bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the cardiovascular risk profile of Ph+ leukemia patients treated with ponatinib.
Authors: Khoury Hanna Jean , Cortes Jorge E. , Kim Dong-Wook , Pinilla-Ibarz Javier , Le Coutre Philipp D. , Paquette Ronald , Chuah Charles , Nicolini Franck E. , Apperley Jane , Talpaz Moshe , DiPersio John F. , DeAngelo Daniel J. , Abruzzese Elisabetta , Rea Delphine , Baccarani Michele , Müller Martin C. , Gambacorti-Passerini Carlo , Lustgarten Stephanie , Yanase Kumiko , Kantarjian Hagop M. 
Published: March 2020

7048 Background: Coronary artery disease (CAD), peripheral arterial occlusive disease and cerebrovascular disease have been observed in pts treated with BCR-ABL tyrosine kinase inhibitors (TKIs). While uncommon, these events can be serious complications of BCR-ABL TKI therapy. Methods: The cardiovascular (CV) profile of ponatinib (45 mg/day) was evaluated in 449 pts with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to prior TKIs in the phase 2 PACE trial. At analysis (23 July 2012), median follow-up was 12 (0.1-21) mos. Myocardial ischemic events including myocardial infarction (MI), CAD, and angina were analyzed. Results: Myocardial ischemic serious adverse events (SAEs) (14 MI, 5 CAD, 2 angina) were reported in 21/449 pts (5%). 10 of these 21 pts had active cardiac disease at entry characterized by prior MI (4 pts), coronary revascularization (4 pts), or documented CAD; 5 had MI reported on study. 5/21 pts had other cardiac disease at entry (eg, valvular or pericardial disease); 5 had MI on study. Thus, 10/14 MIs occurred in 15 pts with known cardiac disease. 6/21 pts had no history of cardiac disease, but 5/6 had ≥1 CAD risk factor; 4 MIs occurred in these pts, all had risk factors. Of 21 pts with myocardial ischemic SAEs (13 CP-CML, 6 AP-CML, 2 BP-CML/Ph+ALL), mean age was 67 (42-87), and median duration since diagnosis was 12 (1-20) yrs. They were heavily pretreated (67% TKI use ≥5 yrs) with multiple CAD risk factors at entry (71% ischemia, 57% hypertension, 38% hypercholesterolemia, 33% diabetes [62% BMI >25]); 81% had ≥2 risk factors, 95% had ≥1. Median time to onset and duration of SAE was 160 (9E402) and 7 (1E98) days, respectively. At analysis, 18/21 pts had the SAE reported as resolved (managed by dose interruption [50%] or no dose change [33%]), and 13/21 pts remained on study. Response rates for the subset of 21 pts with cardiac SAEs were major cytogenetic response 77% in CP-CML; major hematologic response 67% in AP-CML. Conclusions: In this uncontrolled study in heavily pretreated pts, these CV SAEs occurred mostly in pts with preexisting cardiac disease, and were primarily managed with satisfactory outcomes. Pts with preexisting CV co-morbidities should be monitored. Clinical trial information: NCT01207440.
Effect of dose-optimized imatinib (IM) 800 mg on deep molecular responses (CMR 4.5) and prediction of survival: Results from the randomized CML-study IV.
Authors: Hehlmann Rüdiger , Lauseker Michael , Hanfstein Benjamin , Müller Martin C. , Schreiber Annette , Proetel Ulrike , Pfirrmann Markus , Schnittger Susanne , Dengler Jolanta , Falge Christiane , Neubauer Andreas , Stegelmann Frank , Pfreundschuh Michael , Waller Cornelius F. , Spiekermann Karsten , Baerlocher Gabriela M. , Krause Stefan W. , Hochhaus Andreas , Hasford Joerg , Saussele Susanne ,   SAKK and the German CML-Study Group
Published: March 2020

7051 Background: Since complete molecular remission (CMR 4.5) defines a subgroup of patients who may stay in remission even after discontinuation of treatment, we analysed whether CMR 4.5 is reached faster with dose optimized IM 800 mg and whether the achievement of CMR 4.5 at specified points in time results in better survival than the achievement of less deep remissions. Methods: Confirmed CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4 log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from standardized baseline as determined by real-time PCR in 2 independent analyses. Details on CML-Study IV have been published (Hehlmann et al., JCO 2011). Cumulative incidences were estimated under consideration of competing risks. Landmark analyses were performed to evaluate the prognostic impact of different remissions at 4 years on survival. Results: Of 1551 randomized patients with newly diagnosed chronic phase CML 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk. 113 patients were transplanted (73 in first chronic phase), 246 received 2nd generation TKI. 152 patients have died. After a median observation time of 67.5 months, 6-year OS was 88.2%.CMR 4.5 was reached after a median of about 76.1 months with IM 800 and 107.3 months with IM 400. EUTOS low-risk patients reached all remissions faster than high-risk patients. Independent of treatment approach CMR 4.5 at 4 years predicted OS significantly better than complete cytogenetic remission (p=0.043), but not significantly better than major molecular remission (MMR) or CMR4. After a median observation of 3.9 years 1 of 626 patients with CMR 4 has progressed. Only six of the 394 patients with CMR 4.5 have died after a median observation time of 3.0 years, no patient has progressed. An additional finding was that achieving MMR at 3 and at 6 months predicts faster achievement of CMR 4.5. Conclusions: We conclude that dose optimized IM 800 induces CMR 4.5 faster than IM 400 and that CMR 4.5 at 4 years is associated with a survival advantage. Dose optimized IM 800 may provide an improved therapeutic basis for treatment discontinuation in patients with CML. Clinical trial information: NCT00055874.
Pharmacokinetics (PK) of ibrutinib in patients with chronic lymphocytic leukemia (CLL).
Authors: Sukbuntherng Juthamas , Jejurkar Purvi , Chan Stephen , Tran Anh L. , Moussa Davina , James Danelle Frances , Loury David 
Published: March 2020

7056 Background: Ibrutinib is a first-in-class selective small molecular inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. Because of covalent binding to cys-481 of BTK, ibrutinib has a sustained pharmacodynamic (PD) effect. The aim of this study was to determine the PK of ibrutinib in patients (pts) with CLL. Methods: A Phase 1b/2 study (PCYC-1102-CA) of an oral dosing of single agent ibrutinib was conducted in pts with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Pts were enrolled into one of the following groups: R/R pts at 420 mg/day (n=27), TN pts at 420 mg/day (n=26), R/R pts at 840 mg/day (n=34), R/R high-risk pts at 420 mg/day (n=24), TN pts at 840 mg/day (n=5), and R/R pts at 420 mg/day for food-effect evaluation (n=16). One cycle was 28 days. Blood samples for PK assessment were obtained during the first cycle. PK parameters were calculated using non-compartmental analyses. Results: A total of 132 pts (98 males and 34 females) with CLL were treated across the 6 groups. Median ages for Groups 1 through 6 were 64, 71, 64, 68, 71, and 62 years, respectively. Ibrutinib exhibited rapid absorption (median Tmax of 2 h) and a mean elimination plasma half-life of approximately 6-9 hours. The AUCtau increased approximately proportional to doses from 420 to 840 mg/day. No accumulation of ibrutinib was apparent on Day 8. Ibrutinib exposure in males and females was similar. At 420 mg/day, pts ≥ 65 years old had AUC values that were ~30% higher than those of pts < 65 years. In R/R pts, there were no substantive differences in systemic exposure to ibrutinib between the del 17p positive and del 17p negative pts. An increase in ibrutinib exposure (<2-fold) was observed when administration with high-fat breakfast was compared to administration following an overnight fast. In all cases, %CV of AUC ranged from 50 to 100%. Conclusions: Ibrutinib demonstrated rapid absorption and elimination and was well tolerated at doses of 420 and 840 mg/day. Lack of significant exposure differences with respect to age, gender, or 17p del status indicates that dose adjustment in these populations is not required. Because of a sustained PD effect ibrutinib can be dosed once daily despite a relatively rapid clearance. Clinical trial information: NCT01105247.
Final report of phase I/II study of PR104, a hypoxia-activated pro-drug, in relapsed/refractory acute leukemia.
Authors: Arana Yi Cecilia Ysabel , Borthakur Gautam , Thall Peter F. , Coveler Andrew L. , Ravandi Farhad , Jabbour Elias , Faderl Stefan , Thomas Deborah A. , Cortes Jorge E. , Kadia Tapan M. , Kornblau Steven Mitchell , Daver Naval Guastad , Pemmaraju Naveen , Nguyen Hoang Q. , Wilson William R. , Melink Teresa J. , Gutheil John , Kantarjian Hagop M. , Estey Elihu , Konopleva Marina 
Published: March 2020

7074 Background: Hypoxia is prevalent in leukemia bone marrow (BM) microenvironment, suggesting its role as a therapeutic target. PR104 is a pro-drug activated by hypoxia-dependent reductases and by hypoxia-independent aldo-ketoreductase 1C3 (AKR1C3). Methods: Patients (pts) with relapsed/refractory AML (n=40) after 1 or 2 prior treatments; or ALL (n=10) after any number of prior treatments received PR104 as a 1-hr i.v. infusion q 2 weeks. Biomarkers for hypoxia and AKR1C3 were assessed. Results: Pts received PR104 at doses of 1.1 (n=6), 1.6 (n=1), 2.2 (n=1), 3 (n=20) and 4 gm/m2 (n=22) for a median of 1 cycle (range, 1 – 3 cycles). 17 pts had PR104 doses assigned using an adaptive method using toxicity-response trade-offs, patient age, and prior remission duration, and 33 pts were assigned doses by investigators for cohort expansion at 3 and 4gm/m2. Most common treatment-related grade 3/4 adverse events included myelosupression (anemia 44%, neutropenia 56%, thrombocytopenia 52%), febrile neutropenia (22%), infection (22%) and enterocolitis (14%). 3 (14%) PR104-related deaths occurred at the 4 gm/m2 dose level: hepatic failure (n=1), enterocolitis (n=1) and pneumonia (n=1). 49 of 50 pts were evaluable for response. No CRs were seen at doses < 3 gm/m2. 10 of 31 AML pts (32%, (0.19, 0.5)% CI) and 2 of 10 ALL pts (20%, (0.06,0.51)% CI) at 3 or 4 gm/m2 had responses (CR, n=1; CRp, n=5; morphologic leukemia-free state (MLFS), n=6). In AML pts with 1 prior treatment, responses were seen in 7 of 21 pts (CR, n=1; CRp, n=3; MLFS, n=3). Median overall survival of all pts treated at 3 and 4 gm/m2 was 72 days, and of pts who achieved CR/CRp/MLFS 143 days. 3 pts with AML (MLFS, n=2; CRp, n=1) and 1 with B-ALL (CRp, n=1) underwent allogeneic stem cell transplantation. Biomarker studies showed hypoxia in the BM; and levels of AKR1C3 in leukemic blasts did not correlate with responses (Benito et al., ASH 2012). Conclusions: PR104 administered at doses 3 to 4x the solid tumor MTD had moderate toxicity (most commonly myelosuppression and enterocolitis) in pts with relapsed/refractory AML and ALL. Evidence of activity supports continued evaluation of hypoxia-activated cytotoxins in acute leukemias. Clinical trial information: NCT01037556.
Hypomethylating agents as first-line therapy in acute myeloid leukemia (AML).
Authors: Bailey Samuel D , Gul Zartash , Slone Stacey A. , Van Meter Emily Marie , Lawson Amber , Raufi Ali , Hayslip John W. , Monohan Gregory , Howard Dianna S. , McDonagh Kevin T. , Alkadhimi Zaid 
Published: March 2020

7084 Background: Hypomethylating agents are used in older AML patients (pts) who are not considered candidates for standard induction therapy. However, data regarding their efficacy remains unclear. Methods: We retrospectively evaluated a cohort of 24 consecutive AML pts who were placed on hypomethylation therapy at diagnosis between October 2010 and June 2012 at Markey Cancer Center. Results: Baseline characteristics of the patients are described in table 1. Response rate (CR+PR) was 45.8%. Median number of infections were 1 (8 pts), 2 (5 pts), 3 (4 pts).Median hospital admissions required were 1 (10 pts), 2 (4 pts), 3 (5 pts), 4 or greater (2 pts). Average length of hospital stay was 10.3 days (0-37 days). Median units of packed red cell and platelet transfusions were 10 and 11 units (Range=0-64 and 0-78) respectively. After a median follow up of 145.5 days, 13 pts had died. Cause of death was AML (6 pts), infection and end organ failure (7pts).Median overall survival (OS) was 9.7 months (95%CI: 3.2-16.5 months). On multivariate analysis, blast count less than 30% was borderline significantly associated with better OS (P=0.05). However after addition of average hospital stay in the model only age (HR=1.3, CI=1.06- 1.67), gender (HR=11.5, CI=1.2, 110.5), and average hospital stay were significantly associated with OS (HR=1.2, CI = 1.04- 1.32). Conclusions: In this cohort of pts the median OS was 9.7 months. Older pts and those with longer average hospital stay had a higher mortality. Better selection of pts in a larger cohort who are likely to gain more benefit from these agents may impact outcomes. [Table: see text]
Use of flow cytometry during induction chemotherapy to determine outcomes in acute myeloid leukemia.
Authors: Donnellan William Bruce , Ghosh Monalisa Ghosh , Rangarajan Sunil , Jackson Bradley , Borate Uma , Erba Harry P. , Foran James M. 
Published: March 2020

7104 Background: The use of MRD to predict outcome in AML is controversial. We sought to determine concordance between FC and BM biopsy morphology on day 14 (D14BM) and CR bone marrow (CRBM) specimens and whether MRD detected by FC predicted for inferior outcomes. Methods: We performed a retrospective analysis of adult AML patients treated between 2005 and 2010 with standard induction chemotherapy. Based upon BM morphology and FC, patients were designated as BM+FC+, BM+FC-, BM-FC+, or BM-FC-. Outcomes assessed included induction failure, RFS and OS. Results were adjusted for age at diagnosis, NCCN risk classification, and secondary AML status. Results: Of 287 evaluable patients, 74 had D14 BM and FC results and 98 had CR BM and FC results. Using BM morphology as the gold standard, discordance rates for the presence and absence of disease for the D14 BM by FC were 29% and 23% respectively. Multivariate analysis revealed that patients categorized as BM-FC+ at D14 were more likely to experience induction failure (HR 8.62, CI 0.36-208) and had lower RFS and OS (HR 1.47, 1.95 CI 0.40-5.41, 0.52-7.36 respectively). Analysis of the CR BM samples showed similar results. Conclusions: In this retrospective study there was a high discordance rate between FC and BM morphology on D14 BM and CR BM. While there was a trend toward inferior patient outcomes when disease was detected by FC but not morphology, this was not statistically significant. Limitations of our study include the retrospective nature of the analysis, paucity of patient samples that had a FC evaluation, lack of data to see if positive FC at D14 or CR changed clinician therapy choices and interpretation bias by pathologists as a result of access to FC results during BM morphology interpretation. Larger prospective studies are needed to evaluate whether MRD detected by FC as early as D14 during AML therapy affects clinical outcomes.
Identification of pSTAT5 gene signature in hematologic malignancy.
Authors: Sonkin Dmitriy , Regnier Catherine , Rong Xianhui , Fanton Christie , Palmer Michael , Holash Jocelyn , Squires Matthew , Sirulnik L. Andres , Radimerski Thomas , Schlegel Robert , Morrissey Michael , Cao Z, Alexander 
Published: March 2020

7111 Background: The JAK/STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Receptor-associated JAKs are activated following receptor-ligand binding. Activated JAKs phosphorylate STAT proteins, which then dimerize and translocate to the nucleus where they modulate the expression of target genes. Dysregulated JAK/STAT signaling has been implicated in the pathogenesis of multiple human malignancies. Activating mutations in JAK2 and the associated activation of STAT5 in myeloproliferative neoplasia is one example of the involvement of this pathway in human cancer. Additionally, overactivated JAK/STAT signaling has been suggested as a survival mechanism in several human cancers. Given the importance of JAK/STAT dysregulation in human diseases, it is important to identify patients with an overactivated JAK/STAT pathway for possible treatment with JAK inhibitors. Thus, we developed a gene signature assay to detect overactivated JAK/STAT5 signaling. Methods: The cancer cell line encyclopedia (CCLE) and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. First, we used 27 tumor cell lines of hematologic lineage, with predetermined phosphorylated STAT5 (pSTAT5) status, to derive STAT5 activation gene signatures. Next, the putative gene signatures were validated against a different set of 13 hematologic tumor cell lines. Results: With this approach, a collection of 7 target genes were identified (PIM1, CISH, SOCS2, ID1, LCN2, EPOR, and EGR1) whose expression significantly correlated with pSTAT5 status in the 40 hematologic tumor cell lines (P < .0001), either together or in specific subsets of 4 and 6 genes (Table). Conclusions: These 4-, 6-, and 7-gene signatures can be used to stratify or select for a patient population with activated JAK/STAT5 signaling that could potentially benefit from treatments targeting the JAK/STAT5 signaling pathway. [Table: see text]
Characterization of Philadelphia-negative myeloproliferative neoplasm patients with chromosome 12 abnormalities.
Authors: Benton Christopher Brent , Tanaka Maria Florencia , Pierce Sherry , Zhou Lingsha , Cortes Jorge E. , Kantarjian Hagop M. , Verstovsek Srdan 
Published: March 2020

7112 Background: Chromosome 12 (Chr 12) abnormalities have been reported as infrequent events in myelofibrosis (MF). Structural abnormalities at 12q13-15 and 12q24 have been reported in primary MF (PMF), and understanding genes at these loci, such as Hmga2 and Lnk may help in the treatment of Philadelphia-negative (Ph-neg) myeloproliferative neoplasms (MPN). We sought to better characterize Ph-neg MPN patients (pts) with Chr 12 aberrations. Methods: We queried a database of pts with any Ph-neg MPN who were referred to MD Anderson Cancer Center from 1985 to 2012. We identified pts with Chr 12 abnormalities and reviewed available clinical information. We compared characteristics and outcomes of pts who had Chr 12 abnormalities with pts who had no Chr 12 abnormality. Results: Of 1,787 pts with Ph-neg MPN, 36 pts (2%) were found to have a Chr 12 abnormality. Of these, 31 (86%) had MF, 1 (3%) had polycythemia vera (PV), 3 (8%) had hypereosinophilic syndrome, and 1 (3%) had unspecified MPN. Fourteen pts (39%) had successive biopsies demonstrating evolving cytogenetic abnormalities. The percentage of pts with MF was significantly higher among patients with Chr 12 abnormalities (86% vs. 54%, p-value < 0.001). A larger fraction of MF pts with Chr 12 abnormalities had post-PV MF (PPMF) (31% vs. 14%, p-value < 0.001). Age, JAK2 status, and incidence and rate of leukemic transformation from MF were not significantly different between the two groups. Of the 31 Chr 12 pts with MF, 12 (39%) had an abnormality at 12q13, 8 (26%) at 12q24, 6 (19%) had trisomy 12, 5 (16%) at 12q15, and 6 (19%) had another Chr 12 abnormality. Four pts (13%) had a structural abnormality at >1 site along the long arm of Chr 12. Survival of Chr 12 MF pts as a whole or subdivided by chromosomal abnormality was not significantly different than MF pts without Chr 12 abnormalities. Conclusions: Our investigation into pts with Ph-neg MPN harboring Chr 12 abnormalities is the largest of its kind, and shows 3% of MF pts possessed some type of Chr 12 abnormality, most frequently at 12q13. We found that Chr 12 Ph-neg MPN pts were more likely to have MF and PPMF. Further investigation into the functional significance of these structural abnormalities is warranted.
A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617.
Authors: Bradley Jeffrey D , Paulus Rebecca , Komaki Ritsuko , Masters Gregory A. , Forster Kenneth , Schild Steven E. , Bogart Jeffrey , Garces Yolanda I. , Narayan Samir , Kavadi Vivek , Nedzi Lucien Alexander , Michalski Jeff M. , Johnson Douglas , MacRae Robert Malcolm , Curran Walter John , Choy Hak ,   Radiation Therapy Oncology Group
Published: March 2020

7501 Background: The first objective of RTOG 0617 was to compare the overall survival(OS) of patients(pts) treated with standard-dose(SD)(60Gy) versus high-dose(HD)(74Gy) radiotherapy with concurrent chemotherapy(CT). Methods: This Phase III Intergroup trial randomized 464 pts with Stage III NSCLC to the SD(60Gy) vs. HD(74Gy) arms prior to closure of the HD arm. Concurrent CT included weekly paclitaxel(45 mg/m2) and carboplatin(AUC=2). Pts randomized to cetuximab received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2. All pts were to receive consolidation CT. We are reporting the final results on radiation dose. Results: 464 pts were accrued prior to closure of the HD arm in 6/11, of which 419 were eligible for analysis. Median follow up was 17.2 months. There were 2 and 10 grade 5 treatment-related adverse events(AEs) on the SD and HD arms, respectively. Grade 3+AEs were 74.2% and 78.2% on SD and HD arms, respectively (p=0.34). The median survival times and 18-month OS rates for the SD and HD arms were 28.7 vs 19.5 months, and 66.9% vs 53.9% respectively (p=0.0007). The primary cause of death was lung cancer (72.2% vs 73.5%)(p=0.84). Local failure rates at 18 months were 25.1% vs 34.3% for SD and HD patients, respectively(p=0.03). Local-regional and distant failures at 18 months were 35.3% vs 44%(p=0.04) and 42.4% vs 47.8%(p=0.16) for SD and HD arms, respectively. Factors predictive of less favorable OS on multivariate analysis were higher radiation dose, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volume >5 Gy. Conclusions: In this setting of chemoradiation for locally-advanced Stage III NSCLC, 60 Gy is superior to 74 Gy in terms of OS and local-regional control. The effect of the anti-EGFR antibody (cetuximab) awaits further follow up. This project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC U24 CA 81647 from the National Cancer Institute (NCI) and Eli Lilly and Company. Clinical trial information: NCT00533949.