bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and cost of peripheral blood stem cell (PBSC) mobilization with low-dose cyclophosphamide (LD-CY) compared with plerixafor (P) in multiple myeloma (MM) patients (pts) treated with novel induction therapies.
Authors: Chaudhary Lubna , Awan Farrukh Tauseef , Cumpston Aaron , Tse William W. , Craig Michael , Hamadani Mehdi 
Published: March 2020

7040 Background: Efficacy and cost effectiveness of P vs. LD-CY mobilization in MM pts treated with novel induction therapies is not known. Methods: We analyzed the mobilization outcomes of 107 consecutive pts who underwent a planned, single autograft within 1-year of starting induction therapy with novel agents (thalidomide, lenalidomide, bortezomib) between 2003-2012. Pts undergoing mobilization with LD-CY/G-CSF (1.5gm/m2) (n=74) were compared against those receiving P/G-CSF (0.24mg/kg) (n=33). Efficacy of PBSC mobilization was assessed by evaluating peak peripheral blood (PB) CD34+ cell counts, CD34+ cell yield on day1 of collection, total CD34+ cell collection, and total number of apheresis sessions. Mobilization failure was defined as failure to collect ≥2 x106 cells/kg body weight. Mobilization costs were calculated per patient in both groups. Centers for Medicare and Medicaid Services reimbursement rates and Red Book Average Wholesale Price were used for cost determination. Results: At baseline, the LD-CY and P cohorts were well balanced. Compared to LD-CY, P use was associated with higher median peak PB CD34+ cell count (68/µl vs. 36/µl, p=0.048), CD34+ yield on day 1 of collection (6.9 x106/kg vs. 2.4 x106/kg, p=0.001), and total CD34+ cell yield (11.6 x106/kg vs. 7x106/kg, p=0.001). Median numbers of apheresis sessions were 2 in each group (p=0.17). In pts with prior lenalidomide use, mobilization failure rate in the LD-CY group was higher compared to the P group (20% vs. 0%, p=0.01). P group had a higher number of pts collecting ≥10x106/kg CD34+ cells (60.6% vs. 31%, p=0.01). Rate of infectious complications, transfusion requirements and hospitalizations was similar in both groups. The average total cost of mobilization in the P group was significantly higher compared to the LD-CY group ($28,980 vs. $19,627, p-value<0.0001). Conclusions: Our data indicates that although associated with a significantly higher total mobilization cost, plerixafor produced a more robust PBSC mobilization, without any collection failures.
Frequency of rare cytogenetic abnormalities at relapse in acute myeloid leukemia (AML) with FLT3 internal tandem duplication (ITD) and normal karyotype at diagnosis: Evidence for genomic instability?
Authors: Gourdin Theodore Stewart , Ning Yi , Rassool Feyruz , Tidwell Michael , Duong Vu , Emadi Ashkan , Baer Maria R. 
Published: March 2020

7049 Background: FLT3-ITD mutations are present in AML in 30% of patients, most commonly with a normal karyotype, and are associated with short disease-free survival. In vitro and in vivo studies of FLT3-ITD cell lines and patient samples have demonstrated DNA double-strand break repair by an alternative highly error-prone form of non-homologous end-joining (ALT NHEJ), resulting in illegitimate ligation of non-contiguous DNA breaks, causing DNA deletions and translocations that may contribute to disease progression. To look for clinical evidence of genomic instability, we reviewed cytogenetic changes at relapse. Methods: Charts of patients with cytogenetically normal AML with FLT3-ITD treated at the University of Maryland Greenebaum Cancer Center were reviewed along with metaphase analysis results at diagnosis and relapse. Results: Cytogenetic data were available from first and, when applicable, subsequent relapses for 12 patients with cytogenetically normal AML with FLT3-ITD who relapsed, including 5 following allogeneic hematopoietic stem cell transplantation (allo HSCT). Ten patients acquired cytogenetic changes, many of them rare translocations and inversions (Table). Conclusions: AML with FLT3-ITD and normal karyotype at diagnosis has a high frequency of rare cytogenetic abnormalities at relapse, providing clinical evidence for genomic instability. These data may support the potential therapeutic role of inhibitors of ALT NHEJ repair proteins, such as PARP1 and DNA ligase IIIa, in AML with FLT3-ITD. [Table: see text]
Impact of early molecular response to nilotinib (NIL) or imatinib (IM) on the long-term outcomes of newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): Landmark analysis of 4-year (y) data from ENESTnd.
Authors: Saglio Giuseppe , Hughes Timothy P. , Larson Richard A. , Issaragrilsil Surapol , Turkina Anna G. , Steegmann Juan Luis , Lopez Jose L. , Nakaseko Chiaki , Kalaycio Matt E. , Huguet Francoise , Kemp Charisse N. , Fan Xiaolin , Menssen Hans D. , Kantarjian Hagop M. , Hochhaus Andreas 
Published: March 2020

7054^ Background: ENESTnd demonstrated the superiority of NIL to IM in pts with newly diagnosed CML-CP, such as higher rates of molecular response (MR) and reduced risk of progression to accelerated phase (AP)/blast crisis (BC). This landmark analysis of ENESTnd is based on BCR-ABL transcript levels at 3 mo, with 4 y of follow-up. Methods: Rates of major MR (MMR; BCR-ABLIS ≤ 0.1%), MR4.5 (BCR-ABLIS≤ 0.0032%), progression to AP/BC, overall survival (OS), and progression-free survival (PFS) in pts in the NIL 300 mg twice daily (BID; n = 282) and IM 400 mg once daily (QD; n = 283) arms of ENESTnd were evaluated based on 3-mo BCR-ABL levels (≤ 10% vs > 10%). Results: More pts treated with NIL than IM achieved BCR-ABL ≤ 10% at 3 mo (91% vs 67%; Table). Other factors associated with MR at 3 mo included Sokal risk, spleen size, chromosomal abnormalities, white blood cell count, and median dose intensity (for NIL). On both arms, pts with BCR-ABL ≤ 10% at 3 mo had significantly higher rates of MMR and MR4.5and significantly improved PFS and OS than pts with BCR-ABL > 10% at 3 mo. Of the pts with BCR-ABL > 10% at 3 mo, 2 on NIL (8%) and 14 on IM (16%) progressed to AP/BC on study. Half of these progressions occurred between 3 and 6 mo. Analyses of outcomes based on BCR-ABL levels at 6 mo were similar to findings based on 3-mo data. Conclusions: BCR-ABL levels ≤ 10% at 3 mo were associated with superior outcomes, including higher rates of MR4.5 by 4 y and lower risk of disease progression. More pts treated with NIL than IM achieved this early level of MR. Clinical trial information: NCT00471497. [Table: see text]
High-dose cytarabine-mitoxantrone versus hyper-CVAD in adult acute lymphoblastic leukemia and Burkitt’s lymphoma: A single center experience of two induction regimens.
Authors: Lamba Gurpreet Singh , Pawar Rahul , Marballi Abhishek , Lee Sang-Joon , Liu Delong 
Published: March 2020

7076 Background: This is a retrospective analysis of 111 newly diagnosed adult ALL patients treated between January 1994 and January 2012 at Westchester Medical Center. Methods: Patients received induction chemotherapy with either high dose mitoxantrone and high-dose Ara-c (HDAM, n=62) or Hyper-CVAD (n=49). The patient characteristics are summarized in the table. OS, CR duration and time to recurrence were estimated using the Kaplan-Meier product estimate methods and comparative study was conducted based on Log-rank test. Differences in CR rates by treatment and by prognostic factors were analyzed using Chi-squared test and Fisher’s exact test. Results: The CR rate was 85% in the HDAM group and 84% in the HyperCVAD group. The median OS was 22.7 months (m), (95% CI 15.3-38.3 m) for the entire cohort, 21.4 m (95% CI 13.3 - 35.5 m) for HDAM arm and 26.8 m (95% CI 11.7 - 63.3 m) for HyperCVAD arm. The OS for patients with Philadelphia chromosome positive or t(4,11) was 13.2 m (95 % CI 9.5 – 26.8 m). In an analysis of the entire cohort for differences in CR rates based on prognostic factors, WBC < 10,000 was the only favorable factor toward CR (p=0.049). Other prognostic factors including cytogenetics, cell type, age, LDH, were not statistically significant. Conclusions: HDAM and Hyper-CVAD appear to be comparable in CR induction and overall survival in this single institution retrospective analysis. These two regimens should be compared in a large multicenter randomized study. [Table: see text]
Economic benefits of adequate molecular monitoring in patients with chronic myelogenous leukemia (CML).
Authors: Chen Lei , Guérin Annie , Wu Eric Q. , Dea Katherine , Goldberg Stuart L. 
Published: March 2020

7093 Background: Molecular monitoring every 3 months using quantitative polymerase chain reaction (qPCR) of BCR-ABL mRNA transcripts on International Scale is recommended by the National Comprehensive Cancer Network and the European LeukemiaNet for patients (pts) in chronic phase of CML. A previous study has shown an underutilization of qPCR in the community setting. This study assessed the impact of the frequency of molecular monitoring on hospitalization and medical costs among CML pts receiving 1st-line tyrosine kinase inhibitor (TKI) therapies. Methods: Two U.S. administrative claims databases were combined (01/2000-06/2012) to identify adult CML pts initiated on TKIs (imatinib, dasatinib, nilotinib). Pts were followed for 12 months from their first TKI prescription and categorized into 3 cohorts based on frequency of qPCR tests (i.e., 0, 1-2, and 3-4). Number of inpatient admissions and medical service costs (measured from a US payer perspective; adjusted to 2012 U.S. dollars) were compared between cohorts. Multivariate regression models adjusted for confounding factors (e.g., age, gender, CML complexity, TKI). Results: The study included 1,205 CML pts. Over the 12-month study period, 41.0% of the pts had no qPCR test, 31.9% had 1-2 tests, and 27.1 % had 3-4 tests. Compared to pts with no qPCR monitoring, those with 3-4 tests incurred 37% fewer CML-related (i.e., a primary CML diagnosis) inpatient admissions (p=.017) during the study period, leading to a $4,000 (p=.009) reduction in CML-related inpatient costs and $5,663 (p=.005) reduction in all-cause inpatient costs, accounting for the majority of the $5,997 reduction in total medical service costs (p=.049). Pts with 1-2 tests a year showed smaller and statistically insignificant reductions from those with no test in the frequency of hospitalization and medical costs. Conclusions: Among CML pts who initiated 1st-line TKIs, pts with 3-4 qPCR tests a year incurred fewer inpatient admissions and lower medical service costs compared to pts with no test. These findings suggest that pts would benefit from regular qPCR testing and underscore the value of molecular monitoring in the delivery of quality care for Ph+ CML-CP pts on TKI therapies.
Predictors of survival in patients with transformed chronic lymphocytic leukemia (TC).
Authors: Falchi Lorenzo , Keating Michael J. , Wang Xuemei , Schlette Ellen J. , Sargent Rachel L. , Marom Edith M. , Truong Mylene , Wierda William G. , Ferrajoli Alessandra 
Published: March 2020

7098 Background: Patients with CLL that develop Richter’s syndrome (RS) have a very poor prognosis. Similarly, pts with CLL that have clinical and histological features (increased large cells/prolymphocytes in CLL tissue biopsy) of increased aggressiveness (defined as accelerated phase CLL, AP) have a poor prognosis. In order to identify prognostic factors in pts with AP and RS, collectively referred to as TC, we reviewed our center experience. Methods: Pts with TC and complete evaluation including biopsy and concomitant FDG/PET were included. Pts with de novo TC were excluded as their prognosis is substantially superior versus previously treated pts. Pts with N+ or M+ concurrent solid tumors were also excluded. Since FDG/PET-derived SUV reflects tumor proliferative rate, we used SUVmax≥10 to indicate high-risk disease (Falchi, Blood. 2012;120: abstr # 927). We identified factors associated with outcome and performed a multivariable model for OS. Results: One hundred eighty-three consecutive pts with TC (99 with AP and 84 with RS) were evaluated at MDACC between 2002 and 2012. Demographic and clinical characteristics were similar between pts with AP and pts with RS. 30% and 77% of pts with AP and RS, respectively had an SUVmax≥10. Approximately half of the pts were treated with intensive chemoimmunotherapy after the TC diagnosis. CR rates were 21% and 16% and overall response rates were 37% and 26% for pts with AP and RS, respectively. At the time of this analysis 144/183 pts have died, for a median OS of 9.6 months (7.9-14.7). Age ≥65, B symptoms, LDH, β2-microglobulin, del17p, SUVmax≥10, extensive disease by FDG/PET (SUVmax≥5 on both sides of the diaphragm), PS≥2 bulky disease and high Ki67 correlated with shorter OS. In multivariable analysis SUV uptake (max≥10), PS higher than 1 and bulky nodal disease (>5 cm) retained independent significance. Conclusions: Based on our experience, an SUVmax of 10 or higher, PS higher than 1 and bulky nodal disease (>5 cm) are the most important factors predicting outcome in pts with TC. A prognostic model for survival is being developed for pts with TC.
Trends and outcomes of severe sepsis in hematopoietic stem cell transplant recipients.
Authors: Guddati Achuta Kumar , Kumar Gagan 
Published: March 2020

7127 Background: Sepsis is common in hematopoietic stem cell transplant (HSCT) patients due to deficient immune system in the early part of the transplant and in patients with graft versus host disease (GVHD). There is very limited data on outcomes and trends of severe sepsis (SS) in these groups of patients. Methods: Using the Nationwide Inpatient Sample 2000-2008, patients older than 18 years, discharged with SS were identified using ICD-9-CM codes. Status of HSCT was identified using ICD-9-CM codes 41.0x. We also identified subsequent hospital admissions using ICD-9-CM codes V42.81-82 and 996.85 and GVHD using 279.5x. Hospital mortality was the primary outcome studied. Chi square test was used for comparison. Logistic regression model was constructed to examine the independent effect of HSCT on mortality in patients with SS. We adjusted for age, gender, race, insurance, hospital characteristics, Charlson's co-morbidity index and severity of sepsis using number of organ failures. Results: Of the 291,182 admissions with HSCT from 2000 to 2008, 7.5% had SS. The rate of SS was 5 times higher in HSCT when compared to non transplant group. In engraftment period, allogenic transplant had higher rates of SS when compared to autologous (13.2% vs. 5.2%, p<0.001). During engraftment, in-hospital mortality with SS was higher in allogenic transplant (55.1%) compared to autologous group (30.1%) (mortality in non-transplant was 32.9%). On adjusted analysis, compared to non transplant group, the odds of mortality was 4.69 times (95%CI 2.85-7.69) higher in allogenic transplants while it was similar in autologous group. In subsequent admissions, the odds of mortality were 2.38 times (95%CI 2.10-2.69) higher in GVHD and 1.45 times higher (95%CI 1.28-1.65) in non-GVHD patients when compared to the non-transplant group. The in-hospital mortality in HSCT decreased from the year 2000 to 2004 but has not changed ever since, while in the non-transplant group the mortality has continued to decrease. Conclusions: Higher mortality is observed in allogenic transplant patients and in those developing GVHD when compared to non-transplant patients. The mortality due to SS in HSCT patients has not changed since 2004 and may warrant more aggressive interventions.
Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small cell lung cancer: A randomized, placebo controlled phase II study CALGB 30504 (ALLIANCE).
Authors: Ready Neal , Pang Herbert , Gu Lin , Otterson Gregory Alan , Thomas Sachdev P. , Miller Antonius Arthur , Baggstrom Maria Quintos , Masters Gregory A. , Graziano Stephen L. , Crawford Jeffrey , Bogart Jeffrey , Vokes Everett E. 
Published: March 2020

7506 Background: Sunitinib (S) inhibits small cell lung cancer (SCLC) targets VEGFR1-3, PDGFR, and KIT. We tested whether giving S after chemotherapy (C) for extensive stage SCLC improves progression free survival (PFS). Methods: CALGB 30504 was a randomized, double-blind, placebo (P) controlled phase II study for untreated SCLC, performance status 0-2, adequate organ function, and no S risk factors: bleeding, hypertension, or brain metastases. Enrollment was prior to C: cisplatin 80 mg/m2 or carboplatin AUC5 day 1 plus etoposide 100 mg/m2days 1-3 every 21 days 4-6 cycles. Patients without progression after C were stratified cisplatin vs carboplatin, and 4-5 vs 6 cycles C, and randomized 1:1 to P or S 37.5 mg daily until progression assessed every 6 weeks. Prophylactic cranial irradiation was offered to responders (CR or PR) to start about 4-6 weeks after C. S was held during radiation. Crossover from P to S was allowed at progression. Primary endpoint was PFS (from time of randomization) for maintenance (M) P vs S using a 1-sided log rank test with a=0.15; 80 randomized and treated patients provide »89% power to detect a hazard ratio (HR) of 1.67. Results: Between 5/09 and 12/11, 144 enrolled and 138 received C. Ninety five were randomized to P vs S; 10 did not receive M due to progression, refusal, and AE (5 each arm). Eighty five received M, 41 P and 44 S. Demographics were balanced. M toxicities grade > 3 and incidence > 5% included (%): grade 3 (S: fatigue 19, neutrophils 10, leukocytes 7, platelets 7) (P: fatigue 5); grade 4 (S: 1case GI hemorrhage, 1case lipase) P zero; grade 5 zero both arms. Efficacy (90% CI): PFS on maintenance after C was P 2.3 mo (CI: 1.7-2.6) and S 3.8 mo (2.7-4.4) (HR=1.54, CI 1.03-2.32, p=0.04). Overall survival (OS) was P 6.7 mo (5.5-9.5) and S 8.8 mo (8.0-9.8) (HR=1.10, CI 0.71-1.70, p=0.36). At progression on P, 17 received S and among 14 evaluable 10 (71%) had stable disease receiving 2-9 cycles S. Conclusions: The primary objective was met showing improved PFS for maintenance S. There was a non-significant trend toward improved OS despite crossover design. S was well tolerated. Further study of sunitinib after chemotherapy for SCLC is justified. Clinical trial information: NCT00453154.
Comprehensive genomic analysis of small cell lung cancer in Asian patients.
Authors: Umemura Shigeki , Goto Koichi , Mimaki Sachiyo , Ishii Genichiro , Ohmatsu Hironobu , Niho Seiji , Yoh Kiyotaka , Matsumoto Shingo , Takahashi Akiko , Nagai Kanji , Ohe Yuichiro , Esumi Hiroyasu , Tsuchihara Katsuya 
Published: March 2020

7512 Background: Small cell lung cancer (SCLC) is an aggressive disease with poor prognosis. There is an urgent need for detecting well-defined therapeutic targets, however, little is known about the molecular events causing SCLC. This report describes findings from the integrated genomic analyses of 47 human SCLC samples in Asian population. Methods: We performed whole exome sequencing and copy number analysis on surgically resected tumor and matched normal samples from previously untreated Japanese patients with SCLC. Frequency of driver gene alterations were compared with previous two reports intended for non-Asian population (Peifer et al. Nature Gen 2012 and Rudin et al. Nature Gen 2012). Results: The demographics of 47 patients were as follows: median age 67 years (range: 42-86); female 8 (17%); history of smoking 47 (100%) and pathological stage I/II/III/IV=26/12/8/1. The average of protein-altering mutations was 193 (range: 51-633, standard deviation: 129). Genomic alterations including copy number amplifications and deletions in at least one of three frequently occurred driver genes, TP53, RB1, and MYC family, were detected in 93.6% of tumors. Mutation frequencies were 76.6%, 42.6%, and 12.8% for TP53, RB1, and MYC family respectively, which were equivalent to the previous reports. Recently reported candidate new driver genes were also recurrently confirmed in the present study: PTEN 4.3%, CREBBP 4.3%, EP300 4.3%, SLIT2 4.3%, MLL 4.3%, CCNE1 8.5% and SOX2 2.1%. Many of them were potentially targetable with currently available drugs. Conclusions: The genomic landscape of SCLC was not significantly different between Asian and non-Asian population. We perform additional targeted re-sequencing on biopsy samples obtained from metastatic SCLC to further assess the relevance of our results.
Prognostic and predictive effects of a gene expression signature for NRF2 pathway activation in lung squamous cell carcinoma (SqCC).
Authors: Cescon David W. , She Desmond , Zhu ChangQi , Sakashita Shingo , Pintilie Melania , Shepherd Frances A. , Tsao Ming Sound 
Published: March 2020

7517 Background: Genomic profiling of SqCC in TCGA identified somatic alterations that activate the NRF2 transcriptional program – a master regulator of the oxidative stress response – in ~35% of tumors (NFE2L2 mutations/amplifications, KEAP1 or CUL3 mutations/deletions). This pathway has been implicated in resistance to chemotherapy. To evaluate the clinical significance of this molecular subset, we developed a gene expression classifier and tested this signature as a predictor of adjuvant chemotherapy benefit with cisplatin/vinorelbine (cis/vin) in a subset of SqCC patients with microarray data from the NCIC JBR.10 Phase III clinical trial. Methods: Logistic regression (LR) and SAM analysis were independently applied to 104 TCGA SqCC cases that had both microarray gene expression and mutation data to identify genes associated with NRF2 pathway mutational status. Overlapping genes were used to define the signature, which was then tested in 3 independent SqCC datasets (62 JBR.10; 54 UHN; 129 UM) to evaluate the prognostic and predictive values of putative NRF2 pathway activation. Results: 29 genes comprising the signature were identified by overlap between LR (291 genes) and SAM (45 genes). The signature consistently separated SqCC into 2 groups in all datasets, corresponding to putatively activated and wild type (WT) NRF2 pathway tumors. No prognostic effect of the activated signature was observed in independent datasets (UHN HR 0.86, 95%CI 0.28 – 2.67; UM HR 1.43, 95%CI 0.82 – 2.48). Similarly, in JBR10, no prognostic effect was observed in the observation arm (n=24, HR 0.66, 95%CI 0.13 – 3.29). A trend toward improved survival with adjuvant chemotherapy was observed in patients with the WT signature (HR 0.34, 95%CI 0.08 – 1.78, p=0.13), but not in patients with the activated signature (HR 1.16, 95%CI 0.19 – 6.97, p=0.87; interaction p=0.18). Conclusions: A gene expression signature based on mutational activation of the NRF2 pathway may be predictive of benefit from adjuvant cis/vin in SqCC. Patients with NRF2 pathway activating somatic alterations may have reduced benefit from this therapy. Validation of this potentially "actionable" finding in additional datasets is necessary.