scholarly journals Streamline - Study of Relapse or Refractory (R/R) FLT3-Mutated Acute Myeloid Leukemia (AML) Using Electronic Medical Records (EMR): First Analysis from a Multicenter, Retrospective Cohort Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5082-5082
Author(s):  
Amer M. Zeidan ◽  
Adrienne Gilligan ◽  
Santosh Gautam ◽  
Nan Hu ◽  
David L. Grinblatt ◽  
...  
Keyword(s):  
Cohort Study ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Advisory Committees ◽  
Mutational Status ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Testing Patterns

INTRODUCTION: In AML, the ability to target disease-related mutations is an important therapeutic innovation. FMS-like tyrosine kinase 3 (FLT3) mutations (FLT3mut+) are common in AML and confer a negative impact on prognosis. Since FLT3 mutational status can change over the course of the disease and FLT3-targeting therapies may benefit FLT3mut+ patients (pts), FLT3 mutational testing is recommended for R/R AML pts, even if testing was performed at initial diagnosis. As the landscape of FLT3mut+ R/R AML evolves, it is important to understand how the utilization/sequencing of therapies and application of FLT3 mutational testing impacts pts in real-world settings. The objective of this analysis was to examine real-world data from a large, multicenter, collaborative EMR database to learn more about treatment and FLT3 testing patterns in pts with FLT3mut+ R/R AML. METHODS: This retrospective, longitudinal, observational cohort study was designed to describe treatment FLT3 testing patterns in adult (≥18 years) pts in the USA with FLT3mut+ R/R AML. For this analysis, initial diagnosis of R/R AML must have occurred between January 1, 2015 and November 30, 2018. This study focuses on data collected prior to the date of approval of gilteritinib for treatment of FLT3mut+ R/R AML (November 28, 2018). Patients were identified by confirmation of diagnosis of AML, followed by confirmation of FLT3mut+ disease, and then ≥1 R/R event. Data were derived from a consolidated EMR database, which combined data from CancerLinQ and Vector Oncology. Data were extracted through an SQL query and abstracted by clinical research nurses. Descriptive statistics were used to examine potential differences among subsets of pts. RESULTS: In the initial phase, data from 99 pts (52.5% male; n=52) with FLT3mut+ R/R AML were evaluated. The majority of pts were Caucasian (72.7%; n=72) with a median age of 62 years (range: 20-86) at first R/R episode. At the first R/R event, treatment regimens were diverse; a total of 89/99 (89.9%) pts underwent 44 different anticancer therapies and only 10.1% (n=10/99) of pts received best supportive care (BSC). At first R/R, the most common anticancer treatments were cytarabine + fludarabine + idarubicin (29.4%; n=10/34) for pts undergoing high-intensity chemotherapy (HIC) and decitabine (45.4%; n=5/11) for pts undergoing low-intensity chemotherapy (LIC). The percentage of pts receiving FLT3 inhibitors, either as single agent or in combination with chemotherapy, was 33.3% (n=33/99) of the total population (Table). Among pts aged <60 years, 47.7% (n=21/44) were treated with HIC-most commonly with cytarabine + fludarabine + idarubicin (33.3%; n=7/21). Only 4.5% (n=2/44) of pts received LIC and 9.1% (n=4/44) received BSC. In the pts aged ≥60 years, 10.9% (n=6/55) received BSC. A higher proportion of pts aged ≥60 years received HIC +/- FLT3 inhibitors (38.2%; n=21/55) compared with LIC +/- FLT3 inhibitors (25.5%; n=14/55). The most common treatments included cytarabine-usually in combination with fludarabine and/or idarubicin (84.6%, n=11/13)-for HIC, and azacitidine (alone or in combination; 55.6%, n=5/9) for LIC. Approximately 38.2% (n=21/55) of pts aged ≥60 years received a FLT3 inhibitor (alone or in combination with chemotherapy), with midostaurin being the most frequently prescribed (47.6%; n=10/21), followed by sorafenib (38.1%, n=8/21). Although most pts (83.8%; n=83/99) were tested for FLT3 mutations at initial AML diagnosis, the majority of pts were not retested; retest at first R/R was performed in 29.0% (n=9/31) of pts. At first R/R, 22.2% (n=2/9) of pts had a change in FLT3 mutational status (Figure). No significant differences were observed in FLT3 retesting among pts <60 years vs ≥60 years (P=0.456). CONCLUSIONS: During the study period, there was substantial heterogeneity regarding the management of FLT3mut+ R/R AML. A total of 89 pts received 44 different anticancer therapies and approximately one-third of pts received a FLT3 inhibitor (alone or in combination) at first R/R. However, during the study period, approved agents for treatment of FLT3mut+ R/R AML were not available. Despite NCCN guidelines, at first R/R, FLT3 retesting was not often performed. With recent approval of FLT3-targeted therapies, it is important to measure rates of retesting in the R/R setting to better understand how elements of pt care, such as monitoring changes in FLT3 mutational status, may impact pt outcomes. Disclosures Zeidan: Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Medimmune/AstraZeneca: Research Funding; ADC Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding. Gilligan:Astellas: Other: Project. Gautam:Astellas: Other: Project. Hu:Astellas: Other: Project. Grinblatt:Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pandya:Astellas Pharmaceuticals: Employment.

scholarly journals A Phase-Ib/II Clinical Evaluation of Ponatinib in Combination with Azacitidine in FLT3-ITD and CBL-Mutant Acute Myeloid Leukemia (PON-AZA study)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2350-2350
Author(s):  
David Kipp ◽  
Sun Loo ◽  
Andrew Charles Perkins ◽  
Steven W Lane ◽  
Emily Blyth ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Loss Of Function ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Best Response ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Introduction Despite the advent of targeted therapy for FLT3-mutated AML, unmet need still exists for patients unfit for intensive chemotherapy, with no evidence that overall survival (OS) can be improved by combining either venetoclax (Konopleva et al., ASH 2020) or gilteritinib (Astellas press release, December 2020) with azacitidine. Although gilteritinib has been shown to improve median OS from 5.5 to 9.8 months, the majority will relapse (Perl et al., 2019). Adaptive on-target gilteritinib resistance may be due to the FLT3-F691L gatekeeper mutation, whereas off-target resistance may be due to loss-of-function variants in CBL, which encodes an E3 ubiquitin-protein ligase that negatively regulates FLT3 (McMahon et al, 2019). Ponatinib is a type-1 FLT3 inhibitor that is active in vitro against FLT3 F691L (Smith et al., 2013) and had an overall response rate (ORR) of 43% in a small pilot phase-I study (Talpaz et al., 2011). Combination of a FLT3 inhibitor with azacitidine may antagonize the synergistic hypermethylation reported for FLT3-ITD in association with epigenetic mutations (Shih et al., 2015). CBL loss-of-function mutations may also enhance responsiveness to FLT3 inhibitors (Taylor et al, 2015). We thus hypothesize that the combination of ponatinib and azacitidine could mitigate the rapid evolution of drug resistance typical of more selective FLT3 inhibitors used as single agents. Methods A phase-Ib study was conducted with the primary objective safety and key secondary objective preliminary efficacy of azacitidine in combination with ponatinib in patients with FLT3-ITD AML failing prior therapy or unfit for intensive chemotherapy. Exploratory objectives included mechanisms of ponatinib resistance and responsiveness of CBL-mutant AML to FLT3 inhibition. At dose level 1 (DL1), patients received azacitidine 60 mg/m 2 on days 1-5 and 8-9 and ponatinib 30 mg daily on days 5-25 of each cycle. In patients not achieving CR or CRi after cycle 1, the ponatinib dose was increased to 45 mg during cycle 2. For dose level 2 (DL2), the dose of azacitidine was increased to 75 mg/m 2. Results Thirty-one patients were evaluable for response. Median age was 67 years (range, 26-87). Frequency of prior lines of therapy was 0 (15%), 1 (46%), 2 (23%) or 3 (8%). Four patients had a history of prior allogeneic hematopoietic cell transplant and one had previously received a FLT3 inhibitor. FLT3-ITD was present in 28 patients (median VAF 0.33; range, 0.009-17.95) and 3 had inactivating CBL mutations. A total of 20 patients were treated at DL1 and 12 patients at DL2. There were two grade-4 DLTs (raised AST/ALT [DL1] and tubulointerstitial nephritis [DL2]). Three grade-2 thromboembolic events were observed (two cannula-related DVTs and a distal lower-limb DVT). There were two grade-5 AEs (infection and cardiac failure), which were not considered drug related. The most common grade-3-4 AEs were febrile neutropenia (57%), neutropenia (47%), infections (47%), thrombocytopenia (40%) and anaemia (27%). Cardiac arrhythmias (atrial fibrillation/flutter, bradycardia, sinus tachycardia and ventricular tachycardia [1 patient]) were observed in 30% of patients. Of these, 80% were grade 1 or 2 and only one was considered by the investigator to be related to study treatment. Response was evaluable in 23 of 31 patients. Nine patients (39%) achieved CR or CRi, 3 (13%) achieved a PR and 8 (35%) achieved SD (ORR 52%). ORR at DL1 and DL2 was 43% and 66%, respectively. Median time to best response was 1.4 months (range 1.0-11.9). Median duration of best response was 12.9 months at both dose levels. Median OS for DL1 was 6.5 months and not reached for DL2. Despite shorter follow-up, DL2 patients experienced better OS than DL1 patients (p = 0.015). Responses were seen in 2 of 4 patients with post-allograft relapse. Two of three patients with a CBL mutation responded (1 CR and 1 CRi). Eradication of the CBL mutation was seen in one patient, who remains on therapy after 15 cycles. Molecular studies to investigate dynamic changes in molecular architecture are ongoing. Conclusions The recommended phase-II dose of ponatinib is 30 mg on days 5-25 and that of azacitidine is 75 mg/m 2 for seven doses each cycle. The ORR was 52% and durable disease control was observed, especially in patients receiving DL2. Preliminary efficacy was observed in CBL-mutated patients. Further clinical investigation of this regimen is warranted in patients with FLT3- or CBL-mutant AML. Figure 1 Figure 1. Disclosures Kipp: Novartis: Honoraria. Perkins: Celgene: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Lane: Novartis: Consultancy; Geron: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees. Enjeti: Sanofi: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria; Roche: Speakers Bureau; Astra Zeneca: Honoraria. Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Reynolds: Novartis AG: Current equity holder in publicly-traded company; Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company. Wei: Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Servier: Consultancy; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding. OffLabel Disclosure: Ponatinib - used as an experimental therapy for AML in combination with azacitidine

scholarly journals Streamline - Retrospective Cohort Study of Relapsed or Refractory (R/R) FLT3-Mutated Acute Myeloid Leukemia (AML): Real-World Treatment, Testing Patterns, and Outcomes

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Amer M. Zeidan ◽  
Adrienne M. Gilligan ◽  
Santosh Gautam ◽  
David L. Grinblatt ◽  
Dina Elsouda ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Real World ◽  
Targeted Therapies ◽  
Research Funding ◽  
Treatment Patterns ◽  
Advisory Committees ◽  
Mutation Status ◽  
Flt3 Mutation ◽  
Flt3 Mutations

Introduction: The past decade in AML research has led to increased emphasis on disease-related mutations and associated targeted therapies. FMS-like tyrosine kinase 3 (FLT3) mutations (FLT3+) are found in about 30% of AML patients and confer a poorer prognosis. Also, the availability of targeted therapies increases the value of testing for FLT3+ AML. A paucity of data exists regarding the real-world FLT3 testing rates in AML patients in both the newly diagnosed and R/R settings. As the treatment landscape for patients with R/R FLT3+ AML expands, it is important to understand how utilization of these therapies and trends in FLT3 testing impact patient outcomes in real-world settings. These updated results examined FLT3 testing trends, treatment patterns, and overall survival (OS) in patients with R/R FLT3+ AML. Patients were grouped based on the FDA approval of the second-generation FLT3 inhibitor gilteritinib (pre-gilteritinib approval vs. post-gilteritinib approval). Methods: This ongoing (01/01/2015-4/17/2020) retrospective study uses electronic medical record data of US patients from a network of 400+ oncology practices maintained in the Definitive Oncology Dataset, including practices affiliated with CancerLinQ. Eligible adult (≥18 years) patients who had a confirmed diagnosis of AML, FLT3+ status, and had ≥1 R/R event between 01/01/2015 and 02/20/2020 were included. FLT3 testing trends included testing performed at initial diagnosis, re-testing performed in the R/R setting, and changes in FLT3 mutation status. Treatment patterns included all systemic anticancer therapies received (including supportive care) for R/R FLT3+ AML. OS was measured from the first R/R event; patients without evidence of death were censored at the last observed visit. Kaplan-Meier analysis was applied to evaluate differences in OS by subsequent hematopoietic stem cell transplant (HSCT) status. Results: Data from 175 patients (50.9% male, n=89) with R/R FLT3+ AML were evaluated (n=124 pre-gilteritinib; n=51 post-gilteritinib). Most patients were White (72.0%; n=126) with a median age of 62 years (range: 20-86) at first R/R event. Median length of follow-up was limited for the post-gilteritinib cohort (9.2 months vs. 15.0 months for pre-gilteritinib, P&lt;0.001). Patients tested for FLT3 mutations at initial AML diagnosis increased from 84.7% (n=105/124) in the pre-gilteritinib cohort to 98.0% (n=50/51) in the post-gilteritinib cohort, and the rates of re-testing increased from 29.5% (n=31/105) to 46.0% (n=23/50) across the two cohorts (Figure 1). After the first R/R event, 18.9% (n=33/175) reported changes in their FLT3 mutation status. Seventy-four different treatment combinations were utilized at the first R/R event. Use of FLT3 tyrosine kinase inhibitors (TKIs), either alone or in combination with chemotherapy, increased from 30.6% (n=38/124) in the pre-gilteritinib cohort to 49.0% (n=25/51) in the post-gilteritinib cohort (Table 1). In the pre-gilteritinib cohort midostaurin (52.6%, n=20/38) and sorafenib (32.4%, n=13/38) were the most commonly prescribed FLT3 TKIs. In the post-gilteritinib cohort, the most common FLT3 TKI was gilteritinib (52.0%, n=13/25). Median OS (95% CI) across all patients at the first R/R event was 13.4 (9.0-17.6) months in the pre-gilteritinib cohort and 12.9 (7.0, NA) months in the post-gilteritinib cohort. Median OS was significantly shorter among patients that did not receive HSCT among all patients and the subset of treated patients (P&lt;0.05 for both values). Median OS for patients with no HSCT was 3.9 months longer in the post-gilteritinib cohort versus the pre-gilteritinib cohort (Table 2). Conclusion: An increase in FLT3 TKI use (both monotherapy and in combination) and a decrease in high-intensity chemotherapy was observed across the two cohorts. In the 18-month post approval period, FLT3 TKI use increased 60% with gilteritinib accounting for more than half of FLT3 TKIs used in the R/R setting. FLT3 re-testing increased by 55% in the R/R setting between the two cohorts; however, re-testing is suboptimal and there is a need to re-test as patients progress. Among pre- and post-treated patients that did not receive HSCT, there was an improvement in OS by almost 4 months, possibly due to increased use of targeted FLT3 TKIs. With recent approval of these targeted therapies, it will be important to continue to monitor FLT3 testing, treatment patterns, and clinical outcomes. Disclosures Zeidan: Celgene / BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Astex: Research Funding; Cardinal Health: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Taiho: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other. Gilligan:ConcertAI: Current Employment. Grinblatt:Astellas: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau. Elsouda:Astellas: Current Employment. Sullivan:Astellas Pharma: Current Employment. Pandya:Astellas Pharma, Inc.: Current Employment.

scholarly journals First in Human Study of SEL24/MEN1703, First in Class, Orally Available Dual PIM/FLT3 Kinase Inhibitor, in Patients with Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3920-3920
Author(s):  
Scott R. Solomon ◽  
Aziz Nazha ◽  
Stephen A. Strickland ◽  
Roland B. Walter ◽  
Ilaria Valimberti ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Oral Formulation ◽  
Advisory Committees ◽  
Mutational Status ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Equity Ownership ◽  
Dose Levels

Introduction SEL24/MEN1703 is a potent dual inhibitor of proviral integration site for Moloney murine leukemia virus (PIM) and FMS-like tyrosine kinase 3 (FLT3) with increased activity in both primary Acute Myeloid Leukemia (AML) cells and AML cell lines, irrespectively of FLT3 mutational status, when compared to either FLT3 or PIM single agent inhibitors. PIM kinases are thought to be major drivers of resistance to FLT3 inhibitors and their inhibition in relapsed samples restores cell sensitivity to these agents. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. In addition, the broader spectrum of activity of SEL24/MEN1703, which goes beyond PIM/FLT3 inhibition, warrants the compound investigation in AML patients regardless of the genetic aberrations of FLT3. Methods CLI24-001 is a First-in-Human, single-arm, phase I/II trial with a dose-escalation (DE) part followed by a cohort expansion (CE) part in patients with AML (excluding Acute Promyelocytic Leukemia) -newly diagnosed, relapsed or refractory - that are unsuitable for intensive chemotherapy and meet the main inclusion criterion of white blood count (WBC) of ≤30 x 109/L (hydroxyurea/leukapheresis permitted to lower WBC). In both study parts, patients are eligible regardless of mutational status and prior exposure to FLT3 inhibitors; however, prior treatment with PIM inhibitors is not allowed. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle to be repeated until disease progression, or unacceptable toxicity or withdrawal of patient consent. Bayesian modified toxicity probability interval model was implemented in the DE part after achieving 5 incremental dose levels in order to provide the most accurate identification of the Recommended Phase 2 Dose (RP2D). Also, during the DE part, a new oral formulation was introduced and compared to the original one by repeating the 100 mg dose level in order to avoid a subsequent formal bioequivalence study in patients. The primary objective of the study is to identify the RP2D of SEL24/MEN1703 in the DE part that will be further characterized in the CE part for next steps of clinical development. Key secondary objectives include the characterization of pharmacokinetics (PK) and efficacy assessment of SEL24/MEN1703 given as single agent; exploratory objectives include the assessment of relevant biomarkers (e.g. pS6) in peripheral blood and bone marrow, and their correlation with PK at different time points. Correlation of clinical activity and the cell surface antigen CD25 will be also explored. Study update Currently, the study is enrolling at 5 US sites and will be extended both in the US and EU. The recruitment started in March 2017 and, as of July 26th, 2019, 24 patients received SEL24/MEN1703 at dose levels ranging from 25 to 150 mg. Patients had a median age of 69 (25-84) years and a median of 3 (0-8) prior treatments for AML. Adverse prognostic factors such as primary refractory AML, unfavorable cytogenetics and prior MDS history accounted for 45.8%, 37.5%, 33.% of study patients, respectively. The most frequently reported mutations were FLT3-ITD (20.8% of patients) and those of DNMT3A and IDH1 (16.7% each). Conclusions This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to overcome FLT3 inhibitor resistance, but also to be active in AML regardless of FLT3 mutational status. Ongoing adjustment of the DE design, including the switch to an optimized oral formulation, has been performed to obtain more robust data on the RP2D (ClinicalTrials.gov Identifier: NCT03008187). Disclosures Nazha: Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Walter:Boehringer Ingelheim: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy. Valimberti:Menarini Ricerche S.p.A: Employment. Tagliavini:Menarini Ricerche S.p.A: Employment. Mazzei:Menarini Ricerche S.p.A.: Employment. Fiesoli:Menarini Ricerche S.p.A.: Employment. Scartoni:Menarini Ricerche S.p.A.: Employment. Bellarosa:Menarini Ricerche S.p.A.: Employment. Binaschi:Menarini Ricerche S.p.A.: Employment. Chrom:Selvita S.A.: Employment. Baldini:Menarini Ricerche S.p.A.: Employment. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Capriati:Menarini Ricerche S.p.A.: Employment. Pellacani:Menarini Ricerche S.p.A.: Employment; Amgen: Equity Ownership. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding.

scholarly journals Addition of Crenolanib to Induction Chemotherapy Overcomes the Poor Prognostic Impact of Co- Occurring Driver Mutations in Patients with Newly Diagnosed FLT3-Mutated AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1436-1436 ◽  
Author(s):  
Aaron D Goldberg ◽  
Robert H. Collins ◽  
Richard M. Stone ◽  
Roland B. Walter ◽  
Chatchada Karanes ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Driver Mutations ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Support Research

Abstract Background: Patients with AML harboring FLT3 mutations have poor clinical outcomes. Furthermore, FLT3 mutations frequently co-occur with other driver mutations, such as NPM1 with DNMT3A, WT1, and RUNX1, that are associated with poor prognosis. Crenolanib is a highly potent and specific type-I FLT3 inhibitor, which has shown promising safety and efficacy in combination with chemotherapy. Here we report the outcomes of newly diagnosed FLT3 mutated AML patients treated with crenolanib and intensive 7 + 3 based chemotherapy (NCT02283177) by baseline genomic profile. Methods: Patients were treated on clinical trial with 7+3 induction chemotherapy combined with crenolanib, consolidation with high-dose cytarabine (HiDAC) combined with crenolanib, and/or allo-HCT followed by crenolanib maintenance. Of 44 pts enrolled and treated, 36 had sequencing performed at baseline. The median survival follow-up for these patients was 20.7 months with data cut off July 25, 2018. A post hoc analysis was performed to assess the impact of genomic profile on patient outcomes using published data from the German-Austrian AML Study Group as a historical control. Results: Concurrent FLT3-ITD, NPM1, and DNMT3A mutations ("triple mutant") were present in 10 pts. These patients demonstrated improved OS with crenolanib treatment compared with historical controls. Similarly, patients with FLT3-ITD and WT1 mutations (n = 6) showed dramatically improved outcomes, with no deaths occurring by 18 months. Patients with FLT3 (ITD or TKD) and RUNX1 mutations (n = 10) also had improved OS. Conclusions: This analysis suggests that adding a potent pan-FLT3 inhibitor can overcome the poor prognostic implication of adverse mutations co-occurring with mutated FLT3. These data support the combination of crenolanib with chemotherapy to improve the overall outcome of FLT3 mutated AML with diverse mutational profiles. Hence, a randomized trial has been initiated of standard chemotherapy combined with either crenolanib or midostaurin in newly diagnosed patients with FLT3-mutant AML (NCT03258931). Table. Table. Disclosures Goldberg: AROG: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Abbvie: Research Funding. Collins:Arog Pharmaceuticals: Research Funding; Celgene Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Agios: Research Funding. Stone:Ono: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Merck: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Orsenix: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; AbbVie: Consultancy; Amgen: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Cornerstone: Consultancy. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer, Inc: Consultancy; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; AbbVie: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding; BioSight: Other: Advisory board.

scholarly journals Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Maël Heiblig ◽  
Hélène Labussière ◽  
Marie Virginie Larcher ◽  
Gaelle Fossard ◽  
Marie Balsat ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Predictive Value ◽  
Scoring System ◽  
Research Funding ◽  
Risk Group ◽  
Advisory Committees ◽  
Post Induction ◽  
Mutational Status ◽  
Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p&lt;0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p&lt;0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P &lt;0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P &lt;0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

scholarly journals Assessing the Safety of Various VWF Regimens in Patients with Clinically Severe VWD: A Natural History Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1132-1132
Author(s):  
Robert F. Sidonio ◽  
Angela C. Weyand ◽  
Dunlei Cheng ◽  
Crystal Watson
Keyword(s):  
Board Of Directors ◽  
Study Design ◽  
Real World ◽  
Research Funding ◽  
Laboratory Data ◽  
Severe Bleeding ◽  
Advisory Committees ◽  
On Demand ◽  
Type 3 ◽  
Von Willebrand

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans affecting up to 1% of the population, while symptomatic prevalence is likely closer to 0.1%. A deficiency of von Willebrand factor (VWF) can be quantitative (type 1 or type 3) or qualitative (type 2) and lead to a bleeding diathesis of variable intensity roughly correlating with functional activity. Diagnosis can be challenging due to variable penetrance and large influence of multiple pre-analytic variables and a wide testing coefficient of variation. Treatment for VWD is focused on replacement of defective or deficient VWF with a plasma-derived or recombinant VWF-containing product, release and elevation of endogenous stores of VWF with Desmopressin (DDAVP), or prevention of premature fibrinolysis with an antifibrinolytic, such as aminocaproic acid. Although there is relative consensus on the management of mild VWD, there is scarce literature about the optimal treatment of patients with severe disease, especially in regard to factor replacement. Real World evidence for the use of primary (prior to significant bleeding) or secondary (following development of significant bleeding) prophylaxis is lacking with the majority of studies relying heavily on retrospective data. Additionally, ongoing VWD prophylaxis studies typically only allow participants to enroll if they previously have not been on prophylaxis, limiting our ability to learn about this growing population of patients. Study Design and Methods: Approximately 1,900 VWD patients were identified in the ATHNdataset with a VWF:Ag or VWF:RCo of ≤ 30%, with ~170 of these on prophylaxis. This group, in addition to those VWD patients with clinically significant bleeding and ≤ 40% of normal VWF:Ag or VWF:RCo, provide a potential unmet opportunity to examine prophylaxis and treatment patterns. Furthermore, a standardized laboratory assessment (including a standardized diagnostic battery, genetic evaluation of VWF gene, and inhibitor testing) will provide significant enrichment of the ATHNdataset by fully characterizing patients that are highly likely to utilize factor concentrates. Inclusion criteria are patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GP1bM or VWF:Ag≤ 30%, patients with clinically severe VWD as defined by VWF:Rco, VWF:GP1bM or VWF:Ag ≤ 40% with severe bleeding phenotype requiring recurrent use of factor concentrates, and co-enrollment in the ATHNdataset. Patients with platelet-type or acquired VWD are excluded. The primary objective is to assess the safety of various VWF regimens for different indications (on-demand, surgery, and prophylaxis) in adult and pediatric patients with clinically severe VWD. Safety is measured by the number of reported events as defined by the European Haemophilia Safety Surveillance (EUHASS) program. Secondary objectives are to enrich and analyze data from clinically severe congenital VWD patients by collecting laboratory data; to establish sub-studies for patients who are treated with VWF products on demand or who have started on or switched to a particular VWF containing product; to evaluate the use of factor replacement as prophylaxis in a cohort of severe VWD participants over 6 month time periods; to describe bleeding events, changes in overall bleeding, and annualized bleed rate as measured by the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) and if applicable the Pictorial Bleed Assessment Chart (PBAC); and to describe real-world effectiveness of VWD treatment as measured by health care utilization and quality of life measures (PROMIS® and V-WIQ questionnaires). Descriptive statistics will be calculated to analyze the primary and secondary outcomes. For each categorical variable, its frequency and percentage will be reported. In terms of a continuous measurement, its mean, median, standard deviation, interquartile range, minimum, and maximum values will be disclosed. The study will attempt to enroll a target number of at least 50 participants who are receiving VONVENDI but will not mandate the use of VONVENDI. More study design details are outlined in Table 1. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

scholarly journals EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1528-1528
Author(s):  
Sebastian Stasik ◽  
Jan Moritz Middeke ◽  
Michael Kramer ◽  
Christoph Rollig ◽  
Alwin Krämer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutational Status ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

scholarly journals The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3021-3021
Author(s):  
Gregory Lazarian ◽  
Floriane Theves ◽  
Myriam Hormi ◽  
Virginie Eclache ◽  
Stéphanie Poulain ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Snp Analysis ◽  
Advisory Committees ◽  
Exon 2 ◽  
Tp53 Mutations ◽  
Mutational Status

TP53 aberrations, including somatic mutations of TP53 gene or 17p deletion leading to the loss of the TP53 locus, are a major predictive factor of resistance to fludarabin based chemotherapy in chronic lymphocytic leukemia (CLL) and remain an adverse prognostic factor in the chemofree era. Therefore, detection of TP53 alteration before each new line of treatment is required for theranostic stratification. In order to better characterize the distribution and combination of the TP53 variants in CLL, we collected the TP53 sequencing data of 343 patients harboring TP53 mutations from centers of the French Innovative Leukemia Organization-CLL (FILO) and established a large data base of 573 TP53 mutations. Mutations were identified through NGS sequencing (covering exon 2 to 11) allowing the detection of low frequency variants down to 1% VAF. Several distinct low VAF mutations were orthogonally confirmed by digital PCR. TP53 variants were analyzed through UMD_TP53 data gathering 90 000 TP53 mutations from all type of cancers. IGHV mutational status and FISH analysis were available for 224 and 176 patients respectively. Using ACMG criteria from the UMD_TP53 database, we confirmed that 523 could be classified as pathogenic, 42 were likely pathogenic and 8 were VUS (Variants of Unknown Significance). As expected, the mutation distribution along the p53 protein exhibited a clustering of variants in the DNA binding domain of the protein. We also confirmed the presence of a specific hotspot at codon 234 (6%) which is noticeable in other CLL cohorts but absent in solid tumors. 431 TP53 variants led to the expression of a mutant protein whereas the remaining 142 led a TP53 null phenotype. For 8 patients without 17p deletion and a mutation VAF larger than 50%, SNP analysis indicate that these tumors had a copy number neutral loss of heterozygosis at 17p with a duplication of the mutant allele leading to homozygous mutations of TP53. When focusing on the allele burden of TP53 mutations, 264/573 (46%) variants had an allele frequency <10%. Even if they were predominantly found in polymutated cases, presence of only low VAF (<10%) mutations was evidenced in 74 (21%) patients (50 patients with a single TP53 mutation and 24 patients with more than one). All these cases would have been missed by conventional sequencing. Among the 343 patients, 113 (33%) were poly-mutated and harbored more than one pathogenic TP53 variants (2 to 11 variants per patient): 57 (16,7 %) had 2 variants, 32 (9,3%) had 3, 10 had 4 (3%) and 14 patients (4%) had 5 to 11 variants. Using both long range sequencing and in silico analysis, we could show that all these variants were distributed in different alleles supporting an important intratumoral heterogeneity and a strong selection for TP53 loss of function during tumor progression in these patients. Null variants were rarely found as single alteration: only 46 patients (13,4%) patients harbored a single null mutation. Null mutations were predominantly found in patients with multiclonal mutations (87% with 4 or more). Median size of variants significantly decreased with the number of mutations and most of low VAF (less than 10%) variants were found in multiclonal combinations. Multiclonal mutations were predominantly found in previously treated patients (41% treated versus 10 % untreated) but whether all these variants preceded treatment and were further selected is currently unknown. We observed that 71,5 % of patients were IGHV unmutated and multiclonal mutations were surprisingly more frequent in mutated IGHV cases than in unmutated ones. Only 50% of cases carried a 17p deletion, highlighting again the importance of testing for TP53 mutations in addition to FISH analysis. Presence or absence of 17p deletion was unrelated to the number of TP53 mutations. Taken together these observations suggest that the TP53 mutational landscape in CLL is very complex and can involve multiple mechanisms, converging to a total loss of TP53 function and tumor progression. NGS provides a powerful tool for detecting all these alterations including variants with low VAF and should become a standard for CLL screening prior to each line of treatment. Disclosures Leblond: Amgen: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Letestu:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Cymbalista:Abbvie: Honoraria; Roche: Research Funding; Sunesis: Research Funding; Gilead: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

scholarly journals Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2409-2409
Author(s):  
Tiffany Lin Lucas ◽  
Shveta Gupta ◽  
Joanna A. Davis ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Haemophilia A ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

FLT3 Inhibitor Therapy for Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Impact On Survival According to FLT3 Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1026-1026 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Borthakur Gautam ◽  
...  
Keyword(s):  
Research Funding ◽  
Initial Therapy ◽  
Inhibitor Therapy ◽  
Clinical Activity ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Impact On Survival

Abstract Abstract 1026 Poster Board I-48 Background: FLT3 mutations (ITD or D835 point mutation) are frequently observed in patients (pts) with AML and they confer an adverse prognosis, particularly among pts with diploid karyotype. This has made FLT3 an important target for drug development in AML. Several FLT3 inhibitors are currently being developed (eg, sorafenib, PKC-412, AC-220, CEP-701, IMC EB10, sunitinib). Results from early trials with many of these agents suggest they have clinical activity in the treatment of MDS and AML, although most responses are represented by a marked decrease in blast counts, with few complete remissions(CR). Whether these responses ultimately improve long-term outcome of pts, and whether they may be particularly beneficial for pts with FLT3 mutations compared to those with FLT3 wild-type (WT) is being investigated. Aims: To ascertain outcomes of patients given treatment with FLT3 inhibitors, alone or in combination with other therapies, and to compare outcomes in those patients with FLT3 mutations (ITD or D835) versus those with FLT3-WT. Methods: We reviewed the records of patients with MDS and AML who were enrolled on clinical trials with FLT3 inhibitors at our institution. We compared patient outcomes in those who received a FLT3 inhibitor in both FLT3 positive and FLT3 negative patients. Pts were classified as receiving FLT3 inhibitors 1) as part of their initial therapy, 2) as first salvage, or 3) as second salvage or beyond. Results: A total of 128 pts were included: 51 (40%) with FLT3-WT, 56 (44%) with FLT3-ITD, 11 (9%) with D835, and 10 (8%) had both FLT3-ITD and D835. The overall median age was 62 yrs (range, 17-88); by FLT3 status, median age was 70 yrs (35-88) for FLT3-WT pts and 58 yrs (17-81) for FLT3 mutated. Sixty-four pts (50%) were female. Twenty-three (18%) pts received FLT3 inhibitors as part of their induction therapy (18 FLT3-WT, 5 FLT3 mutated; median age 74 yrs); 22 (17%) as first salvage (4 FLT3-WT, 18 mutated; median age 67 yrs); and 83 (65%) as second or later salvage (29 FLT3-WT, 54 mutated; median age 59 yrs). Nine pts overall, all of whom were FLT3 mutated, achieved either CR (n=6) or CRp (n=3) with FLT3 inhibitors. Eight of the nine CR/CRp have been lost with a median CR duration of 8 months (mo) (3-12+). After a median follow-up of 3.5 mo, 115 (90%) pts have died, including 47 (92%) FLT3-WT, and 68 (88%) FLT3 mutated. The median survival is 3.8 mo for the total population. Survival by mutation status and timing of FLT3 inhibitor therapy is presented in table 1. Conclusions: Despite the inferior outcome expected for pts with FLT3 mutations, and the low rate of CR/CRp with FLT3 inhibitors, these results suggest that therapy with FLT3 inhibitors has the potential to improve the outcome of pts with FLT3 mutations. Additional studies incorporating these agents in AML therapy are warranted. Disclosures: Off Label Use: Sorafenib has not been FDA approved for use in MDS and AML. Kantarjian:Novartis: Research Funding. Cortes:Ambit: Research Funding; Novartis: Research Funding; ImClone: Research Funding.

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