Early Discontinuation Of Therapy Research Articles

Assessment of early therapy discontinuation and health-related quality of life in breast cancer patients treated with aromatase inhibitors: B-ABLE cohort study.

The most frequent adverse effects of aromatase inhibitors (AI) are arthralgia and bone loss induction. These reduce the quality of life of patients and their adherence to the treatment. This study evaluates the early AI cessation caused by AI intolerance, and the evolution of joint pain and health-related quality of life (HRQoL) during AI treatment until 1-year after AI completion. Data of 910 women diagnosed with early breast cancer and candidates for AI were recruited in B-ABLE cohort. AI discontinuation was analyzed by survival analysis, including Kaplan-Meier estimation and Cox regression. Patients were distributed in three groups of the study according to previous tamoxifen (TAM) exposure and length of AI treatment: TAM-2yAI, TAM-3yAI, and 5yAI. Evolution of joint pain and HRQoL in osteoporosis was evaluated using Visual Analog Scale (VAS) and ECOS-16 tests, respectively, from baseline to 1-year after AI completion through repeated-measures ANOVA. Risk of AI discontinuation was increased in patients previously exposed to tamoxifen compared to non-exposed (adjusted HR 5.30 [95% CI 2.23 to 12.57]). VAS and ECOS-16 scores of TAM-2yAI and TAM-3yAI groups increased during AI treatment, mainly during the first 3-12months. After 1-year from AI completion, values tend to decrease to baseline levels. In 5yAI group, VAS and ECOS-16 levels increased at three months, and VAS remained significantly higher at 1-year post-treatment. AI therapy increased joint pain and reduced HRQoL, mainly during the first year of treatment. Patients previously treated with tamoxifen experienced greater pain when they switched to AI therapy and had an excess risk of discontinuation during the first 12months. ClinicalTrials.gov: NCT03811509. Registered 28 January 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03811509 .

Socio-Demographic Features and Societal Perspective of Relapse and/or Refractory Multiple Myeloma (RRMM) Patients in Spain: An Interim Analysis of Charismma Study

IntroductionMultiple myeloma (MM) is a plasma cell malignancy, with a range of clinical features including hypercalcaemia, renal insuficiency, anaemia and bone lesions1 (CRAB). MM progression often involves multiple rounds of remissions after treatment followed by subsequent relapses2. Although MM accounts for only a small percentage of all cancer types, the costs associated with treating and managing it are among the highest3.RRMM population is heterogeneous, their characteristics depend on the number and type of treatment used, and the type of relapse3.Selection of treatment for MM patients is challenging due to increased age and the often associated comorbid conditions4. RRMM patients are more symptomatic, vulnerable to adverse events and, more likely to incur a dose reduction or early discontinuation of therapy. Balancing expected efficacy of therapy vs potential toxicities, health care resources and impact on patients' Health Related Quality of Life (HRQOL) is therefore critical in this patient population5.CharisMMa study objective (NCT03188536) is to understand and provide an accurate epidemiological and societal characterization of RRMM patients. Hematologist's choice of therapeutic strategy is crucial, and must be made in consideration of the patient as a whole, and not only in terms of their disease.MethodsCharisMMa is an observational, cross-sectional, multicentre study, involving 30 public hospitals around Spain, which include MM patients that require treatment at any relapse of the disease. An interim analysis has been conducted evaluating socio-demographic characteristics and burden of the disease in the 169 patients with relapse/refractory MM enrolled up to June 2018 (expected n=350). On average, information was collected 2.15 (SD: 1.76) months after the last relapse.ResultsThe median age in the moment of the study visit, was 69.0 (57.0, 75.0) years, being 55.2% male. 71.8% of them lived in urban areas and 88% with their families. Most of them were retired (64.2%) and non-dependent (73.1%). Patients included have been treated with a median of 2.0 (1.0, 3.0) previous lines. Approximately half of them (56.7%) had received stem cell transplant (97.8% autologous). The stage ISS was I (36.3%), II (35.6%) and III (28.1%) and 74.0% presented CRAB symptoms, being bone lesions (65.6%) the most frequent ones. 85.4% were considered intermediate or high risk patients presenting extramedullary plasmocytomas in 16.5% of the cases. 67.5% of the patients suffered from any comorbidity, being the most frequent one cardiovascular (48.1%), diabetes (23.1%) and neuropathy (22.1%).Symptomatic patients are treated mainly with doublets both in second (59.7%) and third/+ lines while those asymptomatic ones with no CRAB symptoms at relapse are treated with doublets in second but with monotherapy (62.5%) in third/+ lines (Table 1).In terms of societal perspective, on average, patients are living 23.9 (40.4) km far from their hospital and they attend 5.4 (5.0) times per month in order to visit the haematologist being 3.8 (2.7) times treatment related. In most of the visits (90.3%) patients attended accompanied by a caregiver who is occupationally active (57.4%). Only during the last relapse patients have been admitted 1.5 (1.0) times to the hospital having spent 15.2 (15.5) days until discharge. The patients are also visiting other specialist during the last relapse due to the disease as primary health care professionals (21.3%), psychologists (4.7%) and others (33.1%).ConclusionsThe heterogeneity in the MM patient´s characteristics is a major factor that should be considered during the management and the evolution of the disease and it has a direct impact in the resources needed. An individual approach including patients and disease characteristics should be considered in order to maximize clinical outcomes and guarantee an appropriate use of the resources in order to maximize patient´s benefit and reduce indirect costs of the disease.ReferencesPalumbo, K. Anderson. N. Engl. J. Med. 364 (2011)1046-1060.National Cancer Institute. SEER Program. Cancer stat facts: myeloma. 2016. Available at https://seer.cancer.gov/statfacts/html/mulmy.htmlLaubach J et al. Leukemia 2016; 30(5):1005-1017.Sonneveld P, Broijl A. Haematologica 101(4):396-406.Larocca A, Palumbo A. Blood 2015; 126 (19):2179-2185. [Display omitted] DisclosuresOcio:BMS: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Pharmamar: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Grande:Takeda: Employment. Ruiz-Zorrilla:Takeda: Employment. Fernandez:Takeda: Employment. Montoto:Takeda: Employment.

Bendamustine in Combination with Gemcitabine and Vinorelbine (BEGEV) Is an Effective Regimen for Heavily Pretreated, Relapsed/Refractory Hodgkin Lymphoma Patients: A Multicenter, Retrospective Real-World Study

INTRODUCTION: The availability of novel monoclonal antibodies (moAbs) including the anti-CD30 Brentuximab Vedotin (BV) and the anti-programmed cell death-1 (anti-PD-1) Nivolumab and Pembrolizumab has introduced innovative options in the process of therapeutic decision making for relapsed/refractory classical Hodgkin lymphoma (R/R cHL). However, multiagent chemotherapy followed by autologous stem cell transplantation (auto-SCT) in chemosensitive patients still remains the standard-of-care treatment of R/R cHL. In a multicenter phase 2 study, the BEGEV (Bendamustine, Gemcitabine, Vinorelbine) regimen was previously reported as a highly effective treatment in the second-line salvage setting (Santoro et al., J Clin Oncol, 2016). Here, we report a retrospective analysis of efficacy and toxicity of the BEGEV regimen administered as second- or subsequent-line therapy to R/R cHL in a real-world setting.PATIENTS AND METHODS: From January 2013 to March 2018, 73 cHL patients (median age, 31 years; range, 16 - 69) were candidate to receive 4 courses of BEGEV as second-line (n= 50) or beyond second-line (n= 23) salvage therapy. Refractory patients were 56% in the second-line group and 78% in the group treated beyond second-line. This latter group received a median of 3 (range, 2-8) lines of therapy prior to BEGEV, including Brentuximab Vedotin (BV) (83%) and auto-SCT (43%).RESULTS: In keeping with the phase 2 study, hematological and non-hematological side effects were acceptable. In fact, 64 (88%) patients completed the planned treatment whereas only 9 (12%) patients experienced early therapy discontinuation due to progressive disease (n= 8) and sepsis (n= 1). Of 72 patients evaluable for response, 50 (69.4%) achieved complete remission (CR) and 7 partial remission (PR) with an overall response rate (ORR) of 79%; 1 patient experienced stable disease (SD) and 14 (19%) progressive disease (PD). All but one patient experiencing PD/SD were chemorefractory (14/15). The probability of achieving response (CR+PR) to BEGEV was significantly higher in chemosensitive vs chemorefractory patients (96% vs 70%, P=0.007) whereas no difference could be detected for patients receiving BEGEV as second-line vs those treated beyond second-line (84% vs 70%, P=0.217). All BEGEV responders (n=57) were offered SCT: 44 received auto-SCT, 9 allo-SCT and 1 tandem auto/allo-SCT; 1 patient is waiting for SCT, and 2 refused. With a median follow-up of 14 months, the 1-yr overall survival (OS) and progression-free survival (PFS) are 93% and 69%, respectively. Disease status (sensitive vsrefractory) at BEGEV had no impact on survival (1-yr OD: 94% vs 92%, P=0.57) likely due post-BEGEV consolidation therapy, whereas timing of BEGEV administraton (second-line vs subsequent-lines) significantly affected survival (1-yr OS: 97% vs 78%, P=0.018).CONCLUSION: Data from this real-world analysis further confirm that BEGEV is an effective and safe salvage treament in R/R cHL even when administered to heavily pre-treated patients, thus representing an optimal therapeutic platform prior to consolidation with SCT or immunotherapy. DisclosuresCarlo-Stella:Sanofi: Consultancy; Genenta Science: Speakers Bureau; AstraZeneca: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; MSD Italia: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau.

Possible Reasons for Discontinuation of Therapy: an Analysis of 571 071 Treatment Cycles From the German IVF Registry.

Introduction Numerous couples discontinue fertility treatment before achieving the objective, the birth of a child. The aim of this retrospective data analysis is to identify the reasons for early discontinuation of therapy (drop-out). Materials and Methods Retrospective data analysis. With the aid of the German IVF Registry (D·I·R ® ), a total of 122 560 “last cycles” in Germany in the period 2012 – 2015 were identified and the courses were analysed. Results From the named cohort of “last cycles”, 37.3% of the female patients (45 699) gave birth to a child and ended the therapy. The remaining 76 861 discontinued the treatment before having a child. The fertility treatment was conducted due to a purely male indication in 46.27% of cases and in 17.96% the cause lay exclusively with the woman. 4.53% of the drop-outs suffered a miscarriage in the last cycle. 73.56% of the drop-out patients ended the therapy after the lack of a positive pregnancy test. After the third therapy cycle, 67% of the couples ended their treatment. Conclusion The results make it possible to provide couples with individual counselling. They offer an option for preparing for the emotional and physical hurdles.

Outcomes and Tolerability of Selective Bladder Preservation by Combined Modality Therapy for Invasive Bladder Cancer in Elderly Patients

The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the United States is 73 years old, and only about half of those over 70 receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of the elderly are undertreated. To address this unmet clinical need, we examined the outcomes and tolerability of bladder-sparing trimodality therapy (TMT) in elderly patients 75 years or older. We retrospectively analyzed 475 patients with cT2-T4a disease treated at our institution between 1986 and 2013 on or per protocol. Patients underwent induction chemoradiation (CRT) after maximal transurethral resection of bladder tumor (TURBT), in most cases with cisplatin-based concurrent chemotherapy. Patients achieving a complete response (CR) received consolidation CRT. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. For comparison of elderly patients (defined as 75 years or older) with younger patients, propensity score matching was performed based on T-stage, presence of hydronephrosis, completion of TURBT, and use of neoadjuvant chemotherapy. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Multivariate analyses were performed using a Cox proportional hazards regression model. Median age was 67 years (range 27-94), and 112 patients (23.6%) were 75 years or older. Median follow-up was 7.2 years for surviving patients. In a propensity score matching analysis of 101 elderly and 101 younger patients, DSS at 5 and 10 years for the elderly was 61.2% and 47.3%, compared to 68.6% and 61.0% for younger patients (P = 0.20). CR to induction CRT was 72.3% in the elderly, compared to 80.2% in the younger cohort (P = 0.25). 23.8% of elderly and 29.7% of younger patients underwent a salvage radical cystectomy (P = 0.43). Elderly patients, in comparison to younger patients, had similar rates of ED visits during treatment (8.9% vs 6.9%, P = 0.80) and unplanned treatment breaks for any cause (20.8% vs. 17.8%, P = 0.72), but had a nonsignificant increase in hospital admissions for any cause (16.8% vs. 9.9%, P = 0.21) and early discontinuation of therapy due to toxicities (6.9% vs. 3.0%, P = 0.33). On multivariate analysis, T3/T4 disease, incomplete response to CRT, ED visits during treatment, and early treatment discontinuation were significantly associated with worse DSS in elderly patients. In elderly patients with MIBC, outcomes and tolerability of bladder-sparing TMT using cisplatin-based CRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.

Elderly patients with multiple myeloma: towards a frailty approach?

To describe how to better identify frail multiple myeloma patients and to treat them appropriately. Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, and immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, have significantly improved the outcome of multiple myeloma patients in the last decade. However, both in clinical trials and in daily clinical practice, elderly multiple myeloma patients have shown lesser benefit. This is mainly due to less stringent use of proteasome inhibitors and IMiDs, increased toxicity, and subsequent early discontinuation of therapy in elderly. Multiple myeloma typically affects elderly patients. Approximately one-third of patients are older than 75 years at diagnosis. Moreover, at least 30% are frail, both due to disease-related symptoms and (age-related) decline in physical capacity, presence of comorbidities, frailty, polypharmacy, nutritional status, and cognitive impairment. Treatment regimens that are investigated in clinical trials for transplant-ineligible patients have largely been investigated in fit, rather than frail patients, the latter being typically excluded or highly underrepresented therein. Data on the feasibility and efficacy of current standards of care are therefore lacking in frail patients. Preliminary data suggest a higher toxicity and discontinuation rate, loss of efficacy, and impaired quality of life in frail patients. Geriatric assessment helps to identify frail patients according to their functional and cognitive status. Both the International Myeloma Working Group (IMWG)-frailty index and Revised Myeloma Comorbidity Index constitute recently proposed algorithms that easily identify intermediate-fit and frail patients. Ongoing and future clinical trials, specifically designed for frail patients, will hopefully define frailty-directed treatment selection.

Adjuvant chemotherapy related toxicities and their impact on treatment cessation in elderly patients with breast cancer.

e21527 Background: Data from the National Cancer Institute’s Surveillance Epidemiology and End Results program show that the incidence of breast cancer is 243.1 per 100,000 in women 65 years of age and older. Guidelines regarding the management of older breast cancer patients are lacking due to their underrepresentation in adjuvant therapy trials and conflicting evidence regarding the benefits of therapy. The objective of this study was to investigate the frequency of adjuvant chemotherapy related side effects and their correlation with early termination of therapy in elderly breast cancer. Methods: We collected retrospective data in patients with in situ or invasive breast cancer diagnosed after the age of 65.Docetaxel & cyclophosphamide, doxorubicin & cyclophosphamide, tratuzumab in combination and other regimens were studied. Fisher’s exact test was used to determine an association between grade 3 or 4 toxicities and therapy termination. Binary logistic regression was used to assess whether a specific toxic effect could predict for early discontinuation of therapy. Treatment termination was defined as inability to tolerate the proposed number of chemotherapy treatment cycles. Results: Among 269 eligible cases, 72 (26.76%) patients were offered adjuvant chemotherapy. Most patients (n = 58, 80.55%) accepted chemotherapy but 14 (19.44%) refused. Nausea (n = 16, 27.6%), vomiting (n = 8, 13.8%), diarrhea (n = 12, 20.7%), stomatitis (n = 3, 5.2%), hypersensitivity (n = 3, 5.2%), rash (n = 10, 17.2%), hepatotoxicity (n = 1, 1.7%), neuropathy (n = 12, 20.7%), cognitive changes (n = 3, 5.2%), bone pain (n = 5, 8.6%), anemia (n = 15, 25.9%), thrombocytopenia (n = 7, 12.1%), neutropenia (n = 16, 27.6%), cardiotoxicity (n = 1, 1.7%), hospitalization due to neutropenic fever (n = 5, 8.6%) and pneumonia (n = 2, 3.4%) were observed. Among 17 patients who discontinued chemotherapy, 23.5% reported bone pain (OR = 12, 95%CI:1.22-117.2, p = 0.024) and 47.1% developed neutropenia (OR = 3.55, 95%CI:1.04-12.13, p = 0.054). Other toxicities were not significantly associated with therapy discontinuation. Conclusions: The odds of terminating chemotherapy early increases for those who experience grade 3 or 4 bone pain and neutropenia.

Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation

BackgroundToxicity can lead to noncontinuation of adjuvant endocrine therapy. We hypothesized that endocrine therapy-induced changes in grip strength would predict for early discontinuation of therapy because of musculoskeletal toxicity and would be associated with a patient's body mass index. Patients and MethodsPostmenopausal women with breast cancer starting a new adjuvant endocrine therapy were enrolled in the present study. The patients were monitored for 12 months to assess their symptoms, endocrine therapy adherence and change in grip strength and baseline body mass index. The association between the change in grip strength and interval to discontinuation was assessed using a joint longitudinal and survival model. ResultsOf the 93 aromatase inhibitor (AI)-treated and 22 tamoxifen-treated patients, 40.9% and 9% discontinued endocrine therapy within 12 months because of toxicity, respectively (P = .019). A trend was seen toward a greater decrease in grip strength in the AI-treated patients over time (P = .055); however, the decrease was not significantly associated with the interval to discontinuation (P = .96). Receipt of an AI (hazard ratio, 5.49; P = .019) and baseline pain (hazard ratio, 1.19; P = .004) significantly decreased the interval to discontinuation. ConclusionIn contrast with the findings from previous reports, the change in grip strength in our study was not associated with the interval to discontinuation of AI therapy. Future research should focus on proactive treatment of patients at increased risk of AI intolerance, such as those with high levels of pre-existing pain.

Efficacy of a Type I FLT3 Inhibitor, Crenolanib, with Idarubicin and High-Dose Ara-C in Multiply Relapsed/Refractory FLT3+ AML

▪Background: Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with in vitro activity against FLT3-ITD and FLT3-tyrosine kinase domain (TKD) mutations. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. As a single agent, an overall response rate (ORR) of 30% (CR/CRi 19%, PR 12%) has been reported among patients (pts) with multiply relapsed/refractory (R/R) AML pts with FLT3 mutations despite sixty-five percent of the patients having prior exposure to FLT3 inhibitors. We report data from the first 13 pts with R/R FLT3+ AML treated with salvage idarubicin (Ida) and high-dose ara-C (HiDAC) followed by crenolanib.Design: Pts received Ida (12 mg/m2 for 3d) with HiDAC (1.5 g/m2/d over 3 hrs for 4d or for 3d if >60y), followed by crenolanib starting on d5 and continued until 72 hrs. prior to next chemotherapy regimen. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Responding pts were eligible to proceed to allogeneic stem cell transplant (allo-SCT) or receive consolidation with ara-C (750 mg/m2 for 3d) and Ida (8 mg/m2 for 2d) followed by crenolanib at the same dose received during induction. Patients could then continue on maintenance with crenolanib. Post-SCT crenolanib maintenance therapy was not allowed.Results: To date, all 3 dose escalation cohorts have been completed, which included 13 pts (11 males, 2 female) with a median age of 51 yrs (range 19-73). All pts had R/R FLT3+ AML. 6/13 pts had relapsed after 1 or 2 prior AML therapies, with the remaining 7 pts having 3-8 prior AML therapies (allo-SCT in 3). Nine pts had received prior FLT3 inhibitors including sorafenib (n=7), quizartinib (n=2), and E6201 (n=2). Nine pts had a FLT3-D835 kinase domain mutation, of which 4 pts also had FLT3-ITD; the remaining 4 pts had FLT3-ITD alone. Conventional cytogenetic testing included: normal karyotype (n=4; 31%), miscellaneous (n=5; 36%), and complex (n=4; 31%). Besides FLT3, multiple other leukemia-associated mutations were present at baseline: NPM1 (36%), DNMT3A (36%), NRAS/KRAS (27%), WT1 (18%), TET2 (18%), RUNX1 (18%), IDH1 (9%), IDH2 (9%), and ASXL1 (9%).No dose-limiting toxicities were observed at any of the dose levels explored and there were no dose reductions required. Non-hematologic adverse events assessed as possibly or probably related to crenolanib were all grade 1 in severity, including: nausea (n=2), vomiting (n=2), diarrhea (n=1), and abdominal pain (n=1). No deaths were attributed to crenolanib.The ORR in 11 pts evaluable for response was 36% (1 CR, 3 CRi; 2 not evaluable because of early discontinuation of therapy). Among 6 pts who received ≤2 prior AML therapies, 4 pts (67%) achieved a CR/CRi (including 2 pts with prior exposure to FLT3 inhibitors). These remissions occurred in pts with FLT3-ITD (n=2), FLT3-D835 (n=1) and FLT3-ITD+FLT3-D835 (n=1) (Table 1). No CRs were seen in the 5 pts who had 3 or more prior therapies (including 3/5 who had received prior FLT3 inhibitors) before coming on study.Three CRi pts have undergone allo-SCT: 1 pt (43/F) achieved CRi (with persistent FLT3-ITD) after 1 cycle and maintained remission with FLT3-ITD negativity for 6 months post allo-SCT, 1 pt (67/M) achieved CRi with FLT3-D835 negativity after 2 cycles and maintained remission for 3 months post allo-SCT, and 1 pt (58/M) achieved CRi after 1 cycle and relapsed 1.5 months post allo-SCT. One pt (73/M) achieved a full CR with FLT3 negativity and count recovery and is currently receiving crenolanib maintenance.The median OS for all patients was 259d; median OS by prior therapies was 259d for pts with ≤ 2 prior therapies, and 53d for pts with ≥ 3 prior therapies (Figure 1).Conclusions: Full doses of crenolanib (100 mg TID) can be safely combined with idarubicin and HiDAC in multiply relapsed/refractory FLT3+ AML. There is suggestion of clinical efficacy particularly among pts with only 1-2 prior therapies. This trial is being expanded to allow combination of full dose crenolanib with other standard salvage chemotherapies, including MEC (mitoxantrone, etoposide, cytarabine) and FLA(G)-IDA (fludarabine, cytarabine, idarubicin w/ or w/o G-CSF). [Display omitted] [Display omitted] DisclosuresKonopleva:Calithera: Research Funding; Cellectis: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Burger:Pharmacyclics: Research Funding. Eckardt:Arog: Employment, Equity Ownership. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Simeprevir and sofosbuvir with or without ribavirin to treat recurrent genotype 1 hepatitis C virus infection after orthotopic liver transplantation.

Although combination simeprevir (SIM) plus sofosbuvir (SOF) is an approved regimen for genotype 1 chronic hepatitis C virus (HCV), data regarding its safety and efficacy in liver transplant recipients remain limited. A multicenter retrospective study was performed to determine the efficacy and tolerability of a 12-week regimen of SIM/SOF with or without ribavirin (RBV) in 56 consecutive liver transplant recipients in 2014; 79% of patients had genotype 1a, 14% had cirrhosis, and 73% were treatment experienced. Sustained virological response at 12 weeks (SVR12) was 88% by intention to treat analysis (95% confidence interval, 84%-90%). Four patients relapsed, but no on-treatment virological failures occurred. The Q80K polymorphism did not impact SVR12, but there was a trend toward decreased sustained virological response with advanced fibrosis (P = 0.18). HCV RNA was detectable at treatment week 4 in 21% of patients, and those who had detectable levels were less likely to achieve SVR12 (58% versus 95%; P = 0.003). Five patients had baseline Child-Pugh class B cirrhosis, and 2 of them died (1 following early discontinuation of therapy). An additional discontinuation resulted from a severe photosensitivity reaction in a patient on concomitant cyclosporine. Seven patients receiving RBV developed progressive anemia requiring intervention. Immunosuppression dose modifications were minimal. SIM/SOF for 12 weeks was effective and well tolerated by compensated liver transplant recipients especially when administered without concomitant RBV or cyclosporine. SIM/SOF appears to have a niche as the only 12-week RBV-free treatment regimen currently recommended by guidelines for compensated transplant recipients. However, 12 weeks may not be the optimal duration of therapy for those with detectable virus at week 4 or possibly for those with cirrhosis. These data require confirmation by prospective randomized clinical trials. Liver Transplantation 22 635-643 2016 AASLD.

Anticoagulant therapy after venous thromboembolism and 10-year mortality

BackgroundPulmonary embolism (PE) is associated with a higher long-term mortality than deep vein thrombosis (DVT). This association may be related to inadequate antithrombotic therapy. MethodsIncident VTE patients during the period 1997–2012 were identified in Danish nationwide registries. Two landmark populations were defined, consisting of patients alive at 30days (30d), and at 180days (180d) after discharge. Patients were classified according to anticoagulant usage at the landmark (30d: prescription purchase 0–30d post-discharge; 180d: prescription purchase in 0–30d and 90–180d). Mortality rates were compared using multivariate Cox regression. ResultsThe 30d mortality risk among PE patients was high compared to DVT patients (19.9% vs. 4.4%). In the 30d-landmark population (n=62695), 34.9% of DVT patients and 21.3% of PE patients had not redeemed a prescription for anticoagulants. There was no material difference in 10-year mortality between anticoagulated PE patients and anticoagulated DVT patients. There was a higher 10-year mortality rate among non-anticoagulated PE patients compared to anticoagulated DVT patients (MRR: 1.26, 95% CI: 1.20–1.33). Findings in the 180d-landmark population also indicated materially similar 10-year mortality rates between anticoagulated PE patients and anticoagulated DVT patients. ConclusionsThe 10-year mortality rate of patients surviving the initial 30d critical period following incident PE was not increased compared to patients with incident DVT, as long as patients initiated and persisted with anticoagulant therapy. Increased focus on antithrombotic therapy in PE patients and reasons for early therapy discontinuation may be warranted.

IMPACT OF THE PEGYLATED-INTERFERON AND RIBAVIRIN THERAPY ON THE TREATMENT-RELATED MORTALITY OF PATIENTS WITH CIRRHOSIS DUE TO HEPATITIS C VIRUS.

Although the protease inhibitors have revolutionized the therapy of chronic hepatitis C (CHC), the concomitant use of pegylated-interferon (PEG-IFN) and ribavirin (RBV) is associated to a high rate of adverse effects. In this study, we evaluated the consequences of PEG-IFN and RBV and their relationship with mortality in patients with cirrhosis.METHODS: Medical records of CHC who underwent treatment with PEG-IFN and RBV in a public hospital in Brazil were evaluated. All the patients with cirrhosis were selected, and their clinical and laboratory characteristics, response to treatment, side effects and mortality were evaluated. RESULTS: From the 1,059 patients with CHC, 257 cirrhotic patients were evaluated. Of these, 45 (17.5%) achieved sustained viral response (SVR). Early discontinuation of therapy occurred in 105 (40.8%) patients, of which 39 (15.2%) were due to serious adverse effects. The mortality rate among the 257 cirrhotic patients was 4.3%, occurring in 06/242 (2.4%) of the Child-A, and in 05/15 (33.3%) of the Child-B patients. In conclusion, the treatment of patients with cirrhosis due to HCV with PEG-IFN and RBV shows a low SVR rate and a high mortality, especially in patients with liver dysfunction.

Persistence with mirabegron therapy for overactive bladder: A real life experience.

To evaluate persistence rates of patients receiving mirabegron therapy for overactive bladder (OAB) within our institution over a 6 month period, identify determinants of early discontinuation of therapy, and assess overall patient satisfaction with treatment. Hospital prescription data were analyzed in order to identify all patients who had been prescribed mirabegron in our institution. Case notes were retrospectively reviewed to obtain demographic data, previous treatments for OAB, reasons for discontinuation of previous treatments, and duration of treatment with mirabegron. Overall satisfaction with treatment was assessed using the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q). One hundred and ninety-seven patients were prescribed mirabegron. Of these, 81% previously discontinued anticholinergic therapy, 14% had previously received intravesical botulinum toxin A therapy, and 19% were prescribed mirabegron first-line. At 3 months 69% persisted with treatment which fell to 48% by 6 months. The commonest reason for discontinuation was lack of efficacy, followed by adverse effects. Overall 32% of patients preferred mirabegron over previous treatments and only 39% were satisfied with mirabegron therapy. Persistence rates with mirabegron in this group of patients for OAB are satisfactory. The commonest reasons for discontinuation are unmet treatment expectations and adverse effects. We had very few treatment-naïve patients and so further studies are required to assess mirabegron persistence rates with longer-term follow up, as first-line treatment and in different groups of OAB severity. Neurourol. Neurourol. Urodynam. 36:404-408, 2017. © 2015 Wiley Periodicals, Inc.

Combination Chemotherapy with S-1 and Oxaliplatin (SOX) as First-Line Treatment in Elderly Patients with Advanced Gastric Cancer.

This study is a retrospective analysis evaluating the efficacy and toxicity of combination chemotherapy with S-1 and oxaliplatin (SOX) as first-line treatment in elderly patients with advanced gastric cancer. One hundred and twenty-nine patients with recurrent or metastatic gastric adenocarcinoma were treated with SOX; S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily on days 1 to 14 followed by a 7-day rest period, 130 mg/m(2) oxaliplatin was given as an intravenous infusion over 2-hours on day one. The cycle was repeated every three weeks. All of the patients were older than 65 years. Among 129 patients enrolled, nine patients could not be evaluated for responses because of the absence of any measurable lesions or early discontinuation of therapy. Assessment of the response of 120 patients was made. The overall objective response rate was 54.2 % (95 %CI, 45.3-63.1 %), with three complete responses and 62 partial responses. The disease control rate was 80.8 % (95 %CI, 73.8-87.8 %). The median follow-up period was 23 months (range, 5-42 months). The median time to progression was 6.9 months (95 %CI, 5.5-8.3 months) and the median overall survival was 12.8 months (95 %CI, 11.4-14.2 months). The one-year survival rate was 57.5 % (95 %CI, 48.7-66.3 %). In 129 patients assessed safety, grade 3 and 4 toxicities included leucopenia (20.9 %), neutropenia (24.0 %), anemia (10.9 %), thrombocytopenia (10.1 %), anorexia (3.1 %), peripheral neurotoxicity (15.5 %), and fatigue (12.4 %). No treatment-related deaths occurred. Combination chemotherapy with SOX offers an effective, safe and well-tolerated regimen for elderly patients with advanced gastric cancer.

Bendamustine in Combination with Rituximab for Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients: An Italian Retrospective Multicentre Study

BACKGROUNDThe combination schedule of rituximab, fludarabine and cyclophosphamide is considered the standard therapy for fit and young untreated chronic lymphocytic leukemia (CLL) patients. However, although this therapy improves progression free survival (PFS) and overall survival (OS), it has been associated with increased toxicity: 76% of the patients experienced at least one grade 3 or 4 event. Recently, encouraging clinical results in terms of safety and efficacy have been obtained using bendamustine in combination with rituximab (R-B) in untreated CLL patients. PURPOSEWe performed a multicentre retrospective study to assess safety and efficacy of R-B in a large group of untreated CLL patients. METHODSOne hundred and thirty six untreated CLL patients were recruited from 16 Italian Institutions and included in the present analysis. The median age was 69 years (range 43–85), with 49.3% of patients older than 70 years; 53.7% of cases were male. All patients had active disease as defined by the NCI-WG, and 27.2% were at Binet stage C. FISH data, available in 86/136 cases, identified a del(17p) in 5.1% of the patients and del(11q) in 5.9%. Sixty-four patients (47.1%) had a creatinine clearance ≤70 mL/min. Fifty-six % of cases showed a WHO performance status (PS) of I-II and 61% a CIRS comorbidity index >0. RESULTSAmong the 136 patients, 90 cases (66.2%) received B at the dosage of 90 mg/m2 on day 1 and 2 every 28 days, the remaining 46 cases received B at the dosage of 70 or 80 mg/m2. R was administered at the dosage of 375 mg/m2 on day 1 of all cycles in 59.6% of cases, while 40.4% received 375 mg/m2 on day 1 of the first cycle and 500 mg/m2 on day 1 of the other cycles. A total of 725 cycles were administered with a median number of 6 cycles per patient. Eighteen patients (13.2%) required early discontinuation of therapy before the sixth cycle for serious infections (n=7), persistent hematological toxicity (n=5), grade 4 dermatological toxicity (n=3), withdrawal of consent (n=2), hypersomnia and depression (n=1). Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 25.8%, 25.8%, and 16.2% of patients, respectively. Grade 3 or 4 severe infections occurred in 6.6% of patients. The overall response rate (ORR) was 93.4%, 48 patients (35.3%) achieved a complete response (CR), 79 (58.1%) a partial response (PR), 8 (5.9%) a stable disease (SD) and in 1 patient (0.7%) no response assessment was performed due to death prior to terminating therapy. In the high-risk group with del17p, 5/7 (71.4%) cases achieved a PR and 2 a SD. Age >70 years (P=0.026) and del17p (P=0.007) were the only two parameters significantly associated with a lower response rate, while del11q and unmutated IGHV, as well as creatinine clearance <70 ml/min, elevated β2-microglobulin, PS and CIRS CI >0 did not seem to impact on achievement of response. The only parameter predictive of the probability of achieving a CR was an age <70 years (P=0.03). When the analysis was restricted to cases with available FISH data, excluding patients with del17p, biological (CD38, ZAP-70, IGHV mutational status, FISH risk) and clinical parameters (age, β2-microglobulin, LDH, PS, CIRS CI, and creatinine clearance) did not significantly impact on the probability of achieving a response or on quality of response. After a median follow-up of 14 months, 2-year PFS was 87% and 2-year OS 84.5% (14 deaths occurred). Eight of 14 deaths were CLL-related (infections in 6 cases and disease progression in 2). CONCLUSIONSThe clinical practice of the Italian centers taking part in the study confirms that chemoimmunotherapy with R-B was an effective and well-tolerated treatment for untreated CLL patients. In patients with del17p the therapy appears to be less efficacious. DisclosuresOff Label Use: Bendamustine in diffuse large B-cell lymphoma. Zinzani:Genentech, inc.: Membership on an entity’s Board of Directors or advisory committees.

Early discontinuation of endocrine therapy for breast cancer: who is at risk in clinical practice?

PurposeDespite evidence supporting at least five years of endocrine therapy for early breast cancer, many women discontinue therapy early. We investigated the impact of initial therapy type and specific comorbidities on discontinuation of endocrine therapy in clinical practice.MethodsWe identified women in a population-based cohort with a diagnosis of early breast cancer and an incident dispensing of anastrozole, letrozole or tamoxifen from 2003–2008 (N = 1531). Pharmacy and health service data were used to determine therapy duration, treatment for pre-existing and post-initiation comorbidities (anxiety, depression, hot flashes, musculoskeletal pain, osteoporosis, vaginal atrophy), demographic and other clinical characteristics. Time to discontinuation of initial, and any, endocrine therapy was calculated. Cox regression determined the association of different characteristics on early discontinuation.ResultsInitial endocrine therapy continued for a median of 2.2 years and any endocrine therapy for 4.8 years. Cumulative probability of discontinuing any therapy was 17% after one year and 58% by five years. Initial tamoxifen, pre-existing musculoskeletal pain and newly-treated anxiety predicted shorter initial therapy but not discontinuation of any therapy. Early discontinuation of any therapy was associated with newly-treated hot flashes (HR = 2.1, 95% CI = 1.3–3.3), not undergoing chemotherapy (HR = 1.4, 95% CI = 1.1–1.8) and not undergoing mastectomy (HR = 1.5, 95% CI = 1.2–1.8).ConclusionsLess than half of women completed five years of endocrine therapy. Women at greatest risk of stopping any therapy early were those with newly-treated hot flashes, no initial chemotherapy, or no initial mastectomy. This suboptimal use means that the reductions in recurrence demonstrated in clinical trials may not be realised in practice.

Management of anaemia and other treatment complications

Antiviral treatment for hepatitis C virus infection has dramatically changed with the advent of triple therapy including telaprevir or boceprevir, which is associated with a new spectrum of adverse events. These may lead to dosage reduction and early discontinuation of therapy. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the telaprevir-based regimen. The first-line management of anaemia is ribavirin dose reductions. In cirrhotic patients, aggressive ribavirin dosage reductions, erythropoietin alpha and blood transfusions are effective in managing anaemia. Several deaths and cases of severe infections and hepatic decompensation were reported in cirrhotics treated in real-life setting. Patients with platelet count ≤ 100,000/mm(3) and serum albumin < 35 g/L should not be treated with triple therapy as it is related to a high risk of developing severe complications. The management of rashes, if well planned, does not require telaprevir discontinuation. However, approximately 5% of rashes were severe and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation. Successful treatment can be enhanced by a strong patient support network including a multidisciplinary team.

P-0217 - Is There an Association Between the Occurrence of Neutropenia and Neuropathy in Patients with Metastatic Colorectal Cancer Treated with Folfox?

Background: Oxaliplatin-based chemotherapy is the standard first line treatment of metastatic colorectal cancer (mCRC). The most common toxicity related to oxaliplatin use is sensory neuropathy, which occurs in up to 80% of patients, grades ¾ in up to 10%, and can lead to early discontinuation of therapy. Haematological toxicity of the FOLFOX regimen is high especially in women, grade ¾ neutropenia occurs in up to 40% of patients, with about 5% of febrile neutropenia. There is sparse literature data evaluating the association between the occurrence of neutropenia and neuropathy in patients treated with FOLFOX regimen. Methods: We retrospectively reviewed data of patients treated for mCRC in our Institute between 2010 and 2012. The patients who were considered eligible had to have received at least eight cycles of FOLFOX in two week intervals in the first line of treatment. Neuropathy was evaluated using CTCAE version 3.0. Statistical analysis was done using Fisher exact test and Pearson &khgr;2 test. Results: Of 52 patients analysed, 25 were male (48.1%) and 27 were female (51.9%), with median age at diagnosis 59 years, range 24 to 78. Metastatic disease at presentation was registered in 23 patients (44.2%), 29 patients (55.8%) relapsed at a later date. Significant comorbidities were present in 29 patients (55.8%), diabetes was present in 8 patients, arterial hypertension in 22 patients and angina pectoris in 4 patients. At the beginning of systemic treatment with FOLFOX regimen, the most common metastatic site was liver, in 43 patients (82.7%), retroperitoneal lymph nodes in 16 patients, lung in 10 patients, peritoneum in 9 patients. Median number of cycles administered was 9 (8 to 12). Neutropenia gr.1 occurred in 49 patients in at least one cycle of chemotherapy (94.2%), gr.2 in 38 patients (73.1%), gr.3 in 28 patients (53.8%), gr.4 or febrile neutropenia in 11 patients (21.2%). Sensory neuropathy gr.1 occurred in 28 patients (53.8%), gr.2 in 10 patients (19.2%) and gr.3 in 2 patients (3.8%). Both sensory neuropathy and neutropenia were registered 26 patients (53.1%). When all data had been analysed, there was no statistically significant association between the occurrence of neutropenia of any grade and sensory neuropathy (Fisher exact test 0.559). However, there was a statistically significant association between the occurrence of neutropenia gr.2 or more and sensory neuropathy (&khgr;2 0.026). Conclusion: This preliminary analysis performed on a limited number of patients showed that there is an association between the occurrence of sensory neuropathy and high grades of neutropenia (gr.2 or higher) during FOLFOX treatment. Whether neutropenia, as a usually earlier event, could predict the occurrence of neuropathy should be further investigated on a much higher patient number. The analysis did not identify a subgroup of patients which are more likely to suffer from both toxicities, which is another direction for a further investigation.

Adherence to anti-osteoporotic therapies: role and determinants of “spot therapy”

A successful therapy needs high level of adherence consisting in right drug intake in terms of persistence and compliance. Our study suggests adherence is higher if spot (less than 30 days) therapies are excluded; the analysis of spot therapy causes underlines the importance of the interpersonal aspects of medical practice. A successful therapy needs a high level of adherence consisting in right drug intake in terms of persistence and compliance. The aim of this study was to evaluate anti-osteoporotic therapies recorded in general practitioner databases in the area of Rome, which used the same computerized medical record management. The study focused on evaluating therapy adherence, any adherence changes excluding spot therapies (less than 30 days), and any cause of early therapy discontinuation in a subgroup of patients randomly selected. Thirty-one databases were evaluated, including a total of 6,390 anti-osteoporotic therapies: 5,853 were prescribed to women and 537 to men. The prescribed drugs were: vitamin D (13 %), calcium (8.7 %), vitamin D + calcium (40.1 %), raloxifene (3.3 %), alendronate (16.4 %), risedronate (7.7 %), clodronate (10.4 %), or other drugs (0.4 %). Spot therapies represented 53.7 % of the total prescriptions. The difference between adherence in the total group (24.64 %) and the group excluding spot therapies (43.38 %) is significant. The main factors influencing low adherence were side effects (27 %), misinformation given by the physician (17 %), insufficient motivation (9 %), difficult intake (9 %), and no perceived benefits (9 %). Our study suggests adherence is high and similar to other chronic diseases if spot therapies are excluded. The analysis of spot therapy causes suggests that an important role is played by the physician and the interpersonal aspects of medical practice, especially at the first prescriptions. The physician should collaborate with patients in choosing a personalized medical treatment. Reducing spot therapy could be the real goal in order to improve anti-osteoporotic therapy adherence.

Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review

To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients. We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk. We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001). Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.