bluuebunny/crossref_metadata_2025_split huggingface dataset:
An assessment of disease features and immune response in breast cancer patients that did not recur after receiving HER2 peptide, AE37 vaccine in a randomized phase II trial.
Authors: Hale Diane F , Perez Sonia A. , Vreeland Timothy J , Trappey Alfred F , Dabney Raetasha Sheavette , Berry John S. , Ardavanis Alexandros , Sears Alan K. , Papamichail Michael , Clifton Guy T. , Pappou Efi , Patil Ritesh , Anastasopoulou Eleftheria , Ponniah Sathibalan , Shumway Nathan M. , Peoples George Earl , Mittendorf Elizabeth Ann 
Published: March 2020

625 Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived peptide AE36 (776-790), administered with immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present analysis of immune markers and patient feature that may impact recurrence from an ongoing prospective, randomized, single-blinded Phase IIb trial of AE37+GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC) patients. Methods: After completion of standard therapy; disease-free, node positive or high risk node negative BC patients (pts) were randomized to receive either AE37+GMCSF or GMCSF in 6 monthly intradermal inoculations. Immunologic responses were measured using [3H]-thymidine incorporation assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts (VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated 109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR were younger (44 v 50 yo p=0.11), had higher grade (67% v 44% p=0.32), more ER/PR- (44% v 38% p=0.75), larger tumors (89% v 50% p=0.06), and node positive (89% v 70% p=0.37). No difference for HER2 status (IHC 3+, 44% v 49% p=0.64). Both VR and VNR responded to vaccine though the mean DTH and proliferative stimulation index was approximately 10% less in VR pts (18 v 20 p=0.73; 1.96 v 2.2 p=0.77 respectively). The most predictive measure was change in Tregs with VR pts less likely to decrease their Tregs levels (50% v 76% p=0.17) after vacination and more likely experience increased Tregs (17% v 8% p=0.48). A decrease in Tregs had an inverse trend towards recurrence (p=0.17). Conclusions: Preliminarily, it appears most pts immunologically respond to vaccine though slightly less for VR in most assays. The changes of Tregs appear to correlate best with disease recurrence. Whether this reflects an association with disease status or a failure of the vaccine is yet to be seen. These levels may become important in predicting risk for clinical recurrence in future vaccine trials.
Functional imaging of HER2-positive metastatic breast cancer using 64Cu DOTA-trastuzumab positron emission tomography (PET).
Authors: Mortimer Joanne E. , Conti Peter , Tong Shan , Reyes Jose , Carroll Mary I. , Poku Kofi , Colcher David , Raubitschek Andrew Antony , Bading James R , Miles Joshua 
Published: March 2020

639 Background: We are developing 64Cu-labeled trastuzumab (tras) as a PET imaging agent for women with HER2+ beast cancer. To maximize image quality and minimize HER2 uptake in normal tissues, we pre-administered 2 different doses of cold tras prior to injection of the imaging agent. Methods: Pts with advanced breast cancer were eligible if they had bx confirmed HER2 + disease, had not received anti-HER therapy for 6 mos. and had > 1 non-hepatic site of metastasis > 2 cm outside the biopsy site. All un-derwent staging FDG/PET and bone scan. Prior to injection of 64Cu-tras, pts. received 5 or 50 mg (2 and 4 pts) of cold tras. PET-CT was obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 18F-FDG scans. Uptake in organs and lesions were measured in terms of body wt-normalized SUV. Lesions with intensity > adjacent tissue were considered positive on PET. The number of metastatic sites identified on 64Cu-tras/PET was compared to the number on FDG/PET. Image quality was assessed according to differences between the 2 pretreatment doses. Results: Six pts have been imaged. Tras dose had a marked effect on liver uptake of64Cu [SUV = 23±3 (mean±sd) and 6.3±0.6 for 5 and 50 mg tras, respectively; P < 0.05]. 72 CT+ lesions (32 bone, 28 nodal, 9 liver, 2 breast, 1 lung) were included in D1 and/or D2 scans. Of these, 66 of 72 (92%), 48 of 63 (76%) and 36 of 44 (82%) were detected on FDG, D1 and D2 scans, respectively. Lesion SUVmax was 9±5 (n=37, range 3-23) on D1 and 11±6 (n=27, range 1-29) on Day 2. 64Cu-tras-to-FDG SUVmax ratios were 1.0±0.8 (range 0.2-4.3) and 1.3±1.1 (range 0.2-3.5) for D 1 and 2. Lesion 64Cuuptake trendedliver > bone > nodes. Conclusions: 64Cu-tras/PET visualizes HER2+ lesions in bone, liver and, to a lesser degree, lymph nodes. Pre-administration of cold tras improves the quality of tras/PET, especially of intrahepatic lesions. In the next phase of study we will perform 64Cu-tras/PET in pts with HER2 1+ and 2+ disease.
Outcome of HER2-positive breast cancer patients following metastatic relapse after adjuvant trastuzumab treatment since EMA regulatory approval.
Authors: Spano Jean-Philippe , Vignot Stéphane , Ho Xuan Dung , Zongo Nayi , Magneux Celine , Genestie Catherine , de la Motte Rouge Thibault , Lefranc Jean-Pierre , Khayat David , Gligorov Joseph 
Published: March 2020

641 Background: Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2) is approved in France since 2005 for HER2-positive breast cancer patients in the adjuvant setting. Efficacy of this treatment is clearly established but little is known related to patient outcome if they develop metastatic relapse after adjuvant trastuzumab. The aim of this study is to analyse these relapses with a special focus on efficacy of anti-HER2 treatment in this setting. Methods: We analysed 456 patients with HER2-positive early breast cancer treated with trastuzumab containing adjuvant therapy between 2006 and 2011 in two Departments of Medical Oncology from Université Pierre et Marie Curie, Paris, France. Data from patients with metastatic relapse were identified. Disease free survival (DFS) between end of trastuzumab and relapse, quality of response, and time to progression after anti-HER2 new treatment are reported. Results: Relapse rate was 3.3 % after adjuvant trastuzumab (15 pts, median age 53 years, ER+ 40 %). DFS between end of trastuzumab and relapse was 244 days (95% CI: 91 - 397 days). One pt actually had a confirmed HER2-negative metastatic disease. The other 14 pts were treated with anti-HER2 agents at relapse. On 12 evaluable pts, an objective response was observed in 8 pts, stabilisation in 2 pts and progression in 2 pts. Median time to progression after first line metastatic treatment was 222 days (95% CI: 114 - 330 days). Additional data about site of relapse and subsequent therapies are available. Conclusions: Relapse after adjuvant trastuzumab remains a rare event in this real life cohort of breast cancer pts. For these pts, we will present data of the patterns of relapse and response. These data may help us to determine if adjuvant trastuzumab has an impact on outcome of HER2 metastatic disease compared to data in trastuzumab naive metastatic HER2-positive breast cancer pts. We also plan to seek international collaboration to expand our analyses, as well as overall survival.
Switch to nilotinib versus continued imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.
Authors: Lipton Jeffrey Howard , Hughes Timothy P. , Leber Brian , De Souza Carmino , Dorlhiac-Llacer Pedro E , Steegmann Juan Luis , Guerci-Bresler Agnes , Schwarer Anthony P. , Cervantes Francisco , Reynolds John , Collins LaTonya R , Szczudlo Tomasz K. , Spector Nelson 
Published: March 2020

6505^ Background: Nilotinib induced significantly faster and deeper molecular responses vs imatinib in the ENESTnd trial. Achieving these deeper molecular responses may increase patient eligibility for future TKI discontinuation studies. Methods: CML-CP pts (N = 207) who achieved a complete cytogenetic response but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg BID (n = 104) or to continue their imatinib dose (400 or 600 mg QD [n = 103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL by RQ-PCR with a sample sensitivity of ≥ 4.5 logs in 2 consecutive samples). Other endpoints included molecular responses (MMR ≤ 0.1%IS, MR4 ≤ 0.01%IS, and MR4.5 ≤ 0.0032%IS) and BCR-ABL ratio over time. Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL in at least 1 sample) by 12 mo was significantly higher on nilotinib vs imatinib (23.1% vs 10.7%; P = .02). Rates of MMR, MR4, MR4.5, and CMR were also superior in pts switched to nilotinib, and these pts had significantly shorter times to achieve these responses. Imatinib-treated pts had minimal evidence of improvement in molecular response vs a median 0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. The nilotinib safety profile was consistent with prior studies. Both drugs were well tolerated. Conclusions: Twice as many pts achieved deeper molecular responses after switching to nilotinib vs staying on imatinib. [Table: see text]
The prognostic significance of early molecular and cytogenetic response for long-term progression-free and overall survival in imatinib-treated chronic myeloid leukemia (CML).
Authors: Hehlmann Rudiger , Hanfstein Benjamin , Müller Martin C , Erben Philipp , Lauseker Michael , Fabarius Alice , Schnittger Susanne , Haferlach Claudia , Goehring Gudrun , Krause Stefan W. , Dengler Jolanta , Falge Christiane , Neubauer Andreas , Stegelmann Frank , Pfreundschuh Michael , Spiekermann Karsten , Baerlocher Gabriela M , Hasford Joerg , Saussele Susanne , Hochhaus Andreas ,   for the SAKK and the German CML Study Group
Published: March 2020

6510 Background: In the face of competing first line treatment options for CML early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of an alternative therapy. We sought to evaluate the prognostic impact of early response landmarks. Methods: A total of 1,303 newly diagnosed imatinib-treated patients (pts) from the randomized CML Study IV were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABLIS). The proportion of Philadelphia-chromosome positive metaphases (Ph+) was determined by conventional metaphase analysis. To confirm the prognostic significance of early molecular response, an independent validation sample of 174 pts treated with imatinib within the IRIS trial was analyzed. Results: The persistence of >10% BCR-ABLIS at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABLIS (41% of pts; 5-year OS: 94%; p=0.012), and from a group with <1% BCR-ABLIS (31% of pts; 5-year OS: 97%; p=0.004). By cytogenetics high-risk patients could be identified by the persistence of >35% Ph+ (27% of pts; 5-year OS: 87%) as compared to ≤35% Ph+ (73% of pts; 5-year OS: 95%; p=0.036). At 6 months the >1% BCR-ABLIS group (37% of pts; 5-year OS: 89%) showed inferior survival compared to ≤1% (63% of pts; 5-year OS: 97%; p<0.001); survival of the >0% Ph+ group (34% of pts; 5-year OS: 91%) was inferior to 0% Ph+ (66% of pts; 5-year OS: 97%; p=0.015). Regarding the IRIS pts 3 month BCR-ABLIS >10% (25% of pts; 8-year OS: 81%) was associated with inferior survival compared to ≤10% (75% of pts; 8-year OS: 93%; p=0.011). Conclusions: Failure to achieve the response landmarks of 10% BCR-ABLIS or 35% Ph+ at 3 months of imatinib treatment and 1% BCR-ABLIS or 0% Ph+ at 6 months identifies high-risk patients which might benefit from an early change of therapy.
Efficacy and safety of bosutinib (BOS) for Philadelphia chromosome–positive (Ph+) leukemia in older versus younger patients (pts).
Authors: Brummendorf Tim H. , Gambacorti-Passerini Carlo , Schafhausen Philippe , Khoury Hanna Jean , Hochhaus Andreas , Kindler Thomas , Fischer Thomas , Besson Nadine , Leip Eric , Kelly Virginia , Cortes Jorge E. 
Published: March 2020

6511 Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity in Ph+ leukemia. Methods: Efficacy and safety of BOS 500 mg/d was evaluated in older (≥65 y; n = 119) and younger (<65 y; n = 451) pts in 3 cohorts: chronic phase chronic myeloid leukemia (CP CML) after imatinib (IM; CP2L cohort; n = 287); CP CML after IM + dasatinib (DAS) and/or nilotinib (NIL; CP3L cohort; n = 119); and accelerated/blast phase (AP/BP) CML or acute lymphoblastic leukemia after IM ± DAS and/or NIL (ADV cohort; n = 164). Results: Baseline events (≥65 y vs <65 y) included respiratory disorders (35% vs 13%), cardiac disorders (29% vs 9%), and diabetes (4% vs 4%). Median baseline medications were 3 (≥65 y) and 5 (<65 y). Median BOS duration was 11 mo and median follow-up was 31 mo for all pts. 80% of ³65 y and 67% of <65 y pts discontinued BOS, including 32% and 18% due to an adverse event (AE; most commonly thrombocytopenia [6% vs 3%]). Rates of response were similar or lower in older versus younger pts (Table). On-treatment transformation to AP/BP CML was similar between groups. Incidences of nonhematologic treatment-emergent AEs were generally similar between older and younger pts, notably (all grades/grade ≥3 for ≥65 y vs <65 y): diarrhea (85%/9% vs 81%/8%), infection (56%/15% vs 49%/10%), and edema (8%/0% vs 4%/<1%). Common grade ≥3 lab abnormalities (≥65 y vs <65 y) were thrombocytopenia (35% vs 35%), neutropenia (21% vs 25%), and anemia (19% vs 19%). Conclusions: BOS demonstrated similar efficacy and acceptable safety in both older and younger pts across Ph+ leukemia cohorts. [Table: see text]
BCR-ABL kinase domain mutations and resistance in Ph+ acute lymphoblastic leukemia from the imatinib to the second-generation TKI era.
Authors: Soverini Simona , Gnani Alessandra , De Benedittis Caterina , Iacobucci Ilaria , Venturi Claudia , Papayannidis Cristina , Luppi Mario , Merante Serena , Malagola Michele , Russo Domenico , Tiribelli Mario , Salvucci Marzia , Vitale Antonella , Elia Loredana , Vignetti Marco , Foà Robin , Baccarani Michele , Martinelli Giovanni 
Published: March 2020

6531 Background: Advent of 2nd-generation TKIs has brought additional treatment options for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients (pts). To analyze the changes they have determined in mutation frequency and type, we have reviewed the database recording the results of BCR-ABL mutation analyses done in our laboratory from 2004 through 2011. Methods: 781 tests on 258 pts were performed by direct sequencing. Results: 143 pts were analyzed because of imatinib resistance; 101 (71%) had one or more mutations (a single mutation in 91 pts; two mutations in 10 pts). Three mutation types were by far the most frequent: T315I (38 pts, 37%), E255K (19 pts, 18%) and Y253H (19 pts, 18%). Of 84 pts who had developed resistance to 2nd- or 3rd-line therapy with dasatinib, nilotinib or bosutinib after imatinib failure, 65 (77%) were positive for Bcr-Abl mutations; 30 (46%) carried multiple mutations (up to four) and in 19 of them (63%) this was consequence of multiple lines of therapy. The most frequent newly acquired mutation in this setting was the T315I, detected in 35/57 (61%) cases acquiring mutations on dasatinib. Mutation analysis was also performed in 15 resistant pts enrolled in a study of dasatinib as 1st-line treatment of Ph+ ALL; 12 pts were positive, 11 of them had a T315I. Taking advantage of a next-generation sequencer (Roche 454), allowing a high sensitive and quantitative mutation scanning of Bcr-Abl, serially collected samples from 24 selected cases who developed mutations and resistance to one or more TKIs were retrospectively analyzed to study the kinetics of expansion of mutant clones. Results will be presented. Conclusions: Although 2nd generation TKIs are more potent and have much fewer insensitive mutations, long-term disease control remains a problem and the T315I becomes an even tougher enemy. The high genetic instability fosters mutational events anytime during TKI treatment and some mutation types (T315I, Y253H) have been observed to emerge and take over very quickly (from <0.01% to 90% in one-two months). Supported by PRIN, AIL, AIRC, Fondazione CARISBO.
Outcomes of patients older than 60 years with acute lymphoblastic leukemia: Survey from the Surveillance, Epidemiology, and End Results (SEER) program.
Authors: Park Jae Hong , Devlin Sean , Tallman Martin S. , Douer Dan 
Published: March 2020

6532 Background: The cure rate of pediatric acute lymphoblastic leukemia (ALL) has increased over the last 4 decades to above 80%, compared to a much smaller improvement in adults aged < 60 years. However, outcome information on older ALL patients (age ≥ 60 years) is limited. Only a few clinical trials include the older patients, apply the same regimens developed for adults of all ages, and report a very poor outcome with no improvement over time. We therefore conducted a population-based survey of older ALL patients focusing on early death (ED) rates and changes in outcome over the last 30 years. Methods: Data from 9 population-based cancer registries that participate in the National Cancer Institute’s SEERprogram were used to identify patients aged 60 or older with a diagnosis of ALL. Survival rates at 1, 6, 12 and 24 months were estimated using actuarial methods for 4 calendar periods: 1980-1985, 1986-1992, 1993-1999, and 2000-2006. ED was defined as death occurring within one month of ALL diagnosis. Results: A total of 1066 ALL patients were identified. The ED rate significantly improved over the four study time periods from 20.2% in 1980-1985 to 13.2% in 2000-2006 (p=0.03). The overall survival (OS) at 6 months improved from 32.8% in 1980-1985 to 45.3% in 2000-2006, but at 24 months, only a modest difference in OS was noted across the time period (13.1% in 1980-85 vs. 17.5% in 2000-06). The median survival increased from 3 months to 6 months from the period 1980-1999 to 2000-2006. Conclusions: Although the long-term OS for patients aged 60 and over remains poor, there has been a slight improvement in early mortality and median OS from 1980s to the early 21st century. While the progress in reducing ED and increasing survival at 6 months is encouraging, and may be reflecting better supportive care measures, the limited improvement indicates poor tolerance and lack of efficacy of the toxic, long and complex chemotherapy regimens designed for younger adults. Therefore, future studies should be designed specifically for older ALL patients, focusing on novel, effective, but less toxic therapies, to further improve the short-term OS seen in the past decades and possibly a better overall outcome.
Randomized phase III trial of haploidentical HCT with or without an add back strategy of HSV-TK donor lymphocytes in patients with high-risk acute leukemia.
Authors: Bordignon Claudio , Bonini Chiara , Sarina Barbara , Lambiase Antonio , Ciceri Fabio 
Published: March 2020

6541 Background: Suicide gene therapy applied to allogeneic stem cell transplantation has been tested in several trials. When exposed to ganciclovir, donor lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK cells) are selectively eliminated. In a phase I-II trial (Ciceri, Bonini, Lancet Oncology 2009,489-500), TK cells were infused in patients after haploidentical transplantation. Of 50 patients enrolled, 28 received transduced-TK cells and 22 achieved rapid immune reconstitution, with a non-relapse mortality of 14%. GvHD after DLI-TK infusion was reported in 30% of patients and in all cases was fully controlled by ganciclovir treatment. Methods: High risk leukemia patients in first or subsequent complete remission are currently randomized in a 2-arm (3:1 ratio) phase III trial with or without the add-back strategy of HSV-TK donor lymphocytes in patients underwent T-depleted haploidentical stem cell transplant. Primary end point is disease-free survival (DFS), while secondary end points included overall survival, non-relapse mortality, immune reconstitution, acute and chronic GvHD incidence, and relapse incidence. For the primary analysis of DFS 170 patients (127 patients in the experimental group and 43 patients in the control) are required to detect an hazard ratio of 0.55 with at least 80% power for 2-sided 0.05 level test. Patients are eligible for the study if they are older than 18 years-old, absence of timely and suitable HLA matched family or unrelated donor, and have a ECOG performance status < 2. Patients are stratified by state of disease, ECOG PS and country before randomization. Results: Transduced lymphocytes are given to patients between day +21 and day +49 after haploidentical HCT in the absence of spontaneous immune reconstitution and/or development of GvHD. In absence of immune reconstitution and GvHD after the first TK-cells add-back further 3 infusions could be administered 30 days after the last infusion. TK lymphocytes dose is 1 x10^7 CD3/Kg. Conclusions: The study (TK008) is currently open to accrual in EU, US, Israel (clinicaltrials.gov:00914628).