bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of lurbinectedin (PM11083) in patients with advanced AML and MDS.
Authors: Benton Christopher Brent , Rodriguez Diaz -Pavon Jose , Maiti Abhishek , Daver Naval Guastad , Ravandi Farhad , Jain Nitin , Alvarado Yesid , Jabbour Elias , Pierce Sherry , Kwari Monica , Santos Margarida A , Martinez Sara , Siguero Mariano , Tefferi Ayalew , Cortes Jorge E. , Kantarjian Hagop M. , Pardanani Animesh Dev , Garcia-Manero Guillermo 
Published: September 2018

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with > 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions > 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.
Quality of life of acute myeloid leukemia patients in a real-world setting.
Authors: Pandya Bhavik J. , Hadfield Anna , Medeiros Bruno C. , Wilson Samuel , Bui Cat N. , Bailey Tom , Flanders Scott , Rider Alex , Horvath Laura E. 
Published: September 2018

e18525 Background: There is currently limited data on the quality-of-life (QoL) of patients with acute myeloid leukemia (AML) in the real-world setting. The objective of this analysis was to understand the impact of AML on patients receiving first-line treatment vs those who were relapsed/refractory to first-line treatment and therefore on later lines of therapy. Methods: The Adelphi AML Disease-Specific Programme, a real-world, cross-sectional survey involving 61 US hematologists/hemato-oncologists and their consulting AML patients, was conducted between February–May 2015. Physicians provided details on patient demographics and clinical information. Each patient was asked to complete both the EQ-5D-3L and Functional Assessment of Cancer Therapy Leukemia (FACT-Leu). Scores range from −1.09–1 (EQ-5D-3L) and 0–176 (FACT-Leu), where a higher score indicates a better QoL. Data from physician-completed record forms and corresponding patient self-completion forms on a matched sample of 75 patients were analyzed. Results: Of the patients who took part in the survey, 75% (n = 56) were receiving first-line treatment for AML and 25% (n = 19) were relapsed/refractory to first-line treatment and had progressed to later lines of therapy. The first-line patients had a mean age of 56.6 years and an average of 2.1 symptoms whereas the relapsed/refractory patients had a mean age of 56.9 years and an average of 2.4 symptoms, according to the physician. First-line patients may have a directionally better QoL scores than those on later lines of therapy, according to both the EQ-5D (0.75 and 0.71 respectively, P= .51) and the FACT-Leu (103.7 and 92.5 respectively, P= .098) measures. Results from the FACT-Leu-Physical Well-Being sub-domain show that relapsed/refractory patients were significantly more likely than first-line patients to be affected physically by their AML condition (13.0 and 17.6 respectively, P= .005). Conclusions: AML patients who have relapsed or become refractory to first-line treatment report worse QoL than those still on first-line treatments. These observational data shows a need for effective and tolerable treatments that can maintain or improve patients’ QoL, especially for patients with relapsed or refractory disease.
Systematic literature review and indirect treatment comparisons (ITC) of glasdegib (GLAS) plus low dose ara-c (LDAC) versus a hypomethylating agent (HMA) for previously untreated acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy (NIC).
Authors: Forsythe Anna , Arondekar Bhakti , Tremblay Gabriel , Chan Geoffrey , Su Yun 
Published: September 2018

e18526 Background: In a randomized phase 2 study, GLAS, an oral, smoothened inhibitor, combined with LDAC, showed significantly better overall survival (OS) vs LDAC alone in previously untreated AML NIC patients. HMAs azacitidine (AZA) and decitabine (DEC) are considered current standard of care in this population. An ITC was conducted to compare OS for GLAS+LDAC vs. AZA and DEC, respectively. Methods: Embase, MEDLINE, Cochrane database, and conference abstracts (ASCO, ESMO and ASH) were systematically searched through 12/2016 for relevant RCTs of GLAS, AZA and DEC in AML patients ineligible for IC. Classical frequentist ITC using the Bucher method was used to indirectly compare OS hazards ratios with 95% confidence intervals (CI) using LDAC as the common comparator. Results: Four studies met inclusion criteria: AZA Fenaux 2010, N (treatment/ comparator) = 14/20, AZA Dombret 2015, N = 241/158, DEC: Kantarjian 2012, N = 242/243, and GLAS+LDAC: Cortes 2016, N = 88/44. Upon review of baseline characteristics, Fenaux 2010 was excluded based on major population differences (% bone marrow blasts). Three studies contributed data to ITC based on comparable populations: age, cytogenic risk and OS of comparator were similar among studies: age 75/73/76 years old, poor cytogenic risk 34%/37%/39%, OS of the comparator 6.4/5.0/4.3 months in AZA/DEC/GLAS+LDAC, respectively. In the ITC, GLAS+LDAC showed significantly better OS HR vs. AZA and DEC (0.51 and 0.56 respectively) (Table). Conclusions: Using ITC, treatment with GLAS+LDAC yielded significantly better OS HR than AZA and DEC in previously untreated AML patients ineligible for treatment with IC. Limitations include mixed IC & NIC population for the AZA trial, and mixed comparator arm of both LDAC and BSC for the DEC trial. Analyses using patient-level data matching baseline characteristics across studies may enable more robust ITC. [Table: see text]
Stroma-free long-term growth of primary acute myeloid leukemia (AML) cells.
Authors: Chen Jing , Ibanez Sanchez Glorymar , Calder Paul , Frattini Mark G. 
Published: September 2018

e18535 Background: To individualize therapy for relapsed/refractory AML patients, optimal in-vitro culture conditions to support primary leukemic cells are essential for drug sensitivity testing. Our lab has validated a high throughput chemosensitivity assay with primary AML cells maintained by growth factors (cytokines); however, growth factors have not been shown to support long-term assays of primary AML cells. Stromal cells of the tumor microenvironment are crucial to maintain normal hematopoiesis and leukemic cells and have been shown to support long term in-vitro expansion of primary AML cells. However, there is little information characterizing these growth conditions. The aim of this study was to compare long-term proliferation and phenotypes of primary AML cells with growth factors or stromal support to best determine their utility as a platform for drug sensitivity testing in functional assays. Methods: Patient-derived AML cells were cultured in 96-well plates in: 1) cell culture medium only 2) Human HS5 or HS27 stromal cells 3) HS5 or HS27 stroma-conditioned media or 4) cytokine cocktail. Viability readout by Guava ViaCount and leukemic cell surface phenotypes by fluorescently-conjugated antibodies were performed weekly over 3 weeks. Results: Primary AML cells cultured with only cytokines maintained proliferation at 3 weeks. In comparison, AML cells cultured in HS5 stroma-conditioned medium also maintained proliferation at a similar rate at 3 weeks, while co-culture with HS5 stromal cells demonstrated significantly higher proliferation. Leukemic immunophenotypes were maintained for all growth conditions over 3 weeks. Conclusions: Contrary to known data, primary AML cells with cytokines continued to expand at 3 weeks, at a similar rate to HS5 stroma-conditioned medium, a finding that has not been reported. Consistent with previous studies, we confirmed that stromal cells such as HS5 can provide long-term in-vitro expansion of primary AML cells, which cannot be substituted by stroma-conditioned medium. The ability to maintain long-term expansion of primary AML cells by both cytokines and stromal cells sets up a platform for a direct comparison of high throughput drug sensitivity testing under these growth conditions.
Influence of acute graft-versus-host disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (HSCT) engraftment admission on hospital length of stay (LOS), charges, and costs.
Authors: Yu Jingbo , Parasuraman Shreekant , Shah Anshul , Narayanan Siva 
Published: September 2018

e18544 Background: aGVHD is a common complication of allogeneic HSCT and a significant cause of transplant-related morbidity and mortality. Limited data exist on healthcare resource use and costs of aGVHD during HSCT engraftment admission. This study estimated LOS, charges, and costs of aGVHD during HSCT engraftment admission in the US. Methods: Inpatient discharges between 2009-2013 using the Nationwide In-patient Sample (NIS) database were analyzed. NIS is a representative (20% stratified) sample of all discharges from US community hospitals included in the Healthcare Cost and Utilization Project (HCUP). Discharges for allogeneic HSCT engraftment admissions with aGVHD (ICD-9 279.51) were compared with those without GVHD. Costs were calculated from hospital charges using a standard HCUP Charge-to-Cost Ratio. LOS, charges, and costs were compared using Wilcoxon rank sum test. Correlation between LOS and charges or costs was calculated using Pearsons coefficient. Results: 729 discharges with aGVHD and 5958 discharges without GVHD were analyzed. Demographic characteristics were similar for both groups except age: female (40% vs 42%), Caucasian (67% vs 68%), private insurance (60% vs 63%); mean age was 39 and 45 years for patients with and without aGVHD respectively (p < 0.001). In-hospital mortality rate was 16% for patients with aGVHD vs 5% without GVHD (p < 0.001). Despite younger age of the aGVHD group, mean unadjusted LOS was significantly longer, and mean unadjusted charges and costs were significantly higher with aGVHD vs without GVHD (54.2 days vs 29.8 days, $690,244 vs $366,213, $218,425 vs $122,387, respectively). Charges and costs were directly proportional to LOS (r = 0.711, p < 0.001). Conclusions: Overall, occurrence of aGVHD during HSCT engraftment admission resulted in almost doubling of LOS, charges, and costs. Mitigating aGVHD may reduce LOS and subsequent inpatient resource use for HSCT. [Table: see text]
Long term efficacy of nilotinib as front- and second-line therapy in Bosnia and Herzegovina: Real life experience.
Authors: Kozaric Amina Kurtovic , Islamagic Erna , Beslija Semir , Kurtovic Sabira , Mehinovic Lejla , Hasic Azra 
Published: September 2018

e18549 Background: In this study we examined the long-term real life clinical outcomes of patients receiving front- line nilotinib and patients who switched from branded or generic imatinib to nilotinib (second-line therapy) in Bosnia and Herzegovina. Methods: Patients in CML-CP (n = 70) who started their TKI treatment in period from June 2005 to August 2016 were included in this multicentre retrospective cohort study. Patients were categorized as: Group 1 (n = 31) contained patients receiving front-line nilotinib (300 mg twice daily) and Group 2 (n = 39) consisted of patients who started with front-line imatinib (Glivec or generic imatinib) and then were switched to nilotinib (400 mg or 600 mg twice daily). Nilotinib became available as front or second-line therapy in March 2011. Standard patients' variables were collected and disease progression was established as loss of CCyR and MMR. Survival probabilities were estimated with the Kaplan-Meier method and compared using the log-rank test. Results: Seventy patients (median age was 54.5 years; 61% was males) were enrolled in this study. The median follow-up was 39 months (range 3-51 months). Median wait period for therapy was 12 months (range 1-62) from diagnosis. In both studied groups, overall survival was 87% at 39 months. According to ITT principle, achievement of CCyR and MMR at 24 months on nilotinib therapy was higher in Group 1 compared to Group 2 (81% vs 67% and 74% vs 49%, respectively). Rate of death was similar in both studied groups (4/31 vs 5/39). In Group 2, five patients who had suboptimal response on front-line imatinib discontinued therapy (median period of 19.5 months) were switched when nilotinib became available. Interestingly, none of these patients died. Conclusions: Our results suggest that at 3 years, there was no difference in the overall suvival between studied groups. However, achievement of CCyR and MMR at 24 months was higher in patients on front-line nilotinib therapy. Patients who waited for therapy had optimal response regardless the wait period on nilotinib therapy.
Early results of lower-dose dasatinib, 50 mg daily, in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.
Authors: Naqvi Kiran , Cortes Jorge E. , Skinner Jeffrey A , Jabbour Elias , Pemmaraju Naveen , Borthakur Gautam , Estrov Zeev , Bose Prithviraj , Thompson Philip A. , Kantarjian Hagop M. 
Published: September 2018

e18551 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. The approved dose in chronic phase is 100mg orally daily. Notable side effects include pleural effusions and myelosuppression.We evaluated the efficacy and toxicity profile of dasatinib 50mg orally daily in patients with newly diagnosed CML-CP. Methods: Adults with newly diagnosed CML-CP were eligible. Prior TKI therapy for up to 1 month was allowed. Eligibility criteria were standard. Patients received dasatinib 50mg daily. Responses were defined according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122:872-884). Results: From March 2016 until January 2017, 30 patients were enrolled. Median age was 47 years (22 to 84). Sokal risk was low in 17 patients, intermediate in 10, and high in 3. Response data are shown below. Among 7 patients not in CCyR at 3 months by FISH (% FISH + 3, 3.5, 4.5, 5.5, 7, 9 and 83%), the respective BCR-ABL transcripts (IS) were 0.49, 0.08, 0.1, 0.09, 0.60, 0.69 and 9.2%. Thus, 6/7 patients with FISH + disease at 3 months had BCR-ABL transcripts (IS) < 1%, and 17/18 patients evaluable at 3 months had BCR-ABL transcripts (IS) < 1% (equivalent to CCyR). Significant myelosuppression requiring treatment interruption occurred in only 1 patient. No patients so far had pleural effusions requiring intervention. To date, there have been no dose modifications. Conclusions: Dasatinib 50mg daily is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule standard-of-care in CML. [Table: see text]
Clinical significance of HFE gene mutations in patients with refractory anemia with ring sideroblasts (RARS).
Authors: Nanah Rama , Patnaik Mrinal , Gangat Naseema , Zblewski Darci , He Rong , Nguyen Phuong L. , Elliott Michelle A. , Hogan William J. , Litzow Mark Robert , Al-Kali Aref 
Published: September 2018

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.
Chronic hepatitis C as an adverse prognostic factor in myelodysplastic syndromes.
Authors: Thibaud Santiago , Kaner Justin D. , Shastri Aditi , Budhathoki Anjali , Sridharan Ashwin , Goel Swati , Mantzaris Ioannis , Janakiram Murali , Kornblum Noah Saul , Braunschweig Ira , Verma Amit 
Published: September 2018

e18557 Background: Chronic hepatitis C virus (HCV) infection has been associated with hematologic malignancies such as B-cell non-Hodgkin lymphoma. In contrast, there is very little known about the relationship between HCV and myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). To determine the effect of HCV on MDS/AML clinical outcomes we conducted a retrospective analysis in a large inner city cohort of patients (pts) Methods: 478 pts with MDS and MDS-transformed AML were identified between 1997 and 2016; 13 pts were HCV-positive (HCV+/MDS) and 465 were HCV-negative (HCV-/MDS). Demographics, hematologic parameters, cytogenetics, IPSS-R scores and molecular profiles were compared for both groups (grp). Survival (surv) analysis was done using the Kaplan-Meier method Results: HCV+/MDS had significantly worse surv than HCV-/MDS pts on univariate analysis (UA) (median surv 16 vs 52 months, HR 2.8, 95% CI 1.4-5.5, p < 0.01). Difference remained strongly significant after exclusion of HIV-coinfected pts (HR 2.7, p = 0.02) and pts w/ AML on presentation (HR 3.1, p < 0.01). Cytopenias were worse in HCV+/MDS (mean Hgb level 8.2 vs 9.4 g/dl, p = 0.04; mean plt count 64 vs 139 103/µL, p = 0.03). Average IPSS-R score was higher in HCV+/MDS pts (5.5 vs 3.8, p = 0.02). IDH1 mutation was more prevalent in HCV+/MDS (25% vs 2%, p < 0.01). Differences in age between HCV+/MDS and HCV-/MDS were non-significant (mean 64 vs 69 respectively, p = 0.2). Male-to-female ratio was higher in HCV+/MDS but difference was non-significant (2.3 vs 0.9, p = 0.2). Interestingly, high HCV viral load and cirrhosis did not correlate with poor surv in the HCV+/MDS grp, suggesting deleterious effect occurs even in early stages of HCV infection. Conclusions: Our analysis suggests that chronic HCV infection strongly correlates with worse surv in UA and is associated with lower blood counts and higher IPSS-R scores at the time of diagnosis of MDS. We observed a high rate of MDS refractory to standard therapies and speculate that HCV may affect biology of the disease. Larger studies are warranted to determine the effect of HCV on surv in this population and to provide a rationale for trials of anti-HCV drugs concomitantly with MDS Tx.