bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost of surveillance imaging in head and neck cancer patients treated with definitive radiotherapy.
Authors: Ng Sweet Ping , Jomaa Mona K , Pollard Courtney , Ayoub Zeina , Mohamed Abdallah , Garden Adam S. , Berends Joel , Gunn Gary Brandon , Frank Steven J. , Skinner Heath Devin , Phan Jack , Rosenthal David Ira , Morrison William H. , Johnson Jason Michael , Sturgis Erich M. , Lai Stephen Yenzen , Fuller Clifton David 
Published: September 2018

6610 Background: The goal of surveillance is to detect potentially salvageable recurrence, allowing early salvage treatment and thereby improving clinical outcomes. Currently, there is limited data on the optimal frequency of imaging for head and neck cancer patients treated with definitive radiotherapy. This study aims to evaluate the cost-effectiveness of surveillance imaging in this group of patients. Methods: Eligible patients included those with a demonstrable disease free interval (≥ 1 follow up scan without evidence of disease and a subsequent visit/scan) treated between 2000-2010. Age, tumor site and stage, induction chemotherapy use, dose/ fractionation, mode of detection of recurrence, salvage therapy, number and modality of scans were recorded. Deaths from disease recurrence or from other causes were also recorded. Imaging costs were calculated based on the 2016 Medicare fee schedule. Results: 1508 patients were included. Mean age was 55.8 years (range: 17-87). Median overall survival was 99 months (range: 6-199). Mean imaging follow up period was 70 months. 190 (12.6%) patients had disease recurrence – 107 locoregional (LR) and 83 distant. 119 (62.6%) of the relapsed group were symptomatic and/or had an adverse clinical finding associated with recurrence. 80.4% of LR relapses presented with a clinical finding, while 60.2% of distant relapses were detected via imaging alone in asymptomatic patients. There was no difference between the successful salvage rates and overall survival between those with relapses detected clinically or via imaging alone. 70% of relapses occurred within the first 2 years post-treatment. In those who relapsed after 2 years, the median time to relapse was 51 months (2 LR and 11 distant relapses). After 2 years, the average cost for detecting a salvageable recurrence for image-detected group was $741 447.41, and the cost for preventing 1 recurrence-related death for image-detected disease was $889 736.89. The number of scans required to detect a salvageable recurrence in an asymptomatic patient after 2 years was 3512. Conclusions: Surveillance imaging in asymptomatic patients without clinically suspicious findings beyond 2 years requires judicious consideration.
Economic impact of immune checkpoint inhibitor therapy in Brazil and strategies to improve access.
Authors: Aguiar Pedro Nazareth , De Mello Ramon Andrade , Tadokoro Hakaru , Lopes Gilberto 
Published: September 2018

6612 Background: Immunotherapy was elected by ASCO as the most important advance in Oncology for the last 2 consecutive years. Nevertheless, the costs of immune checkpoint inhibitors is a limitation to their incorporation in several countries, including Brazil. The objective of this study is to estimate the economic impact of immunotherapy and make suggestions in order to improve the access for patients who benefit the most from treatment. Methods: We assessed Brazilian cancer epidemiology data and the international literature to estimate the number of eligible patients each year. The authors estimated the economic impact according to the medication acquisition costs converted to US dollars. The median duration of the treatment was based upon the clinical trials. Results: We assessed 3 different agents (and one combo) for 7 indications. The results are summarized in the table below. Conclusions: The current cost of immune checkpoint inhibitors is prohibitive in the public health system in Brazil. While the country’s GDP per capita is 78% lower than that of the US, immune checkpoint inhibitors have similar prices in both. Biomarker selection, posology, and lower cost drugs help decrease the total economic impact of therapy. Price discrimination and volume discounts would help improve access. Further studies and discussion with all stakeholders is needed to identify patients who would benefit the most and to implement strategies to increase access to these potentially life-saving therapies. [Table: see text]
Access and price of cancer drugs: What is happening in France?
Authors: Grande Mathilde , Fernandez Judith , Putzolu Jade , Stanel Sorin , Galbraith Margaret , Belorgey Chantal , Albin Nicolas , Guillevin Loic , d'Andon Anne 
Published: September 2018

6623 Background: The French National Authority for Health (HAS) is responsible for health technology assessment (HTA), providing opinion on drugs for reimbursement and pricing purposes. For all indications with a positive opinion for reimbursement, HAS assesses the clinical added value (CAV) on a 5-point scale for pricing negotiations based on clinical data. A major to moderate CAV leads to the highest prices, a minor CAV leads to a higher price than the comparator, and no CAV leads to lower price than the cheapest comparator. Countries increasingly face the policy challenge of harnessing the benefits of cancer drugs while managing healthcare budgets. In this context, we aimed to analyze cancer drugs assessment by HAS. Methods: a retrospective and descriptive analysis comparing all new hematology/oncology cancer indications versus all others new indications assessed by HAS between 2010 and 2015 has been conducted. Results: 87 cancer indications (60 drugs) have been evaluated, representing 17% (87/510) of all new drugs indications assessed by HAS. Almost all cancer indications (92%) obtained a favorable opinion for reimbursement. Seven (8%) had an unfavorable opinion versus 20% in other therapeutic areas. However, 5 of these 7 indications were related to a drug included on the list of reimbursed drugs for another indication and consequently drugs are available. Overall, only 2 drugs were not reimbursed: nintedanib in non small cell lung cancer and tegafur/gimeracil/oteracil in gastric cancer (no impact on survival and lack of results transposability). Of the 80 indications with a favorable opinion, 20 had a major to moderate CAV (25%), 32 a minor CAV (40%) and 28 have no CAV (35%). Major to moderate CAV are mostly composed of hematology drugs (12, 60%). The proportion of major to moderate CAV assessment is higher in oncology than in other therapeutic areas (66% vs. 30%). Conclusions: France benefits from a universal healthcare system offering wide coverage and large access to drugs. Almost all of the new hematology/oncology cancer drugs assessed had a favorable opinion and are fully reimbursed (100%) by health insurance. A high proportion (66%) of CAV is recognized in oncology. Nevertheless, the over DRG list can inadvertently limit access to these new cancer drugs.
Phase 3 trial of momelotinib (MMB) vs ruxolitinib (RUX) in JAK inhibitor (JAKi) naive patients with myelofibrosis (MF).
Authors: Mesa Ruben A. , Kiladjian Jean-Jacques , Catalano John V. , Devos Timothy , Egyed Miklos , Hellman Andrzei , McLornan Donal , Shimoda Kazuya , Winton Elliott F. , Deng Wei , Dubowy Ronald L. , Maltzman Julia D. , Cervantes Francisco , Gotlib Jason R. 
Published: September 2018

7000 Background: MMB, an oral JAKi, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion (Tx) requirements in patients (pts) with MF. This study was designed to test non-inferiority of MMB vs RUX in splenic volume reduction and Sx amelioration, and superiority in Tx requirement, in JAKi naïve MF pts. Methods: Eligibility: MF, IPSS high risk, Int-2, or symptomatic Int-1; palpable spleen ≥5cm; platelets ≥ 50 K/μl, and no Gr ≥2 peripheral neuropathy (PN). Stratification by Tx dependency and platelets (<100, 100-200 and >200 K/μl). Pts were randomized 1:1 to 24 wks of MMB 200 mg qd + RUX placebo or RUX 20 mg bid (or modified per label) + MMB placebo, after which all pts could receive open label MMB. Assessments: spleen volume by MRI, and pt reported Sx using a daily eDiary of modified MPN-SAF Total Sx Score (TSS). Primary endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline) at 24 wks. Secondary endpoints, evaluated sequentially at 24 wks, were rates of TSS response (≥50% reduction from baseline), RBC Tx independence (TI), RBC Tx dependence (TD) and of RBC Tx . Results: 175 of 215 (81%) and 201 of 217 (93%) pts randomized to MMB and RUX, respectively, completed the 24 wk DB phase. Efficacy results are shown in Table. Most common Gr ≥3 AEs in the DB phase with MMB were thrombocytopenia (7%) and anemia (6%), and with RUX were anemia (23%), thrombocytopenia (5%) and neutropenia (5%). Gr ≥3 infections occurred in 7% of MMB and 3% of RUX pts. Treatment emergent PN occurred in 22 (10%) of MMB (all Gr ≤2) and 10 (5%) of RUX (9 Gr ≤2, 1 Gr 3) pts in DB phase, none discontinuing study drug for PN. Overall, AEs led to study drug D/C in 13% of MMB and 6% of RUX pts in DB phase. Conclusions: In pts with JAKi naive MF, 24 weeks of MMB is non-inferior to RUX for spleen response but not for symptom response. MMB treatment is associated with a reduced transfusion requirement. NCT01969838. [Table: see text]
Distinct patterns of somatic mutation clearance and association with clinical outcome in patients with AML.
Authors: Takahashi Koichi , Wang Feng , Patel Keyur , Bueso-Ramos Carlos E. , Issa Ghayas C. , Song Xingzhi , Zhang Jianhua , Tippen Samantha , Little Latasha , Gumbs Curtis , Ravandi Farhad , Kadia Tapan M. , Daver Naval Guastad , Dinardo Courtney Denton , Konopleva Marina , Andreeff Michael , Cortes Jorge E. , Jabbour Elias , Futreal Andrew , Kantarjian Hagop M. 
Published: September 2018

7005 Background: Persistence of somatic mutations at the time of complete remission (CR) was associated with poor outcome in patients (pts) with AML. Methods: We studied 95 pts with AML who were treated with frontline induction and subsequently achieved CR. We sequenced pre-treatment and CR bone marrow samples by targeted capture sequencing of 295 genes (median 280x coverage). We defined 3 levels of mutation clearance (MC) based on variant allele frequency (VAF): MC2.5, persistent mutation with VAF<2.5%; MC1.0, persistent mutation with VAF<1%; and complete mutation clearance (CMC). Results: In the pre-treatment samples, we detected 597 mutations in 78 genes in 87 (92%) patients. In the matching CR samples, 62 (10%) and 82 (14%) mutations persisted at VAF≥2.5% and ≥1%, respectively, which corresponded to 43 (49%), 34 (39%), and 30 (34%) patients achieving MC2.5, MC1.0 and CMC, respectively. Table 1 shows the differential patterns of MC based on the mutations and pathways. Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), DNA methylation, and splicing pathways had low rate of MC, whereas mutations in transcription factors or receptor tyrosine kinase (RTK) had high rate of MC. Pts who achieved MC1.0 (median 31.2 vs. 12.5 months, P = 0.04) or CMC (median 31.2 vs. 12.5 months, P = 0.049) had significantly better relapse-free survival (RFS). Conclusions: Somatic mutations associated with CHIP, DNA methylation, and splicing pathways persisted frequently in CR samples suggesting preleukemic origin. Pts with deeper MC had significantly better RFS. Somatic mutation clearance may help risk prediction of AML. [Table: see text]
An antibody derived from a cured AML patient to identify a unique epitope on CD43 (CD43s) as a novel target for acute myeloid leukemia and myelodysplastic syndrome.
Authors: Hazenberg Mette D. , Gillissen Marijn , De Jong Greta , Yasuda Etsuko , Levie Sophie , Wagner Koen , Bakker Arjen , Kedde Martijn , Hensbergen Paul , Villaudy Julien , Van Helden Pauline , Spits Hergen 
Published: September 2018

7009 Background: Immunotherapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is hampered by the lack of tumor-specific targets. Methods: We took advantage of the tumor-immunotherapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) and searched the B cell repertoire of a patient with a lasting and potent graft versus AML response for AML-specific antibodies. Results: We identified a donor-derived B cell clone that produced an IgG1 antibody, AT1413, that specifically interacted with AML cell lines, with the patient’s autologous AML blasts, but not with lymphocytes or with cells from liver, colon, skin and other tissues. AT1413 recognized a unique, not previously described, sialylated epitope on CD43 (CD43s). CD43s is overexpressed on all types of AML and MDS, as illustrated by its reactivity with freshly isolated blasts of each of more than 60 randomly selected AML and MDS patients in our clinic, representing all WHO 2008 AML and MDS classes. AT1413 induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) of target cells in vitro. To investigate the effect of AT1413 in vivowe first generated mice populated with human effector cells (NK cells, CTL and myeloid cells) by injecting human hematopoietic stem cells into new born immunodeficient mice. After establishment of a human immune system in these mice we inoculated luciferase labeled AML cells via tail vein injection. Following engraftment of the tumor we dosed the mice biweekly with AT1413 or a control antibody. We observed strongly reduced numbers of AML cells in AT1413- but not in control antibody treated mice. Importantly, AT1413 treatment was tolerated well and did not affect numbers of non-malignant human myeloid cell in these mice. Conclusions: We have obtained an antibody from a cured AML patient which recognizes a unique sialylated epitope on CD43 (CD43s) that is selectively over-expressed on all WHO 2008 types of AML and MDS. This antibody was able to eliminate AML cells in vivo and therefore has high therapeutic potential.
Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML to reduce risk of relapse.
Authors: Boddu Prajwal , Jorgensen Jeffrey L. , Kantarjian Hagop M. , Borthakur Gautam , Kadia Tapan M. , Daver Naval Guastad , Alvarado Yesid , Pemmaraju Naveen , Bose Prithviraj , Naqvi Kiran , Yilmaz Musa , Pierce Sherry , Brandt Mark , Dinardo Courtney Denton , Jabbour Elias , Garcia-Manero Guillermo , Cortes Jorge E. , Ravandi Farhad 
Published: September 2018

7018 Background: Persistence of minimal residual disease (MRD) post therapy is a powerful predictor of outcome in patients with AML treated with traditional cytarabine and anthracycline based regimens. The clinical relevance of MRD in the context of hypomethylating agents has not been evaluated extensively. Methods: Among 194 patients with AML treated with single agent azacytidine, decitabine, or gaudecitabine, 116 (median age 76, range 60 - 92) had MRD analysis performed on bone marrow specimens obtained at time of assessment of response or thereafter; among them 69 (59%) achieved either morphologic complete remission (CR) or CR with incomplete recovery of platelets (CRp) or counts (CRi), and 61 (53%) had evaluable MRD data; MRD was assessed using an 8-color flow panel, with a detection sensitivity of 0.01%. Results: Median cycles to achieving response was 2 (range, 1-6). Sixty one patients had evaluable MRD data at the time of response, of whom 19 (28%) became MRD negative (-). This was associated with a reduced cumulative risk of relapse (p = 0.012) but did not translate to an improved relapse-free survival (RFS; p = 0.17) or overall survival (OS; p = 0.79) due to high frequency of non-relapse deaths (attributable to comorbidities and infections) in the MRD- group. Patients who achieved a MRD- state at the time of achieving response had a higher mortality [5/8 (62%)] when compared with those who achieved a MRD- state in subsequent cycles [1/13 (7.6%); p = 0.01], resulting in an inferior OS (6.2 months (mo) vs 20 mo, p = 0.012). Similarly, achieving negative MRD at CR and at any time up to 3 months post response was not associated with improved RFS or OS despite a lower cumulative risk of relapse (p = 0.045). There was no impact of MRD, on OS, whether the MRD- state was achieved after 1st, 3rd or 6thcycle of therapy. Association between depth of MRD response at time of remission and RFS was borderline significant (p = 0.08). On multivariate analysis, response (CR vs CRi/CRp), but not a negative MRD, was predictive for RFS or OS. Conclusions: In this cohort of older AML patients treated with hypomethylating agents, achieving a MRD- state was associated with a reduced risk of relapse but not improved RFS or OS.
A Bayesian randomized phase II study of guadecitabine (SGI-110) based regimens comparing guadecitabine 5 days (SGI5), 10 days (SGI10), 5 days + idarubicin (SGI5 + Ida), 5 days + cladribine (SGI5 + Clad), in untreated patients ≥ 70 years with acute myeloid leukemia (AML).
Authors: Naqvi Kiran , Nogueras-Gonzalez Graciela M. , Cheung Cora M. , Pemmaraju Naveen , Jabbour Elias , Garcia-Manero Guillermo , Dinardo Courtney Denton , Ohanian Maro , Jain Nitin , Takahashi Koichi , Alvarado Yesid , Konopleva Marina , Huang Xuelin , Cortes Jorge E. , Kantarjian Hagop M. 
Published: September 2018

7019 Background: Guadecitabine is a next generation hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. This allows prolonged exposure of leukemia cells to its active metabolite, decitabine. We aimed to compare the efficacy and safety profile of guadecitabine in untreated ≥ 70 years AML patients. Methods: Untreated patients ≥ 70 years with AML were randomized in a phase 2 Bayesian design in one of the 4 arms: guadecitabine 60mg/m2/daily x 5 (SGI5), guadecitabine 60mg/m2/daily x 10 (SGI10), SGI5 + Ida (6mg/m2/daily x 2), or SGI5 + Clad (3mg/m2/daily x 5). The Bayesian design evaluated response and toxicities simultaneously. Primary objective was complete remission (CR) rate and remission duration. Survival was estimated using the Kaplan-Meier method. Results: Between June 2014 and Nov 2016, we treated 34 patients: 8 in SGI5; 9 in SGI10; 8 in SGI5 + Ida and 9 in SGI5 + Clad. Median age was 75 years. 38% had complex karyotype. Median follow-up was 8.3 months. Overall response rate (ORR= CR + CRi) was 53%, shown in the table below. Median remission duration was 7.4 months. 4 week mortality was 3%. Median survival is 13.1 months. A trend for superior survival was observed with SGI5 + Ida (median survival not reached; p=0.22). Common G3/4 toxicity included febrile neutropenia (48%), thrombocytopenia (26%), leukopenia (22%) and anemia (11%). Conclusions: Guadecitabine is clinically active and safe as single agent and in combination in elderly patients with untreated AML. A separate previously reported multicenter study showed no difference between SGI5 vs SGI10 in 103 treatment naïve elderly AML patients (Kantarjian et al. Blood 2015 126:458). CR and ORR were lower with SGI5 + Clad. Based on these findings, the study continues now comparing SGI5 vs SGI5 + Ida. [Table: see text]
CyFi: A phase I study exploring the role of cMET pathway inhibition with ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML).
Authors: Wang Victoria , Mannis Gabriel N. , Olin Rebecca Leah , Logan Aaron , Martin Thomas G. , Damon Lloyd Earl , Kilayko Danielle , Munster Pamela N. , Andreadis Charalambos 
Published: September 2018

7040 Background: Pts with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum HGF level is an adverse prognostic factor in AML (Verstovsek, et al. 2001; Kim, et al. 2005). Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death (Kentsis, et al. 2012). Methods: We initiated a phase I study to assess the safety and tolerability of Fi combined with Cy in patients with AML who are refractory to 7+3 or have relapsed within 1 year of induction. Fi is given in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks, starting on day 0, and Cy at a fixed dose of 2g/m2 on days 2-7, using a 3x3 design. PBMCs, BM and serum are collected at defined time points to assess HGF levels and activation of the c-Met pathway. Results: Dose escalation is complete and there were no protocol-defined DLTs identified in 9 evaluable pts. All pts treated to date were refractory to induction. Four had de novo AML; 2 had undifferentiated leukemia; 2 prior MDS; 1 prior MPN. Most frequent grade 3/4 TEAEs were febrile neutropenia (56%), LFT abnormalities (11%), and electrolyte disturbance (11%). There was 1 death (11%) from sepsis and multi-organ failure on day 23, following ANC recovery. Of the 7 evaluable pts, 3 achieved a CR (43%), all in the 2nddose cohort. Two of the 3 CRs are long lasting 11 and 12 months following AlloHCT. All patients had detectable circulating HGF levels at baseline compared to control subjects without AML. HGF levels increased following exposure to Fi by an average of 193%. Baseline HGF levels or change from baseline were not associated with treatment response. Conclusions: Ficlatuzumab can be safely combined with HiDAC in this high-risk AML population and produce durable clinical responses. Circulating HGF levels were detectable at baseline and uniformly increased with treatment suggestive of a feedback response or immune complex stabilization. Dose expansion is ongoing. Clinical trial information: NCT02109627.
Impact of early landmark responses with ponatinib on 4-yr outcomes in CP-CML patients (pts) in PACE, a pivotal phase II trial.
Authors: Mueller Martin , Baccarani Michele , Deininger Michael W.N. , Guilhot Francois , Hochhaus Andreas , Hughes Timothy P. , Shah Neil P. , Talpaz Moshe , Lustgarten Stephanie , Santillana Sergio , Rivera Victor M , Clackson Timothy Piers , Cortes Jorge E. 
Published: September 2018

7050 Background: Ponatinib is approved for pts with refractory CML or Ph+ ALL for whom no other TKI therapy is indicated, or for patients with T315I. Previously (Mueller ASCO ‘16), we reported the positive association of early landmark responses with ponatinib on survival at 3 yrs in heavily pretreated pts with CP-CML in PACE (NCT01207440). Here, we provide an update with survival outcomes at 4 yrs. Methods: The association of molecular (assessed in a central lab) and cytogenetic responses (CyR) at 3, 6 and 12 mo with 4-yr post-landmark PFS and OS was evaluated in CP-CML pts (n = 267). P values: calculated using log-rank test. Data cutoff: 3 Oct ‘16. Results: At baseline, median time from diagnosis: 7 (range, 0.5–27) yrs; median age: 60 (18–94) yrs; median %Ph+: 100% (3–100), ≤10% Ph+: 19 pts (7%); 61% of pts had ≥3 prior TKIs. Among evaluable pts at 3, 6 and 12 mo, MCyR/CCyR was achieved in 48%/39%, 62%/52% and 71%/56% and MMR in 14%, 29% and 39% of pts, respectively. Greater reductions in BCR-ABL1 levels (Table) and CyR at most landmark time points were associated with improved 4-yr post-landmark PFS and OS. Deeper responses at all landmark time points were associated with achievement of MR4.5 over time. Conclusions: As with the 3-yr landmark analysis, CyR and deep reductions in BCR-ABL1 transcripts at early time points correlated with improved 4-yr post-landmark survival in this refractory population. These data continue to demonstrate the prognostic value of early cytogenetic and molecular responses with ponatinib in heavily pretreated pts with CP-CML. Clinical trial information: NCT01207440. [Table: see text]