Multi-treated Patients Research Articles

Cytokine polymorphisms in patients with autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is due to autoantibodies with or without complement activation and involves cellular and cytokine dysregulation. Here, we investigated cytokine single-nucleotide polymorphisms (SNPs) of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ, along with their serum levels. The former were related to hematological parameters, therapy, and clinical outcome. The study included 123 consecutive patients with primary AIHA [77 warm AIHA and 46 cold agglutinin disease (CAD)], followed up for a median of 49 months. Results show that the allelic frequency of TNF-α -308 G/A polymorphisms was significantly lower in patients versus controls. Moreover, the genotypic frequency of TNF-α -308G/A and TGF-β gene codon 25 G/C genotypes was significantly lower in patients versus controls. Considering cytokine SNP genotypes associated with different gene expression levels, TNF-α high gene expression was significantly more frequent in patients, TGF-β and IL-10 high gene expression was higher in patients with more severe anemia, and TGF-β high gene expression was higher in patients with active disease. Considering treatment, TNF-α and TGF-β high gene expression was more frequent in multitreated patients and particularly in CAD. It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease. Regarding cytokine serum levels, TNF-α and TGF-β were significantly lower, and IL-10 and IL-6 were significantly higher in patients versus controls, underlying the complex interplay between genetic background and disease features.

Single Nucleotide Polymorphisms of Cytokine Genes in Warm Autoimmune Hemolytic Anemias: Relationship with Clinical and Hematological Parameters

Background: Autoimmune hemolytic anemia (AIHA) is due to an increased immune peripheral destruction of red blood cells. The disease is characterized by high heterogeneity regarding anemia severity, treatment requirement and occurrence of complications. It has been shown that Hb levels at baseline, presence of complement activation, and the degree of bone marrow compensation are the main predictors of outcome. Moreover, multi-relapsing cases show bone marrow dysmyelopoiesis, and fibrosis suggesting an immune attack against bone marrow precursors. An interesting area to investigate is the genetic landscape of AIHA, including cytokine gene signature and other molecular mechanisms of refractoriness.Aim: To evaluate the frequency of cytokine single nucleotide polymorphisms (SNPs) in warm AIHA and their correlation with clinical and hematological parameters, including the degree of anemia, treatment refractoriness and number of therapies lines.Methods: We investigated SNPs of five cytokine genes [tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, interleukin (IL)-6 and IL-10] in 72 Italian warm AIHA patients, using the Cytokine Tray (One Lambda, Canoga Park, CA) according to the manufacturer's recommendations. Allele and genotype frequency results were compared to those described in the Italian population by Uboldi de Capei et al. (2003) and Poli et al. (2002).Results: Seventy-two warm AIHA patients have been evaluated: median age 63 years (range 17-90), classified as per DAT positivity in IgG+ (N=48), IgG+C (N=17), IgA+ (N=1), and DAT negative AIHA (N=6). Demographic and hematological characteristics of patients are described in Figure 1A. Regarding cytokine SNP frequencies, we observed that AIHA patients had a significantly higher prevalence of the TNF-alpha-308 high producers genotypes (G/G and G/A) compared to controls (40.3% vs 16% or 23%, p=0.0003 and p=0.006, respectively). No differences were detected regarding genotype frequencies of the other cytokine SNPs (Figure 1B). By dividing patients according to anemia severity at onset, a more frequent low producer genotype of IFN-gamma (A/A) was observed in patients with Hb levels >7.4 g/dL (median value of patients cohort) compared to the other group (p=0.05). Finally, considering the number of relapses or therapy lines, an increased frequency of TNF-alpha -308 high producers genotypes were found among multi-relapsing (> 3 relapses, 70.5% vs 56%) and multi-treated patients (> 3therapy lines, 52% vs 35%), although not significantly.Conclusions: These preliminary data show that wAIHA patients display a more pro-inflammatory cytokine signature at molecular level as compared to the Italian control population. This is highlighted by an increased prevalence of TNF-alpha high producer genotype that is also associated with multiple relapses and greater treatment requirement. Additionally, cytokine SNPs may be also associated with anemia severity at onset, as observed for IFN-gamma low producer genotype that was more frequent in less severe cases. [Display omitted] DisclosuresFattizzo: Alexion, Amgen, Annexon, Apellis, Grifols, Novartis, Momenta: Consultancy, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees.

433P Durvalumab and tremelimumab in combination with FOLFOX in patients with previously untreated RAS-mutated metastatic colorectal cancer: First results of efficacy at one year for phase II MEDITREME trial

Single agent PD-1/PD-L1 inhibition is not effective in metastatic colorectal cancer (MCRC) with microsatellite stable tumors. Signal of efficacy was shown using anti-PD-L1 and anti CTLA-4 in multitreated patients. FOLFOX regimen could induced immunogenic cell death, leading to a potential positive effect on antitumor immune response.

The glaucoma intensive treatment study: interim results from an ongoing longitudinal randomized clinical trial.

The aim of the study was to determine the perimetric rate of glaucoma progression in the ongoing Glaucoma Intensive Treatment Study (GITS) after 3 years of follow-up. This is a randomized, two-centre, prospective open-labelled treatment trial for open-angle glaucoma (OAG). The participants of this study were treatment-naive patients with newly diagnosed OAG, aged 46-78 years, with early to moderate glaucomatous visual field loss scheduled to be followed for 5 years within the study. Patients were randomized to initial treatment with either topicalmonotherapy or with an intensive approach using drugs from three different classes, plus 360° laser trabeculoplasty. Changes in treatment were allowed. Standard automated perimetry and tonometry were performed and side-effects documented. All results are presented using intention-to-treat analysis. A total of 242 patients were randomized. After 3 years of follow-up, eight patients were lost to follow-up, six of whom were deceased. The median untreated baseline intraocular pressure (IOP) was 24 mmHg in both arms. The median IOP was almost constant over the 3 years of follow-up: ≈17 mmHg in the mono-arm and ≈14 mmHg in the multi-treatment arm. Treatment was intensified in 42% of the mono-treated patients and in 7% of the multi-treated patients. Treatment was reduced in 13% of the multi-treated patients. The median perimetric rate of progression was -0.5%/year in the mono-treated group and -0.1%/year in the multi-treated group (p = 0.03). The rate of disease progression was significantly slower in the multi-treated patients than in the mono-treated patients. Further follow-up will show whether this difference is sustained over time.

Utilization study in real clinical practice of ceftolozane/tazobactam vs aminoglycosides and/or colistin in the treatment of multirresistant or extremely resistant Pseudomonas aeruginosa

RESUMENIntroducciónSe necesitan datos comparativos en “vida real” sobre efectividad y seguridad de ceftolozano/tazobactam (C/T) frente otros regímenes (aminoglucósidos/colistina/combinación) en el tratamiento de Pseudomonas aeruginosa (PA) multirresistente (MDR) y extremadamente resistente (XDR) para establecer posicionamientos.Material y métodosEstudio observacional, retrospectivo de pacientes con confirmación microbiológica de PA MDR y XDR desde julio de 2016 a diciembre de 2018 en un hospital terciario. Variables: edad, sexo, comorbilidades, factores de riesgo de multirresistencia, variables relacionadas con infección, foco de infección, microorganismo y tipo de muestra, tratamiento antibiótico, curación clínica, curación microbiológica, recurrencia, mortalidad en ingreso y 30 días post-alta. Pacientes clasificados según tratamiento antibiótico recibido, C/T o aminoglucósidos/colistina/combinación.Resultados405 pacientes con infección por PA MDR y XDR (73,1% hombres, edad media 63 ± 15 años). 87,1% PA XDR y 12,9% MDR. Todos los pacientes recibieron C/T como tratamiento dirigido y en el grupo aminoglucósidos/colistina/ combinación fueron el 73,5%. El grupo C/T presenta factores de peor pronóstico: shock séptico (30,0%) y sondaje (90,0%) (p<0,05). Sin diferencias estadísticamente significativas en curación microbiológica (p=0,412), recurrencia (p=0,880) y curación clínica (p=0,566). Tampoco hubo diferencias estadísticamente significativas en la mortalidad en el ingreso (p=0,352) ni a los 30 días del alta (p=0,231). El 17,2% de los pacientes con aminoglucósidos/colistina/combinación presentaron lesión renal aguda según criterios RIFLE (4,3% con C/T).ConclusionesLos datos obtenidos plantean que no ha habido diferencias de efectividad (curación clínica ni microbiológica) a favor de C/T, si bien, en el periodo estudiado se utilizó en la mayoría de los casos en pacientes multitratados y con peor pronóstico. Se necesitarían estudios aleatorizados y pros-pectivos para establecer un posicionamiento adecuado.

P09.24 Real-World Data in Non-Small Cell Lung Cancer Treated with Checkpoint Inhibitors in a Latin American Institution

While randomized clinical trials (RCT) are the gold standard to determine the effectiveness of cancer therapy, their strict eligibility criteria do not match the conditions that we see in our clinical practice, especially for non-small cell lung cancer (NSCLC) patients. Real-world data (RWD) provides complementary information on use and clinical outcomes. Here we analyzed real-world outcomes of metastatic NSCLC patients treated with checkpoint inhibitors. Retrospective analysis of advanced NSCLC treated with PD-1/PD-L1 inhibitors in a private cancer center at Lima-Peru (Oncosalud-AUNA) from 2015 to 2019. Epidemiological, clinical and pathological data were collected from electronic medical records. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan-Meier method was used to estimate the survival curves, and the influence of different factors on progression-free survival (PFS) and overall-survival (OS) was determined by the log-rank test. The Cox model was used to calculate the hazard ratios. 82 patients were included. Median age at diagnosis was 65 years (range 38-92y); most patients were males (61%), never smokers (62.2%) and had a status performance of 1 (77.8%) or 2 (14.8%). Adenocarcinoma was the most common histological type (84.1%). PDL1 status was negative or unknown for 61% of patients; between 1 and 49% for 19.5%; and ≥50% for 19.5%. 8 patients were EGFR positive. Patients received a PD-1/PD-L1 inhibitors alone or in combination with chemotherapy in 68.3% and 31.7% of the cases, respectively; in either first (48.8%), second (35.4%) or third/later (15.9%) line of treatment. For the complete cohort, the objective response rate (ORR) was 36.6% an 19.5% of patients achieved stable disease. With a median follow-up time of 18.4 months, median PFS was 5 months and median OS was 10.7 months. Duration of response (DoR) was 17.3 months (95% CI 10.29 – 24.38). The type of response was significantly associated with PFS (p<0.01) and OS (p<0.01) (Fig 1). Age, sex, smoking status, histology, PDL1 expression, EGFR status, line of therapy and use in combination or not with chemotherapy, did not appear to impact OS. Status performance of 2-3 vs 0-1 doubled the chances of dying (HR 2.18; 95%CI [1.10-4.32], p=0.025). This analysis suggests that OS in real-world patients is similar to that reported in RCT. Likewise, the subset of responders obtains durable benefit. The lack of difference in OS according to the evaluated clinicopathologic characteristics suggests benefit of PD-1 inhibitors in a wide spectrum of multitreated patients with metastatic NSCLC. Results from this study confirm those obtained in RCT and demonstrate their applicability to a Latin American real-world setting.

Efficacy of certolizumab pegol in naïve versus multi-treated patients affected by psoriatic arthritis.

The efficacy and safety of certolizumab pegol over 52 weeks was compared in two groups of patients: Group 1 comprised patients naïve to biologic treatments; Group 2 comprised patients previously treated with one or more antitumor necrosis factor (TNF)-α and/or anti-interleukin (IL) agents. We reported results in 50 patients affected by both mild psoriasis (PsO) and psoriatic arthritis (PsA). Primary endpoint was a reduction from baseline at week 52 of Disease Activity Score (DAS44-ESR) in both groups of patients. Secondary endpoints were a reduction from baseline at week 52 of Psoriasis Area Severity Index (PASI), Visual Analog Scale for Pain (PAIN VAS), ESR, CRP, and Dermatology Life Quality Index (DLQI). We observed a statistically significant improvement of both cutaneous and rheumatic disease in all patients, with a consistent reduction of DAS44-ESR, PASI, and PAIN VAS from baseline to week 52. DAS44-ESR decreased from 3.9 at BL to 1.5 at W52 (Group 1), and from 3.8 to 1.7 at W52 (Group 2). Mean PASI Score decreased from 3.2 at baseline (BL) to 0.4 at W52 (Group 1), and from 5.4 to 0.7 at W52 (Group 2). Mean PAIN-VAS decreased from a value of 73.5 at BL to 2.5 at W52 (Group 1), and from a value of 62.4 at BL to 9.2 at W52 (Group 2). We also found a reduction in ESR, CRP and DLQI values for each time point. Our results confirm that CZP can be administered safely and effectively to treat both psoriasis and psoriatic arthritis irrespective of previous treatments with biologic agents.

Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated, microsatellite-stable, previously untreated metastatic colorectal cancer (MCRC): Results of the first intermediate analysis of the phase Ib/II MEDETREME trial.

3006 Background: Single agent PD-1/L1 inhibition are not effective in metastatic colorectal cancer (MCRC) with microsatellite stable tumors. However, signal of efficacy was shown using combo therapy of anti-PD-L1 and anti CTLA-4 in multitreated patients. FOLFOX regimen could induced immunogenic cell death and elimination of myeloid derived suppressor cells (MDSCs) thus leading to a potential positive effect on antitumor immune response. Methods: This is a single arm exploratory investigator-initiated trial planned to include 57 pts to receive mFOLFOX6 (6cycles) in combination with durvalumab (150mg/q2W) and tremelimumab (75mg/q4W). After 6 cycles of chemotherapy, patients are treated with durvalumab untils progression. Primary endpoint is 6 months’ progression-free survival rate. Secondary endpoints are response rate, tolerability and translational research evaluating tissue and blood immune parameter. Upon Simon’s design an efficacy intermediate analysis was planned after the 16th patient has passed 6 months. Results: As of 1st of January 2020 the 55/57 pts were enrolled and treated with the MEDETREME regimen at 8 French sites. The intermediate efficacy analysis was conducted on the 1st of January after a median of 13.4 months of treatment. The following adverse events were noted: asthenia (81.25%), neuropathy (87.5%), diarrhea (56.25%) and neutropenia (62.5%). Notable grade 3/4 (CTC AE 4.03) include asthenia (18.75%) diarrhea (12.5%) neutropenia (50%) and elevated blood pressure (25%). Most of adverse events were related to chemotherapy. It has been noted one cytolysis grade 3, one thyroid dysfunction grade 3 and one hypophysitis grade 3 related to immunotherapy. Median PFS was not reached. Progression free survival at 6 months was observed in 10/16 pts (62,5%) given 5 CR, 5 PR and 4 SD. Updated translational data will be presented at the meeting. Conclusions: The interim safety analysis has supported safety and efficacy of the MEDITREME regimen in first- line MCRC. Finally, results will be presented after maturation of follow up. Clinical trial information: NCT03202758 .

Half-dose olaparib reduction: Safe and efficient dose in multi-treated Mexican ovarian cancer patients.

e17101 Background: Ovarian cancer (OC) is the most common gynecological cancer worldwide, and in Mexico stands as the 2nd gynecological cancer-related death cause with 4,759 new cases yearly. PARP inhibitors in BRCA1/2 mutated patients offer disease control after response to chemotherapy with few side effects and minimal impact on quality of life. The primary objective of this study was to evaluate the clinical benefit of Olaparib half-dose reduction in multi-treated Mexican OC patients. Methods: Nineteen OC BRCA1/2 positive patients were enrolled (Nov 2016-Dec 2018), at the Instituto Nacional de Cancerología, Mexico. Eligible patients had received &gt; 2 previous platinum-based lines. Olaparib dose was 800 mg/day, as maintenance therapy after complete or partial response. Half-dose administration was allowed in grade 3 toxicity events. Median PFS curves were estimated by the Kaplan–Meier method. Results: The most common mutation in OC patients was BRCA1 (78.9%), four patients had founder mutation (Del9-12). Eleven patients (57.9%) received Olaparib in ≥4 lines. Nine patients required dose adjustment following hematological (42.1%) and gastrointestinal toxicity (5.2%). There was not statistical differences between complete-dose and half-dose administration groups. However patients with founder BRCA1 mutation did not require dose adjustment ( P= 0.033) and multi-treated (≥4 lines) patients were more susceptible to develop hematological toxicity ( P= 0.030). The median PFS was 12.02 months, patients HGSP histology had a better PFS compared with endometroid histology (14.8 Vs 5.19; P= 0.020). BRCA1 founder mutated patients had a better PFS compared with other BRCA mutations (NR Vs 11.30; P= 0.050). The median PFS in first, second and third or more recurrence was NR Vs 14.8 Vs 8.3; P= 0.050. We did not find statistical difference in the PFS in half-dose reduction compared with complete-dose groups (9.6 Vs NR; P= 0.221). Conclusions: We provide evidence that using Olaparib in first and second recurrence had better outcome compared with third or more recurrence. However the recommended dose exhibits a high toxicity profile; therefore half-dose reduction in multi-treated patients needs to be suggested in Olaparib OC guidelines as a safety and effective strategy.

Clinical benefit of bevacizumab in Mexican ovarian cancer patients according to the intention of treatment by the oncologist.

e17097 Background: Ovarian cancer (OC) is the first cause of gynecological cancer, and the fifth cause of women cancer-death in US. In Mexico, more than 4,500 new cases of ovarian cancer are diagnosed yearly and it represents the second cause of gynecological cancer mortality. Bevacizumab (BVZ) is an antiangiogenic antibody that has been approved for first-line and recurrence therapy in OC patients. The aim of the study was to evaluate the clinical benefit of BVZ in different lines of treatment in Mexican OC patients. Methods: A total of 94 OC patients treated with BVZ were recruited at the Ovarian Cancer Program of the Instituto Nacional de Cancerología, from February 2012 to September 2018. Clinicopathological characteristics and toxicity was correlated with line of treatment. PFS curves were estimated by the Kaplan–Meier method, while comparisons among groups were analyzed with log-rank or Breslow tests. Results: Most of the patients were stage IIIC (69.1%) with HGSP histology (73.4%). 24 patients (25.5%) received BVZ as first-line treatment before debulking surgery (50% for suboptimal and 45.8% for optimal cytoreduction). 48 patients (51.1%) received BVZ for second-line (72.9% after a platinum-resistant and 27.1% after a platinum-sensitive recurrence) and 22 patients (23.4%) for three or more lines of treatment. Venous thromboembolic events (VTE) were more frequent in multi-treated patients ( P= 0.030). The median PFS was 23.7, 11.7 and 5.8 months for first, second and third or more lines, respectively. Patients with optimal debulking surgery had a better PFS compared with suboptimal and BVZ in first-line patients (24.8 vs 20.9; P= 0.050). Patients with BVZ in second-line who are a platinum-sensitive recurrence had better PFS compared to those with a platinum-resistant disease (15.1 vs 7.6; P= 0.040). Conclusions: OC patients had clinical benefit from treatment with BVZ when used as first-line and first recurrence treatments. The use of BVZ for third or later line treatment has a questionable benefit and is associated with a higher rate of VTE. Also, we highlight that 77% of the patients had the greatest-benefit while 33% had limited-benefit.

SAT-435 Optimization of Pharmacological Treatment of Acromegaly: Impact on IGF-1 Levels Comparing Isolated Octreotide LAR and Combined Pharmacological Therapy

Background:Transphenoidal surgery remains the best treatment for acromegaly, although the disease is unlikely to be controlled with surgery in approximately half of macroadenomas. Unfortunately, invasive macroadenomas represents over than 65% of GH-secreting adenomas (1-4). Somatostatin analogues (SSAs) are widely recognized as the first choice of primary and postsurgical pharmacological therapy in patients with acromegaly. However, more than one third of the patients fail to control insulin-like growth factor I (IGF-I) and growth hormone (GH) levels. Previous studies have shown benefits arising from the combination of SSAs, cabergoline and even estrogen therapy in mild activity of disease. Objectives:The aim of this study was to compare the efficacy in decrease and normalization of IGF-I values, of Octreotide LAR treatment isolated compared to associated with cabergoline and or cabergoline and estrogen in patients that have not undergone any other pharmacological treatment. Patients and Methods: Case series studythat enrolled 54 patients, divided in two groups, receiving OCT-LAR initially administrated a dose of 20 mg/month (IM), adjusted individually, after 3 months, with the goal of achieving normal age-matched IGF-I values, reaching the maximum dose of 30 mg/month. The second group received OC-LAR 30 mg/month associated with CBG 2 mg per week.The third group received in combination estrogen therapy Results and Discussion:The baseline mean serum IGF-I was significantly higher than after 6 months of treatment with OCT-LAR (p=0,020) and OCT-LAR+CBG (p=0,004) but no significant difference was shown for the comparison of IGF-I after 6 and 12 months in OC-LAR group (p=0,960) or OC-LAR+CBG group (p=0,929). After de adjustment of IGF-1 levels for age, the data showed a significant reduction in ULNV% comparing the basal and 6 months values in OCT-LAR (p=0,013) and OCT-LAR+CBG (p=0,004). In group OCT-LAR, the best reduction of IGF-1 was obtained after 12 months of treatment. In the group OCT-LAR-CBG, the best control was achieved at six months and was not statistically different from 12 months (p=0,047). In multitreated patients, estrogen therapy benefited IGF-1 reduction. Conclusion: The percentage of patients that reached normalization of serum IGF-I was significantly higher in the OC-LAR + CBG group at 6 months. There was no statistically significant difference at 12 months post treatment .

Abstract P1-18-05: Management of bone marrow involvement in advanced breast cancer: Retrospective multicenter cohort study

Abstract Background: Optimal management of bone marrow metastasis (BMM) in advanced breast cancer (ABC) remains unknown. Associated severe cytopenias often urge treatment, but they are also a challenging factor for delivering chemotherapy (CT). Since BMM in ABC is infrequent, available data are scarce. Aim: Clinical and prognostic characterization of ABC patients with BMM and its management; evaluation of the effectiveness of treating BMM with more myelosuppressive CT regimen (that we hypothesized that could be more active in the BMM) Vs. less myelosuppressive regimen. Methods: Retrospective cohort study of patients with pathological confirmation of BMM (positive myelogram or osteomedullary biopsy) between Jan'2010 and Dec'2016 in the two major Portuguese cancer centers. Patients with diagnosis of a second carcinoma or active hemato-oncological condition within 5 years before BMM were excluded. We considered the more myelosuppressive regimens those with &amp;gt; 5% risk of febrile neutropenia according to Truong et al 2015(1). Kaplan-Meier and log-rank methodology were used to estimate survival and Cox regression to identify the covariates with independent prognostic value. Statistical level of significance was 5%. Results: We included 74 patients: 74% with disease stage I-III at presentation, 74% ductal and 12% lobular invasive carcinomas, 58% grade 2 and 27% grade 3, 80% hormone receptor + / HER2-, 4% HER2+ and 12% triple negative (TN). Median time from ABC diagnosis to BMM was 10 months (IQR 2-36), synchronous in 34%. At diagnosis of BMM, median age was 57 years-old (IQR 47-65), 57% were post-menopausal, 97% had bone metastasis, 50% had visceral metastasis, 53% performed ≥ 2 previous palliative systemic treatments and 53% were exposed to bisphosphonates. The most frequent immunohistochemistry change in BMM biopsy was the loss of progesterone receptor expression (37%). Bicytopenia (anemia/thrombocytopenia) was the trigger for BMM investigation in 69% of cases, with grade 3-4 anemia in 16% and grade 3-4 thrombocytopenia in 26%. Median survival after BMM diagnosis was 5 months (95% CI, 3-11); overall survival at 12 and 24 months were 35% (CI 26-48%) and 24% (CI 15-36%), respectively. First treatment after BMM was CT in 58% (median survival, 11 months) and endocrine therapy in 14% (median survival, 3 months). An anti-HER2 regimen was used in 4% and 22% did not receive any treatment after BMM. On multivariate analysis, TN subtype (HR 4.02, CI 1.46-11.01), thrombocytopenia (G0 reference; G1-2: HR 2.47, CI 1.11-5.56; G3-4: HR 4.89, CI 1.85-12.91) and ≥ 2 palliative systemic treatments (HR 2.77, CI 1.46-5.27) were associated with worse prognosis. Within those treated with CT, there was a trend for a deleterious survival effect of more myelosuppressive regimens (HR 2.19, CI 0.94-5.09; 5 months Vs. 14 months, n=31), after controlling for subtype, number of previous regimens and thrombocytopenia. Conclusion: BMM was not a late event in ABC disease course and had worse prognosis in multi-treated patients, in TN subtype and in the presence of thrombocytopenia. No benefit was shown with the use of more myelosuppressive CT regimens. (1)Truong J et al, Ann Oncol. 2016 Apr;27(4):608-18. Citation Format: Martins-Branco D, Ferreira SC, Pereira I, André S, Varelas A, Leal C, Esteves S, Abreu MH, Sousa S, Moreira A, Brito M. Management of bone marrow involvement in advanced breast cancer: Retrospective multicenter cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-05.

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

P3.02c-092 Nivolumab in Multi-Treated Patients with Advanced Sq-NSCLC: Data from the Italian Cohort of Expanded Access Programme (EAP): Topic: IT Clinical

The prognosis of patients with advanced Sq-NSCLC worsens with the increase of the number of treatment linesand no effective therapeutic options were available for those refractory patients so far.Nivolumab demonstrated significant benefits against the SoC docetaxel in 2nd line treatment of advanced sq-NSCLC. In the real life experience of the EAP we could assess the clinical activity and tolerability of nivolumab not only in patients treated in 2nd line but also in patients who had received at least 2 lines of therapy prior than nivolumab. Nivolumab was provided upon physician request for patients aged ≥18 years who had relapsed after a minimum of 1 prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (version 4.03). 210 patients, corresponding to 56.4% of the entire Italian cohort (n=372), received nivolumab after at least 2 prior lines of chemotherapy in the EAP: 120 (57.1%), 69 (32.9%) and 21 (10%) had received 2, 3 and > 3 prior lines of therapy, respectively. Response was evaluable in 204 patients: with a median number of 8 doses (range, 1–24) and a median follow-up of 5.1 months, the disease control rate was 47%, with 3 patients (1%) in complete response, 30 patients (14%) in partial response and 66 patients (32%) in stable disease. 36 patients (17%) were treated beyond RECIST-defined progression, with 11 of them achieving disease control. As of April 2016, median progression-free survival and median overall survival were respectively 3.8 and 11.2 months. 117/210 patients (55.7%) discontinued treatment for any reason except toxicity; 11 out of 210 (5.2%) discontinued due to AEs. These findings showed that nivolumab provided clinical activity with a manageable safety profile in patients with advanced, refractory Sq-NSCLC. These data suggest that nivolumab can be a treatment option for patients failing more than one line of chemotherapy.

An Efficient Microarray-Based Genotyping Platform for the Identification of Drug-Resistance Mutations in Majority and Minority Subpopulations of HIV-1 Quasispecies.

The response of human immunodeficiency virus type 1 (HIV-1) quasispecies to antiretroviral therapy is influenced by the ensemble of mutants that composes the evolving population. Low-abundance subpopulations within HIV-1 quasispecies may determine the viral response to the administered drug combinations. However, routine sequencing assays available to clinical laboratories do not recognize HIV-1 minority variants representing less than 25% of the population. Although several alternative and more sensitive genotyping techniques have been developed, including next-generation sequencing (NGS) methods, they are usually very time consuming, expensive and require highly trained personnel, thus becoming unrealistic approaches in daily clinical practice. Here we describe the development and testing of a HIV-1 genotyping DNA microarray that detects and quantifies, in majority and minority viral subpopulations, relevant mutations and amino acid insertions in 42 codons of the pol gene associated with drug- and multidrug-resistance to protease (PR) and reverse transcriptase (RT) inhibitors. A customized bioinformatics protocol has been implemented to analyze the microarray hybridization data by including a new normalization procedure and a stepwise filtering algorithm, which resulted in the highly accurate (96.33%) detection of positive/negative signals. This microarray has been tested with 57 subtype B HIV-1 clinical samples extracted from multi-treated patients, showing an overall identification of 95.53% and 89.24% of the queried PR and RT codons, respectively, and enough sensitivity to detect minority subpopulations representing as low as 5–10% of the total quasispecies. The developed genotyping platform represents an efficient diagnostic and prognostic tool useful to personalize antiviral treatments in clinical practice.

The Result of Multiple I-131 Treatments on the Effective Half-Life of Retained Radioactivity in Patients Ablated for Differentiated Thyroid Cancer: Possible Evidence for Thyroid Remnant Function Impairment.

The ablation of differentiated thyroid cancer by ingested I-131 depends on the activity absorbed by the remnant. This depends on the function of the thyroid cells and on the rate that radioactivity is excreted from the blood. The reduction of radioiodine is described by the effective half-life (EHL), which is the time taken to half the retained radioactivity. If the tumor recurs, more treatments are prescribed, often with escalating activities. Patients may receive several treatments during the evolution of the disease, and the total radioactivity administered (TRA) is the sum of all such activities. The patients' archived information permitted the calculation of EHL and TRA. The patient cohort processed here comprised 274 females and 101 males treated during 1997 to 2015. The TRA to the patients ranged between 1.1 and 129.5 GBq (average = 7.93 ± 9.9 GBq) and the EHL varied between 5.06 and 43.87 hours (average = 14.13 ± 5.7 hours). The data were processed as follows: (a) the EHL corresponding to the last treatment of each patient was plotted against TRA to patients who were treated once and to those treated several times for comparison and (b) using a small subgroup of 16 patients who were treated at least 5 times, the EHL and TRA corresponding to each treatment of each patient were plotted. A function of the form y = p-k·ln(x) was fitted on the data in all graphs and k was calculated. For patients treated once, EHL was independent of TRA. A decrease was seen in (a) multitreated patients, with the gradient (k) ranging between -0.541 and -13.880 and (b) 13 out of 16 patients, with the gradient (k) ranging between -5.55 and -31.17, both indicating an impairment of the remnant function, perhaps identified as "stunning." Since this is not avoidable, the uptake may be boosted by splitting the prescribed activity into low radioactivity fractions, which will also reduce patient hospitalization.

C.381 - Red marrow dosimetry in differentiated thyroid cancer (DTC): Comparison between previsional and post therapy dose for multitreated patients and follow-up

C.381 - Red marrow dosimetry in differentiated thyroid cancer (DTC): Comparison between previsional and post therapy dose for multitreated patients and follow-up

Perfil de resistencias y barrera genética de dolutegravir

The resistance profile of dolutegravir differs significantly from those of earlier integrase inhibitors (INI). Dolutegravir displays in vitro activity against mutant HIV-1 harboring any isolated resistance mutations selected during failures to raltegravir or elvitegravir (Y143C/H/, N155H, Q148H/K/R, E92G/Q, T66A/I/K, T97A, E138A/K, G140A/S). Its activity is only compromised by Q148X mutations combined with other mutations, particularly > 1 mutation. The drug has pharmacokinetic/pharmacodynamic properties (plasmatic t1/2 15.3 h, inhibitory quotient 19, dissociative t1/2 from the IN-DNA complex 71 h) that favor a high genetic barrier to resistance. In vitro the selection of HIV-1 resistance to dolutegravir is extremely difficult to achieve. The mutations eventually selected (R263K, H51Y and E138K) do not confer significant resistance, and induce a fitness cost that prevents HIV-1 from evading drug pressure. Suprisingly, HIV-1 is not able to compensate, leading the virus to a previously unnoticed evolutionary pathway with very low chances of developing resistance to INI or the backbone. No treatment-naïve patients starting dolutegravir therapy (+TDF/FTC o ABC/3TC) have selected resistance in IN or against the backbone. No INI- naïve patients with prior virologic failure selected phenotypic dolutegravir resistance. Only 4 out of 354 patients selected resistance mutations in IN, and rates of selection of mutations in IN or against the backbone were significantly lower than with raltegravir. In multitreated patients with widespread resistance including IN resistance, the high efficacy of dolutegravir was confirmed, irrespective of the previous pattern of IN mutations, provided that Q148X associated with other mutations was absent.

CP-014 Trabectedin plus pegylated liposomial doxorubicin in relapsed ovarian cancer: outcomes in award-treated patients and Platinum Free Interval

BackgroundOvarian cancer is the next most lethal gynaecological malignancy after cervical cancer, with about 125,000 deaths each year worldwide. Treatment options are still limited and even though 80% of women...

Mutations in the protease gene associated with virological failure to lopinavir/ritonavir-containing regimens

To assess the most frequent resistance-associated mutations (RAMs) to lopinavir/ritonavir in a cohort of patients attended in daily practice. We retrospectively identified 195 multitreated subjects with virological failure. Patients were classified as follows: (i) 71 (36.4%) never received lopinavir/ritonavir (lopinavir/ritonavir naive); (ii) 75 (38.5%) had previously failed on lopinavir/ritonavir; and (iii) 49 (25.1%) were on lopinavir/ritonavir at failure. RAM patterns were assessed. Medians, IQRs, percentages, Kruskal-Wallis, χ(2) or Fisher's exact test, and multinomial logistic regression were used whenever appropriate. L10I/F, K20R, L24I, L33F, M36I, M46I/L, I47V, G48V, F53L, I54V, A71V, G73S, V82A, I84V and L90M (all with P ≤ 0.037) were protease RAMs overexpressed in patients with lopinavir/ritonavir failure. L10I, M36I, M46I, I54V, L63P, A71V, V82A, I84V and L90M were the most common in lopinavir/ritonavir-naive patients. Other IAS-USA RAMs for lopinavir/ritonavir (L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, A71T, L76V and V82F/T/S) were not associated with previous or current failure to lopinavir/ritonavir. Lopinavir/ritonavir failure was associated with the number of protease RAMs (OR = 1.146, 95% CI = 1.287, 1.626), higher exposure to protease inhibitors, and the presence of E44D, L33F, I54V and I84V. In multitreated patients with previous or current lopinavir/ritonavir failure, some protease mutations are selected at significantly greater rates. L10I, M36I, I54V, L63P, A71V, V82A and L90M were found in >50% of cases. Thus, their presence should be expected when genotypic testing results are not available. The number of protease RAMs and higher prior exposures to protease inhibitors were significantly associated with lopinavir/ritonavir failure.