bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can we satisfactorily measure the clinical value of new oncology agents with a single summary measure?
Authors: Jones Clare Frances , Monnickendam Giles , Zhu Mingshu , McKendrick Jan 
Published: September 2018

6606 Background: Current value frameworks (VFs) assess clinical value primarily through using clinical trial endpoints as survival metrics (e.g., median and hazard ratio (HR)). But, if key assumptions do not hold, the interpretation of these summary statistics can become problematic and fail to adequately capture the expected benefit to a patient. This has been observed with innovative oncology treatments. As a proof of concept analysis, we reviewed how two VFs (ASCO and ESMO) dealt with cases where the assumption of proportional hazards (PH) does not hold. Methods: Oncology agents approved by the FDA since 2011 were reviewed and three agents were identified with survival profiles where the assumption of PH was found not to hold because, on visual inspection, the survival curves displayed non-standard patterns: Divergence followed by convergence – panobinostat OS in RRMM; Curves initially track together then diverge – nivolumab OS in NSCLC; Curves diverge steadily then a plateau emerged in the active treatment curve – pembrolizumab PFS in refractory melanoma. We evaluated these agents to assess which measures of clinical benefit were most valued under each VF and how the issue of non-PH influenced the outcome. Results: Clinical benefit/value scores varied: ASCO: 14-27 (maximum 100), ESMO: grade 1-3. The ASCO VF uses a hierarchical approach (incorporating HR and median survival benefit, always prioritising the former) adding a bonus for survival benefit in the tail of the distribution. The combination of HR, median survival benefit 2 and 3 year survival rates in the ESMO non-curative VF can potentially capture aspects of clinical benefit in some cases of non-PH. Overall, the ASCO VF appears less flexible to accommodate non-PH than the ESMO VF. Conclusions: Despite VFs using summary statistics which cannot be easily interpreted under conditions of non-PH, the case of non-PH is not explicitly catered for. Additionally, both VFs may miss important interpretation where value is differentiated across patients groups with different response profiles which may underlie non-standard survival curves. In these situations, a more flexible approach to assessing clinical value may render VFs more relevant for clinical decision making.
Barriers to MACRA among a cohort of community oncologists.
Authors: Nabhan Chadi , Smith Yolaine , Ernst Frank R , Fillman Jennifer , Feinberg Bruce A. 
Published: September 2018

6613 Background: Value Based Care (VBC) initiatives specifically the Medicare and CHIP Reauthorization Act (MACRA), which includes Medicare Incentive Payment System (MIPS) and Alternative Payment Models (APMs), present challenges for community oncologists. Understanding barriers associated with implementation and compliance are essential for optimal execution. Methods: Using audience response technology, 52 community oncologists and 26 practice managers (PMs) of diverse geography, practice type and affiliations were surveyed in November 2016. Results: Of the attendees, 43% were participating in commercial payer VBC while 33% were participating in the Oncology Care Model (OCM), an APM. Reasons for non-participation: Cost of drugs 58%; data transparency 42%; human resources 33%; technology 29%. The majority of attendees stated limited awareness of MACRA reporting requirements. Once reporting was explained, the stated challenges to MACRA implementation included: inability to measure and track costs 76%; problematic quality improvement activities 56%; lack of patient engagement tools 52%; concern about interpreting CMS reports 52%; meeting meaningful use requirements 33%. In regard to preparation: 52% had survivorship or palliative care plans, 39% made infrastructure investments, and 23% were utilizing clinical pathways. Although 54% stated use of data analytics to maximize efficiency and profitability, half of these were not satisfied with ease of data extraction or output. One third opined that patient satisfaction was irrelevant to quality of care. In the end, nearly half stated reporting requirements could be managed; but 98% stated they were unwilling to assume downside financial risks for hospital and emergency room visits. Conclusions: Identifying and eliminating barriers to MACRA (MIPS/APMs) implementation may be critical to program success. The main reasons for OCM non-participation were costs of drugs and data transparency. There is significant dissatisfaction with available reporting and data extraction tools. Willingness to assume 2-sided risk for total cost of care was identified as the greatest risk to APM adoption.
Spending on antineoplastic agents in the United States: 2011-2016.
Authors: Li Edward C. , Schumock Glen , Hong Samuel 
Published: September 2018

6618 Background: Novel antineoplastic therapies confer advantages in efficacy and safety over traditional cytotoxic agents, but they are costly. There is little information on recent trends in actual antineoplastic expenditures representative of the overall U.S. health care system or by healthcare sector. The objective of this study was to describe antineoplastic expenditures by year and healthcare sector in the U.S. Methods: Quintiles IMS National Sales Perspective data for the period of Jan 1, 2011, to Dec 31, 2016, were evaluated to describe antineoplastic agent expenditures. Actual expenditures were totaled by health care sector and calendar year, and then adjusted for U.S. medical-cost inflation (part of the overall consumer price index) to 2016 dollars. Growth was calculated as the percentage increase from previous years. Descriptive statistical analysis was used. Results: Total antineoplastic expenditures increased from $26.8 billion in 2011 to $38.9 billion in 2016. Compared to the previous year, spending increased by 13.7%, 15.6%, 13.4%, 6.3%, and 0.4% in 2016, 2015, 2014, 2013, and 2012, respectively. In hospitals and clinics, spending on biologics grew by 80% from 2011 to 2016. Rituximab, bevacizumab, and trastuzumab expenditures continue to be high ($3.7, $3.0, and $2.6 billion in 2016, respectively) while nivolumab spending increased from $765 million in 2015 to $2.6 billion in 2016. Cytotoxic drug spending remained flat during the study period due to the availability of multiple generic products. Large percentage decreases in spending were seen for oxaliplatin (-97%), docetaxel (-98%), gemcitabine (-92%), bendamustine (-56%) and decitabine (-94%) in 2016 compared to 2011. Conclusions: Antineoplastic expenditures increased significantly since 2011 and are expected to continue to do so with the anticipated approval of additional novel but costly cancer therapies, and because of an aging population. [Table: see text]
Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy.
Authors: Park Jae Hong , Riviere Isabelle , Wang Xiuyan , Senechal Brigitte , Wang Yongzeng , Mead Elena , Santomasso Bianca , Halton Elizabeth , Diamonte Claudia , Bernal Yvette , Li Daniel , Sadelain Michel , Brentjens Renier J. 
Published: September 2018

7008 Background: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-ALL. However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL (NCT01044069) with a focus to identify those patients who optimally benefit from 19-28z CAR T cell therapy with durable long-term survival and reduced toxicities. Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR following conditioning chemotherapy. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion; patients with < 5% blasts were classified as minimal residual disease (MRD) cohort vs. patients ≥5% blasts as morphologic disease cohort. Response assessment occurred at 4 weeks. Median follow-up duration was 18 months (range, 0.2-57.3). Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p = 0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 – 36.2) (p = 0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p = 0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p = 0.0326 and p = 0.0001, respectively). Conclusions: Despite comparable initial CR rates regardless of pre-treatment disease burden, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL. Clinical trial information: NCT01044069.
Immune-related gene expression deficit of leukemia stem cells (LSC) in AML.
Authors: Chamoun Kamal , Benton Christopher Brent , AlRawi Ahmed , Jacamo Rodrigo , Williams Patrick , Wang Feng , Zhang Jianhua , Daver Naval Guastad , Garcia-Manero Guillermo , Kantarjian Hagop M. , Futreal Andrew , Andreeff Michael 
Published: September 2018

7011 Background: AML LSC are believed to be responsible for residual and resistant leukemic disease leading to relapse. Understanding differences between bulk AML and the LSC subpopulation may allow the identification of novel LSC targets, especially for the most adverse risk AML where few patients are cured. Targeting LSC may be needed to eradicate AML, and immune-based therapies provide an approach for eliminating LSC. The transcriptional landscape of immune-related genes in LSC is not well understood. Methods: Samples were collected at diagnosis from 12 patients with high-risk AML prior to therapy. Bulk (CD45-dim blasts) and LSC (Lin-CD34+CD38-CD123+) AML marrow cells were FACS-sorted and analyzed using whole genome RNA-sequencing. Transcriptomes were analyzed using AltAnalyze software to identify differentially expressed genes in bulk AML cells and in AML LSC populations. These genes were further assessed by gene enrichment analysis using data from Gene Ontology (GO) and the Cancer Genome Atlas Project (CGAP). Results: Sixty-eight genes were identified with greater than 3-fold differential expression between bulk AML and LSC. GO enrichment analysis demonstrated more than 10-fold enrichment of genes involved in the molecular functions, biologic processes, and cell components related to the antigen presentation pathway, with the comparative down-regulation occurring in LSC. Among the top differentially expressed gene clusters, both the MHC class II and interferon-gamma signaling/response pathway gene expression was blunted in LSC. Additional expression analysis revealed that 42% of a CGAP-curated list of 201 antigen-processing and -presentation genes had significantly decreased expression in the LSC subpopulation compared to bulk AML. Conclusions: LSC from primary AML patient samples are characterized by reduction in expression of MHC class II receptor and antigen presentation genes compared to bulk AML. These results suggest that impairment in the presentation and/or processing of tumor associated antigens by MHC class II on LSC, along with tonic sponging of immune response cells and diversion away from LSC by bulk AML, may contribute to LSC evasion of immune surveillance and response.
Five-year results of the ponatinib phase II PACE trial in heavily pretreated CP-CML patients (pts).
Authors: Kantarjian Hagop M. , Pinilla-Ibarz Javier , Le Coutre Philipp D. , Paquette Ronald , Chuah Charles , Nicolini Franck E. , Apperley Jane , Khoury Hanna Jean , Talpaz Moshe , Baccarani Michele , Lustgarten Stephanie , Santillana Sergio , Guilhot Francois , Deininger Michael W.N. , Hochhaus Andreas , Hughes Timothy P. , Shah Neil P. , Cortes Jorge E. 
Published: September 2018

7012 Background: The tyrosine kinase inhibitor (TKI) ponatinib has potent activity against native and mutant BCR-ABL1 and is approved for use in pts with relapsed/intolerant CML or Ph+ ALL, or with BCR-ABL1/T315I. Methods: In the pivotal PACE study (NCT01207440), ponatinib (starting dose 45 mg/d) was assessed in pts with CML or Ph+ ALL resistant/intolerant to dasatinib or nilotinib, or with T315I. In Oct ’13, dose reductions were implemented due to observed arterial occlusive events (AOEs). Efficacy and safety at 5 yrs (data as of 3 Oct ’16) for CP-CML pts are reported. Results: Of 270 CP-CML pts in the safety population, 60% received ≥3 prior TKIs. At initiation of study closure, 99 pts were ongoing; among these pts, minimum follow-up was 52 months, and most (78%) had 15 mg/d as their last dose. In all CP-CML pts (n = 267, efficacy evaluable), cumulative response rates were: MCyR, 60%; CCyR, 54%; MMR, 40%; and MR4.5, 24%. Among pts who achieved MCyR (n = 148) or MMR (n = 108), the Kaplan-Meier (KM) estimated probability of remaining in response at 5 yrs was 74% (95% CI, 62 – 83) and 61% (95% CI, 51 – 70), respectively. Regardless of dose reduction in Oct ’13, maintenance of response was high (Table). KM estimated 5-yr rate for PFS/OS was 49%/77%. TEAEs in ≥45% of CP-CML pts were rash 47%, abdominal pain 46%, and thrombocytopenia 46%. Most newly occurring AEs were observed within the first year. The incidence of any AOEs/serious AOEs for CP-CML pts was 29%/23%. Among CP-CML pts with no prior AOEs who had a prospective dose reduction, 17% (11/63) had a first AOE occurring after Oct ‘13. Conclusions: Long-term (5-yr) results from PACE demonstrate that ponatinib continues to show clinical benefit, irrespective of dose reductions, with deep and lasting responses in heavily pretreated CP-CML pts. Safety results were consistent with the safety profile across the ponatinib clinical program. Clinical trial information: NCT01207440. [Table: see text]
Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2).
Authors: Fathi Amir Tahmasb , Dinardo Courtney Denton , Kline Irina , Kenvin Laurie , Gupta Ira , Attar Eyal C. , Stein Eytan M. , de Botton Stéphane ,   On Behalf of the AG-221-C-001 Study Investigators
Published: September 2018

7015 Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS), with manifestations akin to retinoic acid syndrome seen during acute promyelocytic leukemia Tx. Methods: A phase 1 dose-escalation/expansion study (N = 239) (NCT01915498) included 109 pts with relapsed/refractory AML who received enasidenib 100 mg /day. An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential IDH-DS cases. The DSRC identified and agreed on signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. Of the 109 pts, the DSRC identified and retrospectively reviewed 27 cases (8 investigator reported IDH-DS cases and 19 cases suggestive of IDH-DS) to determine consistency with IDH-DS. Results: The DSRC found 13 of the 27 cases to be consistent with IDH-DS (11.9% of 109 pts). Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in > 2 pts were dyspnea (n = 10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4 cases and hydroxyurea was used for cytoreduction. Enasidenib was interrupted for 9 pts (median 7 days) but dose reductions or discontinuation were not required. Six of 13 pts had clinical responses (2 complete remission [CR], 2 CR with incomplete hematologic recovery, 1 partial remission, 1 morphologic leukemia-free state), 6 had stable disease and 1 had progressive disease. Conclusions: Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective management strategies, should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in m IDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, differentiation. Clinical trial information: NCT01915498.
Effect of cytarabine/anthracycline/crenolanib induction on minimal residual disease (MRD) in newly diagnosed FLT3 mutant AML.
Authors: Stone Richard M. , Collins Robert , Tallman Martin S. , Walter Roland B. , Karanes Chatchada , Patel Prapti Arvind , Vusirikala Madhuri , Coombs Catherine Callaghan , Olson Gretchen , Jain Vinay Kumar , Wang Eunice S. 
Published: September 2018

7016 Background: Baseline characteristics such as age >60, WBC>100,000/µL and FLT3/NPM1/DNMT3A+ve are known to be associated with a poor prognosis in AML. Ivey et al. (NEJM 2016) reported that FLT3-ITD+ve patients (pts) who were MRD+ve after 2 cycles of induction chemotherapy were more likely to relapse as compared to those who became MRD-ve (92% vs 35%). Eradication of FLT3+veclones may lead to reduced relapse rates. Crenolanib is a type I FLT3 TKI, which inhibits both FLT3-ITD and TKD mutations. We here report that a single induction cycle of cytarabine/anthracycline/crenolanib leads to MRD negativity by multiparameter flow cytometry (MPF), and low rate of early relapse in pts with newly diagnosed FLT3+veAML. Methods: This abstract includes 29 consecutively treated, newly diagnosed, FLT3+ve AML pts, who achieved CR1 after one course of cytarabine/anthracycline/crenolanib. Pts received 7+3 induction with cytarabine 100 mg/m2/d for 7d and either daunorubicin (<60 y: 90 mg/m2; ≥60 y: 60 mg/m2) or idarubicin 12 mg/m2 for 3d. Crenolanib (100 mg TID) was started on day 9 until 72 h prior to next chemotherapy. Results: 29 pts (15M, 14F), median age 55y (10pts ≥60y) are included. MRD at time of count recovery was assessed by MPF in 25/29 pts. 20/25 (80%) became MRD–ve. With a median follow up of 7mth, 4/25 pts have relapsed (2/5 MRD+ve, 2/20 MRD-ve).Age ≥60 was a risk factor for MRD+ve and relapse. All 4 pts with WBC>100K as well as 5 pts with FLT3/NPM1/DNMT3A+ve AML became MRD-ve after one induction cycle and none have relapsed. Conclusions: These data suggest, in the context of an ongoing trial (NCT02283177), crenolanib in combination with standard induction is associated with a high rate of achieving an MRD negative state by MPF and a low rate of relapse in previously untreated adults with mutant FLT3. Longer follow-up and comparison of MRD data with similar pts treated with standard chemo alone will be necessary to reach more definitive conclusions. Clinical trial information: NCT02283177. [Table: see text]
Outcomes with lower intensity therapy in TP53-mutated AML.
Authors: Kadia Tapan M. , Boddu Prajwal C. , Ravandi Farhad , Garcia-Manero Guillermo , Borthakur Gautam , Andreeff Michael , Jabbour Elias , Dinardo Courtney Denton , Konopleva Marina , Daver Naval Guastad , Takahashi Koichi , Patel Keyur , Kanagal-Shamanna Rashmi , Cortes Jorge E. , Kantarjian Hagop M. 
Published: September 2018

7017 Background: TP53 mutations confer an adverse prognosis in patients (pts) with AML treated with standard chemotherapy. A recent study reported high response rates using a 10-day regimen of decitabine (DAC10) in pts with TP53-mutated ( TP53-MUT) AML. The question remains whether this benefit is unique to DAC10 or whether the same benefit among TP53-MUT AML applies to other low intensity therapy (Rx). Methods: We reviewed our own experience of pts treated with low intensity Rx from 2012 - 2016. Mutation testing was performed using a whole-exome sequencing panel. We reviewed the clinico-pathologic characteristics of these pts, and compared their outcomes based on the presence/absence of a TP53mutation and by the type of Rx they received. Results: There were 131 pts in our cohort of which 33 (25%) had TP53-MUT. Pt characteristics are outlined in Table 1A. All pts were treated with low intensity Rx and were divided into the following groups: DAC10 [n=34, 26%]; 5-day decitabine, or 7-day azacytidine (DAC5) [n=39, 30%]; or cladribine+low dose araC (CLAD/LDAC) [n=58, 44%]. Response rates and OS by Rx and TP53-MUT status are summarized in Table 1B. While there was no significant difference in response rates or OS by TP53-MUT status within any of the treatment approaches, there was a trend for inferior response rates and OS among pts with TP53-MUT who received either DAC-5 or CLAD/LDAC ; this was not seen in pts receiving DAC10. Conclusions: The presence of a TP53-MUT was associated with a nonsignificant trend towards inferior outcomes among pts receiving DAC5 or CLAD/LDAC, but not among those receiving DAC10. Comparing across groups, the CLAD/LDAC combination was associated with the longest OS, and DAC10 was associated with superior outcomes compared to DAC5, in TP53-MUT cohort. [Table: see text]