scholarly journals Comparative Efficacy Among 3rd Line Post-Imatinib Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients after Failure of Dasatinib or Nilotinib Tyrosine Kinase Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4551-4551 ◽  
Author(s):  
Jeffrey H. Lipton ◽  
Dhvani Shah ◽  
Vanita Tongbram ◽  
Manpreet K Sidhu ◽  
Hui Huang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Comparative Efficacy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract INTRODUCTION Patients with chronic myeloid leukemia (CP-CML) failing 1st line imatinib are most commonly treated with the second-generation (2G) tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib. However, for patients who experience resistance or intolerance (R/I) to 2G-TKIs in 2nd line, there currently is no consensus on the optimal therapy sequence for 3rd line treatment. The comparative efficacy of using ponatinib in the 3rd line after 2G TKI failure was examined in a previous study (Lipton et al., ASH 2013). This study assesses the comparative efficacy of ponatinib versus sequential treatment of alternate 2G TKIs in 3rdline setting in two separate patient populations, post-imatinib and dasatinib patients and post-imatinib and nilotinib patients. METHODS A systematic review was conducted in MEDLINE, EMBASE and the Cochrane Libraries (2002-2014), as well as 3 conferences (ASH (2008-2014), ASCO (2008-2014), and EHA (2008-2013)). Studies evaluating any TKI were included if they enrolled 10 or more post-imatinib adult patients with CP-CML who were also R/I to dasatinib or nilotinib. All study designs were considered and no restriction was applied with respect to therapy dose, due to incomplete reporting of doses in the available studies. Analyses was run on two groups of patients, those failing imatinib and dasatinib (Group Ima/Das) and those failing imatinib and nilotinib (Group Ima/Nil). Bayesian methods were used to synthesize major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) from individual studies and estimate the overall response probability with 95% credible interval (CrI) for each treatment. Bayesian analysis also was used to estimate the likelihood that each treatment offers the highest probability of CCyR/MCyR based on available evidence. RESULTS Six studies evaluating bosutinib, nilotinib and ponatinib for Group Ima/Das (n= 419) and five studies evaluating bosutinib, dasatinib and ponatinib for Group Ima/Nil (n=83) were included in the analysis. All studies reported CCyR in both groups. Five studies evaluating bosutinib, nilotinib and ponatinib reported MCyR in Group Ima/Das and three studies evaluating bosutinib and ponatinib reported MCyR in Group Ima/Nil. Synthesized treatment-specific probabilities and 95% CrI for CCyR are presented in Figure 1. Synthesized treatment-specific probabilities of CCyR for Group Ima/Das were 27% for nilotinib, 20% for bosutinib and 54% (95% CrI 43%% to 66%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Das were 41% for nilotinib, 28% for bosutinib and 66% (95% CrI 55%% to 77%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Das was estimated to be >99% for both CCyR and MCyR. Synthesized treatment-specific probabilities of CCyR for Group Ima/Nil were 25% for dasatinib, 26% for bosutinib and 67% (95% CrI 51%% to 81%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Nil were 33% for bosutinib and 75% (95% CrI 60%% to 87%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Nil was estimated to be >99% for both CCyR and MCyR. CONCLUSIONS The post imatinib and dasatinib group included more studies with larger sample sizes compared with the post imatinib and nilotinib group. Overall, response rates appear higher for TKIs in the post imatinib and nilotinib group compared with the post imatinib and dasatinib group. For both groups, patients on ponatinib had higher CCyR and MCyR rates compared with the sequential 2G TKIs included in this analysis. Based on available data, ponatinib appears to provide a higher probability of treatment response for patients failing imatinib and dasatinib/ nilotinib compared with sequential 2G TKI therapy commonly used in this indication. Figure 1 Figure 1. Disclosures Lipton: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Ariad Pharmaceuticals: Research Funding. Tongbram:Ariad Pharmaceuticals: Research Funding. Sidhu:Ariad Pharmaceuticals Inc.: Research Funding. Huang:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. McGarry:ARIAD Pharmaceutical, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc: Employment, Equity Ownership. Hawkins:Ariad Pharmaceuticals Inc.: Research Funding.

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3768-3768 ◽  
Author(s):  
Richard A. Larson ◽  
Udomsak Bunworasate ◽  
Anna G. Turkina ◽  
Stuart L. Goldberg ◽  
Pedro Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1650-1650 ◽  
Author(s):  
B. Douglas Smith ◽  
Tim H Brümmendorf ◽  
Gail J. Roboz ◽  
Carlo Gambacorti-Passerini ◽  
Aude Charbonnier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Equity Ownership

Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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 Nascent Transcript and Single Cell Rnaseq Analysis Defines the Mechanism of Action of the LSD1 Inhibitor INCB059872 in Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2509-2509
Author(s):  
Gretchen Johnston ◽  
Haley E. Ramsey ◽  
Kristy Stengel ◽  
Shilpa Sampathi ◽  
Pankaj Acharya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Treatment ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Myeloid Differentiation ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Upregulated Genes

Drugs targeting chromatin-modifying enzymes have entered clinical trials for myeloid malignancies, including INCB059872, a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1). LSD1 is a component of the CoREST complex, in which it associates with histone deacetylases 1 and 2, the transcriptional co-repressor, mSin3A or mSin3B, and the REST corepressor (RCOR1), so a role in gene expression was expected. While initial studies of LSD1 inhibitors have suggested these compounds may be used to induce differentiation of acute myeloid leukemia, the mechanisms underlying this effect and dose-limiting toxicities are not well understood. Here, we have used precision nuclear run-on sequencing (PROseq) and single-cell RNA-sequencing (scRNAseq) to show that INCB059872 de-represses GFI1/GFI1B-regulated genes to promote a myeloid differentiation gene signature in AML cells while stalling maturation of megakaryocyte progenitor cells. Within 3 days of treatment with INCB059872, the majority of THP-1, which contain an the MLL-translocation, undergo myeloid differentiation. RNAseq analysis indicated that 24h drug treatment upregulated genes involved in hematopoietic cell lineage, which is consistent with the differentiation. In addition, PROseq was used to measure the effects of INCB059872 on nascent transcription at genes and enhancers, as this is one of the best methods to define enhancer activity. In THP-1 cells after 24h treatment, there were 203 genes with at least a 1.5-fold increase in transcription, while there are nearly 1300 enhancers meeting this threshold. Upregulated genes include those associated with myeloid cell differentiation, such as CSF1R and CD86. Given that LSD1 catalyzes the removal of mono- and di-methyl marks from histone H3, we expected that INCB059872 would cause a buildup of histone methylation. Surprisingly, ChIPseq for H3K4me2 and H3K4me1 showed only subtle changes in these marks after 48h drug treatment in THP-1. Only a handful of LSD1i-induced enhancers overlapped with detectable changes in H3K4 methylation. However, our PROseq data is consistent with the increases in H3K27 acetylation seen with OG86 (a compound that disrupts the LSD1:GFI1 interaction) at GFI1 binding sites (PMID: 29590629). Indeed, motif analysis of INCB059872-upregulated enhancers identified the GFI1 recognition sequence as the most highly enriched. Moreover, siRNA inhibition of key components of LSD1-containing chromatin remodeling complexes pinpointed the CoREST complex as mediating the THP-1 myeloid differentiation effects of INCB059872. To investigate on-target thrombocytopenia seen with LSD1 inhibitors in preclinical studies, we analyzed the bone marrow of wild-type mice treated daily with INCB059872 for 0, 4, or 6 days before harvesting and sorting lin-bone marrow cells for scRNA-seq. Notably, one of the most highly upregulated genes in treated cells was Gfi1b. Unsupervised clustering identified 22 clusters, corresponding to unique subpopulations (Fig. 1A). While the distribution of cells into different progenitor populations was mostly unaffected by drug treatment, these data revealed a striking increase in the proportion of cells from treated mice assigned to a megakaryocyte stem/progenitor cluster. Cells within this expanded cluster expressed stem cell markers such as MYCN and PBX1, but also expressed VWF (Fig. 1B). Thus, LSD1 inhibition caused accumulation of megakaryopoiesis-biased stem cells that failed to mature into efficient platelet producers. Finally, we used scRNAseq to analyze bone marrow from an AML patient who responded to treatment with INCB059872 plus azacytidine (AZA). A pre-treatment bone marrow sample was divided into separate cultures to study the effects of INCB059872, AZA, or the combination. Remarkably, unsupervised clustering of patient cells assigned the majority of INCB059872 and combination-treated cells to clusters that were not found in control- or AZA-treated samples. Cells exposed to INCB059872 had upregulated GFI1 and GFI1B, as well as differentiation-related genes that were also observed in AML cell lines. Overall, these data indicate that INCB059872 affects gene expression with kinetics consistent with a loss of CoREST activity to stimulate differentiation of AML blasts, but the inactivation of GFI1/GFI1B impairs megakaryocyte maturation likely explaining thrombocytopenia seen in preclinical models. Disclosures Stubbs: Incyte Corporation: Employment, Equity Ownership. Burn:Incyte: Employment, Equity Ownership. Hiebert:Incyte Corporation: Research Funding. Savona:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; AbbVie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Patients' Perspectives on the Definition of Cure in Chronic Myeloid Leukemia: A US Based Survey

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5843-5843
Author(s):  
Gemlyn George ◽  
Ehab L. Atallah ◽  
Michael J. Mauro ◽  
Stuart L. Goldberg ◽  
Arielle Baim ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Online Survey ◽  
Oral Medication ◽  
Future Research ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: The development of tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of patients (pts) with chronic myeloid leukemia (CML), with the perception by healthcare professionals that this is now a chronic disease to be managed. However, the need for continuous TKI therapy may result in ongoing toxicities, limits on fertility, and financial hardship. The H. Jean Khoury Cure CML consortium (HJKC3) is a collaborative effort of physicians and researchers at 17 academic centers. The HJKC3-001 2017 Patient Survey sought to define pts' expectations for treatment in CML to serve as a guidepost for future research in this area. Methods: Pts with CML were recruited by HJKC3 physicians, CML advocacy groups, and social media. An online survey platform (Qualtrics®) was used to obtain informed consent and administer the questionnaire. The anonymous survey was designed to gauge priorities for research in CML, understand patient definitions of cure, and elicit patient interest in future directions for CML therapy. Patient demographic and health characteristics were also collected. The data were analyzed using descriptive statistics. Results: Of the 458 pts who completed the survey, the median age of respondents was 54 years (range 18-81); 88% of pts identified as non-Hispanic white, 2% as non-Hispanic black, 2% as non-Hispanic Asian, 4% as Hispanic, and 4% other. Patients rated their overall health as poor (4%), fair (18%), good (40%), very good (28%) and excellent (9%). All but one respondent said that more research was needed for CML, with pts indicating their preferences for where they considered the need was greatest (Table 1). Overwhelmingly, 94% of respondents considered cure in CML as not taking any more pills. All but three respondents had received treatment with a TKI, with 26% (n=119) of pts having previously stopped their TKI medication for at least one month. When presented with the possibility of stopping all future treatment for CML with additional treatment, 97% of pts were willing to add another oral medication to their TKI while 89% of pts would accept intravenous treatment in addition to a TKIs. Half of the pts had discussed treatment discontinuation with their physician, with 45% considering this option in an attempt at treatment-free-remission. Of the pts that stopped taking their TKIs for at least one month, 65% did so because of side effects and another 10% because of cost. Conclusion: This survey demonstrates that pts do not consider disease control with life-long oral medication as cure; rather, cure requires the absence of treatment. Overwhelmingly, pts indicated the importance of continuing CML research with an ultimate goal of treatment-free cure. The advent of oral TKIs has been a tremendous success for pts with this disease. Nevertheless, it remains a source of disruption in pts' lives, particularly through side effects and costs. The HJKC3 was initiated with the goal of curing CML. Disclosures Atallah: Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Abbvie: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding. Goldberg:COTA Inc.: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Druker:ARIAD: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Henry Stewart Talks: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; McGraw Hill: Patents & Royalties; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Oregon Health & Science University: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Celgene: Consultancy. Larson:Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ritchie:Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria.

A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 163-163 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp le Coutre ◽  
Ron Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Treatment Options ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2510-2510 ◽  
Author(s):  
Tara L. Lin ◽  
Laura F. Newell ◽  
Robert K. Stuart ◽  
Laura C. Michaelis ◽  
Stephen E. Rubenstein ◽  
...  
Keyword(s):  
Renal Function ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Dose Adjustment ◽  
Cardiac Repolarization ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar ratio. It is highly effective in patients with high-risk acute myeloid leukemia (AML). This study evaluated the impact of CPX-351 (100 units/m2) on cardiac repolarization. Methods: This open-label, Phase II, pharmacokinetic (PK) and pharmacodynamic (PD) study entered AML and acute lymphocytic leukemia (ALL) patients with good risk hepatic function (Child-Pugh scores <7), and normal cardiac function (LVEF≥50%, QTcF<470 ms). Cardiac repolarization changes were assessed using conventional ECG and Holter monitor recordings. PK was assessed during the first 21 days for total cytarabine, daunorubicin, Ara-U and daunorubicinol. The relationship between CPX-351 PK, QTcF, and renal function using the equation to calculate the estimated glomerular filtration rate (eGFR) was evaluated. Results: Twenty-six patients entered the study and 21 were evaluable for QT interval change from baseline. Evidence that CPX-351 prolongs the QTcF interval was not observed. The largest absolute and mean change from time-matched baseline was 12.56 and 8.03 ms, respectively (Day 1, hour 4). Mean QTcF change on Day 5 was unchanged from baseline. QTcF intervals >480 ms were never observed and no consistent QTcF intervals >450 ms were noted. Absolute QTcF increases between 30 and 60 ms were present in 4 of 25 patients and no changes >60 ms were observed. CPX-351 plasma concentration vs. time curves for day 1 and 5 exhibited a volume of distribution approximately equal to the plasma volume with prolonged single-exponential elimination half-lives for cytarabine and daunorubicin of ≥24 hours. The PK of CPX-351 was independent of renal function. Patients with moderately impaired (eGFR=30-59 mL/min/1.73m2) renal function exhibited similar drug exposure as those with mild and normal renal function. Table 1. Impact of renal function impairment on Day 5 CPX-351 PK parameters (mean, %CV): Analyte Renal Function Cmax (ng/mL) AUClast (ng*hr/mL) AUCinf (ng*hr/mL) T1/2 (hr) Cytarabine Normal (n=3) Mean 59333 2893146 2902641 42.5 %CV 28.7 68.8 69 34.1 Mild (n=7) Mean 58071 3599512 3606695 41.0 %CV 31.9 52.4 52.4 21.8 Moderate (n=3) Mean 57333 3149303 3156738 38.0 %CV 46.6 50.7 50.6 21.9 Daunorubicin Normal (n=3) Mean 25967 754646 870861 24.9 %CV 23.1 63 65.3 56.0 Mild (n=7) Mean 28686 865034 1021420 30.5 %CV 43.9 43.5 43.6 25.3 Moderate (n=3) Mean 21933 671542 814732 35.4 %CV 50.9 35.9 33.5 31.2 Table 2 summarizes response and transplant outcomes. One of two ALL patients achieved CR and was transplanted. Among AML patients there were 7 CR and 2 CRi of which three went on to transplant. An additional four patients became morphologically leukemia free (MLF) and were transplanted before full documentation of CR was achieved. A large majority of patients given first-line treatment with CPX-351 responded or became suitable for transplant (10/13, 77%). Table 2. 206 Study Efficacy Diagnosis n ResponseCR/CRi Transplanted in CR/CRi Induced MLF and Transplanted No Response ALL-Relapsed 2 1/0 1/0 0 1 AML-First Line de novo 8 5/0 0 1 2 AML-First Line sAML 5 1/2 1/1 1 1 AML-Salvage 11 1/0 1/0 2 8 Conclusions: Clinically relevant prolongation of QTcF is not a feature of CPX-351 treatment. CPX-351 exposure was independent of renal function, indicating no need for dose adjustment when renal function is impaired. The high rate of complete remission and referral for transplant corroborate the high level of efficacy observed in earlier studies with CPX-351. Disclosures Stuart: Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Pentikis:Celator Pharmaceuticals: Consultancy. Alvarez:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Mayer:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership.

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase According to Reasons for Switching from Imatinib to Nilotinib: Subgroup Analysis from ENESTop

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 792-792 ◽  
Author(s):  
Timothy P. Hughes ◽  
Carla Maria Boquimpani ◽  
Naoto Takahashi ◽  
Noam Benyamini ◽  
Nelma Cristina D Clementino ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Loss Of Response ◽  
Equity Ownership ◽  
Treatment Free Remission

Abstract Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.

Inecalcitol, a Novel Adjuvant Therapy Inhibiting Chronic Myeloid Leukemia (CML) Stem Cells, Activates a Macrophage Differentiation Pathway in Leukemic Progenitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4020-4020
Author(s):  
Christophe Desterke ◽  
Hyacinthe Johnson-Ansa ◽  
Patricia Hugues ◽  
Jean Francois Dufour-Lamartinie ◽  
Remi Delansorne ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
P Value ◽  
Employment Equity ◽  
Macrophage Differentiation ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Abstract Despite the major success obtained with their use in chronic myeloid leukemia (CML), recent data obtained from treatment discontinuation trials suggest that tyrosine kinase inhibitors (TKI) alone are not sufficient to eradicate the most primitive CML stem cells in the majority of the patients. The mechanisms of this inefficiency might involve cell autonomous (activation of alternate signaling, reduced BCR-ABL expression) or non-cell autonomous (niche-related) pathways. Several strategies of targeting the primitive stem cell compartment, in association with TKI, are currently being studied. Inecalcitol (ICC) is a vitamin D3 analog exerting antiproliferative effects in several types of cancer cells. ICC was tested in CD34+ cells isolated from CML patients at diagnosis (n=18) in clonogenic assays as well as in the more primitive LTC-IC-derived progenitors. ICC alone inhibits the clonogenic growth in the majority of the CML patients at diagnosis (15/18 patients). The combination of ICC with either, Imatinib (IM), Dasatinib (DA) or Nilotinib (NIL) in clonogenic assays showed a synergistic effect for the inhibition of CFC growth (10-25% CFC survival) with no toxicity on normal progenitors. Synergistic effects of ICC and TKI was also demonstrated in LTC-IC-derived progenitors with IM, NIL and DA. To determine possible mechanism of action of ICC in CML stem cells, we have performed a gene profiling analysis of CD34+ cells obtained at diagnosis from 4 CML patients. CD34+ cells were cultured for 7 days in the presence of growth factors with or without ICC. In phenotypic analyses, CD34+ cells treated in the presence of ICC showed an increase of monocyte/macrophage differentiation features with increased expression of CD13/CD14 as well as CD11b expression. Day 0 and Day7 RNA with or without ICC treatment were then studied by transcriptome hybridation on human-v2 (8*60k) Agilent technologies microarrays. Data were treated with Feature Extraction 11.5.11, Genespring GX12, Mev 4.9, R software and GSEA 2.2.20. Gene set enrichment analysis performed at day 7 of culture between ICC condition and control untreated cells showed an increase of cell differentiation markers under ICC (Normalized enrichment score = +1.94, p-value < 0.001) One way ANNOVA with False Discovery Rate (FDR) correction allowed to discover 7176 modulated probes between the 3 experimental conditions (Day 0, Day7 without ICC, Day 7 with ICC). CYP24A1 was the gene with the greatest induction by the treatment (Fold Change = +150). CYP24A1 is responsible of the degradation of 1.25(OH)2D3 by the monocyte/macrophage cells. Unsupervised classification with 372 macrophage connected genes (ANOVA p<0.01, FDR with 1000 permutations) allowed to separate samples by their experimental classes. This macrophage expression profile allows to discriminate samples from Day7 control to those of treated cells at the same time on hierarchical classification. This was confirmed by first factorial map of principal component analysis which explained 72% (PCA1 axis) hematopoietic differentiation during 7 days and 10% (PCA2 axis) effect of the treatment at the end of the differentiation. 23 macrophagic genes were indeed found to be specifically induced by the treatment with a fold change greater than 2 as compared to the untreated control: 11 of them participate to integrin-interleukins-chemokines signalizations pathways (p-value adjust FDR = 4.04e-10). Some macrophagic ligands and receptors are over-expressed in CML cells treated with ICC, including CSF2, OSM, TNFSF11, CXCL12 as well as FAS and CXCR2. In summary, these results suggest that one of the major mechanisms of action of ICC in the leukemic progenitors involve differentiation and activation of macrophagic expression profile. This profile could be used to design further therapeutic actions and to predict response to ICC, which is now tested in combination with IM in a clinical trial in France. Disclosures Dufour-Lamartinie: Hybrigenics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Delansorne:Hybrigenics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Turhan:Bristol Myers Squibb: Consultancy; Novartis: Research Funding.

scholarly journals Outcomes of Chronic Phase Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitors Dose-Reductions

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3093-3093
Author(s):  
Jee Hyun Kong ◽  
Hanna Jean Khoury ◽  
Elliott F. Winton ◽  
Leonard T. Heffner ◽  
Manila Gaddh ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Advisory Committees ◽  
Society Research

Abstract Introduction: Tyrosine kinase inhibitors (TKI) are overall well tolerated in chronic myeloid leukemia (CML) s, but more than 30% require dose reduction or change to another TKIs due to intolerance. Impact of TKI dose-reduction on outcomes in a "real world" setting is unknown, thus, we evaluated the characteristics and outcomes of chronic phase (CP)-CML patients who received doses of TKI lower than the label/FDA recommendation. Method: CP-CML with at least 12 months of follow-up, with ISBCR/ABL1 available after dose reduction were selected. Last TKI was defined as TKI which were taken at the last follow up visit or before disease progression to accelerated (AP) or blast phase (BP). FDA approved doses of imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) were 400mg, 100mg, 600mg (300mg BID), 500mg, and 45mg, respectively . Results: Between January 2005 and April 2016, 173 CP-CML patients, started IM (75%), DAS (18%) NIL (5%) and PON, BOS on clinical trial in 2%. Overall Fifty-eight (33.5%) patients had TKI dose reduction. IM (n=15) dose was reduced to 75% (range, 25-75), DAS (n=15) to 50% (range, 20-80), NIL (n=15) to 50% (range, 13-67), BOS (n=15) to 80% (range, 40-80) and PON (n=15) to 33% (range, 33-67). Median age for patients that received dose-reduced TKI was 55 (range, 18-88), and 27% received > 3 prior TKIs. With a median follow up of 53.6 (range 13.4-183.7) months, only 1 progressed to AP, and none to BP. Overall 60% achieved MMR. Among 35 patients who achieved MMR before dose reduction, MMR was maintained in 25 (71.4%) for a median of 17.2 (2-97.9) months from dose-reduction. CMR was achieved in patients on a maintenance dose of IM, 100mg QD (n=8); DAS, 20mg QD (n=4); NIL 300mg QD (n=3) and BOS, 200mg QD (n=3). Conclusion: Similar to data reported from clinical trials, TKI dose reduction appears to be safe and associated with high response rates. This data confirms that the minimal effective dose for each TKI remains to be defined. Disclosures Heffner: Pharmacyclics: Research Funding; AbbVie: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding. Kota:Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Sign in / Sign up

Export Citation Format

Share Document