bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1b dose escalation study to evaluate safety, tolerability and pharmacokinetics of oral monotherapy with KX2-391 in elderly subjects with acute myeloid leukemia who are refractory to or have declined standard induction therapy.
Authors: Kasner Margaret T. , Ritchie Ellen K. , Cutler David , Fetterly Gerald J. , Kramer Douglas , Hangauer David , Thompson James E. 
Published: September 2018

7043 Background: Treatment of elderly AML patients is complicated by poor tolerance to standard therapies and multi-drug resistance. It is imperative to explore novel agents which are tolerable and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerase. We conducted a phase I open-label safety and activity study in elderly subjects with AML who were refractory to or declined standard induction chemotherapy. Five dose levels were tested from 40 to 160 mg daily. Methods: 24 subjects were recruited from 3 institutions with an average age of 74 years (range 63-86). The majority had previously received HMAs. 1 subject was treated at 40 mg, 2 at 80 mg, 8 at 120 mg, 12 at 140 mg, and 1 at 160 mg. Of the 24 subjects enrolled, 7 (29%) were on treatment for 12 days or less; 9 (38%) from 15 to 29 days, 5 (21%) from 33 to 58 days and 3 (13%) from 77 to 165 days. One subject treated at 120 mg for 165 days had a reduction in splenomegaly from 16 cm to 4 cm BLCM, and survived 373 days. A second subject was treated at 120 mg for 154 days until disease progression. One subject was dosed at 160 mg for 12 days and remained treatment-free for about 18 months. Results: DLTs occurred in 8 subjects at: 120mg (AST/ALT, elevated bilirubin); 140 mg (Mucositis, Allergic Reaction, 2 elevated LFTs, acute kidney injury) and 160 mg (Mucositis). The most common (≥ 25%) treatment-related adverse events were nausea/vomiting; diarrhea; anorexia; fatigue/weakness; increase ALT/AST; hypokalemia; hypotension; febrile neutropenia; dyspnoea; abdominal pain; constipation; dizziness. The RPTD for KX2-391 is 120 mg given once daily. KX2-391 bone marrow concentrations are similar to the target IC50 of 142 ng/mL. Conclusions: This is the first study conducted to determine whether KX01 can be safely given to this high risk, frail AML patient population. The data from this study support proceeding with further studies including alternative dosing phase 1 studies (higher dose, shorter course followed by drug-free intervals) and phase 2 studies to assess efficacy. Clinical trial information: NCT01397799.
Prognostic and therapeutic impact of cytogenetic abnormalities in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable.
Authors: Mangaonkar Abhishek Avinash , Alkhateeb Hassan , Al-Kali Aref , Gangat Naseema , Begna Kebede , Elliott Michelle A. , Hogan William J. , Zblewski Darci , Ketterling Rhett P. , King Rebecca L. , Litzow Mark Robert , Tefferi Ayalew , Patnaik Mrinal Mahesh 
Published: September 2018

7058 Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.
Does supplemental interphase FISH analysis to standard chromosom analysis improve the detection of myelodysplastic syndrome?
Authors: Lang Benjamin Joseph , Minyon Carol , Dhiman Neelam , Gupta Saurabh , Wenceslao Stella , Vuica-Ross Milena , Dobson Robin 
Published: September 2018

7060 Background: Our objective was to evaluate whether the addition of interphase FISH analysis to standard chromosome analysis (CA) improves the detection of chromosomal abnormalities in patients with work up for myelodysplastic syndromes (MDS), acute myeloid leukemia, and myelodysplastic/myeloproliferative disorders and thereby increases diagnostic and prognostic information. We performed a retrospective data review of all MDS orders between January and September 2015 at our institution and evaluated concurrent tests for discrepancies between CA and FISH results. Our aim was to evaluate best practices with regard to diagnostic test utilization, specifically to assess the diagnostic and prognostic value of FISH in addition to CA for patients with potential and known MDS. Methods: Retrospective data review of concurrent test orders of CA and myelodysplastic FISH panel were reviewed. The myelodysplastic FISH panel consists of screening for monosomy 5/deletion 5q, monosomy 7/deletion 7q, CEP7, trisomy 8, and D20S108 (20q12). The results of CA and FISH results were analyzed using a chi-square test to evaluate statistical significance. Results: A total of 1121 samples were queried, of which 55 were excluded due to inability to perform CA and limited diagnostic value of accompanying standalone FISH data on the 4 markers tested in this study. Analysis of the eligible 1066 samples showed that the standalone CA had significantly higher sensitivity (p < 0.0001) in detecting abnormal cases (N = 247, 23.17%) as compared to standalone FISH analysis (N = 180, 16.89%). Overall, 173 (16.23%) cases were determined to be abnormal by both methods. CA correctly interpreted 1059 of 1066 cases (99.34%).Only 7 samples were interpreted as normal by CA but were found to be abnormal by FISH. This results in overall 0.66% (2.76% of the abnormal cases) of abnormalities that would have been missed by CA only. Conclusions: These findings suggest that FISH studies with 4 markers used in this study provide limited additional utility in cases with a complete CA.
First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.
Authors: Flinn Ian , van der Jagt Richard , Chang Julie E. , Wood Peter , Hawkins Tim E. , MacDonald David , Trotman Judith , Simpson David , Kolibaba Kathryn S. , Issa Samar , Hallman Doreen M. , Chen Ling , Burke John M. 
Published: September 2018

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.
Phase IIIb randomized study of lenalidomide plus rituximab (R2) followed by maintenance in relapsed/refractory NHL: Analysis of patients with double-refractory or early relapsed follicular lymphoma (FL).
Authors: Andorsky David Jacob , Yacoub Abdulraheem , Melear Jason M. , Coleman Morton , Kolibaba Kathryn S. , Brooks Heather Dawn , Bitran Jacob D. , Fanning Suzanne R. , Lansigan Frederick , Ricker Justin L. , Foon Kenneth A. , Liu Dongfang , Llorente Mary , Li Jiahui , Sharman Jeff Porter ,   MAGNIFY Trial Investigators
Published: September 2018

7502 Background: Chemoresistant patients with FL and those who progress within 2 y after initial diagnosis have poor outcomes (Casulo. JCO. 2015) and highlight an unmet need. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of relapsed/refractory (R/R) NHL patients, including grades 1-3b or transformed FL (tFL). Patients receive 12 cycles of lenalidomide plus rituximab (R2); those with stable disease or better are randomized 1:1 to maintenance R2 or rituximab alone. The primary endpoint is progression-free survival (PFS). This analysis focuses on FL: double-refractory (DR) patients are refractory to both rituximab (as monotherapy or combination) and an alkylating agent, and early relapse (ER) patients progressed or relapsed within 2 y of initial diagnosis. Results: As of July 19, 2016, the R/R FL population (N = 117) included 32 (27%) DR and 43 (37%) ER patients, median ages of 64 and 65 y, respectively, mostly grade 1-3a FL (94%; 91%) and 2 tFL (1 DR; 1 ER); 72% and 49% were stage IV at study entry. Patients had a median of 2 prior regimens (DR 3; ER 2). Of ER patients, 31 had first-line R-chemo vs 12 with R-mono/other. Response rates are in Table 1. Median time to response was 2.8 mo for DR and 2.7 mo for ER patients, with median duration not reached. 1-y PFS for FL patients was 66% (DR 66%; ER 45%); 1-y PFS for ER patients with first-line R-chemo was 50% vs 27% in others. Common grade ≥3 treatment-emergent AEs for DR and ER patients were neutropenia (53%; 33%), leukopenia (9%; 12%), and lymphopenia (9%; 5%). Conclusions: R2 followed by maintenance showed favorable activity and tolerable safety profiles in FL patients who are double-refractory or had early relapse ( < 2 years) after initial diagnosis. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865. [Table: see text]
Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study.
Authors: Sharman Jeff Porter , Brander Danielle M. , Mato Anthony R. , Kambhampati Suman , Burke John M. , Lansigan Frederick , Schreeder Marshall T. , Lunin Scott D. , Ghosh Nilanjan , Zweibach Alexander , Shtivelband Mikhail , Travis Patrick M. , Chandler Jason Claud , Kolibaba Kathryn S. , Sportelli Peter , Miskin Hari P. , Weiss Michael S. , Flinn Ian 
Published: September 2018

7504 Background: Patients (pts) with high-risk chronic lymphocytic leukemia (CLL) defined by interruptions in TP53 (either by mutation or deletion) or loss of chromosome 11q experience inferior outcomes with ibrutinib (IB) monotherapy (O’Brien ASH 2016). Ublituximab (UTX) is a novel glycoengineered mAb with enhanced ADCC targeting a unique epitope on the CD20 antigen. GENUINE is the first randomized Ph 3 trial conducted assessing the addition of a novel agent to ibrutinib in high-risk rel/ref CLL, and evaluates IB monotherapy vs. UTX + IB. Methods: Eligible pts with rel/ref CLL and centrally confirmed del17p, del11q, and/or a TP53 mutation were randomized 1:1 to receive IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cycle 1, D1 of Cycle 2-6, and Q3 Cycles thereafter). There was no limit on number of prior therapies. Prior IB exposure was excluded. The primary endpoint was overall response rate (ORR) per iwCLL 2008 criteria, with secondary endpoints including CR rate, MRD negativity, PFS, time to response (TTR) and safety. Results: 126 pts were randomized at sites in the US and Israel, with 117 pts treated (59 on UTX + IB, 58 on IB alone). Median age 67, median 3 prior therapies (range 1-8), > 70% of were male. High-risk cytogenetics were relatively balanced with ~ 50% of pts having del17p. UTX+IB was well tolerated, with infusion reactions the most prevalent AE (44%, GR3/4 5%). Neutropenia was comparable with the combination (17%, Gr3/4 7% vs. 10%, Gr3/4 9%), and other AE’s were similar or lower with UTX+IB vs. IB alone (all grades), including fatigue (17% vs. 31%), dizziness (12% vs. 21%), contusion (12% vs. 26%), anemia (10% vs. 16%), and myalgia (9% vs. 14%). At median follow-up of 12 mo, best ORR per independent central review was 80% for UTX + IB vs. 47% for IB alone (p < 0.001). While not powered for secondary endpoints, observed advantages were seen in PFS and radiographic CR rate in the UTX + IB arm. CR and MRD confirmation is ongoing. Median TTR for the combo was 1.97 mo vs. 3.8 mo for IB alone. Both arms have responses pending confirmatory assessments. Conclusions: The addition of UTX to IB demonstrated a superior response rate compared to IB alone without additional clinically significant toxicity. Clinical trial information: NCT02301156.
Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma.
Authors: Jin Michael C. , Kurtz David Matthew , Esfahani Mohammad Shahrokh , Scherer Florian , Craig Alexander F.M. , Soo Joanne , Khodadoust Michael Siavash , Saganty Ruth Sharon , Chabon Jacob J. , Schroers-Martin Joseph , Stehr Henning , Advani Ranjana H. , Rossi Davide , Gaidano Gianluca , Westin Jason R. , Diehn Maximilian , Alizadeh Ash A. 
Published: September 2018

7507 Background: Somatic copy number alterations (SCNAs) are common and clinically important genomic events in lymphomas. For example, MYC and BCL2 amplifications are associated with adverse outcomes (Quesada, ASH 2016), while PD-L1 ( CD274) amplifications are associated with improved response to checkpoint inhibitors (Ansell, NEJM 2015). However, noninvasive detection of these events from circulating tumor DNA (ctDNA) remains difficult. Using CAPP-Seq, a targeted high-throughput sequencing platform, we developed a method to profile both focal and broad SCNAs from plasma. Methods: We profiled plasmas from a cohort of 75 pretreatment diffuse large B-cell lymphoma patients and 48 healthy controls. Focal SCNAs were evaluated at ultra-high depths (~10,000x), allowing for detection of lesions at ~1% ctDNA fraction. Thresholds were tuned to allow a false positive rate of 1%, which was empirically validated in an independent healthy cohort (n = 15), yielding a panel-wide false discovery rate of ~2.3% (0% in our genes of interest). Sequencing reads outside the targeted regions were separately pooled and analyzed to evaluate arm and chromosome level SCNAs. Results: We detected SCNAs in clinically relevant genes at the frequencies reported in literature, including amplifications in MYC (8.0%), BCL2 (24.0%), and BCL6 (14.7%) and deletions in TP53 (13.3%) and CDKN2A (9.3%). Remarkably, 26.7% of the cohort demonstrated amplification of both PD-L1 and PD-L2 ( PDCD1LG2). Furthermore, we discovered amplifications in PD-L2, but not PD-L1, in 13.3% of our patients. Interestingly, PD-L1 amplifications were more common in patients with relapsed lymphoma than in those with treatment-naïve disease (43.5% vs 19.2%, p = 0.02). Most PD-L1 amplifications were focal (65%) while the remainder typically involved > 80% of Chr9p. Corresponding tissue profiling data is in progress and will also be presented. Conclusions: Noninvasive sampling of lymphoma ctDNA enables detection of both focal and broad SCNAs, including amplifications of MYC, BCL2, and PD-L1. The ability to noninvasively profile copy number altered regions allows for biopsy-free discovery of clinically significant structural alterations in lymphoma patients.
Clinical and biologic covariates of outcomes in ZUMA-1: A pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (r-NHL).
Authors: Locke Frederick Lundry , Neelapu Sattva Swarup , Bartlett Nancy L. , Lekakis Lazaros J. , Miklos David Bernard , Jacobson Caron Alyce , Braunschweig Ira , Oluwole Olalekan O. , Siddiqi Tanya , Lin Yi , Timmerman John , Reagan Patrick Michael , Bot Adrian , Rossi John , Navale Lynn , Jiang Yizhou , Aycock Jeff , Elias Meg , Wiezorek Jeffrey S. , Go William Y. 
Published: September 2018

7512 Background: Outcomes in activated B cell subtype diffuse large B cell lymphoma (ABC-DLBCL) and r-NHL are poor (Sehn Blood 2015, Crump ASCO 2016). ZUMA-1 is the first, multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells, axi-cel, in r-NHL. Methods: Dosing and eligibility were per Neelapu ASH 2016. The primary endpoint was objective response rate (ORR); secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Cell of origin (COO) and CD19 status were assessed centrally using Lymphoma Subtyping Test NanoString (Wallden JCO 2015) and a validated immunohistochemistry assay, respectively. Results: As of Jan 27, 2017, 111 patients (pts) were enrolled; the manufacturing success rate was 99% with an average 17-d turnaround time; 101 pts (modified intent-to-treat [mITT] population) received axi-cel. In the mITT population, the ORR was 82% (complete response [CR], 54%). With 8.7 m median follow-up, 44% remain in response and 39% in CR. The median DOR was 8.1 m and not reached (NR) for pts with CR. Median OS was NR. Results for clinical and biologic covariates are listed in the table. In pts who received tocilizumab (n = 43) and/or steroids (n = 27) for cytokine release syndrome (CRS) and/or neurologic events (NE), ORR was 84% and 78%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia (24%), and encephalopathy (21%). Rates of grade ≥3 CRS and NE were 13% and 28%, respectively. There were 3 grade 5 AEs (Neelapu ASH 2016). Conclusions: Axi-cel induced an ORR of 82% in pts with r-NHL, response is ongoing in 44% of pts at 8.7 m. Similar clinical responses were observed in pts with r-ABC-DLBCL. AEs were manageable and the use of tocilizumab/steroids did not appear to impact ORR. Drs Locke and Neelapu contributed equally. Funding source: Kite Pharma and Leukemia & Lymphoma Society Therapy Acceleration Program Clinical trial information: NCT02348216. [Table: see text]
Outcomes by CD30 expression in patients with CTCL receiving brentuximab vedotin (BV) vs physician's choice (PC) in the Phase 3 ALCANZA study.
Authors: Kim Youn H. , Prince H. Miles , Whittaker Sean , Horwitz Steven M. , Duvic Madeleine , Scarisbrick Julia , Quaglino Pietro , Zinzani Pier Luigi , Wolter Pascal , Bechter Oliver , Wang Yinghui , Palanca Wessels Maria Corinna , Wood Kenneth W. , Li Martha , Liu Yi , Lin Hui-Min , Little Meredith , Danaee Hadi , Trepicchio William L. , Dummer Reinhard 
Published: September 2018

7517 Background: The Phase 3 ALCANZA study showed significant, durable responses with CD30-directed antibody-drug conjugate BV vs PC of methotrexate (MTX) or bexarotene (Bex) for CD30-positive (CD30+) cutaneous T cell lymphoma (CTCL). Uniform CD30 expression is characteristic of primary cutaneous anaplastic large cell lymphoma (pcALCL), but is variable among other subtypes including mycosis fungoides (MF). We examined activity of BV and MTX / Bex by CD30 expression in pts treated on the ALCANZA study. Methods: Adults with previously treated CD30+ MF or pcALCL were enrolled. MF pts had ≥2 skin biopsies from separate lesions, pcALCL had ≥1. Patients were scored CD30+ if ≥1 biopsy had ≥10% CD30+ lymphoid cells using an investigational Ventana diagnostic test, centrally assessed by one pathologist. We compared the proportion of MF subgroup pts (n=50 per treatment arm) with objective response lasting ≥4 months (ORR4; ALCANZA primary endpoint) and PFS in pts with all biopsies ≥10% CD30+ (CD30min ≥10%) vs ≥1 biopsy <10% CD30+ (CD30min <10%). Pts were randomized 1:1 to BV 1.8 mg/kg IV, Q3W, or PC for up to 16 three-week cycles. Results: 125/184 (68%) MF and 44/47 (94%) pcALCL pts were screened and scored CD30+. High inter-lesional variability in CD30 expression was seen in MF pts; 55/125 CD30+ MF pts (44%) had ≥1 biopsy with low (<10%) or undetectable CD30. 100/125 CD30+ MF pts were eligible and enrolled. In the BV arm, ORR4 was higher in MF pts with CD30min ≥10% vs <10%; median PFS with BV was higher in the CD30min <10% group (Table). ORR4 with BV was greater than PC over all CD30 expression ranges (CD30min <5%, 38% vs 13%; CD30 ≥5–≤20%, 35% vs 10%; CD30 >20%, 76% vs 7%, respectively). Conclusions: Notable inter-patient or inter-lesional variability in CD30 expression was seen in MF pts. Highly superior ORR4 and PFS endpoints were seen with BV over PC regardless of CD30min expression level. Clinical trial information: NCT01578499. [Table: see text]