Non-neutropenic Infections Research Articles

Ramucirumab, avelumab, and paclitaxel (RAP) as second-line treatment in gastro-esophageal adenocarcinoma, a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

4051 Background: Combination of ramucirumab and paclitaxel is a standard second line therapy in gastro-esophageal adenocarcinoma (GEAC) (RAINBOW trial, Wilke et al., 2014). We integrated the PD-L1 inhibitor avelumab into this regimen aiming for synergistic efficacy. Methods: In a multicenter phase II trial (NCT03966118) pts with metastatic GEAC, after progression on platinum / fluoropyrimidine based palliative 1st-line, ECOG 0 or 1, were treated with ramucirumab 8 mg/kg (d1,15) + avelumab 10 mg/kg (d1,15) + paclitaxel 80 mg/m² (d1,8,15), q4w. Sample size calculation was based on a Simon 2-stage design with overall survival rate at 6 months as the primary endpoint (H0≤50%, H1≥65%). Results: 60 pts were enrolled, 59 were evaluable (ITT), median age 64.0 yrs (range 18-81), male 80%, female 20%, primary gastric 52%, GEJ 48%, histology intestinal 59.6%, diffuse 24.6%, mixed 15.8%. Previous treatment with platin/fluoropyrimidine 100%, previous taxanes 66%. At central pathology MSI-H 7%, PD-L1 CPS < 5: 54%; ≥5: 41%, NA 5%. Response by investigator (%) CR 3.4, PR 27.1, SD 49.2, PD 20.3; DCR 79.7%, independent radiology review will be presented. DOR: 8.2 mo (95%CI 6.7-9.7), PFS 5.4 mo (95%CI 4.2-6.6); 6-mo OS rate 71.2%; 12-mo OS rate 45.8%; med OS (ITT) 10.6 mo (95%CI 8.2-13.1), med OS CPS < 5: 9.4 mo (95%CI 7.2-11.2), CPS ≥5: 14.0 mo (95%CI 12.8-15.3), translational data (ct-DNA) will be analysed. Treatment was generally well tolerated and no unexpected toxicities occurred: Grade 3/4 AE above 5%: anemia 5%, leucopenia 12%, neutropenia 22%, diarrhea 5%, pain 10%, peripheral neuropathy 10%, hypertension 5%, non-neutropenic infection 5% including 1 CTC grade 5 due to an esophago-tracheal fistula. Conclusions: The med OS of 10.6 mo (in a population of 66% pretreated with taxanes) compares very favourably to 8.6 mo in the Western population RAINBOW trial (Shitara et al., 2016) and 7.6 mo in the RAMIRIS trial (Lorenzen et al., 2022). PD-L1 CPS≥ 5 seems to predict for an even better efficacy (med OS 14.0 mo). Second-line RAP is a very efficacious and well tolerated combination. Clinical trial information: NCT03966118.

Predictive Value of Albumin and Neutrophil-to-Lymphocyte Ratio Score for Treatment Completeness and Safety Profiles in Patients With Head and Neck Cancer Receiving Definitive Concurrent Chemoradiotherapy.

Malnutrition and inflammation are common conditions in patients with head and neck cancer (HNC). This study aimed to evaluate the predictive value of albumin combined with neutrophil-lymphocyte ratio (NLR), referring to the albumin-NLR score (ANS), in the prediction of treatment completeness and safety profiles in HNC patients receiving definitive concurrent chemoradiotherapy (CCRT). 461 consecutive HNC patients who received CCRT between 2016 and 2017 at three medical centers in Taiwan were prospectively enrolled and divided into three different groups based on their pretreatment ANS (ANS 0, high albumin and low NLR; ANS 1, low albumin or high NLR; and ANS 2, low albumin and high NLR) for treatment completeness and safety profiles comparison. Overall, 46 patients (10.0%) had incomplete CCRT treatment. Patients in the ANS 2 group experienced a higher rate of incomplete CCRT (20.9%) than those in the ANS 1 (7.4%) and ANS 0 (3.5%) groups. ANS had a better discriminatory ability in predicting CCRT completeness in terms of -2 log-likelihood value, chi-square value, and c-index than the prognostic nutritional index. Patients in the ANS 2 group had significantly higher incidences of grade 3 or higher leukopenia, anemia, neutropenia, thrombocytopenia, non-neutropenic infection, and hypokalemia than those in the other two ANS groups. Our study showed that the ANS can accurately predict the treatment completeness of CCRT in patients with HNC and can be widely used as a simple predictor of treatment tolerance and safety profiles in patients with HNC undergoing CCRT.

Natural History of Hypogammaglobulinemia in Patients with Follicular Lymphoma and the Impact of Anti-CD20-Based Therapy

Introduction: Anti-CD20 monoclonal antibodies (e.g. rituximab) have improved outcomes for patients with B-cell malignancies. Patients with follicular lymphoma (FL) have an excellent expected survival and frequently require multiple course of anti-CD20-based therapy, which has been associated with hypogammaglobulinemia (HG) and recurrent infections.Objective: To evaluate the prevalence of HG and associated recurrent infections in patients with FL treated with anti-CD20-based therapy, and to describe the natural history of immunoglobulin (Ig) levels in groups of patients with different treatment intensities.Patients and methods: This is a retrospective study of FL patients at Memorial Sloan Kettering Cancer (MSKCC) conducted with IRB approval. Patients with FL were identified in the MSKCC FL Database. The analysis was restricted to patients with ≥2 Ig assessments prior to and after anti-CD20-based therapy (largely rituximab). HG was defined as ≥1 documented IgG <600, IgA < 50 or IgM <50 mg/dL. Symptomatic IgG-HG was defined as ≥2 non-neutropenic infections (NNI) or ≥1 serious NNI (resulting in hospitalization, antibiotics, or initiation of intravenous Ig [IVIG]). For subsequent analyses, patients were classified into 5 groups based on exposure to anti-CD20 antibody. The control group consisted of patients with no exposure to anti-CD20 antibody, and included patients on active surveillance or treated with local IFRT. Group 1 received a single course of anti-CD20-based therapy (monotherapy [MONO] or chemoimmunotherapy [CI]). Group 2 received first line MONO or CI followed by maintenance with anti-CD20 antibody. Group 3 received multiple courses of MONO or CI. Group 4 included patients who received high dose therapy with autologous stem cell rescue (HDT/ASCR) and/or allogeneic stem cell transplant.Results: Of 1123 consecutive patients at MSKCC diagnosed between 1998 to 2009 with FL, 380 were eligible for the analysis. Baseline characteristics were similar between eligible patients and the full dataset. 70 patients in the control group and 310 patients for the anti-CD20-based therapy group (75 patients in Group 1; 70 patients in Group 2; 106 patients in Group 3; 59 patients in Group 4). Exposure to anti-CD20-based therapy was associated with an increased risk of HG (74.4% vs 21.1%; p: 0.001) and IgG-HG (45.2% vs 10%; p: 0.001). Despite the frequency of HG, symptomatic IgG-HG prompting treatment with IVIG was uncommon, occurring in 10.3% of patients exposed to anti-CD20-based therapy and 1.4% of patients in the control group (p: 0.016) (Figure 1-A). The development of recurrent sino-pulmonary infections was the most frequent cause of symptomatic IgG-HG. There was a gradual downward trend in IgG levels over time in the control group as well as in Groups 1-4 prior to treatment with anti-CD20-based therapy; however, the degree of decline was significantly greater among patients in Groups 1-4 (minus 26.8 mg/dL/yr versus minus 9.3 mg/dL/yr, respectively; p: 0.001). We evaluated IgG levels subsequent to anti-CD20-based therapy. In Group 1, the IgG level rose gradually to levels close to those at time of diagnosis (increase in 10.3 mg/dL/yr). In contrast, the IgG levels fell in groups 2-4 (Group 2: minus 7.4; Group 3: minus 10.3 and Group 4: minus 0.8 mg/dL/yr). The addition of maintenance therapy following MONO or CI resulted in a long-term decline in IgG levels (Figure 1- B/C).Conclusion: HG was frequently observed in patients with FL who received anti-CD20-based therapy, occurring in three-quarters of patients. Evaluation of the natural history of IgG levels in CD20 therapy naïve patients suggests that disease burden in FL impacts IgG levels. Additionally, anti-CD20-based therapy, except for limited treatment (Group 1) impacted IgG levels over time. Despite HG being a frequent event, few patients developed symptomatic IgG-HG. Given these data, Ig surveillance should be routinely included in follow-up of FL patients. Symptomatic HG may occur as a late event following exposure to anti-CD20-based therapy. [Display omitted] DisclosuresYounes:Novartis: Research Funding; Johnson & Johnson: Research Funding; Seattle Genetics: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Janssen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Takeda Millenium: Honoraria. Zelenetz:Celgene: Consultancy; Amgen: Consultancy.

Liposomal irinotecan pre-emptive dose reduction in patients with pancreatic ductal adenocarcinoma: 667 patients' experience within a population-based study.

Background:Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is currently the standard second-line treatment for patients with pancreatic ductal adenocarcinoma (PDAC) after previous failed gemcitabine-based therapy. This population-based study aimed to evaluate the efficacy and safety of nal-IRI + 5-FU/LV and the association of pre-emptive nal-IRI dosing with treatment outcomes in patients with PDAC.Methods:We retrospectively enrolled a total of 667 consecutive patients with PDAC who received nal-IRI plus 5-FU/LV treatment between August 2018 and November 2020 at 9 medical centers in Taiwan. Patients were allocated into groups according to pre-emptive nal-IRI dosing (⩾75%, 50–74%, <50%) for comparison of treatment efficacy and safety.Results:The median overall survival (OS) and time to treatment failure (TTF) were 5.9 months [95% confidence interval (CI), 5.3–6.5] and 2.8 months (95% CI, 2.6–3.0), respectively. The median OS was 6.5 months (95% CI, 5.7–6.7), 5.0 months (95% CI, 3.4–6.5), and 4.1 months (95% CI, 2.7–5.6), respectively, among the ⩾75%, 50–74%, and <50% pre-emptive nal-IRI dosing groups, whereas the median TTF of the three groups was 3.0 months (95% CI, 2.6–3.4), 2.6 months (95% CI, 2.3–2.9), and 1.9 months (95% CI, 1.6–2.2), respectively. Pre-emptive nal-IRI dosing <50% was an independent negative prognostic factor for OS and TTF in multivariate analyses. The most common severe adverse events were neutropenia (22.9%), anemia (21.1%), and hypokalemia (15.4%). Patients in the <50% pre-emptive nal-IRI dosing group had a significantly lower incidence of neutropenia and non-neutropenic infection than those in the other groups.Conclusion:Our results support the use of nal-IRI + 5-FU/LV as standard clinical practice for treating patients with PDAC based on this large population-based study. Our findings encourage physicians to provide adequate doses of nal-IRI in order to achieve better outcomes without compromising safety profiles.

Risk factors for unplanned hospital readmissions within 30 days of discharge among medical oncology patients: A retrospective medical record review.

This study aimed to identify the risk factors for unplanned hospital readmissions (UHR) within 30 days of discharge among medical oncology patients at a tertiary hospital in Singapore. This study is a retrospective, case-control medical record review of patients admitted to a medical oncology unit at a tertiary hospital between 1 June and October 31, 2017. During the study period, there were 1559 adult patients discharged alive from the medical oncology unit. Of this, 359 patients had experienced at least a 30-day UHR (cases). The cases were matched to those without a 30-day UHR (controls) by their primary reason for index admission and discharge date. After matching, 312 medical records (cases: 156; controls: 156) were analysed. Of the 156 cases with a 30-day UHR, 46.2% (n=72) were readmitted within the first 10 days of discharge. The top reasons contributing to the UHR were non-neutropenic infection (n=41) and pain (n=23). Multivariate analyses identified three independent risk factors that were associated with the 30-day UHR: (1) single marital status, (2) emergency department visit(s) in the past six months, and (3) recent decline in activities of daily living. The study results can guide risk stratification to identify medical oncology patients at high risk for 30-day UHR. In addition, the results warrant the need to refine the inpatient assessments and discharge planning, as well as ensure the accurate referral to and allocation of community and outpatient resources so as to reduce the risk of UHR.

The Use of 20% Subcutaneous Immunoglobulin Replacement Therapy in Patients With B Cell Non-Hodgkin Lymphoma With Humoral Immune Dysfunction After Treatment With Rituximab

BackgroundRituximab is an anti-CD20 chimeric antibody used to treat autoimmune conditions and B cell neoplasms. We characterized immunoglobulin (Ig) levels and vaccine responses in rituximab-treated B cell non-Hodgkin lymphoma (NHL) patients. Patients with impaired vaccine responses were offered therapy with 20% subcutaneous (subq) Ig. Patients and MethodsPatients with a biopsy-proven diagnosis of B cell NHL who had received rituximab within the past 24 months were eligible for the study and underwent the following immune evaluation: serum IgG, IgM, IgA, IgE, T/B cell lymphocyte panel, and pre/post vaccine IgG titers to diphtheria, tetanus, and streptococcus pneumoniae. Patients were vaccinated with tetanus, diphtheria and pneumococcal polysaccharide vaccine. Patients with abnormal vaccine responses were offered prophylactic subq Ig for 52 weeks. ResultsFifteen patients with NHL were enrolled in the study. The median IgG was 628 mg/dL [interquartile range, 489-718 mg/dL]. Three (20%) of 15 patients responded to diphtheria vaccination, 1 (6.7%) of 15 responded to tetanus vaccination, and 3 (20%) of 15 responded to vaccination to streptococcus pneumoniae. Thirteen (86.7%) of 15 met criteria for humoral immunodeficiency. Ten patients received subq Ig, and experienced a significant increase in serum IgG (P = .008). There were no serious adverse events, and there was a decrease in nonneutropenic infections while on subq Ig therapy. ConclusionsPatients with NHL treated with rituximab may have significant humoral immunodeficiency as defined by abnormal vaccine responses even in the setting of relatively normal IgG levels. For these patients, subq Ig replacement therapy is well-tolerated and efficacious in improving serum IgG, and may decrease reliance on antibiotics for the treatment of nonneutropenic infections.

982P - Two-weekly accelerated BEP (aBEP) regimen as induction chemotherapy (CT) in intermediate and poor prognosis patients (pts) with nonseminomatous germ cell tumours (NSGCT): Final results of phase II trial

BackgroundThree-weekly BEP has been a standard of CT of advanced NSGCT for last two decades. We performed a phase II study to assess the efficacy and toxicity of two-weekly aBEP regimen in the first line treatment of NSGCT. Here we report final efficacy and safety results. MethodsCT-naïve NSGCT pts with intermediate or poor prognosis (IGCCCG) received aBEP as follows: cisplatin 20mg/m2 days 1-5, etoposide 100mg/m2 days 1-5, bleomycin 30IU days 1,3,5 with G-CSF support 300mcg days 6-10. Four cycles of aBEP were administered every 2 weeks. The primary endpoint was the progression free rate. ResultsFrom 2010 to 2014, 67 pts were treated. Intermediate and poor prognosis according IGCCCG had 35 (59%) and 32 (41%) of pts, respectively. In poor prognostic group mediastinal primary tumor had 11 (34%) pts, nonpulmonary visceral metastases - 16 (50%) pts. All pts were assessed for toxicity, which included (grade 3/4, per patient) neutropenia 72%, febrile neutropenia 26%, thrombocytopenia 18%, non-neutropenic infection 3%, anemia 31%. There were no toxic deaths. Dose reduction of cisplatin, etoposide and bleomycin were done on 16 (6.4%), 22 (8.9%) and 19 (7.7%) of 247 cycles, respectively. Median number of cycles was 4 (3-5). Two pts could not receive 4-th cycle due to toxicity. Median duration of treatment (from the first to the last doses of CT) was 7.4 (6.7-10.4) weeks. Totally 44 (72%) pts were able to start 4-th cycle of aBEP by day 50 (<1 week of delay). Median time of f.-up was 74 (5-108) months. Five-years PFS and OS were 88% and 85% (intermediate risk), 63% and 53% (poor risk). There were a trend to improvement of OS in poor risk group over 3-weekly BEP regimen in our center (n=79, 5-y OS 45%, p=0.09). ConclusionsTwo-weekly BEP regimen can be safely administered to NSGCT pts with intermediate and poor prognosis. Promising efficacy of aBEP warrants confirmation in ongoing randomized trial. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

777P - Evaluation of the introduction of primary G-CSF prophylaxis to the FLOT chemotherapy regimen

BackgroundFLOT chemotherapy is a standard of care for patients with early gastric & gastroesophageal junction adenocarcinoma: 4 cycles pre- and 4 post-surgery. It was introduced at the Clatterbridge Cancer Centre in October 2017 following the presentation of FLOT4 trial data. Primary prophylaxis with GCSF was not part of the trial protocol but was allowed as per investigator’s discretion. As such GCSF was not included in the FLOT regimen initially in our centre. However, a significant number of patients could not proceed with their second cycle on time due to prolonged grade 3-4 neutropenia or neutropenic infection. Therefore, primary GCSF prophylaxis was introduced from day 5 of each cycle for 5 days at doses of 300 & 480 micrograms for patients with weight <70 and >70kg, respectively. MethodsPatients were identified from chemotherapy-prescribing records and data was collected from their electronic notes. As a primary objective we compared rates of dose delay because of neutropenia before and after introducing primary GCSF prophylaxis. We also looked at other reasons for dose delay & reduction. Results47 patients started FLOT between October 2017 & July 2018; 41 were men and median age was 63.7 years (36-79). 2 patients had FLOT only in the adjuvant setting. In patients who started neoadjuvant FLOT, 27 patients (57.4%) went on to receive FLOT adjuvantly. 19 patients (40.4%) completed 8 cycles and the median number of cycles received was 5.6 (1-8 cycles). 13 patients had FLOT without primary GCSF prophylaxis, 61.6% of them had dose delays because of neutropenia. After the addition of primary GCSF prophylaxis, the rate of neutropenia resulting in dose delay fell to 2.9% (p=0.00). 46.8% of patients had their treatment delayed for reasons other than neutropenia with the highest rates of deferral seen for non-neutropenic infection (10.6%) and nausea & vomiting (10.6%). 31.9% of patients had their treatment dose reduced; this was most commonly for diarrhoea (10.6%) and peripheral neuropathies (8.5%). Conclusions61.6% of patients receiving the FLOT regimen had treatment delays because of neutropenia. Primary GCSF prophylaxis almost eliminated this problem and reduced the overall rate of dose delays. Therefore, primary GCSF prophylaxis should routinely be used with FLOT. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

HCT related toxicities and mortality in frail recipients.

e18534 Background: Frailty is a state characterized by diminished physiological reserve and increased vulnerability to stress, and adversely affects outcomes in older patients with cancer. Geriatric assessments are not routinely used to screen older HCT (hematopoietic cell transplant) recipients. There is limited knowledge of the impact of pre-HCT frailty on severe/ life-threatening (CTCAE, version 5.0) grade 3-4 non-hematologic toxicities within 1y after HCT. We aimed to determine the relationship between pre-HCT frailty and grade 3-4 non-hematologic toxicities and mortality in HCT recipients, and also examined whether age at HCT moderated that association. Methods: In a prospective longitudinal study of 117 patients undergoing HCT at age ≥ 40y, we performed pre-HCT geriatric assessments. Frailty was assessed using Fried’s criteria. Post-HCT toxicities were abstracted through chart reviews Results: Median age at HCT was 60y (40-73). Pre-HCT frailty could be evaluated in 98 (84%) patients [(51 autologous, 47 allogeneic (allo)]. Pre-HCT comorbidity index (CI) was high in 27%, intermediate in 40% and low in 33%. The prevalence of pre-HCT frailty was 21%. Overall, frail recipients (vs. non-frail) had a higher cumulative incidence of any grade 3-4 toxicity [86% (95% CI: 62-100%) vs. 70% (57-83%), p = 0.03]; and the following organ specific grade 3-4 toxicities: non-neutropenic infections [(38% (17-59%) vs. 13% (6-20%), p &lt; 0.01)]; nervous system disorders [(19% (3-35%) vs. 4% (0-8%), p = 0.02)]; and pneumonia [(38% (17-59%) vs. 10% (4-17%), p &lt; 0.01]. Frail recipients also had a higher overall mortality [52%, (30-75%) vs. 19%, (11-28%) (p &lt; 0.01)]. In Cox regression analysis controlling for age, donor type, disease risk, conditioning and HCT-CI, frail recipients were 1.9 fold more likely to suffer any grade 3-4 toxicities (p = 0.03), 4-fold more likely to suffer non-neutropenic infections and pneumonia, both p = 0.01; and 8.6-fold more likely to suffer nervous system disorders, p = 0.01. Frail recipients who underwent an allo-HCT were at 2.7 fold higher risk of death vs. non-frail allo- HCT recipients, p = 0.06. Conclusions: The higher toxicity and mortality in frail recipients needs attention. Studies focusing on pre-HCT interventions to reduce frailty are needed.

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

ABSTRACT Gliotoxin contributes to the virulence of the fungus Aspergillus fumigatus in non-neutropenic mice that are immunosuppressed with corticosteroids. To investigate how the absence of gliotoxin affects both the fungus and the host, we used a nanoString nCounter to analyze their transcriptional responses during pulmonary infection of a non-neutropenic host with a gliotoxin-deficient ΔgliP mutant. We found that the ΔgliP mutation led to increased expression of aspf1, which specifies a secreted ribotoxin. Prior studies have shown that aspf1, like gliP, is not required for virulence in a neutropenic infection model, but its role in a non-neutropenic infection model has not been fully investigated. To investigate the functional significance of this up-regulation of aspf1, a Δaspf1 single mutant and a Δaspf1 ΔgliP double mutant were constructed. Both Δaspf1 and ΔgliP single mutants had reduced lethality in non-neutropenic mice, and a Δaspf1 ΔgliP double mutant had a greater reduction in lethality than either single mutant. Analysis of mice infected with these mutants indicated that the presence of gliP is associated with massive apoptosis of leukocytes at the foci of infection and inhibition of chemokine production. Also, the combination of gliP and aspf1 is associated with suppression of CXCL1 chemokine expression. Thus, aspf1 contributes to A. fumigatus pathogenicity in non-neutropenic mice and its up-regulation in the ΔgliP mutant may partially compensate for the absence of gliotoxin. Abbreviations:PAS: periodic acid-Schiff; PBS: phosphate buffered saline; ROS: reactive oxygen species; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling

A Prospective Phase I/II Study of Docetaxel, Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3)

AimsThis open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma. Materials and methodsPatients with adenocarcinoma or squamous cell carcinoma of the oesophagus or stomach, of good performance status, deemed too advanced for curative treatment, were given systematically increasing doses of 3 weekly DCC to ascertain the MTD. Phase II administered up to six cycles of DCC at the MTD, assessing response and toxicity. ResultsBetween November 2007 and November 2012, 15 patients were recruited into phase I and 41 into phase II. The MDT was a 21 day cycle of docetaxel 60 mg/m2 IV day 1, cisplatinum 60 mg/m2 IV day 1 and oral capecitabine 1000 mg/m2 daily in two divided doses for days 1–21. The most common phase II grade 3–4 toxicities were neutropenia 88% (10% febrile neutropenia), fatigue 15%, sensory neuropathy 10% and non-neutropenic infection 10%. The overall response rate was 51%, median progression-free survival was 7.4 months (confidence interval 6.7–9.4) and median overall survival was 10.9 months (confidence interval 7.7–13.7). ConclusionDCC was tolerable and feasible with promising efficacy, and may be suitable for future investigation in both first-line metastatic and neoadjuvant settings.

Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?

Drugs targeting mammalian target of rapamycin signaling pathway have been recently approved for treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). However, there is lack of real world data from India on the use of this therapeutic strategy. A retrospective analysis of MBC patients who had recurrence or progression while receiving aromatase inhibitors (AI's) and further treated with everolimus and either tamoxifen/AI/fulvestrant between March 2012 and June 2014, was undertaken. There were 41 patients with median age 55 years, 73% with visceral metastasis, and 73% with ≥2 sites of metastases. Thirty (73%) patients had received 3 prior lines of therapy including AI (100%), tamoxifen (94%), fulvestrant (39%), and chemotherapy (100%) while the remaining had received <3 lines of prior therapy. The commonest Grade 3/4 adverse events were stomatitis (19%), hyperglycemia (new/worsening, 17%), fatigue (14.5%), nonneutropenic infections (14%), anemia (12%) and pneumonitis (7%). Everolimus dose reductions were required in 31% patients. There were 30% partial responses, 38% prolonged disease stabilizations and 32% disease progression as best responses to everolimus. The median progression-free survival was 22 weeks (5 months). Everolimus based treatment has meaningful activity in heavily pretreated patients with HR-positive MBC but is associated with considerable toxicity and requirement for dose adjustment.

403P - Phase Ii Study Evaluating Oral Vinorelbine As a Single-Agent As First-Line Chemotherapy for Metastatic Breast Cancer Patients with Bone Metastases (Norbreast-228 Trial): First Efficacy Results

ABSTRACT Background: Oral chemotherapy (CT) is a widely recognized treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by hormone therapy (HT). In this phase II study, we evaluated the efficacy and safety of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. Methods: Main eligibility criteria included: age ≥18 years, documented bone disease previously untreated by CT, hormone receptor positive disease previously treated by at least one HT, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. All pts received a bisphosphonate during the study. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment Results: Between April 2010 and April 2012, 70 patients have been included. Main pts characteristics: median age: 60.6 years (34% ≥65 years); median Karnofsky PS 90%. Prior HT 100% (80% in adjuvant setting, 53% in advanced setting); prior (neo)adjuvant CT 63%; prior anthracyclines/taxanes 59/24%; prior palliative radiotherapy 41%. Bone involvement 100%; other metastatic sites: lymph nodes 14%, soft tissue 3%. Median duration of treatment 5.8 months (range 0.9-18.4), median number of cycles: 6 (range: 1-18); median relative dose intensity: 83.0%. Efficacy: with a median follow up of 26.1 months, median progression-free survival (primary endpoint) was 8.2 months (95% CI [5.5-10.3]). Clinical benefit was observed in 55.7% of pts. Median duration of clinical benefit was 11.1 months (95% CI [8.6-14.7]). Overall survival results are not mature yet, at cut off date 63% of pts being alive. Safety: grade 3/4 adverse events per pt: neutropenia 37%, anemia 4%, neutropenic infection 3%, diarrhoea 3%, nausea 3%, asthenia 1%, liver toxicity 1%, non-neutropenic infection 1%. Grade 2 alopecia was reported in 6% of pts. Conclusion: For this particular population of metastatic pts, with hormone receptor positive disease progressing to HT and bone involvement, OV is an active and safe first-line CT option. Disclosure: G.G. Steger: Honoraria and Travel Grants from Pierre Fabre Medicament; G.R. Villanova: Employee of Pierre Fabre Medicament. All other authors have declared no conflicts of interest.

First safety results of an international phase II study evaluating oral vinorelbine as a single agent as first-line chemotherapy for metastatic breast cancer patients with bone metastases (NorBreast-228 trial).

1048 Background: Oral chemotherapy (CT) is an attractive treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by a hormone therapy. In our phase II study, we evaluated the role of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. In this abstract, first safety results of this trial are presented. Methods: Main eligibility criteria included: age ≥18 years, documented bone involvement previously untreated by CT, hormone receptor positive disease previously treated by at least one hormone therapy, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment. Results: Main pts characteristics in the full population were (n=70): median age: 60.6 years (34% ≥65 years); median Karnofsky PS 90%. Prior hormone therapy 100% (53% in advanced setting); prior (neo)adjuvant CT 63%; prior anthracyclines/taxanes 59/24%; prior palliative radiotherapy 41%. Bone involvement 100%; other metastatic sites: lymph nodes 14%, soft tissue 3%. Median duration of treatment 5.5 months (range 0.9-18.3), median number of cycles: 6 (range: 1-18);61% of pts received at least 6 cycles, 37% of ptsreceived more than 6 cycles and 29% received at least 9 cycles; median relative dose intensity: 83.5%; dose escalation was performed in 79% ofpts.Grade 3/4 adverse events per pt: neutropenia 37%, anemia 4%, diarrhoea 3%, nausea 3%, asthenia 1%, liver toxicity 1%, neutropenic infection 1%, non-neutropenic infection 1%. Grade 2 alopecia was reported in 6% of pts. Conclusions: In this particular population of metastatic pts, with hormone receptor positive disease and bone involvement, OV showed an optimal safety profile. These data shows that OV is a well tolerated first-line CT option in this setting, allowing prolonged active treatment in non-progressing pts.

Accelerated BEP for metastatic germ cell tumours: a multicenter phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)

This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.

Incidence of Non-Neutropenic Infection (NNI) in Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma: The Effects of Rituximab Therapy

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with indolent and aggressive forms of non-Hodgkin’s lymphoma and has become part of the standard therapy for patients with B-cell malignancies. The study was designed to examine if rituximab increases the risk to develop non-neutropenic infection (NNI). Medical records of 202 patients diagnosed as follicular lymphoma or small lymphocytic lymphoma were reviewed. Negative binomial regression was used to estimate relative risk (RR) of NNI. Rituximab (n= 41) and non-rituximab (n= 161) groups had a total of 31.636 and 195.691 reviewed patient days, and recorded a total of 67 and 154 infections, respectively. Negative binomial regression analysis revealed significant effects for the treatment (rituximab vs. non-rituximab) and age (p< 0.01). The RRs of viral and bacterial NNI for rituximab group compared to nonrituximab group were 3.33 and 2.60, respectively; while the RRs for one year increment of age were 1.03 and 1.04, respectively. The time-to-first viral and bacterial NNI for rituximab group were significantly faster than non-rituximab group. Rituximab may increase the risk of NNI in patients with follicular lymphoma or small lymphocytic lymphoma.

Association Between Radiotherapy vs No Radiotherapy Based on Early Response to VAMP Chemotherapy and Survival Among Children With Favorable-Risk Hodgkin Lymphoma

More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects. To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy. Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012. The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy. Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low. Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed. Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival. clinicaltrials.gov Identifier: NCT00145600.

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis

AbstractIn this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis

There are limited data regarding the role of second-line treatment for metastatic pancreatic cancer (mPC) after the failure of initial chemotherapy. No data exist on the use of GTX after the failure of first-line therapy. We identified patients who were given GTX chemotherapy for a diagnosis of mPC after the failure of initial therapy. Demographic features, progression-free (PFS) and overall survival (OS), response to treatment, and toxicities were recorded. The 59 evaluable patients received a median of 2 prior therapies. Three had no prior gemcitabine. Median PS was 1. Median survival was 22weeks; progression-free survival was 9.9weeks. Survival did not correlate with the number of prior regimens but trended with PS. There were no radiologic responses; those with stable disease (n=21) had a better survival than those with progression (n=29) or unevaluable patients (n=9). Median survival was 38.3, 15.0, and 7.4weeks, respectively. Grade 3 and 4 toxicities included leucopenia (n=14), anemia (n=7), and thrombocytopenia (n=6). Hospitalizations were required in 21 patients, for febrile neutropenia (n=7), non-neutropenic infection (n=3), pulmonary embolus (n=2), anemia or failure to thrive (n=9). A 75% drop or more in CA 19-9 correlated with improved survival. GTX is an active regimen in patients previously treated with gemcitabine for mPC. Better performance status and >75% drop in pretreatment CA 19-9 were associated with longer survival. The number of prior regimens did not predict for survival duration.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) could be an effective adjuvant therapy for orthopedic implant-related infections (OIRI)

Bone infections associated with foreign bodies are very difficult to treat satisfactorily. The tissue damage and circulation destruction caused by surgery make the organism susceptible to infection. Meanwhile, the presence of foreign body lowers the threshold of bacterial infection and often generates local immunosuppression. In such cases, antibiotic therapies are usually not efficacious and removing the implant is the only solution for completely eradicating the problem. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been in clinical use for about two decades, most commonly adopted for treating of various types of neutropenia. Many studies have also demonstrated that rhG-CSF play important roles in nonneutropenic infections, angiogenic response and tissue repairing. In addition to increasing the number of neutrophils, rhG-CSF helps to enhance the neutrophil microbicidal functions. More importantly, orthopedic implant-related infections (OIRI) are especially good indications for the administration of rhG-CSF in therapeutic regimens. rhG-CSF may also play important roles in the process of postsurgery revascularization and tissue repairing, which would help a lot in treating infections and preventing implant failure. So far, there has been no report of such cases in this field. Therefore, a hypothesis is put forward in the paper that application of rhG-CSF may well be an effective adjuvant therapy for OIRI.