bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of smoking for quality of life and illness perceptions of lung cancer patients.
Authors: Danson Sarah , Rowland Christine , Eiser Christine , Rowe Richard , Ellis Sue , Crabtree Carol , Horsman Janet M , Wadsley Jonathan , Hatton Matthew , Woll Penella
Published: March 2020

6113

Background: Adverse publicity about smoking may lead to feelings of guilt among lung cancer patients or pessimism about their future, potentially compromising health-related quality of life (QoL) and adherence with medical advice. QoL is an important outcome in clinical trials, particularly where survival rates are low. We aim to compare QoL and illness perceptions of lung cancer patients depending on smoking history. Methods: Clinical data, measures of QoL (EORTC-QLQ-C30+LC13) and illness perceptions (Brief IPQ – includes items to assess perceived severity, causality, timeline, understanding, emotional impact, and control over illness) were completed by 190 newly diagnosed lung cancer patients (Non-small cell: 75%; Mean age: 68 years, range: 48-85 years; 58% males). Of these, 24% were current smokers, 69% former smokers, and 7% never smoked. Results: Although overall QoL was similar between the three smoker groups, there was a significant effect of smoking status on QoL subscale emotional function (EF)(F(2,168)=4.08,p=.019). Those who never smoked had significantly higher EF than current smokers (p=.03). There was also a significant effect of smoking history on cough (F(2,166);=5.40 ,p=.005) with smokers reporting significantly greater levels than former smokers (p=.004). Smokers were more likely than former smokers (p=.015) to attribute their lung cancer to smoking (F(2,161)=16.49,p<.000). Furthermore, there was a significant effect of smoking on the perceived timeline of illness (F(2,144)=3.33,p=.039), with smokers being more pessimistic about this than former smokers (p=.043). Conclusions: These findings have implications for planning the care of lung cancer patients. In addition to the different treatment needs of smokers and former smokers, smokers may need greater support to cope with the emotional effects of their illness. Our findings suggest that smokers blame their illness on their own behaviour, and have a more pessimistic view of likely survival time, so they may need more encouragement to accept life-prolonging treatments. These results may also inform tailored smoking-cessation advice.
Impact of oncology drug shortages on patient treatment.
Authors: Becker Daniel Jacob , Talwar Sumit , Levy Benjamin , Thorn Molly , Roitman Janna , Blum Ronald H. , Harrison Louis Benjamin , Grossbard Michael L.
Published: March 2020

6114

Background: Cancer drug shortages increased considerably over the past 5 years, but quantitative analyses of the scope and effects are limited. We assessed the effects of drug shortages on outpatient medication use in a single New York City university hospital. Methods: We examined pharmacy records for drug shortages, defined by the ASHP as supply issues that affect “how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent.” We examined outpatient records for all cancer patients treated with infusional antineoplastic and/or supportive medications from 4/2010-9/2010 and from 4/2011-9/2011, and performed subgroup analysis on Aug/Sept 2011, the peak of medication availability problems at our hospital. We compared proportions of patients treated with specific medications in 2010 and 2011 with Pearson’s chi-square test. Results: Twelve medications were in shortage during the study period in 2010 and 22 in 2011. Between 4/1/10 and 9/30/10, 335 cancer patients were treated, and 379 patients were treated between 4/1/11 and 9/30/11. Median patient age was 60 years. Cancer site of origin was comparable between years: breast (40%), GI (15%), lymphoma (10%), GU (8%), and lung (7%). Drugs considered in shortage were used for 170 (50.8%) patients in 2010 and 241 (63.6%) patients in 2011 (p=0.0005). Of 235 patients treated in Aug/Sept 2011, there were 23 (9.8%) documented therapy changes due to shortages, compared with 0 changes among 211 patients treated in Aug/Sept 2010 (p<0.0001). Among patients treated in Aug/Sept 2010 24 (11.4%) patients received paclitaxel and 19 (9.0%) received docetaxel. Among patients treated in Aug/Sept 2011, 11 (4.7%) received paclitaxel and 38 received docetaxel (16.2%), a 69% decrease for paclitaxel and 80% increase for docetaxel from 1 year prior (p=0.009, and p=0.024, respectively). The estimated cost of a single treatment with paclitaxel for 1 patient with BSA 1.75 was $47.59 versus $858.39 for docetaxel, a 1704% increase. Conclusions: Oncology drug shortages affected the majority of patients in our center and increased at an alarming rate. Drug shortages have substantial economic costs and mandate treatment changes that may affect efficacy and toxicity.
Financial burdens (FB), quality of life, and psychological distress among advanced cancer patients (ACP) in phase I trials and their spousal caregivers (SC).
Authors: Hlubocky Fay J. , Cella David , Sher Tamara G. , Ratain Mark J. , Daugherty Christopher
Published: March 2020

6117

Background: FBs have been identified as a significant predictor of stress for cancer patients and their caregivers/partners. FBs may indirectly affect the quality of life and psychological distress of clinical trial subjects, particularly those with advanced disease on Phase I trials. Methods: A convenience sample of ACP enrolling in phase I trials was assessed at baseline (T1) and one month (T2) using several measures including: depression (CES-D), state-trait anxiety (STAI-S/T), quality of life/qol (FACIT-Pal), and global health (SF-36). Data on FB were obtained via the questions of Ell (2008), querying subjects on: employment status, unexpected medical costs, concerns regarding wages (e.g. termination, use of sick time), and financial stress. Results: 104 subjects (52 Phase I ACPs and 52 SC) were separately interviewed at T1 and T2. For the total population: median age 61 (28-78y); 50% male; 100% married; 87% Ca; 67%> HS educ; 55% GI dx; 53% income <$65,000 yr, with45% ACPs employed full/part-time; 55% retired; 66% SC employed full/part-time with 34% retired. At T1, 82% of ACP reported medical cost concerns and 79% reported financial stress. For SC at T1, 69% reported medical costs concerns; 83% employed SC reported wage concerns; and 81% reported financial stress. For both ACP and SC, rates remained consistent with the exception of increased self-report re medical cost concerns at 85% and 72% respectively at T2. At T2, ACP who reported unexpected medical costs had higher STAI-S (31 ± 10 v 29 ±12, p=0.02) and CES-D scores (12 ± 11 v 10 ± 9, p=0.04). SC with self-reported financial stress had higher STAI-S anxiety (39 ± 17 v 35 ± 13, p=0.03) at T2. In regression analyses, ACP with medical costs concerns had poorer FACIT-Pal QOL over time. Also, SC with medical cost concerns at T2 was negatively associated with SF-36 scores. ACP and SC qualitative responses re FBs revealed salient themes: insurance coverage, unexpected costs associated with research study participation, Medicare, bankruptcy, and worry re financial stability after ACP death. Conclusions: FBs are negatively associated with quality of life among clinical trial subjects and SC in phase I trials.
Variation in health-related quality of life (HRQOL) by ECOG performance status (PS) and fatigue among patients with chronic lymphocytic leukemia (CLL).
Authors: Flowers Christopher , Pashos Chris L , Weiss Mark Adam , Lamanna Nicole , Farber Charles Michael , Kipps Thomas J. , Lerner Susan , Kay Neil E , Sharman Jeff Porter , Grinblatt David L. , Flinn Ian W. , Kozloff Mark , Swern Arlene S , Khan Zeba M. , Street Thomas , Sullivan Kristen , Keating Michael J. , Yu Ren
Published: March 2020

6122

Background: Clinicians and investigators commonly use ECOG PS and clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multi-faceted construct that comprehensively looks at the pt perspective on disease and well-being. Because limited data exist on the relationships between PS, fatigue, and HRQOL for CLL pts, we examined the associations between these measures, and 3 validated HRQOL instruments: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, and Brief Fatigue Inventory (BFI). Methods: Data were collected in CONNECT CLL, a prospective US observational registry initiated in 2010. Patient demographics and clinical characteristics were provided by clinicians. Patient HRQOL was self-reported at enrollment using the FACT-Leu, EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and clinician-reported fatigue (yes, no). Differences in HRQOL scores were assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 148 community, 10 academic, and 3 government centers. ECOG PS was available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS severity and was worse in pts with fatigue (all p<0.0001). All FACT-Leu domains except social/family were worse in pts with fatigue and those with higher ECOG PS. Mean EQ-5D pain/discomfort, mobility, self care and usual activities domain scores worsened in severity as ECOG worsened and for pts with fatigue (all p<0.011). BFI data indicated that global fatigue, fatigue severity and fatigue-related interference worsened by ECOG severity and were associated with clinician-reported fatigue (all p<0.0001). Conclusions: Initial CONNECT CLL results confirm that HRQOL worsens with worsening ECOG PS and was worse among pts with fatigue, especially in physical/functioning domains, pain/discomfort, and mobility. These results indicate that baseline ECOG PS and physician-rated fatigue are rapid assessments that predict robust measures of HRQOL. Future analyses are planned to examine how HRQOL, ECOG PS and fatigue change over time with changes in treatment and CLL disease status.
Relationship of MRI tests and referral of malignant adnexal masses to gynecologic oncologists for surgery.
Authors: Kupets Rachel , Miroshnichenko Gennady , Paszat Lawrence Frank
Published: March 2020

6134

Background: To evaluate the patterns of radiologic imaging by family physicians and gynecologists in the work up of women found to have an adnexal mass on pelvic ultrasound. To evaluate whether advanced imaging tests are associated with improved referral of high risk adnexal masses to gynecologic oncologists. Methods: Centralized provincial databases of healthcare utilization were used to identify women aged 45 and older who received a pelvic ultrasound between 2006-2008. Subsequent imaging tests ordered by physician specialty were identified. Of those women who proceeded to laparotomy, logistic regression was performed to determine which imaging tests were associated with referral of high risk adnexal tumors to a gynecologic oncologist. Results: 193, 261 women had a pelvic ultrasound; 19, 949 (10.3%) had a laparotomy. 2223 and 627 women were categorized with benign and malignant adnexal masses respectively. Up to 12% of women had a pelvic MRI and 58% of women had a CT scan after a pelvic ultrasound.Family physicians referred 58% and gynecologists referred 47% of high risk ovarian masses to a gynecologic oncologist respectively after imaging.Gynecologic Oncologists operated on only 55% of women with malignant adnexal masses. On multivariate analysis factors significant for surgery by a gynecologic oncologist include a preoperative CT Scan OR 3.58 (p<.001) and CT Scan and MRI OR 7.78 (p<.001). Preoperative MRI alone had an OR of 1.86 (p=0.09) and was not significant. Mean time to surgery significantly increased when further imaging tests were performed after a pelvic ultrasound (100 days), CT (131 days), MRI (170 days), CT and MRI (179 days),P 0.002. Conclusions: The addition of a pelvic MRI to a pelvic ultrasound does not improve the referral of high risk adnexal masses to a gynecologic oncologist. A consensus on appropriate imaging and triage is needed when an adnexal mass is identified on ultrasound.
Long-term follow-up (FU) of patients with durable complete response (DCR) after chemotherapy (CT) and trastuzumab (T) for HER2-altered (HER2+) metastatic breast cancer (MBC).
Authors: Gullo Giuseppe , Zuradelli Monica , Sclafani Francesco , Ballot Josephine , Defrein Anne Marie , Santoro Armando , Crown John
Published: March 2020

615

Background: Durable CT-induced complete response (DCR) of MBC is reported only anecdotally. The addition of monoclonal antibody T to conventional CT results in significant increase in response rates and prolonged survival for patients (pts) with HER2+ MBC. Though CRs are reported in most phase II and III clinical trials of CT+T, there is lack of data about clinical features and long-term outcome of these pts. Methods: We retrospectively reviewed all pts with HER2+ MBC treated at our Institutions with any CT+T and identified cases who achieved DCR. HER2 positivity was defined as 3+score at immunohistochemistry and/or amplification at FISH test. DCR was defined as a CR according to RECIST 1.0 criteria lasting >36 months. Results: We identified 13 pts with HER2+ MBC who met criteria for DCR following CT+T. Their characteristics are: median age: 56yrs (range 30-65), stage at diagnosis: M0 54%/M1 46%, histology: ductal 84%/mixed ductal-lobular 8%/unknown 8%, tumour grade: G3 54%/G2 23%/unknown 23%, oestrogen receptors (ER): neg 62%/pos 38%, sites of metastatic disease: liver only 54%/other visceral 15%/bone and soft tissues only 31%, chemotherapy regimen: taxane+carboplatin 54%/single-agent taxane 23%/docetaxel+lapatinib 15%, capecitabine 8%. Metastatic disease was biopsy-proven in 54% of pts. All pts received maintenance T. Median follow-up (FU) is 6.5 yrs (range 3.0-11.6). Median duration of T was 59 months (17-121). At database cut-off date 12 pts (92%) are alive. Five pts (38%) had disease relapse (3 on maintenance T, 2 after T discontinuation), 2 of whom had radical surgery. In 8 pts (62%) disease has not relapsed (characteristics: all 1st-line therapy, ER negative 75%, liver only distant disease 75%). Conclusions: This is the largest series to our knowledge analyzing long-term FU of HER2+ MBC pts with DCR following CT+T. DCR pts appear to have prolonged survival and a substantial subgroup of them have no further disease relapse. These pts are usually treated in the 1st-line setting, have more frequently ER-negative disease and liver-only metastases. We are currently investigating the molecular profile of this subset of pts.
Impact of PIK3CA mutations and p95HER2 expression on the outcome of HER2-positive metastatic breast cancer patients treated with a trastuzumab-based therapy.
Authors: Fontana Andrea , Allegrini Giacomo , al Zoubi Mazhar , Collecchi Paola , Mazzanti Chiara , Stasi Irene , Lucchesi Sara , Bona Eleonora , Ferrarini Ilaria , Salvadori Barbara , Arrighi Giada , Marcucci Lorenzo , Filidei Mario , Orlandini Cinzia , Falcone Alfredo , Bevilacqua Generoso , Zavaglia Katia
Published: March 2020

629

Background: Currently, no biomarkers of trastuzumab (T) clinical resistance have been validated. The aim of this pilot study was to evaluate the impact of PIK3CA mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a T based-therapy in a HER2-positive metastatic breast cancer (MBC) patients (pts). Methods: 107 HER2-positive MBC pts, treated in the last 10 years, were evaluated. Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all pts received several lines of treatment including T; biomarkers molecular analysis was performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated by a monoclonal antibody that specifically recognizes only the HER2 external domain; the HER2 integrity was defined by the presence of a homogeneous membrane staining (moderate or intense) in at least 30% of the cells, otherwise the HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were detected by automated sequencing. The molecular data were correlated to Time to progression (TTP) of the first line treatment including T and the Overall Survival (OS) by using the Kaplan-Meir method and the log-rank-test. Results: p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs 41,0 months, p= 0,046). Conclusions: These preliminary results suggest a possible role of PIK3CA mutational status in predicting the outcome of MBC pts treated with T.
Lapatinib or trastuzumab? Which anti-HER2 treatment is more effective in the treatment of patients with HER2-positive breast cancer with brain metastases? An Anatolian Society of Medical Oncology Study.
Authors: Kaplan Muhammet Ali , Isikdogan Abdurrahman , Koca Dogan , Kucukoner Mehmet , Gumusay Ozge , Yildiz Ramazan , Oztop Ilhan , Demir Lutfiye , Geredeli Caglayan , Kocer Murat , Yalçintas Arslan Ülkü , Inal Ali , Coskun Ugur , Sener Nur , Inanc Mevlude , Elkiran Emin Tamer , Ozdemir Nuriye , Gok Durnali Ayse , Suner Ali , Alici Suleyman
Published: March 2020

638

Background: In the present study, we investigate that which treatment choice is more effective in the human epidermal growth factor receptor 2 (HER2) positive breast cancer patients with brain metastases. Methods: Of 405 metastatic breast cancer patients with brain metastases at referral centers in Turkey, 111 patients treated with lapatinib or trastuzumab after brain metastases eligible for the analyses were identified. Patients received both drugs consecutively or sequentially were excluded from the study. Results: Median age was 44 years (27-76) and 46 of the 111 patients (41.5%) had received lapatinib. Median time to development of brain metastases was 12.2 months (0-71). Sixteen patients (14.4%) had undergone surgery, 33 (29.7%) radiosurgery, and 108 (97.2%) whole brain radiation therapy (WBRT). Median overall survival (OS) after brain metastases was 15 months(95% confidence interval (CI): 12.3-17.6). Lapatinib usage was prolonged OS over trastuzumab alone (19.1 months vs 12 months, p=0.039).Other parameters affecting the survival were Karnofsky performance score (KPS, >70), number of brain metastases (>3), extracranial metastases (≥2), performed neurosurgery, and received radiosurgery. After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival [Odds ratio (OR), 0.57; p=0.02). Conclusions: Although this retrospective multi-center study had several limitations, study results suggest that the usage of lapatinib after brain metastases prolonged survival compared to the usage of trastuzumab. This result should be support with prospective studies.
Trastuzumab treatment in patients with advanced breast cancer (ABC) confined to locoregional and skeletal sites: Results from a large noninterventional study.
Authors: Jackisch Christian , Schoenegg Winfried , Selbach Johannes , Welslau Manfred , Harich Hanns-Detlev , Schroeder Jan , Schmidt Marcus , Goehler Thomas , Hinke Axel , Eustermann Heidi , Ringel Ralf
Published: March 2020

640

Background: In a prospective observation study routine trastuzumab (T) treatment in HER2+ ABC was evaluated in a total of 1,687 patients (pts) since 2001. This large number allows the subgroup analysis of patients with the involvement of specific sites. Methods: Information on extent of advanced disease was available in 1,674 pts (99%) with HER2 overexpressing ABC. Pts were either pre-treated (39%) or naïve to palliative chemotherapy (CT). The following subgroups and their characteristics were analysed: I: locally ABC only; II: bone metastases allowing for concomitant local tumour; III: other. Results: Locally advanced lesions were found to be the sole BC manifestation in 145 pts (8.7%), while bone metastases ± locally ABC were found in 209 pts (12.5%). This leaves a comparative population of 1320 pts with metastases to other sites, predominantly visceral metastases. The table shows the baseline and treatment characteristics, as well as the long term outcome based on progression/death observed in 79%/56% of pts. Concurrent CT (74% of total group) predominantly consisted of a taxane (46%) or vinorelbin (24%), with no major differences between the groups. Conclusions: In this HER2+ cohort, palliative pts with local lesions only show a comparatively high-risk profile with respect to grading, hormone receptor status and adjuvant CT. Nevertheless, locally ABC only is a significant favourable prognostic factor in HER2+ BC treated with T combinations, with a median survival of 4 to 5 years. [Table: see text]
Estrogen receptor in HER2-positive early breast cancer: Two different diseases?
Authors: Ciruelos Gil Eva Maria , Ghanem Ismael , Manso Luis , Hoyos Sergio , Castañeda Carlos , Lora David , Mendiola Cesar , Sancho Blanca , Pascual Tomas , Cortes-Funes Hernan
Published: March 2020

642

Background: HER2+ breast cancer (BC) is a well characterized subtype of BC, due to the predictive value of HER2 overexpression for anti-HER2 targeted therapies. Nevertheless, around 50% of HER2+ BC are ER+ and clasiffied as luminal B/HER2+, but their biological and clinical behaviour may be different from HER2+/ER- tumors. Methods: We retrospectively reviewed 347 HER2+ (Herceptest +++ or FISH+) early BC patients (see Table) diagnosed at our institution in 1997-2007, and were divided into two study groups: HER2+/ER+ (group A) and HER2+/ER- (group B). ER+ was defined if expressed in > 10% tumor cells. Results: See table below. Mean age: 54.7 y (44.6 – 65). Mean Ki 67 was higher in B (37,2 vs 22,4%, p<0.0001). At the current FU, n¼ of events were insufficient to reach median DFS/OS. Mean DFS was 6.9 y (3.5 – 10.2); recurrent disease was higher (p 0.003) for B (54 pts, 43%) vs A (62 pts, 28%). 5-year DFS estimates: 78.4 % (95% CI 72.3 – 83.3) and 62.3 % (95% CI 53 – 70.27) for A and B, and 10-year DFS was 73.4% (95% CI 66.6 – 79) and 52.5% (95% CI 42.4 – 61.6) for A and B, respectively (p 0.0006). Most common recurrent sites were local (18) and bone (9) for HER2+/ER+ and liver (8) and lung (8) for HER2+/ER-. Mean OS was 8.03y (5.4 – 10.8); 28 (12,6%) pts died in A, vs 26 (21%) in B (p 0.043). 5-year OS estimates: 93.9 % (95% CI 89.7 – 96.4) and 87.6 % (95% CI 80.3 – 92.3) for A and B, and 10-year DFS was 84.2% (95% CI 77.5 – 89.0) and 74.1% (95% CI 63.4 – 82.2) for A and B, respectively (p 0.01). Conclusions: ER expression in HER2+ early BC defines two clinically distinct diseases with different long-term prognosis. These data may help to better individualize adjuvant therapies and future clinical trial designs. [Table: see text]
Correlation of TOP2A expression in HER2-positive breast cancer with pathologic response and clinical outcomes in patients undergoing neoadjuvant treatment based on anthracycline.
Authors: Santos Elizabeth S. , Costa Felipe D'Almeida , Bezerra Stephania , Lessa Rafael Costa , Cordeiro De Lima Vladmir Claudio , Gagliato Debora De Melo , Lima Geraldine Eltz , Fanelli Marcello Ferretti , Rocha Rafael Malagoli , da Costa Alexandre Andre Balieiro , Pereira Augusto Akikubo Rodrigues , Padua Fernando Vidigal , Sousa Carlos Eduardo Pires , Freitas Paulo Henrique Aires , Pinto Flavio Augusto Ismael , Rodrigues Newton Augusto Ferreira , Benevides Carlos Frederico Lopes
Published: March 2020

643

Background: Factors predictive of response to anthracyclines can help selecting patients who really benefit from its use. TOP2A (a target of anthracyclines) and HER2 genes are both amplified in 40% of breast cancers. Data from literature are conflicting regarding the potential of TOP2A as a predictor of response to anthracyclines. Methods: We retrospectively analyzed data on the outcome of patients undergoing neoadjuvant anthracycline-based chemotherapy and evaluated nuclear TOP2A protein expression in breast cancer biopsies by immunohistochemistry (IHC) and reviewed the pathological responses after completion of neoadjuvant treatment. Results: From 2002 to 2011, data from 82 patients was reviewed. Forty nine patients had the paraffin blocks corresponding to the pre-treatment biopsy. All biopsies had some degree of TOP2A IHC expression. Patients were considered positive for TOP2A if the level of expression in IHC was higher than 10%. This was found in 77.6% of cases. Forty percent of the patients achieved pathologic complete response in pos-treatment surgical specimens. Correlation was observed between TOP2A IHC expression and tumor pathological response (p0.02). It was observed a difference in pathological complete response in favour of the group positive for TOP2A (47.4% vs. 22.7%), although not significant (p=0.09). No difference in PFS and OS was observed between patients with complete response after median follow-up of 34 months. Conclusions: The expression of TOP2A seems to be a promising marker to predict pathological response to antracycline-based neoadjuvant chemotherapy in HER2 breast cancer; however these findings would be better evaluated in prospective trials.
Relationship between changes in left ventricular ejection and use of angiotensin-converting enzyme inhibitors and/or betablockers during adjuvant trastuzumab chemotherapy in early breast cancer: Data from the real world.
Authors: Giotta Francesco , Oliva Stefano , Boccardi Lidia , Frattini Silvia , Fioretti Agnese Maria , Simoncini Edda , Pulignano Giovanni , Cioffi Gianni , Lestuzzi Chiara , Maurea Nicola , Tarantini Luigi
Published: March 2020

645

Background: Adjuvant trastuzumab chemotherapy (aTrastC) improves DFS of pts with breast cancer and overexpression of HER-2. However, cardiovascular complication (CV) such as heart failure (HF) or significant left ventricular ejection fraction (LVEF) reduction may appear especially in those pts at increased CV risk. Methods: 253 women treated with aTrastC for EBC in 7 italian oncologic centers during the period 2008-2009 entered in a multicenter registry and were retrospectively studied in 4 subgroups according to the treatment with ACEi and/or BB. Occurrence of symptoms of HF and/or decrease in 10 points % of LVEF were recorded during the follow up. LVEF was measured at baseline and 3-6-9-12 months. Results: Symptoms of HF occurred in 2% of pts who did not take either ACEi/ARB or BB. HF event-rate was similarly increased in pts receiving one or both medications, partially justified by the increased CV risk in these subgroups. Prevalence of decrease in LVEF > 10 points% was similar in all study subgroups. Trends in LVEF were characteristics for each study subgroup: at 3-month evaluation a significant decrease in LVEF was detected in ACEi/ARB and ACEi/ARB + BB group. Multiple logistic regression analysis showed that combined ACEi/ARB + BB therapy depended on history of hypertension (OR 36.7, CI 4.3-315.5) and reduction of LVEF from baseline to 3-month evaluation (OR 0.88, CI 0.78-0.97) (best prediction – 3.5 points %, AUC 0.78, IC 0.65-0.91). Conversely, no association was found between changes in LVEF and ACEi/ARB or BB therapy alone. LVEF recovery from 3 to 12-month evaluation was inversely related to the changes in LVEF from baseline to 3-month evaluation and did not depend on any pharmacological treatment. Conclusions: In clinical practice, a history of hypertension and changes in LVEF during the first 3 months of aTrastC for early breast cancer influence the use of ACEi/ARB and BB. This behaviour may explain the characteristic trend in LVEF showed in the subgroups of patient receiving or receiving not ACEi/ARB or BB. Subsequent recovery of LVEF does not seem to be related to any medical treatment.
Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL.
Authors: Topp Max , Goekbuget Nicola , Zugmaier Gerhard , Viardot Andreas , Stelljes Matthias , Neumann Svenja , Horst Heinz-August , Reichle Albrecht , Marks Reinhard , Monika Brueggemann , Ritgen Matthias , Klappers Petra , Mergen Noemi , Goebeler Marie-Elisabeth , Einsele Hermann , Hoelzer Dieter , Bargou Ralph
Published: March 2020

6500^

Background: Blinatumomab is a bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19 expressing target cells. Methods: In adult patients with relapsed/refractory B-precursor ALL, a phase II dose ranging trial is being conducted to evaluate efficacy and safety of blinatumomab. The primary endpoint is the rate of hematological complete remission (CR) or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment. Blinatumomab is administered by continuous intravenous infusion for 28-days followed by a 14-day treatment-free interval. Responding patients can receive 3 additional cycles of treatment or proceed to bone marrow transplantation. Three dose levels were explored as shown in the table. Results: In total 36 patients have been enrolled, 25 are currently evaluable. Seventeen out of 25 treated patients (68%) reached a hematological CR/CRh* and a minimal residual disease (MRD) response (MRD level <10-4) within the first 2 cycles. Five out of 17 responders (29%) showed a CRh* due to partial recovery of platelets. For the first 18 patients, response duration is 7.1 months and the median follow-up time for overall survival (OS) is 9.7 months (median not reached). Six cases of relapses have been recorded of which 3 were CD19+, and 3 CD19-. As final dose 5 µg/m²/day in week 1 and 15 µg/m²/day for the remaining treatment (cohort 2a and 3) was selected. In these cohorts (n=12), the most common treatment emergent adverse events (TEAEs, all grade 1-2) were pyrexia (67%), headache (33%) and tremor (33%). TEAEs of grade ≥3 (7 in 5 patients, no grade 4), irrespective of relationship, were infections, confusion, epilepsy, hypertension and thrombocytopenia. Conclusions: The final dose was well-tolerated and produced an exceptionally high complete remission rate. A global phase 2 study to confirm these data is underway. [Table: see text]
The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.
Authors: Byrd John C. , Furman Richard R. , Coutre Steven E. , Burger Jan Andreas , Blum Kristie A. , Sharman Jeff Porter , Flinn Ian W. , Grant Barbara W. , Heerema Nyla A. , Johnson Amy J , Navarro Tasheda , James Danelle Frances , Hedrick Eric , O'Brien Susan Mary
Published: March 2020

6507

Background: Fludarabine based therapy, while effective, carries significant risk of morbidity and mortality in the elderly pts. As such, older CLL pts represent a high priority for new therapeutic approaches. PCI-32765 (P) an oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts is reported. Methods: Pts >65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until disease progression (PD). Response was evaluated according to 2008 IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort was terminated after comparable activity and safety between doses was shown in R/R pts. Median age 71 yrs (range 65-84) with 74% of pts >70 yrs. 19/31 (61%) had baseline cytopenias (Hgb < 11g/dl or plts <100,000). Unmutated IgVH was present in 43% of pts. The majority of AEs have been Gr<=2 in severity, most commonly diarrhea, nausea, and fatigue. Gr >3 non-heme AEs potentially related to P in 19% of pts. 10% of pts experienced Gr >3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial responses (PR) and 8% complete remissions with no morphologic evidence of CLL on marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high ORR, including marrow clearance and very low PD rate with the single agent suggests that P warrants further study as a first-line treatment approach in elderly pts.
Reductions in JAK2V617F allele burden with ruxolitinib treatment in COMFORT-II, a phase III study comparing the safety and efficacy of ruxolitinib to best available therapy (BAT).
Authors: Vannucchi Alessandro M. , Kiladjian Jean-Jacques , Gisslinger Heinz , Passamonti Francesco , Al-Ali Haifa Kathrin , Sirulnik L. Andres , Stalbovskaya Viktoriya , Squires Matthew , Hunter Deborah S. , Burn Timothy , Knoops Laurent , Cervantes Francisco , Barbui Tiziano , Barosi Giovanni , Harrison Claire N
Published: March 2020

6514^

Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF) based on results of the phase 3 COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life of patients (pts) with MF. Since one measure of efficacy is molecular response, this analysis correlates changes in mutant allele burden (%V617F) with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg twice daily (BID) with BAT. The primary endpoint was a ≥ 35% reduction in spleen volume from baseline (BL) at week 48. Change in %V617F was measured by allele specific qPCR. Pts were stratified by reduction in %V617F (< 10%, 10-20%, > 20%) and results were correlated with achievement of the primary endpoint. Results: More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT (41% vs 5%; P = .01; Table). The majority of reductions > 20% were gradual and progressive over the course of the study; 2 pts had rapid reductions from 48% to 1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly more pts with a > 20% V617F reduction achieved the primary endpoint compared with pts with a < 10% reduction (79% vs 30%; P = .004); in each group, gender did not affect spleen response. For pts with < 10% reductions (15 mg BID, n = 16; 20 mg BID, n = 24), the average total daily dose (TDD) was ruxolitinib 29.6 mg; pts with > 20% reductions (15 mg BID, n = 3; 20 mg BID, n = 11) had a TDD of 35.3 mg. Conclusions: Pts who received ruxolitinib had larger reductions in JAK2V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the 48-week study; longer follow-up is needed to determine the extent of allele burden reduction. [Table: see text]
Pretreatment prognostic factors associated with outcomes for first-line FCR-based treatments in previously untreated CLL.
Authors: Wierda William G. , O'Brien Susan Mary , Faderl Stefan , Ferrajoli Alessandra , Burger Jan Andreas , Estrov Zeev , Tambaro Francesco Paolo , Kadia Tapan M. , Lerner Susan , Kantarjian Hagop , Keating Michael J.
Published: March 2020

6517

Background: First-line chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) demonstrated improved outcomes, including survival, for fit patients (pts) with CLL. Modifications of this regimen, including intensified rituximab (FCR3), addition of mitoxantrone (FCMR) or addition of alemtuzumab fir high-risk CLL (CFAR), were evaluated but did not improve outcomes in historic comparisons. Methods: We correlated outcomes, including complete remission (CR), time-to-treatment failure (TTF) and overall survival (OS), with new and traditional pretreatment prognostic factors to identify high-risk pts. Results: All pts (N=473) had an NCI-WG indication for treatment and received a first-line FCR-based regimen on trial; the intended treatment was 6 courses. Patient characteristics correlated with outcomes are presented in the table. Factors not associated with outcomes included absolute lymphocyte count; platelet count; performance status; spleen size; liver size; and number of involved lymph node sites. Conclusions: We identified the following as high-risk pretreatment features for patients going on first-line FCR-based therapy: advanced age, presence of 17p del, high B2M (≥4mg/l), and unmutated IGHV gene. Pts with these features should be pursued with new treatment modalities and novel agents in order to improve outcomes. [Table: see text]
A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3Kδ) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL).
Authors: Furman Richard R. , Barrientos Jacqueline Claudia , Sharman Jeff Porter , De Vos Sven , Leonard John , Coutre Steven E. , Schreeder Marshall T. , Wagner-Johnston Nina D. , Boyd Thomas E. , Fowler Nathan Hale , Flinn Ian W. , Boccia Ralph V. , Holes Leanne , Lannutti Brian Joseph , Johnson Dave , Jahn Thomas Michael , Miller Langdon L.
Published: March 2020

6518^

Background: PI3Kδ is expressed in cells of hematopoietic origin where it regulates the survival and proliferation of malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ and is highly active in patients with hematologic malignancies. Methods: This Phase 1/2 study evaluated repeated 28-day cycles of GS‑1101 in combination with ofatumumab. GS-1101 (150mg BID) was co-administered with a total of 12 infusions of ofatumumab over 24 weeks (300mg initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101), followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects received single-agent GS‑1101 as long as the subject was benefitting. Results: Accrual is complete with 21 subjects enrolled and 11 evaluable. Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2. Median [range] age was 63 [54‑76] years. The majority (9/11; 82%) of patients had bulky adenopathy. The median [range] number of prior therapies was 3 [1‑6], including prior exposure to alkylating agents (10/11; 90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab (3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the median [range] treatment duration was 5 [0‑7] cycles. Almost all subjects (9/11;82%) experienced marked and rapid reductions in lymphadenopathy within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. Early follow up data support a favorable safety profile and confirm a lack of clinically significant myelosuppression. Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were significantly reduced after 28 days of treatment. Conclusions: GS-1101/ofatumumab offers a well-tolerated noncytotoxic combination regimen with substantial activity in previously treated patient with bulky adenopathy. Data on the complete cohort of 21 subjects will be presented.
Evaluation of the first-in-class antimitochondrial metabolism agent CPI-613 in hematologic malignancies.
Authors: Pardee Timothy S. , DeFord-Watts Laura M , Peronto Erica , Levitan Denise A. , Hurd David Duane , Kridel Steven , Harrelson Robin , Manuel Megan , Lyerly Susan , Powell Bayard L.
Published: March 2020

6524^

Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. Most tumor cells use glycolysis even under aerobic conditions (the Warburg effect). This altered metabolism is a possible therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in vitro and in vivo. It is also the subject of a phase I clinical trial for patients with hematologic malignancies. Results: CPI-613 was active against HL60, Jurkat, and K562 cells, with an average IC50 value of 14 μM (range 12.2 – 16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index (CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown of p53 or MN1 expression, despite their increased resistance to standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABL-expressing cells and with sorafenib against Flt3 ITD-expressing cells. CI values for nilotinib + CPI was 0.059 (+/-0.002) and for sorafenib + CPI was 0.581 (+/-0.052). In vivo, CPI-613 synergized with doxorubicin; median survival improved from 12 days with doxorubicin to 16 days with CPI-613 plus doxorubicin (p=0.0001). In the phase I clinical trial, 7 of 13 evaluable patients had a response of stable disease or better, for an overall response rate of 54% (see table). CPI-613 was well tolerated, with no evidence of marrow suppression and no dose limiting toxicity identified. Conclusions: The novel agent CPI-613 has activity against a variety of hematological malignancies, including acute leukemias. The therapeutic index appears high, with only minor toxicities observed. [Table: see text]
Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity.
Authors: Widemann Brigitte C. , Jayaprakash Nalini , Howard Scott C. , Daugherty Claire , Chauhan Nikhil , King Thomas , Rush Janet
Published: March 2020

6530

Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma (NHL), and other cancers. MTX-associated renal impairment with delayed MTX elimination develops after 2 to 10% of treatment cycles, exposing patients to elevated MTX concentrations with potential for enhanced MTX toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and provides an alternate way of clearance in patients with delayed MTX elimination. Methods: From November 1993 to June 2009, 492 patients experiencing renal toxicity and delayed elimination of MTX were treated with glucarpidase (50 U/kg intravenously) in compassionate use trials conducted in the US and EU. Their outcomes are presented here. Results: The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs). Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic sarcoma, 23% ALL, and 7% other malignancies. The median pre-glucarpidase MTX concentration was 17 µmol/L. Seventy-six percent of patients received 1 dose of glucarpidase, 22% received 2 doses, and 2% received 3 doses. The first dose of glucarpidase was given at a median of 3 days after MTX administration. One-hundred and fifty-six patients had MTX concentrations determined by HPLC. At the first measurement (median 15 minutes post-glucarpidase) MTX was reduced by a median of 99% relative to the pre-glucarpidase baseline. At the last measurement (median 40 hrs post-glucarpidase) median MTX reduction remained at 99% compared with baseline. In 410 patients with pre-glucarpidase renal impairment measured as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated overall; adverse events included paresthesia (2.0%), flushing (1.8%) and headache (1.0%). Eight percent of patients died within 30 days of glucarpidase administration of causes unrelated to glucarpidase, as judged by the treating physician. Conclusions: Glucarpidase is well-tolerated and reduces MTX concentrations by 99% within 15 min of administration in patients with impaired renal clearance of MTX.
Impact of ATG on new HLA groups for unrelated donor allogeneic stem cell transplantation.
Authors: Lee Soo Jung , Kim Jong Gwang , Chae Yee Soo , Kang Byung Woog , Moon Joon Ho , Sohn Sang Kyun , Baek Jin Ho , Cho Yoon Young , Lee Yoo Jin , Choi Jun Young
Published: March 2020

6536

Background: The outcomes of unrelated donor transplantation have improved with refinements in HLA testing. Recently, grouping of HLA matching for unrelated donor was suggested, defining by well-matched, partially-matched, and mismatched. In the current study, the role of ATG for each group was evaluated. Methods: A total of 92 patients diagnosed as hematologic diseases and received allogeneic stem cell transplantation (SCT) from unrelated donor were retrospectively analyzed. Results: Nineteen patients were classified as well-matched, 42 as partially-matched, and 31 as mismatched. Among them, 57 patients received anti-thymocyte globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis. The overall survival (OS) rate was higher for well-matched group (83%) compared to partially-matched (54%) and mismatched (34%, p=0.076). For partially-matched group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). But, the OS was not different between groups with or without ATG for well-matched (87.5% vs. 66.7%, p=0.487) and mismatched (32.4% vs. 41.7%, p=0.215). ATG decreased the cumulative incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). The use of ATG (HR=0.248, p=0.029) was related with favorable OS for partially-matched group. However, the favorable effect of ATG was not observed in well-matched and mismatched groups. Conclusions: ATG effectively improved survival rate for partially-matched group in unrelated donor transplantation. However, the positive effect of ATG was not observed in well-matched and mismatched group.
Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.
Authors: Hanash Alan M. , Van Den Brink Marcel R. M. , Hua Guoqiang , Kolesnick Richard , Blazar Bruce R.
Published: March 2020

6539

Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.