scholarly journals Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1357-1357 ◽  
Author(s):  
Hannah Asghari ◽  
Dasom Lee ◽  
Yehuda E. Deutsch ◽  
Onyee Chan ◽  
Najla Al Ali ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Groups ◽  
Initial Therapy ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Significant Difference ◽  
Frontline Therapy ◽  
Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: 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; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

scholarly journals Low-Dose Azacitidine, Pioglitazone and All-Trans Retinoic Acid Versus Standard-Dose Azacitidine in Patients ≥ 60 Years with Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy (AMLSG 26-16/AML-ViVA): Results of the Safety Run-in Phase I

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1382-1382 ◽  
Author(s):  
Daniel Heudobler ◽  
Sebastian Klobuch ◽  
Florian Lüke ◽  
Joachim Hahn ◽  
Matthias Grube ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Committees ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Refractory Aml

Introduction: Patients (pts) with acute myeloid leukemia (AML) who are refractory to intensive frontline treatment have a dismal outcome. In case of ineligibility for allogeneic stem cell transplantation (HSCT), the median survival of chemo-refractory AML is about 2 months and less than 5% of these pts are alive after 1-year (retrospective analysis from the AMLSG database). To date, there is no universally accepted standard approach for the treatment of chemo-refractory AML in older pts. Several retrospective studies have assessed the role of hypomethylating agents in this patient group, but complete remission (CR) rates were disappointingly low (≤10%) when compared to first line treatment. The presented study represents a novel approach focusing on hematopoietic tissue reprogramming (i.e. anakoinosis) (ClinicalTrials.gov Identifier: NCT02942758). Methods: The initial dose-finding phase I of the study evaluated the combination of azacitidine (AZA) 75 mg/d s.c. for 7 days, repeated every 28-days, pioglitazone 45 mg/d p.o. continuously from day 1 and all-trans retinoic acid (ATRA). A modified 3+3 design has been used to establish the maximum-tolerated dose of ATRA. Patients have been enrolled at an ATRA dose of 45 mg/m²/d from day 1 to day 28 and 15 mg/m²/d continuously thereafter if no dose limiting toxicity (DLT) occurred until start of next cycle on day 29. The safety DLTs were defined as toxicities attributable to ATRA, expected or unexpected, except if these are likely associated with another cause. Eligible patients had confirmed diagnosis of AML refractory to induction therapy and were not eligible for further intensive induction therapy or were not immediate candidates for allogeneic HSCT. The severity of adverse events was graded using the Common Terminology Criteria for Adverse Events (CTCAE) V. 4.03. The response to treatment was evaluated using standard criteria defined by the expert panel on behalf of the European LeukemiaNet and international working group (IWG) response. Results: Ten pts were enrolled in the safety-run-in phase I (one pt withdrew informed consent on day 9 of cycle 1). Among all treated pts, the median age was 67 years (range, 62-76 years), and the majority of pts (70%) had an ECOG PS of 1 (see table 1). Two pts had secondary AML; another two pts had therapy-related AML (t-AML). Eight pts had a complex karyotype. Concerning safety, hematological adverse events (AEs) were the most common toxicities observed. Because pts with baseline cytopenia were included (leukopenia n=8; 80%; thrombocytopenia n=9; 90%), occurrences of many hematological AEs began before study drug initiation and were attributed to underlying hematologic disease. Common 3°/4° AEs included neutropenia (50%), anemia (50%), thrombocytopenia (30%), and infections (40%). 50% of pts experienced a serious AE; one 5° AE (gastric hemorrhage) occurred. No DLTs were observed. Five pts discontinued the study, with progressive disease (PD) or relapse being the most common reason for discontinuation. Concerning efficacy, 3 pts (30%) achieved a CR and one pt a long-lasting stable disease (14 months). Morphologic review showed signs of differentiation of blasts in responding pts, which has already been shown in in-vitro analysis. In line with this observation, one pt demonstrated resolution of fungal pneumonia during the study. Conclusions: In summary, the low-intensity, biomodulatory regimen of low-dose AZA, pioglitazone, and ATRA demonstrated a tolerable safety profile and encouraging signals for efficacy in pts with AML refractory to standard induction chemotherapy warranting further investigation. S.T. and A.R. contributed equally to this abstract as senior co-authors. Disclosures Paschka: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Travel expenses; Takeda: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria. Thomas:Celgene: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Medigene AG: Consultancy, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Other: Travel support; Janssen: Other: Travel support.

scholarly journals Epigenetic Phenocopying Expands Molecular Risk Assessment in Acute Myeloid Leukemia (Alliance)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 803-803
Author(s):  
Brian Giacopelli ◽  
Salma Abdelbaky ◽  
Kyoko Yamaguchi ◽  
Jessica Kohlschmidt ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Board Of Directors ◽  
Genetic Markers ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Prognostic Markers ◽  
Risk Groups ◽  
Advisory Committees ◽  
Biological Features ◽  
Acute Myeloid

Abstract Genetic profiling of leukemic cells forms the basis for risk stratification in acute myeloid leukemia (AML). Genetic markers in AML are used to make recommendations for distinct treatment approaches, such as remission consolidation with chemotherapy rather than stem cell transplant for patients with favorable risk genetics as defined by the current guidelines from the European LeukemiaNet (ELN). Yet, several limitations remain, such as overall rarity of many mutations, hierarchical complexity in cases with multiple mutations, conflicting reports of associations with outcomes for some genetic markers, and the absence of markers with prognostic significance in some patients. We have recently described genome-wide DNA methylation signatures that underlie biological features of AML cells and their utility to classify patients [Giacopelli et al. Genome Res. 2021;31:747]. The additional value of epigenetic information for risk assessment in AML in the context of current genetic and other clinical prognostic markers remains largely unexplored. In this study, we have first developed a targeted approach for assessment of DNA methylation-based signatures and employed it to classify 1,262 patients with de novo AML enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. We successfully classified 87.5% of patients into one of 13 DNA methylation subgroups, termed 'epitypes' (Figure 1A,B). We found that epitypes are composed of a majority of patients with a specific genetic alteration (or a unique combination of alterations) in 9 of 13 epitypes. However, we also identified subgroups of patients that lack these highly recurrent alterations, and, instead, represent an epigenetic phenocopy of the dominant genetic feature (epiphenocopy). Epiphenocopies within epitypes were often enriched in specific lower frequency mutations, suggesting convergence of biological function(s) for these rare mutations. Epiphenocopying was also exhibited by patients displaying a DNA methylation signature involving hypomethylation of STAT DNA sequence motifs (termed the STAT hypomethylation signature, SHS) that mimicked FLT3-ITD mutations. Epitype and SHS DNA methylation signatures affected clinical outcomes separately to ELN risk groups (P<0.0001; Figures 1C,D), and FLT3-ITD status (P<0.0001; Figure 1E), respectively. To broadly examine the prognostic power of DNA methylation signatures, we combined methylation-based classifications into a knowledge bank containing a compendium of other prognostic markers. Using a recently developed machine-learning approach [Gerstung et al. Nat Genet. 2017;49(3):332], we found that DNA methylation retained a high degree of importance for clinical outcomes, including overall survival (Figure 1F). Specifically, SHS and 6 epitypes were the most significant features negatively associated with overall survival along with age (P<0.0001; Figure 1G). SHS and epitype were among the most significantly associated features for all other endpoints, such as early death, remission and relapse (P<0.0001) and improved concordance between all predicted to actual outcomes. Finally, we used DNA methylation to reconstruct all 4 genetic features that define the ELN Favorable risk group. We found that patients with epiphenocopies of t(8;21)/inv(16) (CBF-AML), and CEBPA-dm had favorable outcome indistinguishable from that of patients with the respective genetic markers. NPM1-mutated, FLT3-ITD-negative patients displaying SHS-positivity had adverse risk despite lacking FLT3-ITD. Re-classifying patients with CBF-AML and CEBPA-dm epiphenocopies from more unfavorable risk groups into favorable group and excluding KMT2A/MLL-like and SHS-positive patients substantially improves the definition of favorable risk AML (P<0.0001; Figure 1H). Our study demonstrates that DNA methylation signatures advance our understanding of the biology of AML and improve risk stratification through the identification of patients with epiphenocopies that mimic genetic mutations and other biological features. Use of DNA methylation signatures may lead to more effective assignment of patients to existing and novel therapeutic approaches. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifiers: NCT00048958 (8461), NCT00899223 (9665), and NCT00900224 (20202) Figure 1 Figure 1. Disclosures Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Blum: Abbvie: Honoraria; AmerisourceBergen: Honoraria; Celyad Oncology: Research Funding; Xencor: Research Funding; Nkarta: Research Funding; Forma Therapeutics: Research Funding; Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria. Stone: Agios Pharmaceuticals Inc, Novartis;: Research Funding; ACI Clinical, Syntrix Pharmaceuticals, Takeda Oncology: Other: Data Safety & Monitoring; AbbVie Inc, Actinium Pharmaceuticals Inc, Aprea Therapeutics, BerGenBio ASA, ElevateBio, Foghorn Therapeutics, GEMoaB, GlaxoSmithKline, Innate Pharma, Syndax Pharmaceuticals Inc, Syros Pharmaceuticals Inc, Takeda Oncology: Other: Advisory Committee. Eisfeld: Karyopharm (spouse): Current Employment. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Dose Escalation Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1391-1391 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Uma Borate ◽  
Melhem Solh ◽  
Gautam M. Borthakur ◽  
Amy E. DeZern ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Plasma Concentrations ◽  
Target Engagement ◽  
Advisory Committees ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Azacitidine in Patients with Acute Myeloid Leukemia: Impact of Intermediate-Risk Vs High-Risk Cytogenetics on Patient Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 955-955 ◽  
Author(s):  
Lisa Pleyer ◽  
Sonja Burgstaller ◽  
Reinhard Stauder ◽  
Michael Girschikofsky ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Negative Impact ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Bone Marrow Blasts ◽  
Acute Myeloid

Abstract Background Several studies, including retrospective analyses of patient registries1,2 and a subanalysis of the phase III MDS-AZA-001 trial3 suggest that poor-risk cytogenetics negatively impact overall survival (OS) in patients with myelodysplastic syndrome (MDS) and World Health Organization (WHO)-defined acute myeloid leukemia (AML) treated with azacitidine (AZA). There are few data available to indicate whether AZA has improved clinical activity vs conventional care in AML patients with adverse cytogenetics. However, in a subanalysis of MDS-AZA-001 (MDS and AML [20–30% bone marrow blasts]) patients with –7/–7q abnormalities had better OS with AZA than low-dose cytarabine (21.4 vs 3.5 months, respectively) supporting significant activity of AZA in patients with adverse cytogenetics.4 Methods In this retrospective study of the Austrian AZA Registry (N=346), we compared patients with WHO-AML and intermediate- (n=228) vs high-risk (n=74) cytogenetics according to Medical Research Council (MRC) criteria. Outcomes were also assessed with respect to AZA treatment line. Results The intermediate-risk cytogenetics group comprised 228 patients (AZA 1st line, n=109; AZA ≥2nd line, n=119), and the high-risk cytogenetics group comprised 74 patients (AZA 1st line, n=39; AZA ≥2nd line, n=35; Figure 1). Comparison of baseline characteristics of both groups revealed significant differences with regard to prevalence of males and Eastern Cooperative Oncology Group Performance Status (ECOG PS) >2 for patients with high-risk cytogenetics receiving AZA 1st line, but not in those receiving AZA ≥2nd line. Peripheral blood blasts were present in a significantly larger proportion of high- than intermediate-risk patients (Figure 1). In patients who received AZA 1st line, median number of AZA cycles was 6 for both the intermediate- and high-risk cytogenetic groups (range: 1–46 and 1–25, respectively). Median time from diagnosis to AZA start was <1 month for AZA 1st line and >7.6 months for AZA ≥2nd line. Median time from AZA stop to death was <2 months in all cohorts. In the whole cohort, the overall response rate (ORR) according to International Working Group (IWG) 2003 criteria5 was similar for patients with intermediate- and high-risk cytogenetics (complete response [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR]: 32.0 vs 20.3%; p=0.106; Figure 1). Rates of hematologic improvement (HI) according to IWG 2006 criteria6 were also not significantly different (54.4 vs 75.6; p=0.063), and when ORR and HI were combined, the difference remained non-significant (47.4 vs 46.0%; p=0.885; Figure 1). Median OS was consistently higher in patients with intermediate- than high-risk cytogenetics (9.8 vs 5.4 months for the total cohort; p=0.046 [Figures 1 and 2a]; 13.5 vs 9.5 months for AZA 1st line [not significant]; and 7.6 vs 3.5 months for AZA ≥2nd line; p=0.005 [Figure 1]). However, median OS for responding patients (CR/CRi/PR/HI) was similar for patients with intermediate- and high-risk cytogenetics, irrespective of treatment line (19.9 vs 19.3 months for all responders; 20.5 vs 21.7 months for AZA 1st line; and 18.5 vs 15.0 months for AZA ≥2nd line). Furthermore, presence of a monosomal karyotype had a significant negative impact on OS (Figure 2b). None of the baseline factors analyzed had an impact on OS in patient subgroups with intermediate- or high-risk cytogenetics, except number of comorbidities >3. Conclusions Here, we compared outcomes of 302 WHO-AML patients with intermediate- vs high-risk cytogenetics treated with AZA. In line with recent data of MDS patients,1 baseline cytogenetics did not seem to have a significant effect on response to AZA. However, in agreement with other studies of AZA in MDS/WHO-AML patients,1–3 high-risk cytogenetics had a negative impact on survival compared with intermediate-risk cytogenetics in WHO-AML treated with AZA. 1. Sebert M, et al. Oral presentation at ASH 2013. Abstract 389 2. Thepot S, et al. Am J Hematol 2014;89:410–6 3. Fenaux P, et al. J Clin Oncol 2010;28:562–9 4. Fenaux P, et al. Br J Haematol 2010;149:244–9 5. Cheson BD, et al. J Clin Oncol 2003;21:4642–9 6. Cheson BD, et al. Blood 2006;108:419–25 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pleyer: AOP Orphan Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for haematopoietic stem cell transplantation with 20–30 % blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML-patients with >30% bone marrow blasts.. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy. Stauder:Novartis: Research Funding; Ratiopharm: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Pfeilstöcker:Janssen-Cilag: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lang:Celgene: Consultancy. Sperr:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Phadia: Research Funding. Valent:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Greil:Sanofi Aventis: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; GSK: Research Funding; Ratiopharm: Research Funding.

A Phase 1 Study of Lenalidomide in Combination with Mitoxantrone, Etoposide, and Ara-C in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2550-2550
Author(s):  
Daniel J. DeAngelo ◽  
Amir T. Fathi ◽  
Lillian Werner ◽  
David Avigan ◽  
Katarina Luptakova ◽  
...  
Keyword(s):  
Complete Remission ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Dose Group ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Refractory Aml ◽  
Count Recovery

Abstract Background: The prognosis for patients with relapsed acute myeloid leukemia (AML) remains extremely poor. Standard reinduction regimens, such as mitoxantrone, etoposide, and ara-C (MEC), have been associated with complete remission rates in the 23 to 30% range. Lenalidomide (Len), an immunomodulatory drug, has efficacy in relapsed AML and has been shown to augment the effects of standard chemotherapies (anthracyclines and ara-C) in preclinical AML studies. These data prompted the current phase 1 study of Len in combination with MEC in pts with relapsed AML. Methods: The trial included pts (≥ 18 yrs) with relapsed or refractory AML. The primary objective was determination of the maximum tolerated dose (MTD) of Len when given in combination with MEC. Secondary objectives included safety, efficacy and time to count recovery. The study examined escalating doses (5-10 mg) of Len given daily for the first 14 days in combination with standard MEC doses of mitoxantrone (8 mg/m2/d), etoposide (100 mg/m2/d), and ara-C (1000 mg/m2/d) on days 4 through 8. Due to observations of prolonged count recovery, the Len dosing schedule was amended by reducing the duration of treatment to 10 days starting on Day 1. The dose of len was then re-escalated starting at 5 mg/d (5-10-25-50). A standard 3+3 dose-escalation design was used. Dose limiting toxicity was defined as Grade IV rash or Grade IV neuropathy during the first 28 day period, or delayed neutrophil (ANC <500/mL) or platelet (platelet count <20,000/mL) recovery beyond Day 45 after start of re-induction chemotherapy in the absence of persistent AML. Pts achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) went on to consolidation chemotherapy or hematopoietic stem cell transplantation at the discretion of the treating physician. Results: A total of 33 pts have been enrolled in the study (25 escalation phase [5 mg days 1-14, n=3; 10 mg days 1-14, n=6; 5 mg days 1-10, n=3; 10 mg days 1-10, n=3; 25 mg days 1-10, n=3; 50 mg days 1-10, n=6] and 8 expansion phase pts at 50 mg/d days 1-10). One patient was enrolled, found to be ineligible, and not treated. The median age was 62 years (range, 28-74), 45% were male and the median number of prior treatments was 2. Three dose limiting toxicities, all due to delayed count recovery past day 45, were observed in the escalation phase (n = 2/6 pts in the 10 mg/d day1-14 dose group and n = 1/6 in the in the 50 mg/d day1-10 dose group). The RP2D of Len in combination with MEC was 50 mg/d on days 1-10. Among the 14 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic including febrile neutropenia (36%). Overall 4 pts including none treated at the RP2D died during treatment. All of the on-treatment deaths, (grade 5 sepsis, n =1; infection, n=1; respiratory failure, n =2), were determined to be unrelated to the study drug. 32 pts were evaluable for response (one pt too early for assessment) with 12 pts achieving a CR and 1 pt a CRi with a total CR/CRi rate of 41% (95% CI: 24-59%). The median time to a neutrophil count of 1500/mL was 30 days and to a platelet count of 100,000/mL was 22 days. Conclusions: Len in combination with MEC re-induction chemotherapy for pts with relapsed or refractory AML was generally well tolerated and associated with an improved response rate as compared to historical controls. The safety profile was consistent with reported events in other MEC chemotherapy trials. Overall, these data suggest further exploration of high-dose Len in combination with MEC. Disclosures DeAngelo: Celgene: Consultancy; Agios: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Off Label Use: lenalidomide in AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Attar:Agios: Employment. Stone:Abbvie: Consultancy; Amgen: Consultancy; Agios: Consultancy; Celator: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Roche/Genetech: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Juno: Consultancy.

Gemtuzumab in Children with Relapsed and Refractory Acute Myeloid Leukemia Treated on Compassionate-Use Basis: A Report of the AML-BFM Study Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1637-1637 ◽  
Author(s):  
Mareike Rasche ◽  
Beate Lerius ◽  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
C. Michel Zwaan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Options ◽  
Refractory Disease ◽  
Compassionate Use ◽  
Advisory Committees ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use. PATIENTS AND METHOD: In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients. RESULTS: Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock. CONCLUSION: To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future. Disclosures Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.

scholarly journals Reduced Intensity Vs. Non-Myeloablative Conditioning Regimens for Haploidentical Transplantation in Complete Remission Acute Myeloid Leukemia: A Study from the ALWP of the EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
Raynier Devillier ◽  
Jacques-Emmanuel Galimard ◽  
Myriam Labopin ◽  
Didier Blaise ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Advisory Committees ◽  
Significant Difference ◽  
Conditioning Regimens ◽  
Conditioning Intensity ◽  
Reduced Intensity

Background: In the context of a haploidentical stem cell transplantation (Haplo-SCT) platform with post transplantation cyclophosphamide (PT-Cy) for acute myeloid leukemia (AML) patients, the optimal conditioning regimen remains unknown. A non-myeloablative conditioning (NMAC) regimen (cyclophosphamide + fludarabine + 2Gy TBI [CyFluTBI]) was initially reported by the Johns Hopkins group as a safe approach in this setting, notably to treat patients of advanced age and/or with comorbid conditions. However, relapse incidence after NMAC Haplo-SCT remains high in AML where it can reach 45%. Alternatively, a reduced intensity conditioning (RIC) regimen containing an antileukemic drug combination like thiotepa and reduced-dose busulfan in addition to fludarabine (TBF) may decrease AML relapse. However, this anticipated benefit may be counterbalanced by a higher incidence of toxicity, graft-versus-host disease (GVHD) and non-relapse mortality (NRM). To date, no study comparing TBF vs. CyFluTBI has been published in complete remission (CR) AML. We performed this retrospective comparison on behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Methods: We retrospectively analyzed 398 patients from the EBMT registry database with the following inclusion criteria: 1) adult patient in CR1 or CR2 AML; 2) T-replete Haplo-SCT with PT-Cy; 3) no in vivo depletion using antithymocyte globulin or alemtuzumab; and 4) receiving either TBF RIC (equivalent of 2-day iv busulfan dose) or CyFluTBI NMAC regimen. We compared separately TBF vs. CyFluTBI in patients younger (n=170, 82 TBF vs. 88 CyFluTBI) and older (n=228, 141 TBF vs. 87 CyFluTBI) than 60 years. Results: In patients younger than 60 years, the 2-year cumulative incidence of relapse (CIR) was significantly lower in the TBF group compared with the CyFluTBI group (TBF vs. CyFluTBI: 14% vs. 43%, p&lt;0.01). No significant increase in 2-year NRM was observed (TBF vs. CyFluTBI: 22% vs. 16%, p=0.15). This led to a significantly higher 2-year leukemia-free survival (LFS) probability in the TBF group (64% vs. 41%, p=0.03). After adjustment in multivariate analysis, CyFluTBI was associated with a higher risk of relapse (hazard ratio [HR] 3.4, 95%CI [1.4-6.9], p&lt;0.01), lower LFS (HR 1.8, 95%CI 1.1-3.0, p=0.03) and lower overall survival (OS) (HR 1.8, 95%CI 1.1-3.1, p=0.02), without significant impact of conditioning regimen on incidence of GVHD and NRM. In patients older than 60 years, univariate analysis did not show any significant difference in outcome according to the type of conditioning regimen (2-year NRM: TBF vs. CyFluTBI: 33% vs. 25%, p=0.23; 2-year CIR: TBF vs. CyFluTBI: 23% vs. 28%, p=0.20; 2-year LFS: TBF vs. CyFluTBI: 44% vs. 47%, p=0.96). Multivariate analysis showed a significant reduction in the risk of NRM after CyFluTBI (HR 0.5, 95%CI [0.2-0.9], p=0.04), while a non-significant increase in the risk of relapse was observed (HR 1.9, 95%CI [0.8-4.2], p=0.13). Finally, there was no significant difference in LFS (HR 0.9, 95%CI [0.5-1.5], p=0.67) and OS (HR 0.9, 95%CI [0.5-1.5], p=0.67). Conclusion: Our study suggests that in CR AML patients aged younger than 60 years, the use of TBF RIC provides better outcomes than NMAC CyFluTBI due to lower incidence of relapse, without significant increase in the risk of NRM. Conversely, it seems that older patients do not benefit from such conditioning intensification, due to a significantly higher risk of NRM after TBF RIC. Thus, in CR AML patients who will not receive a truly myeloablative regimen prior to PT-Cy Haplo-SCT, age could be used for determining the conditioning intensity from the wide variety of reduced toxicity conditioning regimens. Beyond the patient age, further prospective trials should assess patient-based parameters that may be useful for a fine tuning of conditioning intensity in a more individualized approach. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Bug:Sanofi: Other: Travel; Neovii: Other: Travel; Jazz: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hexal: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Mohty:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4432-4432
Author(s):  
Gautam Borthakur ◽  
Brian A. Jonas ◽  
Emily L Roberts-Thomson ◽  
Glenn C. Michelson ◽  
Mark R Bray
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Cancer Center ◽  
Advisory Committees ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in a number of effects including the centrosome amplification often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. A Phase 1 study has been completed evaluating CFI-400945 as a monotherapy in solid tumors, showing a tolerable safety profile and promising signs of activity. Given acute myeloid leukemia (AML) is characterized by genomic instability, CFI-400945 has been evaluated in pre-clinical and clinical studies in AML. In pre-clinical studies, CFI-400945 showed potent activity towards leukemia cell lines and primary human samples in vitro, as well as marked efficacy in two subcutaneous models of leukemia. A prior Phase 1 trial in AML was initiated at the Princess Margaret Cancer Center (PMCC), and of six patients evaluable for response, two (33%) achieved complete remission (CR) at 96 mg and 128 mg, and 3 patients (50%) had stable disease (with one patient having a 78% reduction in marrow blast count) at 64 mg (2 patients) and 96 mg [re: Murphy et al, ASH 2020]. Responses were seen in patients with adverse cytogenetics. The optimal dosing of CFI-400945 and its potential role as a combination agent are not yet clinically defined. Study Design and Methods: The study (TWT-202) has 4 parts, Part 1A (1A): a single agent dose escalation portion, Part 1B (1B): a food effect portion once the MTD of 1A is determined, and combinations with azacitidine (2A), and decitabine (2B). TWT-202 uses an updated version of investigational product which is identical in formulation to the drug used in the PMCC study, but which may result in higher exposures at a given dose. This study will therefore refine the dose through escalation cohorts. For parts 1A and 1B, patients with relapsed and/or refractory AML, MDS, or CMML after &gt;1 prior therapy will be included. Patients with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For parts 2A and 2B, patients should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated patients who decline or are ineligible for intensive therapy may be included. The study will use a standard 3 + 3 design. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose limiting toxicities (DLTs) is &lt;1 out of 6 at highest dose level below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: As of June 21, 2021, 2 patients had been enrolled into the study, one of the patients (50%) received &gt;3 prior therapies (including venetoclax). Neither patient had had stem cell transplant at study entry. Both patients had secondary AML (one with antecedent MDS with excess blasts and the other with CMML). Both patients received 32 mg of CFI-400945 for 21 days followed by a 7-day rest. Both patients completed cycle 1 and neither experienced a DLT. Both patients experienced a single serious treatment emergent adverse event (SAE) of febrile neutropenia each, with neither event considered related to CFI-400945. There were 13 Grade 3 or greater TEAE's, including anemia, thrombocytopenia (3 events each), febrile neutropenia (2 events), agitation, angioinvasive fungal sinusitis, acute kidney injury, hypotension and neutropenia (1 event each). None of the grade 3 or greater TEAE's were considered related to CFI-400945. Neither patient responded to therapy at 32 mg and both came off treatment after one cycle due to progressive disease. PK and PD studies are pending. Conclusion: CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in the Part 1A and Part 1B monotherapy cohorts. Updated safety, efficacy, PK, and PD data for the study will be presented at the time of the meeting. Disclosures Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy. Roberts-Thomson: Treadwell Therapeutics: Current Employment. Michelson: Treadwell Therapeutics: Consultancy. Bray: Treadwell Therapeutics: Current Employment.

scholarly journals Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Norbert Vey ◽  
Corentin Orvain ◽  
Christian Recher ◽  
Arnaud Pigneux ◽  
Marc Bernard ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Risk Groups ◽  
Advisory Board ◽  
Intermediate Risk ◽  
Phase 2 ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
Consolidation Phase

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals RUNX1 Mutation Is Associated with Poor Outcome in Patients with Acute Myeloid Leukemia Receiving Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2052-2052
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Hannah H Asghari ◽  
Jinming Song ◽  
Mohammad Hussaini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Group ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Risk Patients ◽  
Acute Myeloid

Background: Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoiesis, and aberrant expression of this gene can facilitate leukemogenesis. RUNX1 mutations (RUNX1mut) are thought to carry a poor prognosis and have been recently incorporated into the risk stratification systems for acute myeloid leukemia (AML) by European LeukemiaNet (ELN) (Dohner et al. 2017) and National Comprehensive Cancer Network (NCCN et al. 2019). However, the clinical significance of this mutation after allogeneic stem cell transplantation (allo-SCT) is controversial with a recent study suggesting that allo-SCT may reverse the unfavorable influence of RUNX1mut(Qin et al. 2017). In this study, we describe the prognostic impact of RUNX1mutin patients with AML undergoing allo-SCT and compare the outcomes to ELN-defined adverse risk, RUNX1wtAML patients and patients with intermediate risk AML. Methods: We retrospectively reviewed our database of 407 patients who received allo-SCT at the Moffitt Cancer Center between 2013 and 2018. Only AML patients undergoing allo-SCT during first complete remission that had molecular information prior to transplant were included. This cohort was divided into three subgroups: 1) RUNX1mutAML 2) ELN-defined adverse risk, RUNX1wtAML and 3) ELN-defined intermediate risk AML. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Cumulative incidence function was performed as defined by the Fine and Gray model. Kaplan-Meier analysis with log-rank test was used to estimate median overall survival (mOS) from the time of diagnosis. Results: Among 407 AML patients reviewed, we identified 28 patients with RUNX1mut, 71 adverse risk RUNX1wtpatients, and 69 intermediate risk patients. Of the 28 patients (18 males/10 females) with RUNX1mut, 53.6% were under age 60, two-thirds had de novo AML (dAML), and 92.9% had intermediate risk cytogenetics as defined by ELN 2017 at diagnosis. Baseline characteristics are described in Table 1. Univariate analysis identified RUNX1mutto be predictive of inferior OS compared to the intermediate risk cohort (HR 2.29, 95% CI 1.12-4.64, p=0.022). Subsequent multivariate regression using covariates of age, sex, AML type, lines of therapy prior to allo-SCT, and conditioning regimen confirmed RUNX1mutas an independent covariate for reduced OS (HR 2.51, 95% CI: 1.18-5.33, p=0.016). At a median follow-up of 29.3 months for the entire cohort, Kaplan-Meier analysis confirmed an inferior mOS in patients with RUNX1mutcompared to the intermediate risk group (25.7 months vs. 59.8 months, p=0.029) and was not different from RUNX1wtadverse risk group (25.7 months vs. 45.7 months, p=0.872) (Figure 1A). Cumulative incidence of relapse after allo-SCT for patients with RUNX1mutis significantly higher than intermediate risk patients (p=0.005, Figure 1B); however, there was no difference compared to RUNXwtadverse risk AML (p=0.295). There was no difference in non-relapse mortality (NRM) between RUNX1mutand intermediate risk patients (p=0.789, Figure 1B) or RUNX1mutand RUNX1wtadverse risk AML (p=0.323). When impact of concomitant somatic mutations on disease recurrence in RUNX1mutcohort was assessed, no discernible trends were identified. RUNX1mutwas mutually exclusive with NPM1 and frequently co-occurred with DNMT3A (21.4%), IDH2 (17.9%), and SRSF2 (17.9%) (Figure 2). Interestingly, 92.9% of the patients with RUNX1muthad ELN-defined intermediate risk cytogenetics and only 7.1% of the cohort had ELN-defined adverse risk cytogenetics. Conclusions: Our findings indicate that allo-SCT AML patients with RUNX1muthave poor outcomes analogous to RUNX1wtadverse risk AML. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Agios: Honoraria. Kuykendall:Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria; Celgene: Honoraria. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Speakers Bureau; Agios: Consultancy; Incyte: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Agios: 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; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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