Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study

Background: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. Results: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0–46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. Conclusions: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran

Disease Burden in Patients with Acute Hepatic Porphyria: Experience from the Phase 3 ENVISION Study

BACKGROUND: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. RESULTS: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0-46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. CONCLUSIONS: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran

Prognostic Role of a Multimarker Analysis of Circulating Tumor Cells in Advanced Gastric and Gastroesophageal Adenocarcinomas

Objective: We aimed to assess the prognostic value of circulating tumor cells (CTC) in patients with advanced gastric and gastroesophageal adenocarcinomas. Methods: The presence of CTC was evaluated in 62 patients with advanced gastric and gastroesophageal adenocarcinomas before systemic therapy and at follow-up through immunomagnetic enrichment for mucin 1- and epithelial cell adhesion molecule (EpCAM)-positive cells, followed by real-time RT-PCR of the tumor-associated genes KRT19 , MUC1 , EPCAM , CEACAM5 and BIRC5 . Results: The patients were stratified into groups according to CTC detection (CTC negative: with all marker genes negative; CTC positive: with at least 1 of the marker genes positive). Patients who were CTC positive at baseline had a significantly shorter median progression-free survival (PFS; 3.5 months, 95% CI: 2.9–4.2) and overall survival (OS; 5.8 months, 95% CI: 4.5–7.0) than patients lacking CTC (PFS 10.7 months, 95% CI: 6.9–14.4, p < 0.001; OS 13.3 months, 95% CI: 8.0–18.6, p = 0.003). Alterations in the marker profile during the course of chemotherapy were not predictive of clinical outcome or response to therapy. Yet, a favorable clinical response depended significantly on CTC negativity (p = 0.03). Conclusion: Our data suggest that the presence of CTC is a major predictor of outcome in patients with gastric and gastroesophageal malignancies

Multimarker Gene Analysis of Circulating Tumor Cells in Pancreatic Cancer Patients: A Feasibility Study

Objective: The aim of this study was to develop an immunomagnetic/real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay and assess its clinical value for the molecular detection of circulating tumor cells (CTCs) in peripheral blood of pancreatic cancer patients. Methods: The presence of CTCs was evaluated in 34 pancreatic cancer patients before systemic therapy and in 40 healthy controls, through immunomagnetic enrichment, using the antibodies BM7 and VU1D9 [targeting mucin 1 and epithelial cell adhesion molecule (EpCAM), respectively], followed by real-time RT-PCR analysis of the genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5. Results: The developed assay showed high specificity, as none of the healthy controls were found to be positive for the multimarker gene panel. CTCs were detected in 47.1% of the pancreatic cancer patients before the beginning of systemic treatment. Shorter median progression-free survival (PFS) was observed for patients who had at least one detectable tumor-associated transcript, compared with patients who were CTC negative. Median PFS time was 66.0 days [95% confidence interval (CI) 44.8–87.2] for patients with baseline CTC positivity and 138.0 days (95% CI 124.1–151.9) for CTC-negative patients (p = 0.01, log-rank test). Conclusion: Our results suggest that in addition to the current prognostic methods, CTC analysis represents a potential complementary tool for prediction of outcome in pancreatic cancer patients.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Prognostic and predictive value of circulating tumor cell analysis in colorectal cancer patients

Abstract Objective The aim of this study was to assess the prognostic and predictive values of circulating tumor cell (CTC) analysis in colorectal cancer patients. Patients and methods Presence of CTCs was evaluated in 60 colorectal cancer patients before systemic therapy - from which 33 patients were also evaluable for CTC analysis during the first 3 months of treatment - through immunomagnetic enrichment, using the antibodies BM7 and VU1D9 (targeting mucin 1 and EpCAM, respectively), followed by real-time RT-PCR analysis of the tumor-associated genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5. Results Patients were stratified into groups according to CTC detection (CTC negative, when all marker genes were negative; and CTC positive when at least one of the marker genes was positive). Patients with CTC positivity at baseline had a significant shorter median progression-free survival (median PFS 181.0 days; 95% CI 146.9-215.1) compared with patients with no CTCs (median PFS 329.0 days; 95% CI 299.6-358.4; Log-rank P Conclusion The present study provides evidence of a strong correlation between CTC detection and radiographic disease progression in patients receiving chemotherapy for colorectal cancer. Our results suggest that in addition to the current prognostic factors, CTC analysis represent a potential complementary tool for prediction of colorectal cancer patients’ outcome. Moreover, the present test allows for molecular characterization of CTCs, which may be of relevance to the creation of personalized therapies.</p

Disease Burden in Patients With Acute Hepatic Porphyria: Experience From the Phase 3 ENVISION Study

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases caused by defects in hepatic heme biosynthesis. Intravenous (IV) hemin is the standard of care for acute attacks and is at times used off label prophylactically, but can have acute (e.g. phlebitis) and chronic (e.g. iron overload) complications. The phase 3 ENVISION study (NCT03338816) showed givosiran reduced annualized attack rate (AAR) by 73% versus placebo in the double-blind (DB) period. Open-label extension data showed 85% of patients continuing givosiran were attack free at &gt;15–18 months. Here we summarize data from ENVISION to assess the spectrum of disease burden associated with AHP. Methods: Patients (N=94) enrolled in ENVISION had experienced ≥2 attacks requiring hospitalization, urgent care, or IV hemin at home in the 6 months before the study. This analysis assessed AAR, daily worst pain (eDiary), comorbidity, concomitant medication, and quality of life (12-Item Short Form Health Survey [SF-12]). Results: Patients had severe disease burden at study entry, consistent with AHP burden shown in natural history studies. Patients reported a median of 4 (range, 0–46) attacks during the previous 6 months, despite 40% being on prophylactic hemin. Of all patients, 34% did not have attacks requiring hospitalization. Chronic symptoms, including pain, were experienced by 52% of patients daily or on most days between attacks. Baseline median SF-12 bodily pain score was 40 (scale 0–100), suggesting interference with normal functioning. Overall, 29% of patients used opioids daily or on most days between attacks. Most patients had comorbidities at baseline (47% had psychiatric disorders) (Table 1) and were taking concomitant medications. The median (Q1–Q3) ferritin level was 209 (48–719) µg/L (normal: female, 13–150 µg/L; male, 30–400 µg/L). A moderate linear correlation between longer time since AHP diagnosis and higher AAR with placebo during the 6-month DB period (r=0.403) suggests patients may experience worsening disease and complications over time. Givosiran provided clinical benefit, including reduction of daily worst pain and analgesics use. Conclusion: AHP disease burden, including the number of attacks, comorbidities, and concomitant medication use, has negative impacts on daily functioning. Earlier initiation of treatments, such as givosiran, that prevent attacks and reduce chronic manifestations of AHP may lead to improved prognosis for patients

Additional file 1 of Detect Acute Porphyrias in Emergency Departments (DePorED) – a pilot study

Supplementary Material