bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (BC): Relationship between perceived and measurable cognitive deficits.
Authors: Heflin Lara , Fang Sally , DeLuca Amy N , Melisko Michelle E. , Moasser Mark M. , Park John W. , Chien Amy Jo , Munster Pamela N. , Esserman Laura , Landau Susan M , Jagust William J , Kramer Joel H , Rugo Hope S.
Published: March 2020

6619

Background: Cognitive complaints are common among patients (pts) receiving adjuvant therapy (Rx) for early stage BC. Longitudinal prospective data is needed to help understand the relationship between measured cog fcn, patient reported cognitive changes, and patient reported depression and fatigue. We conducted a prospective trial to evaluate the effects of chemo- (CTX) and hormone therapy (HRx) on brain and cog fcn in pts with early stage BC using multiple objective and subjective tests as well as MRI/PET imaging. Here we report relationships between objective measures and patient reported outcomes (PRO). Methods: Eligibility included female pts planning to receive adjuvant Rx for ESBC. Pts were enrolled in 3 Rx groups (grps): CTX, CTX & HRx, and HRx, with a 4thno Rx age/education matched control group. All pts underwent a battery of objective and subjective cog tests before start of rx, 1 mo after CTX or 5 mo after start of HRx (FU1), then 9 mo (FU2) and 18 mo (FU3) after CTX. Brain MRI, PET and serum estradiol were performed at baseline, FU1 and FU2. Results: 81 pts were enrolled as follows: 14 CTX, 33 CTX & HRx, 22 HRx, and 12 control. 90% completed FU1, 72% FU2, and 62% FU3, with 29 pts waiting to complete testing. Demographics were similar between grps, median age was 54 (range 34-71), 78% were Caucasian. At FUP1, depression (BDI-II) and fatigue predicted poorer overall perceived cog fcn (FACT-Cog); decline in letter fluency (FAS) on cog testing also predicted poorer overall perceived cog fcn (FACT-Cog). Decline in verbal memory (CVLT-II) predicted perceived memory deficits (FACT-Cog Memory), even after controlling for depression and fatigue. Conclusions: In pts receiving adjuvant Rx for early stage BC, depression, fatigue, and decline in letter fluency predicted poorer perceived cog fcn. Decline in verbal memory independently predicted perceived memory deficits, demonstrating that PRO are related to actual deficits in cog fcn. Future intervention studies should focus on these factors. Funding: NIH R01 1AG025303-01A2. Clinical trial information: NCT00755313.
Results of a feasibility analysis of quality indicators for outpatient cancer care.
Authors: Hermes Kerstin , Baumann Walter , Zimmermann Andreas , Schmitz Stephan H.
Published: March 2020

6623

Background: Quality indicators are increasingly used for measuring quality of care, for internal quality assurance, confidential benchmarking processes and anonymous quality reporting. The WINHO quality indicators project aims to develop and examine process quality measures for outpatient cancer care in Germany. This project is fully funded by the German Cancer Aid (Deutsche Krebshilfe). Currently, a set of 46 quality indicators exists. To gain better insights into what data can be retrieved from patient records and documentation systems in oncology practices, a feasibility analysis was conducted prior to data collection. Methods: 2176 questionnaires focusing on different aspects of the feasibility of quality indicators were sent to 295 doctors of WINHO partner practices. 1089 questionnaires were answered. Hence, for each of the 46 WINHO quality indicators 20 to 27 answers are available. Results: Although about 80% of the data required for the indicators are documented in patient charts, less than 30% of the data can be retrieved electronically. Particularly, data for indicators of the quality of pain management, holistic and palliative care often cannot be retrieved easily. By contrast, data on basal documentation, therapy planning and implementation are easier to obtain from patient charts. As a result, these indicators experience better evaluations by the office-based oncologists regarding frequency of occurrence, acceptance and reliability. However, high standard deviations show that documentation habits vary considerably within the group of office-based cancer specialists. Conclusions: Despite the large amount of data documented by oncologists in everyday practice, the information required to measure quality of care with indicators is complicated by low retrievability of data. Facilitating improved documentation and IT systems in oncology practices would ease the collection and examination of the rich information documented by office-based oncologists.
The lifetime economic burden of inaccurate HER2 testing: Comparing false positive and false negative HER2+ early breast cancer patients in the United States.
Authors: Garrison Louis , Babigumira Joseph , Masaquel Anthony , Wang Bruce , Lalla Deepa , Brammer Melissa
Published: March 2020

6626

Background: Trastuzumab is administered to patients with early breast cancer (EBC) whose tumors test positive for HER2 using IHC or FISH diagnostic tests. However, due to test characteristics and testing heterogeneity, patients may be misdiagnosed as false positive (FP) or false negative (FN). This analysis estimates the lifetime economic burden of inaccurate HER2 testing in the US. Methods: We developed a national-level economic model to estimate the impact on healthcare costs and quality-adjusted life years (QALYs) in both groups in 2012. The model estimates the expected number of FP and FN patients using literature-derived estimates of each test’s sensitivity, specificity, and utilization. Based on estimates from the literature, a FP patient would generate unneeded trastuzumab costs of about $56,000 and experience a chance (2.9%) of related cardiotoxicity; an FN patient would save $56,000 in trastuzumab costs, but lose 1.7 QALYs of life expectancy and face a greater likelihood of recurrence and associated costs ($42,000) to treat metastatic disease. A net monetary benefit approach (valuing healthy life years at $100,000) is used to compare the lifetime economic burden for FP and FN. Results: The estimated overall proportions of FP and FN are 2.8% and 2.2% of 227,000 EBC patients, resulting in about 6,400 and 5,000 women in each group, respectively. Overall, approximately 8600 QALYs would be lost among FN patients who do not receive trastuzumab. We estimate the incremental per-patient lifetime burden of an FP to be about $57,000, and for an FN to be about $118,000. The implied incremental loss to society for FPs is $362 million and for FNs is $596 million. Conclusions: Current testing practices and treatment patterns for HER2+ EBC patients result in misdiagnosis and non-optimal treatment in approximately 11,500 patients each year: the combined total economic loss to society is nearly $1 billion. The greater share of the loss is among FN patients who would have benefited from trastuzumab, but did not receive it. The significant annual burden of HER2 misdiagnosis suggests that substantial societal investments to improve HER2 test accuracy should be considered.
Shifting revenue from drug sales to cognitive services: Impact on physician prescribing behavior.
Authors: Feinberg Bruce A. , Cooper Joseph , Wong Winston , Winn Daniel , Olson Tim , Trehan Ram Swarup , Scott Jeffrey A.
Published: March 2020

6629

Background: Extensive literature has cited fee-for-service physician reimbursement methodology as a critical driver of resource utilization constituting overtesting, overtreatment, and an impediment to bending the cost curve in cancer care. CareFirst BlueCross BlueShield (CFBCBS) partnered with Cardinal Health Specialty Solutions to launch the first cancer clinical pathway in the US in Aug 2008. Physician participation was voluntary and reimbursement remained fee-for-service. Due to its early success with regard to savings and physician participation and compliance, an oncology medical home (MH) program was piloted in Jan 2011 offering a new physician reimbursement model, which shifted the source of revenue from margin on drug sales to cognitive services. This would allow physicians to focus on optimal patient (pt) care without the financial incentive to prescribe chemotherapy (chemo). We analyzed physician behavior modification after this change in reimbursement structure 1 year after implementation of the MH program. Methods: Practices that participated in the first pathways program were eligible to join the MH program. Claims data from CFBCBS were collected from Apr 2010 to Mar 2012. New and established pt visits, chemo administrations (admins) per pt and per practice, and % generic drug use were compared for year +1 versus year -1 of the MH program. Results: Fourteen practices (31 physicians, 478 pts) joined the MH program. In year +1, new pt visits increased by 2.7%, visits per established pt increased 1%, chemo admins per pt increased by 3%, and the percentage of regimens utilizing all generic drugs increased by 3.9%. Conclusions: Switching financial incentives from drug administration toward cognitive services did not significantly alter physician behavior with regard to the type or frequency of chemo admins or the frequency of pt visits. Whether this is because the physicians were mature pathways participants, influenced by brand-name prescription drug detailing, following National Comprehensive Cancer Network guidelines, or influenced by cognitive dissonance is speculative. Assumptions regarding fee-for-service reimbursement may not be applicable to chemo and will be further studied.
Predictors of significant emotional distress in cervical cancer patients.
Authors: Osann Kathryn , Hsieh Susie , Nelson Edward L. , Cella David , Wenzel Lari B.
Published: March 2020

6632

Background: Cervical cancer patients experience serious quality of life (QOL) disruptions, which may include persistent emotional distress. Predictors of persistent or significant depression and anxiety are examined in this study. Methods: A randomized trial tested the efficacy of a psychosocial telephone counseling intervention designed to improve QOL and decrease emotional distress.The FACT-Cx Trial Outcome Index (FACT-Cx-TOI), depression and anxiety (PROMIS short forms) were collected at baseline (T1), 4 months (T2) and 9 months (T3) post enrollment. Multivariate linear and logistic regression models were used to identify predictors of distress at follow-up. Tested predictors included demographic information, stage, treatment assignment, and baseline FACT-Cx TOI and PROMIS scores. Results: 115 women were randomized to PTC and 89 to usual care, with 82% compliance for T2 and 75% at T3. PTC patients experienced a significantly greater reduction in depression from T1 to T2 compared to UC (p=0.014). At baseline, 45% of participants reported depression T-scores above 55 (0.5 SD above the US general population average), and 26% reported levels greater than 60 (>1 SD worse than average). PTC patients were significantly less likely to have depression scores >55 at T2, and significantly more likely to improve by ≥5 points at T2 after adjusting for baseline and disease characteristics. Participation in PTC, higher baseline depression and higher baseline TOI were significant independent predictors of improvement in depression from T1 to T2. Conclusions: Early identification of patients with poor QOL and significant depression can inform supportive care interventions, with potential to improve health outcomes. Funding Source: NCI R01 CA118136-01. Clinical trial information: NCT00496106.
Rothman index as a predictor for type of discharge and readmission rates in a cancer hospital: The Yale experience.
Authors: Morgensztern Daniel , Xia Bing , Kournioti Chryssanthi S. , Hofstatter Erin Wysong , Raucci Maureen , Keyes Ashley , Morrione Alienne , Blasiak Elizabeth , Rosenberg Elizabeth , Rimar Joan , Rothman Michael J , Lilenbaum Rogerio
Published: March 2020

6635

Background: There is limited data on predictors of discharge (DC) and readmission (RA) for oncology inpatients. The Rothman index (RI) is a single score calculated from 26 parameters including nursing assessments, vital signs, and laboratory tests, integrated with the hospital’s electronic medical record and automatically updated when new data are entered. Scores are inversely related to patient impairment. We evaluated the role of RI in the prediction of DC types and RA rates at the Smilow Cancer Hospital at Yale. Methods: Patients (pts) with solid tumors, length of stay longer than 24 hours, admitted between 6/1/11 and 12/31/11 were enrolled. Elective admissions were excluded. DC types were classified as home without hospice (Hm), nursing home (NH), hospice (Hp) and death (D). The RI at the time of DC was evaluated as a predictor for RA at 7 or 30 days and the type of DC. Analysis of variance (ANOVA) was used to determine whether there were statistically significant differences between RI means and DC categories, followed by pair-wise contrast using the Tukey method. Results: Among the 476 admissions from 331 pts, the median age was 63 (range 21-92, 23% age 70 or older), and 55% males. The most common tumors were lung (24%) and breast (8%). The number of DCs were 313 Hm (66%), 75 NH (16%), 55 Hp (11%) and 33 D (7%). RI at DC for H, NH, Hp and D were 74, 62, 47 and 23. All comparisons among RI at DC and type of DC were significant (p < 0.05). Among the Hm pts, the rates of RA at 7 days were significantly higher for RI < 50 (45%) and 50-60 (32%) compared to 81-90 (13%) and > 90 (7%) (Table). RA rates at 30 days were also related to RI at DC, ranging from 65% in RI < 50 to 33% in RI > 90. Conclusions: RI is a useful tool in the evaluation of inpatients by providing an objective metric at the time of DC. The high correlation between RI scores and both DC type and RA rate underscores the need for a more consistent and reproducible evaluation at the time of DC and may be used by health care providers to guide disposition planning. A prospective study is being planned at our institution. [Table: see text]
Incidence of posttransplantation lymphoproliferative disorder (PTLD) following allogeneic blood or marrow transplantation (alloBMT) using post-transplantation cyclophosphamide (PT-Cy) for graft-versus-host disease (GVHD) prophylaxis.
Authors: Kanakry Jennifer Ann , Kasamon Yvette L. , Swinnen Lode J. , Bolanos-Meade Javier , Gladstone Douglas , Symons Heather J. , Mogri Huzefa J. , Kanakry Christopher George , Gocke Christopher D , Luznik Leo , Fuchs Ephraim Joseph , Jones Richard J. , Ambinder Richard F.
Published: March 2020

7009

Background: Immunosuppression to prevent graft rejection and GVHD is associated with an increased incidence of PTLD in the first year after alloBMT. AlloBMTs using partially HLA-mismatched or unrelated donor grafts, particularly when coupled with selective T-cell depletion approaches and/or anti-thymocyte globulin therapy, are associated with PTLD rates of 4-8%. The incidence of PTLD after umbilical cord blood alloBMT ranges from 2-7%. We evaluated the incidence of PTLD associated with the use of PT-Cy as GVHD prophylaxis at Johns Hopkins Hospital. Methods: After IRB approval, the Blood and Marrow Transplant Research database was queried for adult patients (age > 18) who received PT-Cy as GVHD prophylaxis. Medical records from the first year after alloBMT, including clinical notes, pathology reports, and laboratory assays for Epstein-Barr virus (EBV), were reviewed. Results: From 2000-2011, 765 alloBMT patients received PT-Cy (50 mg/kg/day on days 3 and 4 after alloBMT) as GVHD prophylaxis. Of these, 734 patients had 1-year follow-up or death. In patients receiving myeloablative conditioning and HLA-matched grafts (n=289, 117 unrelated donors), PT-Cy was the sole GVHD prophylaxis. Other patients undergoing alloBMT received mycophenolate mofetil and tacrolimus in addition to PT-Cy. These included recipients of HLA-matched (n=63) or haploidentical (n=352) grafts who were conditioned with reduced intensity regimens, as well as recipients of HLA-haploidentical grafts who received myeloablative regimens (n=30). Forty-one patients with CD20(+) tumors received rituximab after alloBMT as part of a clinical protocol. There were no cases of PTLD. Conclusions: The absence of PTLD in this series, even among high-risk recipients of haploidentical or unrelated donor grafts, suggests that PT-Cy is less associated with PTLD than other GVHD prophylaxis strategies. We hypothesize that multiple mechanisms may account for the lack of PTLD with PT-Cy, including destruction of B cells that harbor EBV, sparing of EBV-specific memory T cells, and rapid immune reconstitution.
Impact of monosomal karyotype and FLT3 status on post-transplant relapse in acute myeloid leukemia (AML).
Authors: Jimenez Antonio Martin , De Lima Marcos , Popat Uday R. , Borthakur Gautam , Abruzzo Lynne , Andersson Borje , Garcia-Manero Guillermo , Jabbour Elias , Chen Julianne , Bashir Qaiser , Ciurea Stefan O. , Kebriaei Partow , Ahmed Sairah , Khouri Issa F. , Kongtim Piyanuch , Qazilbash Muzaffar H. , Rondon Gabriela , Shpall Elizabeth J. , Champlin Richard E. , Oran Betul
Published: March 2020

7010

Background: Relapse remains the major cause of treatment failure in AML patients (pts) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We aimed to identify prognostic factors for relapse and leukemia free survival (LFS) after allo-HCT in AML pts. Methods: We retrospectively analyzed 987 consecutive pts who underwent their first allo-HCT for AML between January 2001 and June 2012. 124 pts had monosomal karyotype (MK+), 440 had other cytogenetic abnormalities (core-binding factor [CBF] n=67; MK-, n=373). 113 pts had diploid cytogenetics and FLT3 mutations (CN-FLT3+), 235 were diploid without FLT3 mutations (CN-FLT3-); FLT3 data was unavailable for 75 CN pts. Pts were stratified based on disease status at HCT: complete remission (CR, n=627) and active disease (n=360). Results: In this cohort, median age was 52 years (range: 19 – 76) and 191 pts (20%) had secondary AML (sAML). Conditioning intensity was non-myeloablative in 230 pts (23%). On multivariate analysis in pts with CR at HCT (adjusted for age, donor type and conditioning intensity) factors that predicted inferior LFS included: sAML (HR=1.5, 95% CI=1.1-2.2, p=0.009), >=CR2 vs. CR1 (HR=1.6, 95% CI=1.2-2.1, p=0.002), CN-FLT3+ (HR=1.7, 95% CI=1.1-2.5, p=0.02), MK- (HR=1.4, 95% CI=1.1-2.0, p=0.04) and MK+ disease (HR=2.1, 95% CI=1.4-3.2, p <0.001). Three-year LFS rates for CN-FLT3+ and MK+ were 45.3% and 34% vs. 53.3% for CN-FLT3- pts. For pts with active disease; CN-FLT3+ (HR=2.6, 95% CI= 1.5-4.2, p<0.001) and MK+ (HR=2.3, 95% CI= 1.5-3.5, p<0.001) predicted worse 3-year LFS: 10% and 6% vs. 30.8% in pts with CN-FLT3- . For CR pts, cumulative incidence of relapse (CIR) was higher for those with CN–FLT3+ (HR=1.9, 95% CI=1.1-3.1, p=0.01) and MK+ disease (HR=2.1, 95% CI=1.2-3.5, p=0.005). Among active disease pts, CN-FLT3+ (HR=2.5, 95% CI=1.4-4.3, p=0.002) and MK+ (HR=1.9, 95% CI=1.2-3.0, p=0.009) also predicted for higher CIR. Conclusions: Although pts with CN-FLT3+ and MK+ represent a high risk group for decreased LFS with increased relapse incidence after allo-HCT, they may still enjoy LFS of 30% - 45% if transplanted in CR. Post-transplant strategies to minimize the risk of relapse should be investigated in this setting.
Comparison of allogeneic stem cell transplantations in chronic myeloid leukemia before and after the era of tyrosine kinase inhibitors.
Authors: Ozcan Muhit , Ozturk Bengi , Ozen Mehmet , Topcuoglu Pervin , Arat Mutlu , Arslan Onder , Ilhan Osman , Akan Hamdi , Beksac Meral , Konuk Nahide , Gurman Gunhan
Published: March 2020

7038

Background: In this retrospective study we aimed to evaluate the rates and the clinical outcomes of allo-HSCT in CML following the advent of TKIs. Methods: We compared the transplantations (Txs) performed prior to 2002 (old era), the first year of TKIs, with the Txs during and after 2002 (new era). Results: Between 1989 and 2012 inour Tx unit a total of 189 allo-HSCTs were performed in 185 CML patients (second Tx for 4 patients). The ratio of Tx for CML among the whole Tx group decreased from 40 % to 12 % after 2002. The ratio also dropped to less than 5 % after 2008 and increased again to 15% in 2012. Time from diagnosis to Tx was longer in the old era than in the new era (9.2 months vs 15.4 months, p<.0001). The ratio of patients with advanced disease (accelerated or blastic phase) was higher in the new era. Although the progression free survival (PFS) was shorter in the new era than in the old era (median 13.8 months vs 37.1 months, p=0.09), overall survival, Tx outcomes and survival curves did not change. Conclusions: AlloHSCT rates sharply decreased after the TKIs, but a slight increase in recent years have been observed compatible with the TKI’s failure in years. Despite the fact that patients who underwent allo HSCT in the new era had more challenging disease biologically, overall survival was not affected possibly due to post-Tx interventions such as use of TKI alone or with donor lymphocyte infusion. [Table: see text]
Open label evaluation of ECG in patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib monotherapy.
Authors: Loury David , Sukbuntherng Juthamas , Clow Fong , James Danelle Frances , Kunkel Lori A.
Published: March 2020

7057

Background: Ibrutinib is a first-in-class selective small molecule inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. The aim of this study was to characterize the possible effect of ibrutinib on ECG intervals in patients with CLL. Methods: A Phase Ib/II study (PCYC-1102-CA) of oral dosing of ibrutinib was conducted in patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Patients were enrolled into 6 groups treated with ibrutinib at 420 mg/day or 840 mg/day (n=132). One cycle was 28 days. ECG data were obtained along with the blood samples during Cycle 1. Additional ECG measurement was performed on Day 28 of Cycles 3, 6, 12, 18, and 24 and at the end of study. An interim ECG analysis was performed using the data from R/R patients at 420 mg/day (n=18), TN patients at 420 mg/day (n=20), and R/R patients at 840 mg/day (n=29). For ECG analysis, the pre-dose values on Cycle 1 Day 1 were used as the baseline for each post-dose time-point for all ECG parameters. The QT and RR values for each beat were used for both Fridericia's correction (QTcF) and Bazett's correction (QTcB). The relationship between plasma concentrations of ibrutinib and ΔQTcF (change-from-baseline QTcF) was investigated by a linear mixed-effects modeling approach. Results: Median ages for R/R 420 mg, TN 420 mg, and R/R 840 mg dose groups were 59, 71, and 62 years, respectively. There was no clinically significant change in heart rate (HR) relative to baseline observed in either dose groups or between R/R and TN populations. There was no evidence of PR interval prolongation above 240 msec. There were no treatment-related effects on QRS duration in any of the Treatment Groups. A total of 467 ΔQTcF measurements were included in the analysis. The population mean of baseline QTcF values was 402.0 msec with a SD of 15.2 msec. A concentration-dependent effect of ibrutinib on QTcF was not identified. Conclusions: Interim analyses of the data indicated that there was no evidence of clinically significant ECG findings or QTc prolongation with continuous daily dosing of ibrutinib at either the 420 mg or 840 mg dose in patients with TN or R/R CLL. Clinical trial information: NCT01105247.
Chemokine receptors as novel targets of the oncogene Notch1 in acute lymphoblastic leukemia.
Authors: Mirandola Leonardo , Chiriva-Internati Maurizio , Cobos Everardo , Yu Yuefei , Figueroa Jose A. , Garavelli Silvia , Colombo Michela , Lazzari Elisa , Platonova Natalia , Zepeda Kristopher , Jumper Cynthia A. , Jenkins Marjorie , Alalawi Raed , Konala Venu , Aulakh Amardeep , Radhi Saba , Chiaramonte Raffaella
Published: March 2020

7060

Background: Malignant cells from different cancers express different profiles of chemokine receptors (CKR). Their presence may influence site-specific spread of tumor cells, by enabling them to respond to chemokine gradient, and may increase cell sensibility to chemokine mediated proliferative and anti-apoptotic stimuli. Notch ability to positively regulate CKR has been reported: stimulation of Pax5-/- pre-B cells with the Notch ligand Delta-1 results in induction of transcripts for CCR4, CCR8 and CXCR 6; the Delta-1-dependent regulation of Langerhans cell development includes induction of CCR6 expression resulting in the activation of chemotactic response to MIP-1a; Notch controls CCR7 signaling a regulator of CNS infiltration in T-acute lymphoblastic leukemia (T-ALL). Methods: This work aims to explore the correlation between the activation of the Notch oncogenic pathway in T-ALL and multiple myeloma (MM) cells and the aberrant expression CKR. Human T-ALL cell lines were treated with the Notch activation inhibitor, DAPT, or with a potent inhibitor of the Notch target, C-MYC, and evaluated the expression and functions of CCR9, CCR5, and CXCR4. Results: Treatment of human T-ALL and MM cell lines with pharmacologic inhibitors of Notch receptor activation produced a significant reduction of CCR9, CCR5 and CXCR4 expression, at both mRNA and protein levels. Results were confirmed by chemotaxis and survival assays. We identified the product of C-MYC gene as a possible mediator of Notch effect in regulating CKR networks in T-ALL and MM. Conclusions: These results suggest that Notch receptors play a previously unknown role in cancer progression and metastasis, by maintaining the expression levels of CKR. In conclusion, the identification of the potential axis Notch/CKR could have a prognostic value and provide the rationale for a tailored approach, since both Notch and CKR are targeted by emerging drugs.
Genetic and cytokine profiles associated with symptomatic stage of CLL.
Authors: Agarwal Amit Balkrishna , Cooke Laurence , Riley Christopher , Mount David , Mahadevan Daruka
Published: March 2020

7062

Background: Pathogenesis of symptomatic CLL involves genetic changes associated with the CLL clone and changes within the microenvironment which contribute to chemo-resistance. To further understand these processes we compared early stage CLL to symptomatic late stage CLL using gene expression profiling as well as serum cytokine profiling for a better insight of the genetic and microenvironment changes associated with the most severe forms of the disease. Methods: We obtained pretreatment blood samples from CLL patients (10 low stage and 14 high stage) at the time of diagnosis. Patients were classified as low stage (Rai stage 0/I/II) and high stage (Rai stage III/IV). Gene expression profiles were obtained on a subset of patients using the HG-U133A 2.0 Affymetrix platform and analyzed for differential gene expression profiles. Serum from a subset of patients was used to perform cytokine profiling using the Raybiotech Cytokine Array platform (AAH-CYT-G1000) that allows for simultaneous measurement of >100 different cytokines. Results: Comparison of low versus high stage CLL revealed a set of 21 differentially expressed genes. 15 genes were up regulated in the high stage versus low stage, while 6 genes were down regulated. GO Molecular function analysis revealed that 9 of the 21 genes are involved in transcription factor activity. Other genes up regulated in the high stage group include CSNK1- shown to be involved in Myc derived oncogenesis and SETD8- a histone lysine methyltransferase previously implicated in several cancers. Serum cytokine profiles showed 6 cytokines to be significantly different in high stage patients. Two chemokines SDF-1/CXCL12 and uPAR known to be involved in stem cell mobilization and homing are increased in the serum of high stage patients. IGFBP-2, BMP-4 and MCP-4 were lower among high stage patients. Conclusions: Our study revealed a novel group of transcription factors are associated with higher stage CLL. Cytokine profiling showed increased levels of SDF-1/CXCL12, a chemokine that plays a key role in mobilization and homing of hematopoietic stem and CLL cells in high stage patients. Our study identifies putative therapeutic targets including CSNK1, SDF-1 and SETD8 for patients with high stage CLL.
Effect of obesity on overall survival in patients diagnosed with chronic myelomonocytic leukemia (CMML).
Authors: Alfakara Dima , Swedeh Amer , Kaufman Gregory , Patnaik Mrinal M. , Hashmi Sharukh , Hogan William J. , Elliott Michelle A. , Wolanskyj Alexandra P. , Liu Shujun , Litzow Mark Robert , Al-Kali Aref
Published: March 2020

7064

Background: Obesity is a growing medical challenge that has strong association with many comorbid diseases. Body mass index (BMI) is used as one indicator for obesity. A few papers have linked hematological cancers with a worse prognosis if obesity was present. Aim: to study the influence of obesity clinical outcome in patients (pts) with CMML. Methods: A retrospective chart review of pts with CMML at Mayo Clinic Rochester between 1994–2011 was done. BMI was calculated at diagnosis or first time visit. Overweight was defined as BMI ≥25, while obesity as BMI >30. IRB approval was obtained. Comparison between medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier estimates via JMP software v.9. Results: We found227 pts with a median follow-up of 311 days, 68% of which weremales. Median age was 71 years, hemoglobin 11 gm/dL, white blood cells (WBC) 12x 109/L, and platelets 90x 109/L. Obese pts had a median age of 68 (p=0.0058), hemoglobin 11 gm/dL (p=0.0018), WBC 13.5 x 109/L, platelets 115x109/L (p=0.012), PB blasts 0, bone marrow (BM) blasts 3.5% compared to non-obese pts (73, 10, 11, 78, 0, 3%, respectively). Diploid cytogenetics were similar in both groups (68% vs 64%, respectively, p=0.54). Leukemic transformation into acute myeloid leukemia (LT) was found in 13% vs 10% (p=0.83). Overall response (OR) was 24% and 23%, respectively (p=0.2), when limited to hypomethylating agents OR was 33% vs 27%, respectively (p=0.62). Median OS was found to be similar (571 day vs 569 days, respectively, p=0.56). When compared, overweight pts had similar outcome to non-overweight. Median LT was 11% vs 15% respectively, OR was 21% vs 28% respectively (p=0.5), and OS was 571 days vs 549 days respectively (p=0.21). On a multivariate analysis age, hemoglobin, platelets, BM blasts%, gender, and obesity (p=0.048) were of a significant value for OS. Conclusions: When compared, both obesity and overweight did not affect demographic characteristics, overall response, or transformation into AML. When comparing median overall survival, obesity was not a significant factor, possibly due to short follow-up. However, on multivariate analysis obesity did have a negative impact on overall survival.
Treatment response monitoring in chronic phase CML (CP-CML) patients receiving tyrosine kinase inhibitor (TKI) therapy in US Oncology network.
Authors: Kolibaba Kathryn S. , Chung Hsing-wen , Dhanda Rahul , Rembert Debra , Lustgarten Stephanie , Marantz Jing L. , Huang Hui
Published: March 2020

7065

Background: To identify pts with TKI resistance in a timely manner, the National Comprehensive Cancer Network (NCCN) guidelines recommend monitoring pts at specific time points. We evaluated the relationship between NCCN guidelines and current treatment response monitoring patterns and outcomes of CP-CML pts in community practice. Methods: A retrospective longitudinal cohort study was conducted on newly diagnosed CP-CML pts initiating TKI therapy from Jan 1, 2008 to Dec 31, 2010. Data was extracted from the MSH/USON iKnowMed electronic health record database and chart reviews through Jul 31, 2012. Pts were stratified by presence of any cytogenetic monitoring by 12 mos or any molecular monitoring by 18 mos. Results: Of the 410 pts identified, 91% received imatinib and 9% received dasatinib/nilotinib. Median follow-up was 28 mos. Cytogenetic and molecular monitoring did not occur in 69% and 27% of pts, respectively. BCR-ABL mutation testing occurred in 10% of pts who were monitored for response. Pts ≥65 yrs old (vs <65 yrs, p<0.01), with public insurance (vs private insurance, p<0.001), or with Karnofsky Score ≤80 (vs >80, p<0.05) were less likely to have cytogenetic monitoring. Similar differences for age (p<0.05) and insurance (p<0.001) were seen for molecular monitoring. For pts with available monitoring results, 36% had complete cytogenetic response by 12 mos, and 59% had major molecular response by 18 mos. 4-yr overall survival (OS) rates were higher in pts with cytogenetic (98% vs. 89%, P=0.0003) or molecular (95% vs. 82%, P≤0.0001) monitoring vs. those with no monitoring. Conclusions: In these CP-CML pts, 69% did not receive any cytogenetic monitoring by 12 mos and 27% did not receive any molecular monitoring by 18 mos. Obstacles related to monitoring may include age, payer status, and performance status. Pts that were monitored for cytogenetic and molecular responses had significantly higher OS rates at 4 yrs. Increasing the proportion of pts that are monitored according to NCCN guidelines in the community setting could improve patient outcomes.
Do quality of life and physical function at diagnosis predict short-term outcomes during intensive chemotherapy in acute myeloid leukemia patients?
Authors: Timilshina Narhari , Breunis Henriette , Brandwein Joseph , Minden Mark D. , Gupta Vikas , Li Madeline , Tomlinson George A. , Buckstein Rena , Alibhai Shabbir M.H.
Published: March 2020

7067

Background: Intensive chemotherapy (IC) used to treat acute myeloid leukemia (AML) is associated with multiple short-term toxicities including mortality, particularly in older adults. Emerging data suggest that baseline quality of life (QOL) assessment and/or objective physical function tests may predict outcomes in oncology, although there are no data in AML patients. We investigated the association between baseline QOL and physical function with short-term treatment outcomes in adult and elderly AML patients. Methods: We conducted a prospective, longitudinal study of adult (age 18+) AML patients undergoing IC. Prior to starting IC, patients completed the EORTC QLQ-C30 and FACT-Fatigue in addition to physical function tests (grip strength, timed chair stands, and 2-minute walk test). Outcomes included 60-day mortality, intensive care unit (ICU) admission, and achievement of complete remission (CR). Univariate and multivariable logistic regression were performed to evaluate each outcome. Results: Of the 243 patients (median age 57.5 y), 56.7% were male and median Charlson comorbidity score was 0. 60-day mortality, ICU admission, and CR occurred in 9 (3.4%), 15 (6.2%), and 171 (70.4%), respectively. In univariate regressions, neither QOL nor physical function tests were predictive of 60-day mortality (all P>0.05), whereas cytogenetic risk group (P=0.04), ICU admission (P=<0.001), and remission status at 30 days (P=0.006) were. Fatigue was a significant predictor of ICU admission (p=0.02) whereas QOL and baseline physical function were not significant predictors. In univariate analyses, higher Charlson score was found to be a significant predictor of both ICU admission (P=0.01) and remission status at 30 days (P=0.002). Cytogenetic risk group was correlated with achievement of CR whereas neither QOL nor physical function were predictive (all P>0.05). Findings were similar when the subset of 96 elderly patients (age 60+) were examined. Conclusions: Baseline QOL and physical function tests in this prospective study were not associated with short-term mortality, ICU admission, or achievement of CR after the 1st cycle of chemotherapy.
Result of APL treatment associated with more experience of centers and more treatment as consolidation.
Authors: Ghavamzadeh Ardeshir , Alimoghaddam Kamran , Jalili Mahdi , Rostami Shahrbano , Ghaffari Seyed Hamidolah , Jahani Mohammad , Mousavi Seyed Asadollah , Bahar Babak , Vaezi Mohammad , Esfandbod Mohsen
Published: March 2020

7069

Background: The first line therapy strategy remains controversial in acute promyelocytic leukemia (APL) patients. Arsenic trioxide (AS2O3) approved in relapsed or resistance patients and recently studies reveals benefits of AS2O3in first line therapy. Regardless of these, important challenges are early mortality during remission induction and post treatment relapse. Methods: Between 2000 and 2012, patients suffered APL whose was new case and confirmed by t(15;17) translocation with RT-PCR, enrolled in study. Until 2007, patients received 28 days AS2O3(0.15 mg/kg iv) as induction and after 28 days rest, treatment continued for 2 courses of consolidation therapy with the same dose and after 2007, two additional consolidation courses, one and two year after start treatment, was added for prevent post treatment relapse. At beginning of 2nd and 3th consolidation, consider CSF cytology and RT-PCR for detection of APL cells and weekly CNS prophylaxis by MTX and cytarabine, IT chemotherapy start if needed. Patients received no other treatment. Results: Totally 271 patients enrolled in study. Ninety six patients received 3 dose and 175 patients received 5 dose of AS2O3. Fifty four (20%) patients died during remission induction before achieve remission. In recent years, early mortality rate reduced below 10% compared with more than 24% in the early years. With median follow-up of 30 months, 170 (78.4%) patients among 217 patients (whose survived after successful induction therapy) were alive (mortality rate: 21.6%) and 2.5-year overall survival and leukemia free survival was 85% and 73% respectively. The cumulative incidence of relapse in group which received three courses of AS2O3 and group which received five courses of AS2O3was 41.5% and 12.6%, respectively (95%CI: 2.5-9.6, P-value=0.0001). Conclusions: Currently according recent studies, AS2O3 has been considered as first line therapy in APL patients but either early mortality or post treatment relapse remain challengeable factors which affect treatment result. Expedite the referral of patients and improvement of emergencies care can reduce early mortality. The next step might be in order to achieve best treatment strategy for reduce post treatment relapse.
Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory CLL.
Authors: Patel Manish R. , Kahl Brad S. , Horwitz Steven M. , Younes Anas , Foss Francine M. , Oki Yasuhiro , Sweeney Jennifer , Allen Kerstin , Faia Kerrie , Kelly Patrick Francis , Flinn Ian
Published: March 2020

7070

Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) from an ongoing Phase I study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on modified IWCLL guidelines criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with continuous 24 hr inhibition of pAKT (Ser473) in primary pt CLL cells after a single dose of 25 mg. In the 16 pts with CLL (5 pts in dose escalation < 25 mg BID and 11 pts in a 25 mg BID EC), the median [range] number of cycles was 2.7 [1–14] and 81% remain on study. Treatment-related adverse events (TRAEs) occurred in 10 (63%) pts with CLL, a similar incidence as seen in the total study population (56%). The most common > Grade 3 TRAE in pts with CLL was neutropenia (25%). No > Grade 3 ALT elevations occurred in pts with CLL. Among evaluable pts with CLL (n=11), 82% (n=9) had a PR or nodal response after 2 cycles of IPI-145, with a best response to date of 6 PR, 4 SD (all nodal responses), and 1 PD. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity at the doses examined in pts with relapsed/refractory advanced CLL. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with CLL enrolled in dose escalation and ECs evaluating 25 mg BID and a higher dose (<MTD) of IPIE145 will be presented. Clinical trial information: NCT01476657.
Phase I study of NRC-an-019, a tyrosine kinase inhibitor, in imatinib-resistant chronic myeloid leukemia (CML) in an Indian tertiary care hospital.
Authors: Digumarti Raghunadharao , Myneni Praveen Chowdary , Gogula Venkata Ramana , Uppalapati Srihari , Jiwatani Sangeeta Premchand
Published: March 2020

7080

Background: NRC-AN-019 is an orally administered tyrosine kinase inhibitor (TKI) of the Bcr-Abl protein-tyrosine kinase. The drug was given to patients as a ready-to-use liquid formulation. Methods: The primary objectives of the Phase-I study were to estimate the Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) of NRC-AN-019 and also to establish the safe dose for Phase II clinical trial. The secondary objectives were to study the pharmacokinetic properties and antileukemic activity of NRC-AN-019. Philadelphia positive CML patients in all phases, in the age group of 18-65 years were eligible. They had to be resistant or intolerant to Imatinib, with ECOG ≤ 2. Dosing was initiated at 50 mg/day and dose escalation was done in increments of 50 mg per each additional cohort. The maximum dose administered was 450 mg/day. The protocol-specific study duration was 30 days; patients continued to receive the study drug subsequently based on Investigator’s decision. Results: A total of 30 patients were enrolled (3 at 50 mg, 4 at 100 mg, 3 at 150 mg, 3 at 200 mg, 4 at 250 mg, 4 at 300 mg, 3 at 350 mg, 3 at 400 mg, and 3 at 450 mg). DLT was not observed and MTD was not reached. The recommended Phase II-A dose is 300 mg/day, with a scope for escalation up to 450 mg/day. The maximum plasma concentration of NRC-AN-019 was 9,342 ng/mL and AUC was 1,262,191 ng.hr/mL. Common adverse events were skin rash, nausea, and vomiting. Hematological response was observed in 11 patients, cytogenetic response in 7 patients and molecular response in 5 patients. The maximum duration a patient has been on NRC-AN-019 is 863 days. Conclusions: Based on the Phase-I data, NRC-AN-019 showed considerable safety and response; it could be a potential treatment option for imatinib-resistant CML. Clinical trial information: CTRI/2009/091/000204.
Clinical features and outcome of T-cell acute lymphoblastic leukemia in patients older than 9 years: A single center experience of 110 patients from AIIMS, New Delhi, India.
Authors: Cyriac Sunu Lazar , Biswas Bivas , Bakhshi Sameer , Sharma Atul , Gupta Ritu , Kumar Lalit , Kumar Rajive , Raina Vinod
Published: March 2020

7081

Background: It is known that T cell acute lymphoblastic leukemias (ALL) have poorer outcomes than their B cell counterparts. Data on T-ALL in the age group of >9 years from India is minimal. Methods: This is a single institutional analysis of patients of above 9 years who were treated from January 2000 to December 2010. All patients who completed at least 4 weeks of induction therapy were analysed for various outcomes. Results: T-ALL formed 30% of all ALL in this age group. Of the 110 newly registered patients of T-ALL, the median age was 17 years (Range 10-50 years) with an M:F ratio of 5.9:1. Of this 62%, 30% and 18% patients belonged to 10-18, 19-30 and > 31 years age group respectively. Eighteen (19%) and 2 (2%) and 33 (30%) had CSF, testicular and other extramedullary sites involvement respectively. Twenty eight per cent had a total leucocyte count (TLC) of above 100x109/L. Patients available for survival analysis were 104(94.5%). Complete remission (CR)rate was 68.2% and induction mortality was 14.4%. At a median follow up of 56.4 months 5 year leukemia free survival was 52.3% (median not attained). Twenty seven (38%) patients relapsed (median relapse time of 15.2 months, range 0.7 to 47.3 months), 55% during maintenance phase. The 5 year overall survival (OS) was 46.9% (median OS of 35.4 months). The 5 year OS of 10-18, 19-30 and > 31 years age groups were 42.8%, 71% and 16.6% respectively (p value not significant). Not attaining CR in 1st induction, spontaneous tumor lysis syndrome and peripheral blood blast count of > 80% were significant poor prognostic factors for survival. Conclusions: This is one of the largest study of T-ALL outcomes in patients above 9 years from a single center from India. Attainment of CR in 1st induction was the most important risk factor for survival. 5 year OS was 47%.
Prognostic impact of trisomy 8 cytogenetic abnormality in acute myelogenous leukemia: Analysis of a large cohort (N=2187) of newly diagnosed patients.
Authors: Borthakur Gautam , Arana Yi Cecilia Ysabel , Cortes Jorge E. , Qiao Wei , Kadia Tapan M. , Ravandi Farhad , Faderl Stefan , Garcia-Manero Guillermo , Brandt Mark , Kantarjian Hagop M.
Published: March 2020

7089

Background: Trisomy 8 is grouped as intermediate risk in cytogenetic (CG) classifications of acute myelogenous leukemia (AML). In a multi-variate analysis of MRC data, trisomy 8 was associated with worse overall survival (OS). Methods: Between years 1993-2012, 2,187 patients (pts) with newly diagnosed AML presented at MD Anderson Cancer Center and 21 (10%) were with a trisomy 8 CG abnormality. The median age of trisomy 8 pts was 63 years (range, 17-89 years) and 59% were males. Sixty four (30%) had isolated trisomy 8, 45 (21%) had trisomy 8 +≤2 additional cytogenetic abnormalities and 102 (49%) had trisomy 8 + ≥3 additional abnormalities. Thirty three percent of pts with trisomy 8+≤2 additional abnormalities, had secondary AML compared to 21% of diploid CG (p=.007). Mutations in the FLT3 gene was seen in 9% and N or KRAS gene in 8%. Results: The overall remission rate (RR) was 47%, 53% and 43% among pts with trisomy 8 alone, trisomy 8+≤2 and trisomy 8+≥3 abnormalities respectively. Among pts <60 years of age and with trisomy 8 + ≤2 abnormalities, RR was 71% and the same was 77% for pts with diploid CG. For pts ≥ 60 years, the RRs were 26% and 57% respectively. Among pts ≥ 60 years and trisomy 8 with complex CG (≥3 additional abnormalities) the RR was 38% and that for patients with complex (non-trisomy 8) CG was 41%. Patients with trisomy 8 either alone or ≤2 additional abnormalities had a shorter OS (p= .04 and .05 respectively, median 10.8 and 8.6 months vs 16.5 months) compared to those with diploid CG. Event free survival was also shorter among patient with isolated trisomy 8 versus those with diploid CG (p=.008, median 2.9 versus 7.5 months). On the other hand, patients with trisomy 8+≥3 abnormalities had outcomes comparable to non-trisomy 8 CG group. Conclusions: Non-complex CG trisomy 8 is associated with worse clinical outcome in patients with AML than those with diploid CG and its inclusion in intermediate risk group may need reconsideration. The most adverse impact appears to be from lower RR among patients with trisomy 8+≤2 additional abnormalities and ≥60 years of age.