AB0001 INTERFERON SIGNATURE IN CHILDREN WITH CHRONIC NON-BACTERIAL OSTEOMYELITIS AND IT’S DYNAMIC AFTER BISPHOSPHONATES TREATMENT

Background:Chronic non-bacterial osteomyelitis (CNO) is an immune-mediated chronic inflammatory bone disease which predominantly affects children and adolescents. The pathogenesis of CNO related to imbalance between pro-inflammatory and anti-inflammatory cytokines. Interferon-I mediated pathway is associated with pathogenesis of different pediatric rheumatic diseases, such as juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), systemic onset of juvenile idiopathic arthritis (soJIA), and, most of all, with macrophage activation syndrome. The data on interferon-I- regulated pathway in CNO is absent. NSAIDs, non-biologic and biologic anti-inflammatory drugs and bisphosphonates (BF) are treatment options for patients with CNO. The main adverse event of BF is a flu-like syndrome probably caused by the excessive cytokine release stimulated by BF.Objectives:The aim of our study was to evaluate activity of Interferon-I mediated pathway in CNO patients and it’s dynamics after BF treatment.Methods:This prospective study included children with CNO requiring BF treatment (n=9), patients with soJIA (n=8), JDM (n=11) and jSLE (n=40) and healthy controls (HC, n=21). The activity of Interferon-I mediated pathway was assessed using interferon I score (IFN1 score). The score represented the median expression of 5 IFN1-regulated genes (IFI44L, IFI44, IFIT3, LY6E, MX1) measured by quantitative real-time PCR. Patients with CNO were treated with standard 3-day regimen (1 mg/kg/day). We measured interferon score before pamidronate (Day 0, n=9) and after (Day 3, n=7).Results:Median interferon score was 1.09 (0.96; 1.67) in CNO patients, 1.95 (1.3; 5.75) in soJIA, 7.6 (1.78; 29.0) in JDM and 16.9 (2.55; 40.3) in jSLE and 0.95 (0.82; 1.17) in HC (p=0.00001). Where were no difference in the IFN1 score between CNO and HC (p=0.222). In 6/7 CNO patients interferon score increased after pamidronate (p=0.015). The median interferon score after pamidronate increased and became 3.06 (0.87; 4,9, p=0.043); this may possibly explain the development of BF-related flu-like symptoms (cytokine release syndrome).Conclusion:While interferon I-regulated pathway is not directly associated with CNO pathogenesis, BF likely activates interferon-I-regulated pathway and thus could be a possible cause of flu-like syndrome.This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001).Disclosure of Interests:None declared

Clinical characteristics and outcomes of pregnant women with COVID-19 and the risk of vertical transmission: a systematic review

Purpose This systematic review summarizes the clinical features and maternal–infant outcomes of 230 pregnant women (154 patients gave birth) infected with COVID-19 and their 156 infants, including the possibility and evidence of vertical transmission. Methods An electronic search of PubMed, Embase, Medline, MedRxiv, CNKI, and the Chinese Medical Journal Full Text Database following PRISMA guidelines was performed through April 18, 2020. Search terms included COVID-19, SARS-CoV-2, pregnant women, infants, and vertical transmission. Results A total of 230 women with COVID-19 (154 deliveries, 66 ongoing pregnancies, and 10 abortions) and 156 newborns from 20 eligible studies were included in this systematic review. A total of 34.62% of the pregnant patients had obstetric complications, and 59.05% of patients displayed fever. Lymphopenia was observed in 40.71% of patients. A total of 5.19% of women received mechanical ventilation. Seven women were critically ill. One mother and two newborns died. A total of 24.74% of newborns were premature. Five newborns’ throat swab tests of SARS-CoV-2 were positive, all of which were delivered by cesarean section. For eight newborns with negative throat swab tests, three had both elevated IgM and IgG against SARS-CoV-2. Nucleic acid tests of vaginal secretions, breast milk, amniotic fluid, placental blood, and placental tissues were negative. Conclusion Most pregnant patients were mildly ill. The mortality of pregnant women with COVID-19 was lower than that of overall COVID-19 patients. Cesarean section was more common than vaginal delivery for pregnant women with COVID-19. Premature delivery was the main adverse event for newborns. The vertical transmission rate calculated by SARS-CoV-2 nucleic acid tests was 3.91%. Serum antibodies against SARS-CoV-2 should be tested more frequently, and multiple samples should be included in pathogenic testing.

A phase II Japanese trial of fludarabine, cyclophosphamide and rituximab for previously untreated chronic lymphocytic leukemia

Objective Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group. Methods The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year. Results Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0–96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G. Conclusion Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL. Clinical trial number JapicCTI-132285.

Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma

BackgroundTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, in combination with the programmed cell death-1 (PD-1) antagonist pembrolizumab.MethodsThe study was divided into two parts; parts A and B, where part A was the dose escalation part and part B was an extension part of the study. Patients with metastatic melanoma were treated with efti plus the standard dose of pembrolizumab. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect efti antibody formation and determine long-lived CD8 T cell responses and associated pharmacodynamic parameters.ResultsTwenty-four patients with melanoma received pembrolizumab and bi-weekly subcutaneous (s.c.) injections of efti at doses 1 mg, 6 mg or 30 mg/injection for up to 6 months (part A) or 30 mg/injection for up 12 months (part B). No dose-limiting toxicities were reported and the main adverse event for efti was injection site reactions. Sustained systemic exposure to the product was obtained in all patients following s.c. injections of 30 mg dose. Treatment induced an increase in activated CD8 and CD4 T cell counts, and in some of the soluble biomarkers, particularly interferon (IFN)-γ, a Th1 signature cytokine. An overall response rate (ORR) of 33% was observed in patients partly with pembrolizumab-refractory of part A and ORR of 50% was observed in patients with PD-1 naïve of part B.ConclusionsEfti was well tolerated in combination with pembrolizumab with encouraging antitumor activity. This warrants further clinical studies of this new combination therapy combining an antigen-presenting cell activator with an immune checkpoint inhibitor.

Phase I pilot study of RRx-001 + nivolumab in patients with traditionally non-checkpoint inhibitor-responsive cancers (PRIMETIME).

e15119 Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received > 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of > SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .

Phase II expansion cohort in colorectal cancer to evaluate the safety and tolerability of RRx-001 blood mix.

e16144 Background: In a 34 patient randomized Phase 2 trial in 3rd/4th line colorectal cancer called ROCKET (NCT02096354) of RRx-001 + irinotecan versus regorafenib + irinotecan, RRx-001 + irinotecan demonstrated improved overall survival (OS) (8.6 vs 4.7 months) and progression free survival 2 (PFS2) (7.5 vs. 1.7 months) compared to the regorafenib control arm. The main adverse event attributed to RRx-001 treatment, which involved once weekly peripheral or central infusion, was a painful infusion-related superficial phlebitis in 80% of patients. Following the randomized portion of the ROCKET trial, another 18 colorectal patients were enrolled in an expansion cohort to evaluate the safety and tolerability of an RRx-001 “blood mix”, the objective of which was mitigation of the phlebitic complications of direct RRx-001 infusion. Methods: Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly via blood mix until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle. Results: The median OS and PFS2 were 6.3 and 5.2 months, respectively, which was similar to that of RRx-001 administered by direct infusion in the randomized part of the trial. No patients experienced phlebitis. The adverse event profile was otherwise unchanged compared with direct IV infusion of RRx-001. Conclusions: The results of this expansion cohort demonstrate similar activity of RRx-001 given by blood mix followed by irinotecan to RRx-001 given by direct IV infusion followed by irinotecan.RRx-001 alleviated the pain that had been observed in the direct IV infusion and therefore allowed for a shorter infusion time without any apparent compromise in activity (based on OS/PFS2 comparability to earlier results). Finally, since phlebitis in theory may progress to deep venous thrombosis or suppurative thrombophlebitis in hypercoagulable and immunosuppressed cancer patients, blood mix RRx-001 is the preferred method of infusion. Clinical trial information: NCT02096354 .

Impact of Edoxaban on Thrombin-Dependent Platelet Aggregation

Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use. As the main adverse event is bleeding, it is relevant whether edoxaban has additional effects on platelet function. We aimed to assess in vitro aggregation in patients with atrial fibrillation (AF) receiving edoxaban. We evaluated 20 AF patients treated with edoxaban. We assessed light transmittance platelet aggregation (LTA) with 100 nmol/L γ-thrombin. The LTA was performed at 2 time-points. The thrombin-induced platelet aggregation was significantly lower 2 hours after edoxaban was taken compared to baseline measurement (27.25% ± 30.8% vs. 60.35% ± 33.3%). In addition, we also performed 16 subanalyses in order to identify the differences in the outcome of different comorbidities, age, dosage, liver and kidney function tests, and concomitant treatment. Results of the subgroup analyses were consistent with the findings of the main analysis; there was no apparent heterogeneity across the prespecified subgroups. The thrombin-induced platelet aggregation is reduced in non-valvular AF patients receiving edoxaban.

Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer.

5586 Background: Lurbinectedin (L) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and modulates the tumor microenvironment. Advanced endometrial cancer (EC) is an unmet medical need. Methods: Activity in EC patients was reviewed in 3 trials: a phase IB study of lurbinectedin combined with doxorubicin (L+DOX), a phase I study of PM combined with paclitaxel (L+TAX) and a phase II single-agent basket trial (L). Baseline characteristics, safety and efficacy were analyzed. Results: 97 patients were evaluated: 34 (2 cohorts) with L+DOX, 11 with L+TAX and 52 with L. Median age was similar in the 3 studies. Endometrioid was the most frequent histology. Median (range) of prior chemotherapy lines for advanced disease was: L+DOX, 1(0-2); L+TAX, 2(1-3); L, 1(0-2). Responses were observed in the 3 studies (see table). Main adverse event was myelosuppression (grade 3-4 neutropenia/thrombocytopenia/febrile neutropenia: L+DOX Cohort A, 94%/26%/40%; L+DOX Cohort B, 79%/10%/16%; L+TAX, 54%/0%/0%; L, 33%/6%/6%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea and vomiting, and transaminase increase. Conclusions: Lurbinectedin is active as single agent and in combination in patients with advanced EC, with remarkable activity in terms of response rate, duration of response and PFS when combined with doxorubicin. Safety was acceptable in L+DOX Cohort B, L+TAX and L, and myelosuppression was well managed. Clinical trial information: NCT01970540. [Table: see text]

Double akylating agents treatment with ifosfamide (IFOS) and cyclophosphamide (CYCLO) for relapsed pediatric solid tumors.

10057 Background: CYCLO and IFOS are two of the most active agents in childhood cancer. There is non-cross resistance between CYCLO and IFOS and they have dissimilar toxic side effects. In vitro, tumor model systems document that alkylator resistance may be overcome by several fold increases in drug concentration. We developed a strategy in attempt to limit side effects and increase anticancer activity of high doses oxazaphosphorines therapy: an association of IFOS plus CYCLO, giving an equivalent to 20g/m2 of IFOS or 5g/m2 of CYCLO. The schedule is the association of these two drugs: CYCLO 2,5g/m2 (corresponding to 10g/m2 of IFOS) plus IFOS 10g/m2. Methods: Eligibility included recurrent/refractory measurable disease, life expectancy > 6 weeks, adequate renal, hepatic and bone marrow function. CYCLO (2,5g/m2) and IFOS (10g/m2) with Mesna, with interval of 21 days. Responses were evaluated after 2 cycles.So far, 13 patients were enrolled: median age 17 years (5-26), 9M:4F,6 osteosarcoma, 1 hemangioperycitoma, 2 medulloblastoma, 1 nasopharyngeal carcinoma, 1 Wilms tumor,1 synoviosarcoma, 1 retinoblastoma. Six patients received IFOS previously (Total= 38 - 63 g/m²) and 5 CYCLO. Results: Thirty four cycles were evaluated. Toxicity was tolerable with no death. Main adverse event was neutropenia grade (GR) 4 in all cycles, median duration of seven days (3-15), GCS-F was used in all cycles; anemia GR 3 and 4 and thrombocytopenia GR 4 in 14 cycles; infection GR 3 and 4 in 15 cycles; hemorrhage cystitis GR 1 in 2 cycles and neurologic toxicity GR 2 in 6 cycles. No acute renal toxicity was observed. Responses were 2 complete response (CR), 5 partial responses (PR), 3 stable disease, and 3 progress disease. Conclusions: This schedule is feasible with high response rate (CR+PR=54%). Due to lack of new agents, innovative approaches for high risk patients can have a potential benefit. More patients are warranted.

Long-Term Use of Atazanavir in the Treament of HIV-Infected patients

Atazanavir (ATV) is an HIV protease inhibitor (PI) that was approved as antiretroviral agent in year 2003. Ritonavir (RTV) enhances ATV plasma exposure and increases its barrier to resistance. Antiretroviral therapy with ATV plus RTV (ATV/r) has demonstrated high potency for achieving virological suppression in antiretroviral-naive patients and in simplification strategies. In rescue interventions, ATV/r-based combinations have shown to be equivalent in terms of viral response to other PI/r-containing regimens. In contrast with all other PIs, ATV has also demonstrated efficacy when given unboosted with RTV, an option attractive in special situations. Other benefits of the drug are its good metabolic and gastrointestinal profile. Its main adverse event is hyperbilirubinemia, since ATV inhibits the hepatic uridin-glucoronyl-transferase. A signature mutation at the protease gene, I50L, confers loss of susceptibility to the drug whereas it may confer hypersusceptibility to other PIs. Many ATV studies have provided data until or beyond week 96, supporting the efficacy and safety of the drug in the long-term.