Momelotinib Is a Highly Potent Inhibitor of FLT3-Mutant AML

Abstract Approximately one-third of AML patients harbor kinase activating mutations in FLT3. Several small-molecule first generation FLT3 tyrosine kinase inhibitors (TKIs) have been evaluated in the last two decades, but none could induce a durable response possibly due to poor pharmacokinetics and target selectivity. Second generation FLT3 inhibitors such as, quizartinib, gilteritinib, and crenolanib, were designed for greater selectivity with a narrow kinome-profile and better pharmacokinetic properties, but they failed to induce a durable response. Possibly due to intrinsic resistance conferred by growth factor signaling in the bone marrow resident leukemic cells, which serve as a reservoir to develop resistance resulting to disease relapse. Activation of Jak2 signaling by chemokines and cytokines from the stroma have been reported to confer TKI refractoriness. Recent studies from Martin Carroll's group showed that both GMCSF and IL-3 confer resistance by activating JAK2 signaling, which can be suppressed by combined FLT3 and JAK2 inhibition. However, so far, it is not established whether upfront FLT3/Jak2 inhibition will provide durable response. For instance, AML patients who achieved complete remission lacking FLT3-ITD clones showed better overall survival than patients with measurable MRD, suggesting that eradicating the FLT3-ITD clones will have a deeper response with better overall survival. Thus, an ideal FLT3 inhibitor should be able to suppress FLT3-ITD resistant mutants, and growth factor activated JAK2 signaling while sparing c-KIT receptor and hERG to avoid myelosuppression and cardiotoxicity, respectively. Here we show that Jak2 inhibitor, momelotinib, is an equipotent type-I FLT3 inhibitor (Fig 1A-D). Biochemical and structural modeling revealed that it binds to an active conformation of FLT3 kinase. Therefore, like gilteritinib, it efficiently suppresses the resistance conferred by activation loop mutations (Fig1 E-H). Moreover, its lack of activity against c-KIT and inhibition of ACVR1 provides additional benefit in alleviating myelosuppression and anemia, which is commonly observed with currently used JAK2 and FLT3 inhibitors (ruxolitinib, fedratinib, and quizartinib). Perhaps more interestingly, momelotinib efficiently suppressed the disease in a preclinical model of AML using NSGS mice which recapitulates cytokine induce refractoriness as usually observed in clinical setting (Fig1 I-L). Our preclinical data provide evidence that momelotinib is an equipotent dual JAK2/FLT3 inhibitor and suppresses resistance conferred by both activation-loop mutations and growth-factor signaling. These data provide evidence that momelotinib treatment will have clinical activity in FLT3-mutated AML. Thus, warrants its clinical evaluation. Figure 1 Figure 1. Disclosures Starczynowski: kurome Inc: Consultancy.

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Momelotinib is a highly potent inhibitor of FLT3-mutant AML

10.1101/2021.03.18.436047 ◽

2021 ◽

Author(s):

Mohammad Azhar ◽

Zachary Kincaid ◽

Meenu Kesarwani ◽

Tahir Latif ◽

Daniel Starczynowski ◽

...

Keyword(s):

Growth Factor ◽

Kinase Inhibitor ◽

Initial Response ◽

Leukemic Cells ◽

Activation Loop ◽

Growth Factor Signaling ◽

Durable Response ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors

Kinase activating mutation in FLT3 is the most frequent genetic lesion associated with poor prognosis in acute myeloid leukemia (AML). Therapeutic response to FLT3 tyrosine kinase inhibitor (TKI) therapy is dismal, and many patients relapse even after allogeneic stem cell transplantation. Despite the introduction of more selective FLT3 inhibitors, remissions are short-lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are two principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to more profound and lasting clinical responses. Here we show that the JAK2 inhibitor, momelotinib, is an equipotent type-1 FLT3 inhibitor. Momelotinib showed potent inhibitory activity on both mouse and human cells expressing FLT3-ITD, including clinically relevant resistant mutations within the activation loop at residues D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by FLT3 ligand (FL), and hematopoietic cytokine activated JAK2 signaling. Interestingly, unlike gilteritinib, momelotinib inhibits the expression of MYC in leukemic cells. Consequently, concomitant inhibition of FLT3 and downregulation of MYC by momelotinib treatment showed better efficacy in suppressing the leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.

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Momelotinib is a highly potent inhibitor of FLT3-mutant AML

Blood Advances ◽

10.1182/bloodadvances.2021004611 ◽

2021 ◽

Author(s):

Mohammad Azhar ◽

Zachary Kincaid ◽

Meenu Kesarwani ◽

Arhama Ahmed ◽

Mark Wunderlich ◽

...

Keyword(s):

Growth Factor ◽

Kinase Inhibitor ◽

Leukemic Cells ◽

Activation Loop ◽

Growth Factor Signaling ◽

Durable Response ◽

Allogenic Stem Cell Transplantation ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors

Kinase activating mutation in FLT3 is the most frequent genetic lesion associated with poor prognosis in acute myeloid leukemia (AML). Therapeutic response to FLT3 tyrosine kinase inhibitor (TKI) therapy is dismal, and many patients relapse even after allogenic stem cell transplantation. Despite the introduction of more selective FLT3 inhibitors, remissions are short-lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are two principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical responses. Here we show that the JAK2 inhibitor, momelotinib, is an equipotent type-1 FLT3 inhibitor. Momelotinib showed potent inhibitory activity on both mouse and human cells expressing FLT3-ITD, including clinically relevant resistant mutations within the activation loop at residues, D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by FLT3 ligand (FL) and hematopoietic cytokine activated JAK2 signaling. Interestingly, unlike gilteritinib, momelotinib inhibits the expression of MYC in leukemic cells. Consequently, concomitant inhibition of FLT3 and downregulation of MYC by momelotinib treatment showed better efficacy in suppressing the leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.

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

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00964-5 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Musa Yilmaz ◽

Mansour Alfayez ◽

Courtney D. DiNardo ◽

Gautam Borthakur ◽

Tapan M. Kadia ◽

...

Keyword(s):

Overall Survival ◽

Phase Ii ◽

Median Overall Survival ◽

Second Generation ◽

Single Agent ◽

Response Rates ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors ◽

First Time

Abstract 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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Improvement in Clinical Outcome of FLT3 Mutated AML Patients over the Last One and a Half Decade

Blood ◽

10.1182/blood.v124.21.949.949 ◽

2014 ◽

Vol 124 (21) ◽

pp. 949-949

Author(s):

Talha Badar ◽

Hagop M. Kantarjian ◽

Gautam Borthakur ◽

Guillermo Garcia Manero ◽

Michael Andreeff ◽

...

Keyword(s):

Overall Survival ◽

Complete Remission ◽

Clinical Outcome ◽

Induction Therapy ◽

Research Funding ◽

Median Overall Survival ◽

Treatment Strategies ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors ◽

Time To Relapse

Abstract Background: FMS-like tyrosine kinase 3 gene (FLT3) mutations occur in approximately 30% of all AML patients. The overall prognosis of FLT3 mutated AML patients (pts) remains poor. As we have learned more about the aggressive nature of this disease our treatment strategies have changed. Incorporating FLT3 inhibitors with chemotherapy and allogeneic stem cell transplant in first remission are routinely pursued in these pts. In this context we reviewed data to evaluate clinical outcome of FLT3-ITD mutated AML pts since 2000 in a single institution. Methods: We retrospectively analyzed 1441 pts referred to our institution between 2000 and 2014. FLT3 internal tandem duplications (FLT3-ITD) were found in 334 pts with AML. After excluding pts with core binding factor leukemia and acute promyelocytic leukemia, 224 pts were included in this analysis. Among these 224 pts, 21 (9%) pts also had tyrosine kinase domain D835 (TKDs) mutated. Patients are evaluated for response to therapy, treatment related mortality and overall survival. Results: Patients were divided into 5 cohorts by era: 2000-02 (Era 1, n=19), 2003-05 (Era 2, n=41), 2006-08 (Era 3, n=53), 2009-11 (Era 4, n=55), 2012-14 (Era 5, n=56). The median age from Era 1-5; 57, 61, 59, 61, and 65 yrs respectively, p= 0.55. None of the pts in Era 1 received FLT3 inhibitor (inh.) therapy, 4 (10%) in Era 2, 17 (32%) in Era 3, 34 (49%) in Era 4, and 34 (61%) in Era 5 received FLT3 inh. Among these 2 (5%) pts in Era 2, 11 (27%) in Era 3, 9 (16%) in Era 4 and 30 (54%) pts in Era 5 received FLT3 inh. with their frontline therapy. SCT in 1st remission occurred in 4 (21%) pts in Era 1, one in Era 2, 10 (19%) in Era 3, 18 (33%) in Era 4, and 14 (25%) in Era 5. Two (5%) pts in Era 2, 5 (9%) pts in Era 3, 3 (5%) pts in Era 4, and 2 (4%) pts in Era 5, had SCT in 2nd remission. The overall response rate (ORR) to induction chemotherapy in the 5 Eras were 74%, 51%, 77%, 84% and 82%, respectively. The rate of complete remission (CR) from Era 1-5 were 63%, 46%, 70%, 65%, and 57% respectively. Complete remission without platelet recovery (CRp) from Era 1-5 was 5%, 2%, 2%, 7% and 18% respectively. The ORR from Era 1-5 in pts who received FLT3 inhibitor combinations induction therapy was 85%; CR 60%, CRp 17%, HI 6% and PR 2%. Whereas ORR to non-FLT3 inhibitor induction therapy from Era 1-5 was 72%; CR 62%, CRp 6%, PR 2% and HI 2%. Among 21 (10%) pts who were FLT3-ITD and TKDs mutated, CR/CRp was achieved in 14 (67%) pts, compare to 139 (69%) pts with only FLT3-ITD mutated, p= 0.84. At 1 year (yr) from diagnosis through Era 1-5 42%, 29%, 58%, 72% and 61% were alive respectively. Four (10%) pts in Era 2, one pt each in Era 4-5 and none in Era 1 and 3 died ≤4 weeks from start of induction therapy. The median time to relapse was 10.6 months (mo) in Era 1, 6.1 mo in Era 2, 9.5 mo in Era 3, and 8.5 mo in Era 4. The median time to relapse was not reached in Era 5 with 63% of patient in CR/CRp at 1 yr, p= 0.45 (Fig.1). The median overall survival (OS) have improved over time, 9.6 mo in Era 1, 7.6 mo in Era 2, 14.4 mo in Era 3, 15.7 mo in Era 4 and 17.8 mo in Era 5, p= 0.0001 (Fig.2). The median OS in all pts who received FLT3 inhibitors in induction chemotherapy from Era 1-5 was 14 mo, compare to 13 mo in pts who had non FLT3 inhibitor induction therapy (p= 0.25). Patients who received FLT3 inhibitors any time in the course of their treatment, the OS was 14.2 mo, compare to 13 mo in pts who never had FLT3 inhibitor therapy (p= 0.941). In the subset analysis, excluding pts who received SCT in 1st CR, the median overall survival from Era 1-5 was 9.2, 6, 11, 13.4 and 17 mo respectively, p= 0.05. Conclusion: Our data suggested some improvement in outcome of FLT3- ITD mutated AML pts over the last decade and a half. This is probably due to more aggressive treatment strategies including integration of FLT3 inhibitors in chemotherapy regimens and increase use of SCT. Efforts are still needed to continue to improve outcome for these subset of poor prognostic AML patients. Figure 1 Figure 1. Disclosures Cortes: Ambit: Research Funding; Astellas: Research Funding; Ariad: Research Funding; Arog: Research Funding; Novartis: Research Funding; Astellas: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

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Next Generation Sequencing to Delineate the Mutational Landscape of Chronic Myelomonocytic Leukemia (CMML): Novel Disease Genes and Correlations with Survival

Blood ◽

10.1182/blood.v124.21.4637.4637 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4637-4637

Author(s):

Clinton C. Mason ◽

Jamshid S. Khorashad ◽

Srinivas K. Tantravahi ◽

Todd W. Kelley ◽

Anthony D. Pomicter ◽

...

Keyword(s):

Overall Survival ◽

Growth Factor ◽

Research Funding ◽

Deleterious Mutation ◽

Chronic Myelomonocytic Leukemia ◽

Growth Factor Signaling ◽

Hypomethylating Agents ◽

Discovery Cohort ◽

Mutational Landscape ◽

Myelomonocytic Leukemia

Abstract Purpose: Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous myelodysplastic/myeloproliferative neoplasm with short overall survival. Emerging data based on sequencing of candidate genes with a known role in myeloid leukemia have identified recurrent CMML mutations, some of which have been associated with poor prognosis. A comprehensive evaluation of the mutational landscape of CMML and its prognostic significance is lacking. Patients and Methods. We comprehensively characterized the mutational landscape of CMML by a 2-step design. We initially performed whole exome sequencing (WES) of paired leukemia and germline DNA from 21 patients with a confirmed CMML diagnosis (discovery cohort) to identify genes with somatic mutations. From this discovery cohort, 215 genes showing potential mutations as well as 61 genes selected from the literature were examined by targeted resequencing in a second cohort of 69 clinically annotated CMML patients, using two independent platforms for orthogonal confirmation Blood or marrow samples from 22 young and 17 old controls were included as controls. Results. We identified 22 genes with mutations in >3% of CMML patients, and 67/69 patients (97%) had one or more mutations in at least one of these genes. SRSF2, ASXL1 and TET2 were the most frequently mutated genes. Several novel CMML genes were identified, including FAT4 with a mutation prevalence of 10% and BCR, CBFA2T3, and TRPM1 with a prevalence of 3 – 9% (see Table). Total deleterious mutations per patient ranged from 0 – 11, with significant exclusion or association of various combinations of mutations in SETBP1, ASXL1, KRAS, TET2, and EZH2 observed. In univariate analysis hemoglobin < 9g/dL, white blood cell count > 15x109/L, no treatment with hypomethylating agents, mutations in ASXL1, EZH2, or NRAS and mutations in growth factor signaling genes were associated with shorter overall survival. In multivariate analysis, mutations in NRAS (P<0.05) and lack of therapy with hypomethylating agents (P<0.005) retained statistical significance (see Figure). In additional exploratory analyses mutated genes were grouped according to function. Patients with mutations in genes related to growth factor signaling had significantly shorter survival (P<0.005), while mutations in other functional groups were not predictive of outcome. Conclusion. (i) The mutational landscape of CMML is complex and involves mutations in multiple genes, many affected with relatively low prevalence. (ii) Mutations in FAT4, a putative tumor suppressor and key regulator of the Hippo pathway, occur in approximately 10% of patients. (iii) Absence of therapy with hypomethylating agents and mutations in NRAS or the functional group of growth factor signaling genes are predictive of poor survival. Table. Count and prevalence of N=69 CMML patients having a deleterious mutation in one of the genes observed mutated at a prevalence ≥ 10%. Gene # CMML Patients with Mutation (%) SRSF2 34 (49%) TET2 28 (41%) ASXL1 25 (36%) RUNX1 14 (20%) SETBP1 11 (16%) KRAS 10 (14%) EZH2 8 (12%) FAT4 7 (10%) CBL 7 (10%) NRAS 7 (10%) Figure. Overall survival of N=48 CMML patients by HMA use and presence of deleterious mutation in NRAS. Figure. Overall survival of N=48 CMML patients by HMA use and presence of deleterious mutation in NRAS. Disclosures Mason: Agilent, Inc.: Research Funding. Deininger:Celgene: Research Funding; Agilent, Inc.: Research Funding.

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Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101496118 ◽

2021 ◽

Vol 118 (33) ◽

pp. e2101496118

Author(s):

Linda Truebestein ◽

Harald Hornegger ◽

Dorothea Anrather ◽

Markus Hartl ◽

Kaelin D. Fleming ◽

...

Keyword(s):

Crystal Structure ◽

Growth Factor ◽

Protein Kinase ◽

Second Messengers ◽

Kinase Domain ◽

Activation Loop ◽

Growth Factor Signaling ◽

Ph Domain ◽

Protein Kinase Akt ◽

Spatiotemporal Control

The protein kinase Akt is one of the primary effectors of growth factor signaling in the cell. Akt responds specifically to the lipid second messengers phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] via its PH domain, leading to phosphorylation of its activation loop and the hydrophobic motif of its kinase domain, which are critical for activity. We have now determined the crystal structure of Akt1, revealing an autoinhibitory interface between the PH and kinase domains that is often mutated in cancer and overgrowth disorders. This interface persists even after stoichiometric phosphorylation, thereby restricting maximum Akt activity to PI(3,4,5)P3- or PI(3,4)P2-containing membranes. Our work helps to resolve the roles of lipids and phosphorylation in the activation of Akt and has wide implications for the spatiotemporal control of Akt and potentially lipid-activated kinase signaling in general.

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Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling.

Molecular and Cellular Biology ◽

10.1128/mcb.15.3.1182 ◽

1995 ◽

Vol 15 (3) ◽

pp. 1182-1191 ◽

Cited By ~ 192

Author(s):

D Graus-Porta ◽

R R Beerli ◽

N E Hynes

Keyword(s):

Growth Factor ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

Growth Factor Signaling ◽

Single Chain ◽

Single Chain Antibody ◽

Related Family ◽

Mitogen Activated Protein ◽

Epidermal Growth

ErbB-2 becomes rapidly phosphorylated and activated following treatment of many cell lines with epidermal growth factor (EGF) or Neu differentiation factor (NDF). However, these factors do not directly bind ErbB-2, and its activation is likely to be mediated via transmodulation by other members of the type I/EGF receptor (EGFR)-related family of receptor tyrosine kinases. The precise role of ErbB-2 in the transduction of the signals elicited by EGF and NDF is unclear. We have used a novel approach to study the role of ErbB-2 in signaling through this family of receptors. An ErbB-2-specific single-chain antibody, designed to prevent transit through the endoplasmic reticulum and cell surface localization of ErbB-2, has been expressed in T47D mammary carcinoma cells, which express all four known members of the EGFR family. We show that cell surface expression of ErbB-2 was selectively suppressed in these cells and that the activation of the mitogen-activated protein kinase pathway and p70/p85S6K, induction of c-fos expression, and stimulation of growth by NDF were dramatically impaired. Activation of mitogen-activated protein kinase and p70/p85S6K and induction of c-fos expression by EGF were also significantly reduced. We conclude that in T47D cells, ErbB-2 is a major NDF signal transducer and a potentiator of the EGF signal. Thus, our observations demonstrate that ErbB-2 plays a central role in the type I/EGFR-related family of receptors and that receptor transmodulation represents a crucial step in growth factor signaling.

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A noncanonical FLT3 gatekeeper mutation disrupts gilteritinib binding and confers resistance

10.1101/2021.01.27.428336 ◽

2021 ◽

Author(s):

Sunil K. Joshi ◽

Setareh Sharzehi ◽

Janét Pittsenbarger ◽

Daniel Bottomly ◽

Cristina E. Tognon ◽

...

Keyword(s):

Binding Pocket ◽

Resistance Mutations ◽

Intrinsic Resistance ◽

Fda Approval ◽

Flt3 Inhibitor ◽

Clinical Resistance ◽

Flt3 Inhibitors ◽

Evolution Of Resistance

ABSTRACTThe recent FDA approval of the FLT3 inhibitor, gilteritinib, for AML represents a major breakthrough for treatment of FLT3 mutated AML. However, patients only respond to gilteritinib for 6-7 months due to the emergence of drug resistance. Clinical resistance to gilteritinib is often associated with expansion of NRAS mutations, and less commonly via gatekeeper mutations in FLT3, with F691L being the most common. We developed an in vitro model that charts the temporal evolution of resistance to gilteritinib from early microenvironmental-mediated resistance to late intrinsic resistance mutations. Our model system accurately recapitulates the expansion of NRAS mutations and the F691L gatekeeper mutations found in AML patients. As part of this study, we also identified a novel FLT3N701K mutation that also appeared to promote resistance to gilteritinib. Using the Ba/F3 system, we demonstrate that N701K mutations effectively act like a gatekeeper mutation and block gilteritinib from binding to FLT3, thereby promoting resistance. Structural modeling of FLT3 reveals how N701K, and other reported gilteritinib resistance mutations, obstruct the gilteritinib binding pocket on FLT3. Interestingly, FLT3N701K does not block quizartinib binding, suggesting that FLT3N701K mutations are more specific for type 1 FLT3 inhibitors (gilteritinib, midostaurin, and crenolanib). Thus, our data suggests that for the FLT3N701K mutation, switching classes of FLT3 inhibitors may restore clinical response. As the use of gilteritinib expands in the clinic, this information will become critical to define clinical strategies to manage gilteritinib resistance.

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Efficacy of a Type I FLT3 Inhibitor, Crenolanib, with Idarubicin and High-Dose Ara-C in Multiply Relapsed/Refractory FLT3+ AML

Blood ◽

10.1182/blood.v128.22.2744.2744 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2744-2744 ◽

Cited By ~ 10

Author(s):

Maro Ohanian ◽

Hagop M. Kantarjian ◽

Gautam Borthakur ◽

Tapan M. Kadia ◽

Marina Konopleva ◽

...

Keyword(s):

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Kinase Domain ◽

Prior Exposure ◽

High Dose ◽

Type I ◽

Cell Transplant ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors

Abstract Background: Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with in vitro activity against FLT3-ITD and FLT3-tyrosine kinase domain (TKD) mutations. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. As a single agent, an overall response rate (ORR) of 30% (CR/CRi 19%, PR 12%) has been reported among patients (pts) with multiply relapsed/refractory (R/R) AML pts with FLT3 mutations despite sixty-five percent of the patients having prior exposure to FLT3 inhibitors. We report data from the first 13 pts with R/R FLT3+ AML treated with salvage idarubicin (Ida) and high-dose ara-C (HiDAC) followed by crenolanib. Design: Pts received Ida (12 mg/m2 for 3d) with HiDAC (1.5 g/m2/d over 3 hrs for 4d or for 3d if >60y), followed by crenolanib starting on d5 and continued until 72 hrs. prior to next chemotherapy regimen. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Responding pts were eligible to proceed to allogeneic stem cell transplant (allo-SCT) or receive consolidation with ara-C (750 mg/m2 for 3d) and Ida (8 mg/m2 for 2d) followed by crenolanib at the same dose received during induction. Patients could then continue on maintenance with crenolanib. Post-SCT crenolanib maintenance therapy was not allowed. Results: To date, all 3 dose escalation cohorts have been completed, which included 13 pts (11 males, 2 female) with a median age of 51 yrs (range 19-73). All pts had R/R FLT3+ AML. 6/13 pts had relapsed after 1 or 2 prior AML therapies, with the remaining 7 pts having 3-8 prior AML therapies (allo-SCT in 3). Nine pts had received prior FLT3 inhibitors including sorafenib (n=7), quizartinib (n=2), and E6201 (n=2). Nine pts had a FLT3-D835 kinase domain mutation, of which 4 pts also had FLT3-ITD; the remaining 4 pts had FLT3-ITD alone. Conventional cytogenetic testing included: normal karyotype (n=4; 31%), miscellaneous (n=5; 36%), and complex (n=4; 31%). Besides FLT3, multiple other leukemia-associated mutations were present at baseline: NPM1 (36%), DNMT3A (36%), NRAS/KRAS (27%), WT1 (18%), TET2 (18%), RUNX1 (18%), IDH1 (9%), IDH2 (9%), and ASXL1 (9%). No dose-limiting toxicities were observed at any of the dose levels explored and there were no dose reductions required. Non-hematologic adverse events assessed as possibly or probably related to crenolanib were all grade 1 in severity, including: nausea (n=2), vomiting (n=2), diarrhea (n=1), and abdominal pain (n=1). No deaths were attributed to crenolanib. The ORR in 11 pts evaluable for response was 36% (1 CR, 3 CRi; 2 not evaluable because of early discontinuation of therapy). Among 6 pts who received ≤2 prior AML therapies, 4 pts (67%) achieved a CR/CRi (including 2 pts with prior exposure to FLT3 inhibitors). These remissions occurred in pts with FLT3-ITD (n=2), FLT3-D835 (n=1) and FLT3-ITD+FLT3-D835 (n=1) (Table 1). No CRs were seen in the 5 pts who had 3 or more prior therapies (including 3/5 who had received prior FLT3 inhibitors) before coming on study. Three CRi pts have undergone allo-SCT: 1 pt (43/F) achieved CRi (with persistent FLT3-ITD) after 1 cycle and maintained remission with FLT3-ITD negativity for 6 months post allo-SCT, 1 pt (67/M) achieved CRi with FLT3-D835 negativity after 2 cycles and maintained remission for 3 months post allo-SCT, and 1 pt (58/M) achieved CRi after 1 cycle and relapsed 1.5 months post allo-SCT. One pt (73/M) achieved a full CR with FLT3 negativity and count recovery and is currently receiving crenolanib maintenance. The median OS for all patients was 259d; median OS by prior therapies was 259d for pts with ≤ 2 prior therapies, and 53d for pts with ≥ 3 prior therapies (Figure 1). Conclusions: Full doses of crenolanib (100 mg TID) can be safely combined with idarubicin and HiDAC in multiply relapsed/refractory FLT3+ AML. There is suggestion of clinical efficacy particularly among pts with only 1-2 prior therapies. This trial is being expanded to allow combination of full dose crenolanib with other standard salvage chemotherapies, including MEC (mitoxantrone, etoposide, cytarabine) and FLA(G)-IDA (fludarabine, cytarabine, idarubicin w/ or w/o G-CSF). Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Burger:Pharmacyclics: Research Funding. Eckardt:Arog: Employment, Equity Ownership. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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Expert Curation of Somatic FLT3 Variants By the Clingen Somatic Hematologic Cancer Taskforce (ClinGen HCT)

Blood ◽

10.1182/blood-2021-153546 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4387-4387

Author(s):

Xiangqiang Shao ◽

Shruti Rao ◽

Coumarane Mani ◽

Jason Saliba ◽

Rong He ◽

...

Keyword(s):

Tyrosine Kinase ◽

Atp Binding ◽

Evidence Based ◽

Type I ◽

Type Ii ◽

Prediction Of Response ◽

Clinical Interpretation ◽

Hematologic Cancer ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors

Abstract Clinical significance of somatic gene variants needs to be comprehensively characterized for their diagnostic, prognostic and/or therapeutic actionability in patient management. However, challenges remain due to discrepancies in interpretation and reporting of these somatic variants among different testing labs. Therefore, standardized curation, clinical interpretation and reporting of somatic variants in hematologic cancers is critical. To address this issue, the Hematologic Cancer Taskforce (HCT), composed of 52 multi-disciplinary experts including oncologists, molecular pathologists, lab directors, genomic scientists and biocurators, was formed in January 2020 within the ClinGen Somatic Cancer Clinical Domain Working Group (CDWG) with a goal to undertake systematic curation and evidence-based clinical interpretation of genes/somatic variants associated with hematologic malignancies. In collaboration with the Clinical Interpretation of Variants in Cancer (CIViC) (civicdb.org) knowledgebase, HCT members curate, edit, and verify Evidence Items for each variant extracted from peer-reviewed publications. Monthly discussions based on these Evidence Items lead to the preparation of variant Assertions, which summarize the state of the field consensus variant interpretation and include tiering based on the AMP/ASCO/CAP guidelines (PMID: 27993330). FMS-like tyrosine kinase 3 (FLT3) encodes a class III receptor tyrosine kinase expressed in hematopoietic cells. FLT3 mutations, including both internal tandem duplication (ITD) and mutations in the tyrosine kinase domain (TKD), are the most common mutations in acute myeloid leukemia (AML), occurring in approximately 30% of all AML cases. Implementing FLT3 tyrosine kinase inhibitors (TKIs) in different treatment regimens for FLT3 mutated AML patients has led to significantly improved overall survival. Type I FLT3 inhibitors, including midostaurin, gilteritinib, sunitinib, lestaurtinib, and crenolanib, bind to the ATP-binding site when the receptor is in active conformation. Type II FLT3 inhibitors, including sorafenib, ponatinib, and quizartinib, interact with a hydrophobic region directly adjacent to the ATP-binding domain that is only accessible when the receptor is inactive, which prevents receptor activation. Generally in AML cells, type I FLT3 inhibitors prevent activity for both ITD and TKD mutations, while Type II inhibitors target ITD but lack efficiency against TKD mutations. The development of TKD mutations in AML cells with ITD have proved to be a mechanism of acquired, or secondary resistance to Type II FLT3 inhibitors. The HCT is piloting curation assessments of FLT3 alterations, including ITD, TKD and non-TKD variants, in AML. So far, the HCT has curated 75 evidence items for FLT3 somatic variants. FLT3-ITD, as well as D835 and I836 were asserted as tier 1 level A variants based on the prediction of response to gilteritinib in relapsed/refractory AML (PMIDs: 27993330, 31665578, 28645776, 28516360, 27908881). Recent curation activities are focused on FLT3 D839G and N676K, as clinical trials using large AML patient cohorts are lacking in their ability to validate drug response/resistance associations of these two TKD variants due to their low frequency. Functional studies showed both variants result in increased proliferation and protection from apoptosis, supporting the oncogenic potential of these two variants (PMIDs: 26891877, 2468088). FLT3 D839G combined with ITD confers resistance to pexidartinib and ponatinib, both Type II FLT3 inhibitors (PMIDs: 25847190, 23430109). FLT3 N676K predicts response to the Type I FLT3 inhibitor, gilteritinib, when N676K is present alone or in combination with ITD. Interestingly, FLT3 N676K in the absence of ITD predicts response to sorafenib, a Type II FLT3 inhibitor (PMIDs: 32040554, 32984009). However, these results are mostly derived from in vitro studies. Two separate Tier II, Level D Assertions have been submitted for FLT3-ITD&D839G for its response to pexidartinib and ponatinib, and more evidence is being collected to form an Assertion for FLT3 N676K. The complexity of the prediction of response/resistance associated with FLT3 D839G and N676K supports the importance of evidence-based curation and collection for these variants in the context of the overall mutation profile, disease context and specific FLT3 TKIs to clearly define their clinical impact. Disclosures Pullarkat: Stemline Therapeutics: Honoraria.

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