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In: Rheumatology, Oxford University Press (OUP), Vol. 53, No. 12 ( 2014-12-01), p. 2314-2315

Type of Medium: Online Resource

ISSN: 1462-0332 , 1462-0324

URL: Article

DOI: 10.1093/rheumatology/keu374

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2014

detail.hit.zdb_id: 1474143-X

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3975-3975

Abstract: Background: The incorporation of intensive chemotherapy, hematopoietic stem cell transplantation (HSCT), targeted therapies including rituximab and tyrosine kinase inhibitors contributes substantial improvement in the outcome of patients with ALL over decades. VAD was changed to hyper-CVAD in 1992; rituximab was added to hyper-CVAD for CD20 positive ALL in 1999/2000; inotuzumab ozogamicin in combination with low-intensity chemotherapy was offered to elderly patients starting in 2011. The aim of this study is to describe the outcome of patients with ALL over decades by age groups. Methods: From 1980 to 2016, patients with newly diagnosed ALL at our institution were analyzed. Burkitt leukemia was excluded from our analysis. Patients were divided into age groups as follows: age 15-39, age 40-60, and age 〉 60. Patients were subsequently divided into diagnostic year cohorts by decade: 1980-1989, 1990-1999, 2000-2009, and 2010-2016. Overall survival was defined as time interval from diagnosis to the date of death regardless of any cause. Kaplan-Meier method with a log-rank test was used for survival comparison between cohorts. Stepwise multivariate analysis with Cox proportional hazards model was used to evaluate the impact of diagnosis year on OS. P-values were two-sided, and a p-value less than 0.05 was considered statistically significant. Results: Overall, 972 patients were identified and analyzed in our study. Median age at diagnosis was 39.5 years (range, 16-92) with a median follow-up of 10.4 years (range, 0.0-31.3). Patients were divided into 486 patients (50%) in the age 15-39 category, 301 patients (31%) in the age 40-60 category, and 185 patients (19%) in the age over 60 category. Baseline patient characteristics are summarized in Table 1. Overall, the median OS durations were 4.5 years, 2.8 years, and 1.3 years in age 15-39, age 40-60, and age 〉 60, respectively (p 〈 0.001; p 〈 0.001). Of the 486 patients in age 15-39, the improvement in OS was observed from 1980-1989 to 1990-1999 (p 〈 0.001); of the 301 patients in age 40-60, from 1980-1989 to 1990-1999, and from 1990-1999 to 2000-2009 (p=0.042; p=0.003); of the 185 patients in age 〉 60, from 2000-2009 to 2010-2016 (p=0.039). Stepwise multivariate analysis identified leukocytosis, thrombocytopenia, hypoalbuminemia, elderly age, poor performance status, lack of complete response, and diagnostic year as adverse prognostic factors for OS. Each year since 1980 had an impact on OS with hazard ratio of 0.961 (95% confidence interval, 0.951-0.971; p 〈 0.001). Conclusion: Patients with ALL have significant improvement in OS throughout all ages over decades. However, the decade time points of improvement in OS were different between age cohorts. Different treatment strategy and clinical trial designs by each age group are needed for further improvement in patient's outcome. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Pemmaraju:incyte: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; cellectis: Consultancy, Research Funding; affymetrix: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding. Jain:Genentech: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Servier: Consultancy, Honoraria; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3975.3975

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4375-4375

Abstract: Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to promote cell death in various cancer cells, including malignant human hematopoietic cells. The novel, proteasome inhibitor carfilzomib is an attractive candidate for combination regimens due to diminished neurotoxicity, irreversible proteasome inhibition, favorable tolerability profile relative to bortezomib, and preclinical and clinical evidence of activity in bortezomib-resistant cells and patients. Preclinical studies demonstrated synergistic interactions between carfilzomib and vorinostat in human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells both in vitro and in vivo as well as in bortezomib-resistant cells (Dasmahapatra et al., Blood 115:4478; 2010; Mol Cancer Ther 10:1686, 2001). These preclinical findings prompted a phase 1 trial, using a 3+3 design, with the goal of determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the combination of carfilzomib and vorinostat in patients with recurrent or refractory B-cell lymphomas. Eligible patients included those with recurrent or refractory non-Hodgkin’s lymphoma. The schedule of administration was vorinostat orally twice-daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Initial dose levels were 20/27 mg/m2 (carfilzomib) and 200 mg (vorinostat). To date, 20 patients have been treated at 4 dose levels. Patient characteristics included the following disease types: DLBCL, n = 6; follicular lymphoma, n = 2; MCL, n = 10; and transformed lymphoma, n = 2. The male to female ratio was 14:6, the median age was 67 years (range: 36-79), ECOG performance scores ranged from 0 to 2, and the median number of prior therapies was 3.5 (range: 1-13). Dose-limiting toxicities (DLTs) and adverse events were determined using CTCAE version 4. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment occurring in ≥ 5% of patients included anemia (grade 3, 15%), leukopenia (grade 4, 10%; grade 3, 15%), lymphopenia (grade 3, 10%), neutropenia (grade 4, 5%; grade 3, 25%), thrombocytopenia (grade 3, 10%), catheter-related infection (grade 3, 5%), dyspnea (grade 3, 5%), fatigue (grade 3, 5%), febrile neutropenia (grade 3, 5%), hypokalemia (grade 3, 5%), hyponatremia (grade 3, 5%), lymph node pain (grade 3, 5%), and pneumonitis (grade 3, 5%). Two grade 5 events were observed; 1 was attributed to disease progression and not related to study treatment; 1 was attributed to pneumonia possibly related to treatment. Common grade 2 AEs possibly, probably or definitely related to treatment in ≥ 15% of patients included anemia (25%), diarrhea (15%), fatigue (20%), hyperglycemia (15%), hypokalemia (15%), nausea (15%), neutropenia (15%), thrombocytopenia (20%), and vomiting (15%). There were 2 DLTs at dose level 1, grade 3 pneumonitis and febrile neutropenia, and there were no DLTs at dose level -1 (carfilzomib 20/20 mg/m2 and vorinostat 100 mg twice daily). Two intermediate dose levels (-1a and -1b) were added between dose-levels 1 and -1. No DLTs or significant differences in toxicities were observed at dose levels -1a and -1b. Consequently, two MTD/RP2D levels have been identified: carfilzomib 20/20 mg/m2 and vorinostat 200 mg twice daily (level -1a) and carfilzomib 20/27 mg/m2 and vorinostat 100 mg twice daily (level -1b). All 20 patients treated were evaluable for response. The best response on this phase 1 study was 1 partial response; 2 patients had stable disease. Correlative studies evaluating pre- and post-treatment plasma levels of IL-10 and TNF are currently undergoing analysis. Collectively, these findings indicate that the combination of carfilzomib and vorinostat is reasonably tolerable in this patient population. Two dose levels have been identified for the MTD/RP2D. The regimen appears to have modest activity in heavily pre-treated patients with relapsed and/or refractory B-cell lymphomas. Disclosures: Friedberg: Merck & Co.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.4375.4375

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1127-1127

Abstract: Background: AZA is a DNA methyltransferase (DNMT) inhibitor with a modest response rate (20-25%) and duration (Å4 months) in MF. Ruxolitinib and azacytidine may target distinct clinical and pathological manifestations of myelofibrosis. Aim:To determinethe efficacy and safety of the combination in pts with MF requiring therapy(ClinicalTrials.gov Identifier: NCT01787487). Methods:A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets 〉 200) continuously in 28-day cycles for the first 3 months followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. Pts would be treated on study for 15 months followed by continuation of the combination off-study at the discretion of the treating physician. Results: 41 pts were enrolled between March 1, 2013 and June 30, 2016. Baseline characteristics are shown in table 1. 23 (56%) had received a median of 2 (range, 1-3) prior therapies for MF. 27 pts remain alive after a med follow-up of 20.4+ months (range, 0.5-37.3+). 39 pts were enrolled before January 1 2016 and are evaluable for response. International Working Group for Myelofibrosis Research and Treatment 2013 (IWG-MRT)objective responses were noted in 27 (69%), including PR in 2 (5%), CI for spleen and total symptom score (TSS) in 7 (18%), CI for TSS and hemoglobin in 2 (5%), CI for spleen only in 7 (13%), and CI for TSS only in 9 (21%). Ten (26%) pts had no IWG response and 2 (5%) pts had progression to AML on therapy. Three ptshave achieved a complete cytogenetic remission (baseline cytogenetics were +8 in two and del 20q in one). Responses occurred in 14 of 23 (61%) previously treated patients and 13 of 16 (81%) untreated pts (P=0.57). Median time to all responses was 1.0 month (range, 0.7-19.3 months). Median time to CI in spleen size was 1.8 months (range, 0.9 - 16.8), to CI TSS was 1.8 months (range, 0.7-15.8), CI Hb was 5.8 months (range, 1.1-14.7), and cytogenetic remission was 5.5 months (5.4-5.5). 29 pts had a baseline spleen ³5 cm and 14 (48%) achieved 〉 50% palpable spleen length reduction at 24 weeks and 23 (79%) achieved 〉 50% palpable spleen reduction at any time on study. 6/23 (26%) of the 〉 50% palpable spleen reductions occurred after the addition of azacytidine. Among the 29 pts with baseline spleen ³5cm best spleen response included: 50-100% reduction in 23 (79%), 25-49% reduction in 4 (14%), no reduction in 2 (7%). Serial JAK2 allele burden assessment was available in 15 of 17 JAK2 mutated responders. A reduction in the baseline JAK2V617F allele burden was noted in 13 of 15 (87%) serially evaluable responders with a median V617F allele burden reduction of 21% (range, 1-82%). Serial evaluation of bone marrow fibrosis was available in all 27 responders and revealed a reduction in EUMNET fibrosis score in 11 (41%) responders, including ³2 grade reduction in 2 pts and 1 grade reduction in BM fibrosis in 9pts with a median time to fibrosis improvement of 13.2 months (range, 5.1-13.2). Three pts experienced grade 3/4 non-hematological toxicity including fatigue (n=2), nausea (n=1), and pneumonia (n=1). New onset grade 3/4 anemia and thrombocytopenia were seen in 25 pts [61%; of which 7 (17%) had a 2+ grade change] and 11 (27%) pts, respectively. The med overall survival is 38.7+ mos. The AZA was administered in 34 (83%)pts: as planned in cycle 4 in 28pts(63%), earlierdueto increased blasts in 1pt, and later in 5pts[cycle 5 (n=2), cycle 7 (n=2), cycle 9 (n=1)]. Twoptsprogressed before starting AZA and 3 never started AZA due to prohibitive cytopenia. Twoptsare too early to start AZA. Six of 34 (18%)ptswho started AZA have required discontinuation of AZA: low platelets (n=3), fatigue (n=2), and low ANC (n=1). Twenty fourpts remain on study. Reasons for discontinuation in 17 pts included stem cell transplant (n=6), lack of response (n=3), AML (n=2), toxicity (n=3), death (n=1), patient preference (n=2). Fourteen pts have died: AML (n=4), pneumonia (n=3), unknown cause (n=3), sepsis (n=2), post SCT complications (n=1), and other cancer (n=1). Conclusion: Concomitant RUX with AZA was feasible and resulted ina IWG-MRT response rate of 69%. The 〉 50% spleen length reduction at 24 weeks and at any time on study were superior to single agent RUX and 26% of the spleen reductions occurred after addition of AZA. This combination warrants further evaluation on a large scale. Disclosures Daver: Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Verstovsek:Celgene: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1127.1127

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 478-478

Abstract: Introduction: Anemia is common in MPN-associated myelofibrosis (MF), and current therapies (e.g., erythropoiesis stimulating agents, androgens, danazol, immune modulatory drugs and corticosteroids) are unsatisfactory. Furthermore, anemia is not improved and initially worsened by ruxolitinib, an important MF therapy. New drugs with novel mechanisms of action are needed. Sotatercept is a first-in-class activin receptor type IIA (ActRIIA) ligand trap consisting of the extracellular domain of ActIIRA linked to the human IgG1 Fc domain. Sotatercept binds to and sequesters ligands of the transforming growth factor beta (TGF-ß) superfamily, thus relieving their blockade of terminal erythroid differentiation. Pre-clinically, sotatercept corrects ineffective erythropoiesis in ß-thalassemia (Dussiot, M. et al. Nat Med 2014) and its murine ortholog RAP-011 improves erythropoiesis in Diamond Blackfan anemia (Ear, J. et al. Blood 2015). Clinical trials in persons with lower risk myelodysplastic syndromes (Komrokji, R. et al. ASH 2014) and chemotherapy-induced anemia (Raftopoulos, H. et al. Support Care Cancer 2016) have shown promising results. Methods: This is an ongoing phase-2 study of sotatercept, 0.75 or 1 mg/kg subcutaneously every 3 weeks (1 cycle), in subjects with MF, whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). Subjects must be RBC-transfusion-dependent (Gale, R.P. et al. Leuk Res 2011), have hemoglobin 〈 10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin 〈 10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Primary endpoints include anemia response and safety. Secondary endpoints include time to and duration of anemia response. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response. Results: 18 subjects are enrolled to date. 1 subject received 6 cycles at a sub-therapeutic dose of 0.3 mg/kg and was not considered for efficacy evaluation, but was evaluable for safety. Of the remaining 17 subjects, 11 received 0.75 mg/kg and 6, 1 mg/kg. Median age was 67 years (range, 47-84 years); 10 were male and 7 female. 14 had PMF and 3, post-ET MF. 12 subjects had JAK2 V617F, 1 had MPLW515L and 2 had CALR exon 9 mutations. 1 subject was triple negative and 1 subject had no JAK2 or MPL mutation but was not tested for CALR mutations. All 17 subjects had intermediate-2 or high risk disease by the Dynamic International Prognostic Scoring System. Table 1 summarizes baseline variables for these 17 subjects. Median number of cycles of sotatercept received is 5 (range, 1-13). 14 of the 17 subjects received ≥5 cycles and were evaluable for response. The 3 other subjects received 1, 2 and 2 cycles and discontinued due to unrelated medical problems, hypertension and stem cell transplant (SCT), respectively. 5 of 14 (36%) evaluable subjects have responded; 4 of whom continue on study in ongoing response. All responders are female and all female subjects evaluable for response responded. Responses occurred across phenotypic driver mutation categories and in both transfusion-dependent (n=3) and -independent (n=2) subjects. 40% and 25% of evaluable patients responded in the 0.75 mg/kg and 1 mg/kg dose cohorts, respectively. Most adverse events (AEs) were grades 1 or 2. The only AEs possibly attributable to sotatercept include grade 3 hypertension leading to discontinuation, and grade 1 myalgia, bone pain, pain in extremity and injection site reaction. 5 subjects remain on study. 12 have discontinued because of no response (5), SCT (2), unrelated medical problems (1), hypertension (1), disease progression (1), transformation to AML (1) and withdrawal of consent (1). Conclusion: Sotatercept improves anemia and RBC-transfusion-dependence in persons with MF and is well-tolerated. Enrollment to the trial is ongoing; updated results will be presented. A separate cohort of subjects receiving ruxolitinib has been added and will also be discussed. Based on the preponderance of responses at the 0.75 mg/kg dose, this dose has been selected for the combination cohort. Disclosures Daver: Incyte: Consultancy, Other: Advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.478.478

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3105-3105

Abstract: Background: There is no standard therapy for patients (pts) with intermediate (Int)-2 or high risk myelofibrosis (MF) who have failed or are intolerant to Janus kinase (JAK) inhibitors such as ruxolitinib. Second mitochondria-derived activator of caspases (SMAC) mimetics, or inhibitors of apoptosis (IAP) antagonists, lead to increased apoptotic cancer cell death, especially in high TNFα-expressing tumor models. An emerging concept in myeloproliferative neoplasm (MPN) tumor pathobiology is the finding of significantly increased levels of TNFαin pts with MF(Fleischman AG et al, Blood 2011). Objectives: Primary objective: to determine efficacy (IWG-MRT, 2013) of LCL161 as monotherapy for pts with MF. Secondary objectives: to determine safety, durability of response, and changes in symptom burden [Myeloproliferative Neoplasm (MPN)-Total Symptom Score]. Exploratory objectives: to assess JAK2V617F and CALR allele burden; 28-gene panel for molecular mutations via next generation sequencing; and markers of IAP pathway degradation. Methods: We conducted an investigator-initiated, single-center, phase II study of LCL161 for pts with MF in a Simon's Optimal two-stage design. Pts age ≥18, PS=0-2, Int to high risk MF, who were intolerant to, ineligible for, or relapsed/refractory to JAK inhibitors were eligible. There was no threshold requirement for spleen size or platelet (plt) count, and pts with prior allogeneic stem cell transplant (SCT) were eligible. LCL161, an oral (po) drug, was given at starting dose 1500mg po once weekly. Each cycle=28 days. After 3 cycles, bone marrow exam and objective response assessments were performed. Results: From January 2015 to July 2016, 21 pts have been enrolled. Baseline characteristics: Median Age: 72 years [56-81], 86% with primary MF. Baseline laboratory values: Hb 9 g/dL (6.3-12); WBC 5.3 K/uL [1.1-38] ; platelets 45 K/uL [6-1365]. JAK2V617F mutations were present in 14(67%), CALR mutations in 3(14%), and MPLW515L mutation in 1(5%) pt. Additionally, the most common other molecular mutations were: TET2(n=4); DNMT3A(n=3); RAS(n=1); EZH2(n=1). 17 (81%) had ≥2 prior therapies. Most common prior therapy was a JAK inhibitor (67%). 2 pts had prior SCT. By IPSS, 14 (67%) were high risk MF; 6(28%) were Int-2. Median number of cycles received=3[1-19] , median treatment duration=2.8 months (mos)[0.2-16.7]. 19 pts are alive, with median follow-up of 7 mos[0.2-17.7] . Among 21 pts, 5 have been recently enrolled and have not yet reached 12-week evaluation period; among 16 evaluable pts, 6 pts had 9 objective responses (3 pts achieved 2 separate IWG-MRT 2013 response categories): Clinical improvement (CI) (anemia) in 2 pts; CI (Symptom) in 5 pts; CI (Spleen) in 1 pt; Cytogenetic remission in 1 pt. Grade 3/4 non-hematologic adverse events: syncope, n=2. No pts had cytokine release syndrome. Most common grade 1/2 non-hematologic toxicities: fatigue (n=10), nausea (n=10), dizziness/vertigo (n=9). Dose reductions: 7 pts: 6 pts to dose -1 level (1200 mg po once weekly) and 1 pt to dose -2 (900mg po once weekly); importantly, the most common reason was due to grade 2 fatigue (n=6). 10 pts are now off study [n=5 no response; n=3 toxicity; n=1 transformation to AML; n=1 patient on study proceeded to SCT]. Preliminary, ongoing correlative studies demonstrate on-target inhibition (by Western blot) of CIAP1 in eight pts: strong (n=4) or moderate (n=4); among the 6 clinically responding pts, 4 of 4 of these pts with viable/available samples for analysis demonstrated strong on-target CIAP1 inhibition. Conclusions: In this study, in a cohort of older pts with MF, 67% IPSS high risk, with median plt count of 45 at study entry, in whom 81% had received ≥2 prior therapies, we have observed objective responses in 38% (6/16 evaluable for response). LCL161 has a convenient (po, weekly) dosing schedule, represents a novel target for pts with MPNs, and is able to be administered to pts who have failed or intolerant/ineligible for JAK inhibitor therapy. Notably, grade 2 fatigue was commonly observed, and represents the most common reason for dose reduction and study discontinuation. Based on early responses observed, this study has met criteria for the pre-planned analysis for efficacy (Simon Stage 1) and therefore is able to proceed to Simon Stage 2. This clinical trial is registered at www.clinicaltrials.gov/ct2/show/NCT02098161. Disclosures Carter: PRISM Pharma/Eisai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Bose:Novartis: Research Funding. Verstovsek:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3105.3105

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2959-2959

Abstract: Abstract 2959 Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell cycle and survival signaling pathways. We have previously reported that the cyclin-dependent kinase inhibitor alvocidib interacts with bortezomib, a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene 22:7108, 2003; Dai et al, Blood 104:509, 2004). These actions were associated with inhibition of NF-κB DNA binding, increased expression of pJNK, and down-regulation of XIAP and Mcl-1. Based on these findings, a phase I trial was initiated in which bortezomib was administered in conjunction with alvocidib on the same days, according to 2 separate schedules: a “hybrid” infusion schedule (half the dose over 30 minutes and half over a 4-hour infusion); and a bolus infusion schedule in which alvocidib was administered over 1 hour. Results of the hybrid infusion schedule have recently been reported (Holkova et al, Clin Cancer Res 17:3388, 2011). The primary objective was to identify the maximum tolerated doses (MTDs) for the combination in the treatment of recurrent or refractory indolent B-cell neoplasms. Eligible patients included those with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL), with recurrent or refractory disease following at least 1 prior systemic therapy. To date, 43 patients have been treated at 9 dose levels. Patients with the following disease types have been treated: MM n=25 (Waldenstrom's macroglobulinemia n=2), NHL n=18 (mantle cell lymphoma n=5). The male:female ratio was n = 31 (72%):12 (28%); the median age was 65 (range: 40–79) years; ECOG performance scores ranged from 0–1; and the median number of prior therapies was 3 (range: 1–10). The schedule of administration was bortezomib via intravenous push over 3–5 seconds followed by alvocidib via intravenous 1-hour infusion on days 1, 4, 8, and 11; on a 21-day cycle, with indefinite continuation for responding patients and those with stable disease. Adverse events (AEs) were evaluated using CTCAE version 4. Dose limiting toxicities (DLTs) observed to date are shown in Table 1. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment tht occurred in ≥ 5% of patients were dehydration (7%), diarrhea (19%), fatigue (16%), febrile neutropenia (5%), leukopenia (37%), lymphopenia (28%), neutropenia (58%), peripheral neuropathy (12%), and thrombocytopenia (44%). No grade 5 events were observed. One patient developed tumor lysis syndrome and required hospitalization for 48 hours with complete recovery. Common grade 2 AEs possibly, probably or definitely related to treatment were anemia (30%), anorexia (28%), diarrhea (47%), fatigue (60%), leukopenia (47%), lymphopenia (28%), and thrombocytopenia (56%). Of the 43 patients treated, 38 have been evaluable for response. Patient responses are shown in Table 2. Correlative studies examining expression of pJNK, Mcl-1, XIAP, PARP, and NFκB are being collected for processing at the end of the study. Collectively, these findings indicate that the combination of bortezomib and alvocidib, the latter administered as a 1-hour infusion, is tolerable. The regimen appears active in patients with relapsed and/or refractory MM or NHL, justifying phase II studies to determine the activity of this regimen more definitively. The MTD has not yet been reached. Table 1. Dose levels and DLTs Dose Level Bortezomib (mg/m2) Alvocidib (mg/m2) Patients treated/# DLTs DLT 1 1.0 15 3/0 2 1.3 15 5/0 3 1.3 22 3/0 4 1.3 30 3/0 5 1.3 40 7/1 Grade 3 back pain 6* 1.3 50 5/1 Grade 3 fatigue 7** 1.3 60 8/2 Grade 3 febrile neutropenia Grade 3 tumor lysis syndrome 8** 1.3 75 6/2 Grade 3 diarrhea Grade 3 esophagitis/oral mucositis 9** 1.3 90 3/2 Grade 3 febrile neutropenia Grade 4 absolute neutrophil count decrease * Study is currently enrolling to dose level 6 ** Exceeded MTD Table 2. Response by diagnosis NHL MM Total (n = 15) (n = 23) (n = 38) Complete Remission 2b,c 1a 3 Partial Remission 3 7d,e 10 Complete + Partial Remission N(%) 5 (33) 8 (35) 13 (34) a Includes 1 patient with prior bortezomib b Includes 1 patient with prior autologous SCT c Includes 1 patient with mantle cell lymphoma d Includes 1 patient with Waldenstrom's macroglobulinemia e Includes 1 patient still under active treatment Disclosures: Baz: Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2959.2959

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1313-1313

Abstract: Introduction : Acute myeloid leukemia (AML) is a heterogeneous disease with various cytogenetics and molecular abnormalities that lead to different clinical outcomes. The overall prognostic significance of specific mutations at diagnosis has been described. Some are associated with better prognosis (eg, mutations in the myeloid transcription factor gene CEBPA, mutations in the NPM1 gene in the absence of FLT3-ITD, downregulated HOX expression) and some with an adverse prognosis (eg, FLT3-ITD, high expression of the BAALC gene, overexpression of the ETS-related gene ERG, certain mutations in IDH1 and IDH2). However the impact of these mutations in a salvage setting is not well described. Methods: We retrospectively analyzed the patients with AML who received 1st or 2nd salvage treatment (Salvage 1 & Salvage 2) from September 2012 to June of 2015. All patients included in the study had received induction treatment at MD Anderson. The somatic mutations used in the study were obtained at the time of diagnosis. A total of 108 patients with known mutations who eventually received Salvage 1 were included; these also included the 41 patients who later received Salvage 2. Eight mutations (FLT3, CEBPA, IDH1, IDH2, TP53, NPM1, RAS, and JAK2) were evaluated for their correlation with outcome after salvage therapy, specifically event-free survival (EFS) and overall survival (OS) after salvage 1 and salvage 2. Any new evolving mutation after the treatment was also investigated. Results: Out of 108 patients that received salvage 1 treatment, 27% patients had IDH mutations, 19% had TP53 mutations, 16% had RAS mutations, 15% had FLT3-ITD mutations, 11% had NPM1 mutations, 11% had CEBPA mutations and 6% had JAK2 mutations at the time of diagnosis. Median age was 65 years (range: 19-84), median WBC count 5.9 x 109/L (range: 0.8-250), bone marrow blast 45% (range: 0-93) and peripheral blood blast 15.5% (range: 0-96). Cytogenetic abnormalities according to SWOG/ECOG classification were 5% favorable, 50% intermediate, 41% unfavorable and 12 % indeterminate cytogenetics. Forty-two percent of patients were refractory to induction treatment and 58% had achieved complete remission and relapsed after a median of 7 months (range: 1-22). Complete remission and complete remission with incomplete count recovery (CR/CRi) rate after 1st salvage therapy was 30% (95% CI: 21-39%). Median EFS and OS were 2.2 and 5.0 months, respectively. Among 30 pts with repeat molecular analysis prior to salvage 1, some patients developed new mutations, including 4 that acquired FLT3-ITD, and 1 patient each with new TP53, NPM1 and RAS mutations. Using cox univariate analysis stratified by the cytogenetic risk group, CEBPA (HR: 2.3, 95%CI: 1.1-4.7), TP53 (HR: 2.3, 95%CI: 1.1-4.7), JAK2 (HR: 3.3, 95%CI: 1.3-7.9) mutations were significantly associated with shorter OS after start of salvage 1 (Figure 1 & 2). Patients with CEBPA and/or TP53 and/or JAK2 mutations had a significantly shorter median OS compared to patients without any of these mutations (2.9 vs 7.6 months, respectively). IDH1, IDH2, FLT3-ITD, NPM1 and RAS mutations were not significantly associated with survival outcome. Among these 108 patients, 41 (38%) later received salvage 2 therapy. After Salvage 1 1 of 5 pts assessed developed a new mutation (TP53) prior to salvage 2. Overall remission (CR/CRi) rate was 29% (95%CI: 16-46%) with 2nd salvage therapy. Median OS was 3.5 months and EFS 1.5 months. Using Cox-univariate analysis stratified by the cytogenetic risk, CEBPA mutation (HR: 8.7, 95%CI: 2.3-33.0) and TP53 mutation (HR: 5.9, 95%CI: 1.3-26.2) were significantly associated with shorter OS. Conclusion: This analysis suggests that CEBPA and TP53 mutations are associated with shorter OS in patients receiving 1st or 2nd salvage therapy after failure of induction therapy. The adverse prognostic influence of CEBPA is particularly notable and requires further study. In addition, occasionally new mutations may arise after treatment failure. Mutation profiling at diagnosis as well as prior to each salvage treatment can thus be used for risk stratification of patients undergoing salvage treatment and to consider for targeted drugs to improve the outcome. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1313.1313

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 47-47

Abstract: Abstract 47 Background In adults with newly diagnosed, poor-risk AML we previously demonstrated that induction therapy with Flavopiridol in combination with Ara-C and Mitoxantrone (FLAM,) in a timed-sequential manner, yields complete remission (CR) rates of 67% and median disease-free survival (DFS) of 13.6 months. These data suggest that FLAM might improve outcomes relative to standard “7+3” in newly diagnosed AML with poor-risk features. Thus, we are conducting a phase II randomized trial comparing the CR rates with FLAM vs. 7+3 induction for all newly diagnosed adult patients with AML with intermediate and poor-risk features. We also previously identified a population of CD34+CD38− cells with intermediate aldehyde dehydrogenase (ALDH) activity that appears to represent a leukemic stem cell (LSC) population. We are examining the effects of FLAM vs. 7+3 in eradicating this LSC population and determining if persistence of LSC's predicts for relapse. Objectives The primary objective is to compare the rate of CR after 1 cycle of FLAM vs. 1 cycle of 7+3. The secondary objectives are to compare toxicities, survival rates, and presence or absence of minimal residual disease (MRD) after both induction regimens. Methods All newly diagnosed adult patients aged 18–70 without favorable risk features were randomized in a 2:1 fashion between FLAM and 7+3 at 90 mg/m2 of Daunorubicin. To achieve balanced randomization, patients were stratified by age, secondary AML and leukocyte count. CD34+ cell subsets were analyzed by flow cytometry for CD38 expression and ALDH activity by Aldefluor. The trial is ongoing. Results To date, 62 patients are evaluable for the primary end point. Demographics and results are depicted in table 1. Patient characteristics were similar in both arms, although there were more patients with poor risk features in the FLAM arm than 7+3. Overall grade 〉 3 toxicity was similar between both arms. However, there were 3 cases of grade 〉 3 tumor lysis syndrome (TLS) with FLAM, with 1 death, vs. 0 with 7+3. There were also 3 deaths with FLAM before day 60 vs. 0 with 7+3. CR rate with FLAM was 68% (28/41), with 1 cycle of 7+3 was 48% (10/21) (p = 0.17), and with 2 cycles (7+3 + 5+2) was 52% (11/21). CR rates based on specific risk factors are depicted in table 2. There was a trend toward improved CR rates in patients with adverse genetics with FLAM (p = 0.17). Putative AML LSC's were distinguished from normal hematopoietic stem cells based on ALDH activity. The persistence of putative LSC's in patients after therapy was highly predictive of subsequent clinical relapse. Conclusions Based on the current CR rate of 68%, FLAM holds promise as a therapeutic option for patients with newly diagnosed AML with intermediate and poor risk features. In this preliminary analysis, there is a suggestion that FLAM leads to higher CR rates in patients with adverse genetics than 7+3. Additionally, the detection of MRD consisting of a residual putative LSC population strongly portended subsequent relapse, even in patients without evidence of leukemia. Disclosures: Off Label Use: Flavopiridol (Alvocidib) is an anti-leukemia agent.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.47.47

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 645-645

Abstract: Background: Acute myeloid leukemia (AML) remains a therapeutic challenge in elderly or unfit patients (pts) and high-risk subgroups. DEC10-VEN has shown high efficacy in these pts. However, outcomes in specific mutational subgroups are unknown. Here we present the results in mutational subgroups and resistance patterns in pts treated with DEC10-VEN (NCT03404193). Methods: This single-institution phase II study enrolled pts with newly diagnosed (ND) AML ( & gt;60 years) ineligible for intensive chemotherapy, relapsed or refractory (R/R) AML, and secondary AML (sAML) with or without prior therapy. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given for 21-28 days in cycle 1 and day 1-21 or shorter duration thereafter. BCR-ABL1 and FLT3 inhibitors (FLT3i) were allowed as appropriate. Amplicon-based next-generation sequencing targeting the entire coding regions of 81 myeloid genes was performed on screening bone marrow aspirate with a MiSeq platform. The analytical sensitivity was established at 5% mutant reads in a background of wild type reads. Previously described somatic mutations registered in COSMIC were considered as potential driver mutations. Results: High response rates were noted across mutational subgroups of both previously untreated and previously treated AML (Table 1 and 2). The median follow-up for the entire cohort was 8.1 months (mo). In previously untreated AML (ND AML and untreated sAML, n=49), the CR/CRi rate in NPM1mut pts was 100% (n=13), in RUNX1mut pts was 100% (n=8), in IDH1/2mut pts was 92% (n=12), in TP53mut pts was 85% (n=13), and in N/KRASmut pts was 77% (n=13, Table 1). The median overall survival (OS) among previously untreated NPM1mut pts was not reached (NR), for RUNX1mut pts was NR, for IDH1/2mut pts was 12.4 mo, for TP53mut pts was 5.8 mo, and for N/KRASmut was 12.4 mo. The median DOR for NPM1mut pts was 8.5 mo, for RUNX1mut pts was NR, for IDH1/2mut pts was NR, for TP53mut pts was 5.7 mo, and for N/KRASmut pts was 6.7 mo (Table 1). The one pt with NPM1mut who relapsed had co-occurring ASXL1mut and NRASmut at screening. In previously treated AML (treated sAML and R/R AML, n=52), the CR/CRi rate in NPM1mut pts was 60% (n=10), in IDH1/2mut pts was 50% (n=8), and in TP53mut pts was 21% (n=14, Table 2). The median OS for NPM1mut pts was NR, for IDH1/2mut pts was 7.8 mo, and for TP53mut pts was 4.5 mo. The median DOR for NPM1mut pts was NR, for IDH1/2mut pts was NR, and for TP53mut pts was 3.2 mo (Table 2). The only grade 4 TLS event occurred in a pt with NPM1mut and IDH2mut and baseline WBC of 28x109/L. 2 other pts with high % of PB blasts and FLT3mut experienced grade 3 TLS. Among 15 pts with FLT3-ITD/TKD, 8 pts received sorafenib, 5 pts received midostaurin, and 2 pts did not receive FLT3i (1 insurance non-approval and 1 very low ITD ratio). Among ND FLT3mut AML pts (n=7), the CR/CRi rate was 100% (n=5) in pts receiving FLT3i with negative MRD by flow cytometry (FCM) in 80% pts, with median OS of 8.8 mo and median DOR not reached (Table 1). Of the 2 FLT3-ITD pts not receiving FLT3i, 1 pt with FLT3-ITD of 0.47 did not respond, and 1 pt with low FLT3-ITD of 0.02 achieved CR MRD-. Among previously treated FLT3mut pts (n=8), all received FLT3i with a CR/CRi rate of 38% (n=5) and negative MRD by FCM in 75% pts tested (3/4). The median OS was 6.4 mo and the median DOR was 6.6 mo (Table 2). 2 pts had received prior FLT3i, 1 pt achieved morphologic leukemia-free state (MLFS), and the other pt did not respond. 1 pt with new t(9;22) identified at 4th relapse achieved a MLFS after 1 cycle with addition of ponatinib and transitioned to allogeneic transplant. Overall, pts with durable CR/CRi/MLFS sustained without relapse till data cut-off, had significantly higher proportion of mutations in NPM1 and DNA methylation pathways (DNMT3A, TET2, IDH1/2) compared to pts refractory to, or relapsing after DEC10-VEN (Table 3, Fig. 1). Pts with relapsed or refractory disease to DEC10-VEN had significantly higher frequency of N/KRASmut, ASXL1mut, and TP53mut compared to pts with durable CR/CRi/MLFS (Table 3, Fig. 1). TP53mut associated with worse OS on multivariable analysis (HR 2.9, 95% CI 1.4-5.7, p=0.003). Conclusion: DEC10-VEN is an effective regimen for AML. Addition of FLT3i to DEC10-VEN was safe and may improve upon responses in FLT3mut pts. Mutations in NPM1 and DNA methylation pathways were associated with more durable responses while mutations in ASXL1, RAS and TP53 were associated with refractory disease or relapse. Disclosures Maiti: Celgene: Other: research funding. Cortes:BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Pemmaraju:samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; 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. Daver:Servier: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; NOHLA: Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Borthakur:Cyclacel: Research Funding; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; GSK: Research Funding; BMS: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Novartis: Research Funding; Eisai: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:AbbVie: Consultancy, Research Funding; Amgen: 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, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Daiichi-Sankyo: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding. DiNardo:agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: FLT3 inhibitors, used in combination with decitabine and venetoclax

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128547

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7