteritinib, including activating mutations in NRAS (13/41 patients; 31.7%), KRAS (3/41 patients; 7.3%), PTPN11 (3/41 patients; 7.3%), CBL (2/41 patients; 4.9%), and BRAF (1/41 patients; 2.4%). 37 We also identified 2 patients with new BCR-ABL1 fusions, consistent with prior reports. 37,38 These results suggest that acquisition of new or parallel oncogenic driver mutations will be common, as has been reported with crenolanib.…”

Section: Discussionsupporting

confidence: 90%

“…37 We also identified 2 patients with new BCR-ABL1 fusions, consistent with prior reports. 37,38 These results suggest that acquisition of new or parallel oncogenic driver mutations will be common, as has been reported with crenolanib. 32,37 Ultimately, although gilteritinib has activity against a wide variety of FLT3 mutations and appears less clinically vulnerable to on-target resistance, rational combination therapies will be required to suppress outgrowth of heterogeneous resistant leukemic clones.…”

Section: Discussionsupporting

confidence: 90%

“…32 This finding is congruent with results of our study and reinforces that type I inhibitors may be overall less susceptible to on-target resistance, as is suggested by prior mutagenesis studies which often identify less resistance mutations associated with type I inhibitors 17,33 than type II inhibitors 12,15,25,26 (supplemental Table 2) as well as by our recent report of non-FLT3 dependent gilteritinib resistance mechanisms. 37 The increased vulnerability of type II inhibitors to TKD mutations is likely attributable to the fact that type II inhibitors bind to allosteric sites in the inactive kinase conformation. Type II inhibitors are therefore susceptible both to mutations which change kinase conformation as well as mutations at drug contact sites.…”

Section: Discussionmentioning

confidence: 99%

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Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

et al. 2020

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Key Points• Gilteritinib is active against a wide range of clinically relevant activating FLT3 mutations.• Resistance-conferring FLT3 kinase domain mutations are responsible for a minority of clinical resistance to gilteritinib.Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at ,200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

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“…Cell capture rates were between 5% and 10%; however, the microdroplet cell capture process is not selective or size dependent, and should not introduce biases in resolving the underlying clonal architecture. 17 The limit of detection of the platform is 0.1%, which has been reported with cell line spike-in experiments prepared at different ratios. 13 Baseline patient characteristics are provided in Table 1, and additional clinical information is provided in supplemental Table 2.…”

Section: Resultsmentioning

confidence: 62%

“…9 The lower limit of detection by SCS was similar to published results using the Tapestri platform. 17 We have previously reported on the heterogeneity of relapsed AML, showing multiple distinct patterns of clonal evolution, including relapse with the predominant clone from diagnosis, with a minor subclone from diagnosis, or with further clonal evolution. 18 Individual cases from the current cohort also display diverse patterns of clonal evolution with similar patterns as our initial findings.…”

Section: Resultsmentioning

confidence: 99%

Single-cell mutational profiling enhances the clinical evaluation of AML MRD

et al. 2020

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SCS of patients with AML detected clones at remission that expanded into the dominant clone at relapse.• SCS provides unique information on mutation cooccurrence and clonal diversity that may enhance MRD evaluation.Although most patients with acute myeloid leukemia (AML) achieve clinical remission with induction chemotherapy, relapse rates remain high. Next-generation sequencing enables minimal/measurable residual disease (MRD) detection; however, clinical significance is limited due to difficulty differentiating between pre-leukemic clonal hematopoiesis and frankly malignant clones. Here, we investigated AML MRD using targeted single-cell sequencing (SCS) at diagnosis, remission, and relapse (n 5 10 relapsed, n 5 4 nonrelapsed), with a total of 310 737 single cells sequenced. Sequence variants were identified in 80% and 75% of remission samples for patients with and without relapse, respectively. Pre-leukemic clonal hematopoiesis clones were detected in both cohorts, and clones with multiple cooccurring mutations were observed in 50% and 0% of samples. Similar clonal richness was observed at diagnosis in both cohorts; however, decreasing clonal diversity at remission was significantly associated with longer relapse-free survival. These results show the power of SCS in investigating AML MRD and clonal evolution.

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Acute myeloid leukemia in elderly patients: New targets, new therapies

Park

Gregory

2023

Aging and Cancer

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Prior to the past few years, the development of new therapies for acute myeloid leukemia (AML) has been disappointingly slow. For several decades, the standard therapy for AML has consisted of intensive induction chemotherapy, and potentially a subsequent hematopoietic stem cell transplant. Unfortunately, older patients are less responsive to, and are frequently unfit to tolerate, such intensive chemotherapy. Given that a majority of AML patients are elderly, this population has been most affected by the lack of newer less toxic therapies.However, in recent years, the treatment landscape for AML has dramatically shifted with the approval of many new drugs. As summarized in this review, several of these new drugs are targeted agents that are better tolerated than standard chemotherapy and could substantially benefit elderly patients. Although drug resistance remains a major concern, the treatment options for elderly AML patients are more numerous than ever before, bringing new promise for improved patient outcomes. ACUTE MYELOID LEUKEMIAAcute myeloid leukemia (AML) comprises a heterogenous group of malignant disorders characterized by aberrant clonal expansion and accumulation of immature myeloid precursors (myeloblasts) in the bone marrow (BM), peripheral blood, and other tissues. The expansion of myeloblasts occurs at the expense of normal production of myeloid lineage cells including erythrocytes, monocytes, granulocytes, and megakaryocytes. 1 Diagnosis and clinical presentationThe median age at AML diagnosis is 67 years old, with approximately 30% of diagnosed patients above the ageThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia

Cited by 337 publications

References 35 publications

Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Single-cell mutational profiling enhances the clinical evaluation of AML MRD

Acute myeloid leukemia in elderly patients: New targets, new therapies

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