Marcel Reiser

MET amplification status in therapy-naïve adeno- and squamous cell carcinomas of the lung

Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-naïve non–small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907–15. ©2014 AACR.

Treatment of patients with multifocal motor neuropathy with immunoglobulins in clinical practice: the SIGNS registry.

Objectives: The management of patients with multifocal motor neuropathy (MMN) under everyday clinical conditions has been insufficiently studied. We therefore collected comprehensive observational data on patients with MMN who received intravenous (IV) or subcutaneous (SC) immunoglobulins (IGs) as maintenance therapy. Methods: This was a prospective, noninterventional study (registry) in neurological centres (hospitals and offices) throughout Germany. Results: As of 1 December 2015, 80 patients with MMN were included (mean age 55.4 ± 9.8 years, 67% males, mean disease duration 10.7 ± 10.2 years). The affected limb regions were predominantly distal muscle groups of the upper extremities. On the inflammatory neuropathy cause and treatment (INCAT) scale, 94% of the patients had some disability in the arms and 61% in the legs. At inclusion, 98.8% received IVIG and 1.3% SCIG. Substantial variation was observed between IVIG treatment intervals (every 0.7 to 17.3 weeks) and dosage (0.2–2.1 g/kg body weight received during a single administration; mean monthly dosage, 0.9 g/kg body weight). However, the mean monthly dosage was steady over time. At 1-year follow up, improvement was seen in muscle strength, INCAT and quality of life (QoL) scores (SF-36 questionnaire). Conclusions: The management of patients with MMN in everyday clinical practice demonstrates a wide range of absolute dosages and treatment intervals of IG, supporting the recommended practice of determining treatment dose on an individual patient basis. The improvements in muscle strength and reduction in disability, accompanied by increased QoL, strengthen the case for use of IG as a maintenance treatment for MMN.

Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia.

Abstract The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17 979 per QALY (€15 773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone.

[Assessment of immunoglobulins in a long-term non-interventional study (SIGNS Study). Rationale, design, and methods].

Non-modified human immunoglobulins (IgG) are standard of care for replacement therapy with primary (inherited) immunodeficiencies, and secondary immunodeficiencies due to multiple myeloma (MM) or chronic lymphocytic leukemia (CLL). Further, they have effectively been used as immunomodulation in neurological autoimmune diseases such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). A variety of IgG preparations for intravenous and subcutaneous use are available. In view of the broad range of indications, data on the utilization of the IgG preparations in everyday clinical care are of high clinical interest. Furthermore, data on the outcomes of IgG therapy outside the setting of controlled clinical trials are needed. Therefore, the SIGNS study (Assessment of Immunoglobulins in a Long-Term Non-Interventional Study) was set up as a non-interventional prospective open-label cohort study and was approved by the ethics committee. Led by an interdisciplinary steering board, hospital- and office-based investigators in 30-40 centers throughout Germany (neurologists, pediatricians, oncologists, other) will document approximately 300 patients, and will follow them for at least 2 years. Patients of both genders and any age are eligible if they have received, or are scheduled for, IgG therapy for primary or severe secondary immunodeficiency or neurological autoimmune diseases, and have provided written informed consent. No exclusion criteria have been defined in order to minimize selection bias. Long-term outcome data will be collected on patient characteristics in the various indications, drug utilization (e.g., treatment and dosing patterns), effectiveness (i.e., number of infections), tolerability, health-related quality of life, and economic variables (number of hospitalizations, sick-leave days, etc.) with the possibility to estimate direct costs. For the neurological autoimmune diseases, detailed data will be gathered, among others, on neurological function, muscular function, physical function (grip strength, INCAT disability scale, etc.) and stabilization or progression of symptoms over time. Data collection in SIGNS is performed using a secure internet site and an MySQL database. A number of quality measures are routinely performed including automated plausibility checks at data entry, queries, and on-site monitoring with source data verification. It is expected that SIGNS will contribute to optimization of therapy in this diverse patient population.ZusammenfassungNichtmodifizierte humane Immunglobuline (IgG) sind der Standard für die Substitutionstherapie von Patienten mit primären (angeborenen) Immundefekten (PID) sowie sekundären Immundefekten (SID) aufgrund von multiplem Myelom (MM) oder chronischer lymphatischer Leukämie (CLL). Außerdem werden sie zur Immunmodulation bei neurologischen Autoimmunerkrankungen wie Guillain-Barré-Syndrom (GBS), chronisch-inflammatorischer demyelinisierender Polyneuropathie (CIDP) und multifokaler motorischer Neuropathie (MMN) eingesetzt. Eine Vielzahl von IgG-Produkten steht für die intravenöse und subkutane Anwendung zur Verfügung. Hinsichtlich des breiten Indikations- und Produktspektrums sind Daten zur Anwendung in der täglichen Praxis von großem Interesse. Außerdem werden Daten zu den Therapieergebnissen außerhalb kontrollierter klinischer Studien benötigt.Die SIGNS-Studie (Assessment of Immunoglobulins in a Long-Term Non- Interventional Study) wurde durch ein interdisziplinäres klinisches Expertengremium als nichtinterventionelle, prospektive, offene Kohortenstudie (Versorgungsforschungsstudie) konzipiert. Neurologen, Pädiater, Onkologen und weitere Fachgruppen schließen in 30–40 Zentren in ganz Deutschland ca. 300 Patienten ein und werden sie über mindestens 2 Jahre beobachten. Patienten beiderlei Geschlechts und aller Altersgruppen sind für die Dokumentation geeignet, wenn sie zur Behandlung von PID, SID oder neurologischen Autoimmunerkrankungen IgG-Präparate erstmals oder zum wiederholten Mal erhalten und ihr schriftliches Einverständnis erklären. Um Selektionsbias zu minimieren, wurden keine Ausschlusskriterien definiert. Dokumentierte Parameter im Langzeitverlauf umfassen Patientencharakteristika, Anwendungsmuster (u.a. Dosierungen, Präparatewechsel), Wirksamkeit (z.B. Zahl und Schwere der Infektionen bei PID und SID), Verträglichkeit und ökonomische Variablen, um direkte Kosten erfassen zu können (Fehltage in Beruf und Schule, Arztbesuche). Besonderes Augenmerk liegt auf der detaillierten Erfassung der gesundheitsbezogenen Lebensqualität und Krankheitsbelastung (u.a. bei Erwachsenen mittels SF-36, EQ-5D und WHO-5 bzw. bei Kindern mittels EQ-5D-Y, CHQ-PF-50, Kidscreen-27 und Disabkids- 37). Bei neurologischen Autoimmunerkrankungen werden u.a. Daten zur neurologischen Funktion, muskulären und physischen Funktion (Greifkraft, INCAT-Behinderungsskala etc.) und Stabilisierung/Krankheitsprogression gesammelt. Die Datenerfassung erfolgt über eine SSL- und passwortgesicherte Internetseite und eine MySQL-Datenbank. Zur Sicherung der Datenqualität werden Plausibilitätsprüfungen bei der Dateneingabe, Rückfragen bei den Zentren (Queries) und Monitoringbesuche durchgeführt. Die SIGNS-Studie soll zur Optimierung der IgG-Therapie in diesen Patientengruppen beitragen.AbstractNeuroimmunologie Non-modified human immunoglobulins (IgG) are standard of care for replacement therapy with primary (inherited) immunodeficiencies, and secondary immunodeficiencies due to multiple myeloma (MM) or chronic lymphocytic leukemia (CLL). Further, they have effectively been used as immunomodulation in neurological autoimmune diseases such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). A variety of IgG preparations for intravenous and subcutaneous use are available. In view of the broad range of indications, data on the utilization of the IgG preparations in everyday clinical care are of high clinical interest. Furthermore, data on the outcomes of IgG therapy outside the setting of controlled clinical trials are needed.Therefore, the SIGNS study (Assessment of Immunoglobulins in a Long-Term Non-Interventional Study) was set up as a non-interventional prospective open-label cohort study and was approved by the ethics committee. Led by an interdisciplinary steering board, hospital- and office-based investigators in 30–40 centers throughout Germany (neurologists, pediatricians, oncologists, other) will document approximately 300 patients, and will follow them for at least 2 years. Patients of both genders and any age are eligible if they have received, or are scheduled for, IgG therapy for primary or severe secondary immunodeficiency or neurological autoimmune diseases, and have provided written informed consent. No exclusion criteria have been defined in order to minimize selection bias. Long-term outcome data will be collected on patient characteristics in the various indications, drug utilization (e.g., treatment and dosing patterns), effectiveness (i.e., number of infections), tolerability, health-related quality of life, and economic variables (number of hospitalizations, sick-leave days, etc.) with the possibility to estimate direct costs. For the neurological autoimmune diseases, detailed data will be gathered, among others, on neurological function, muscular function, physical function (grip strength, INCAT disability scale, etc.) and stabilization or progression of symptoms over time. Data collection in SIGNS is performed using a secure internet site and an MySQL database. A number of quality measures are routinely performed including automated plausibility checks at data entry, queries, and on-site monitoring with source data verification. It is expected that SIGNS will contribute to optimization of therapy in this diverse patient population.

Management of patients with malignancies and secondary immunodeficiencies treated with immunoglobulins in clinical practice: Long-term data of the SIGNS study

We aimed to describe the current management and outcomes of patients with secondary immunodeficiencies (SID) on intravenous (IV) or subcutaneous (SC) immunoglobulins (IG) as maintenance therapy to prevent infections.

Rituximab in combination with chemotherapy for the treatment of chronic lymphocytic leukaemia in clinical practice

This study was conducted to investigate the real‐world effectiveness and tolerability of rituximab‐containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real‐life population was compared with older, comorbid patients.

Rituximab maintenance therapy of follicular lymphoma in clinical practice

Standard of care for patients with symptomatic, advanced‐stage follicular lymphoma (FL) is rituximab‐containing chemoimmunotherapy followed by rituximab maintenance. This prospective, multicenter, noninterventional study analyzed how efficacy and safety data from randomized controlled trials translate into clinical practice in Germany. Both treatment‐naïve and relapsed/refractory patients with FL, who responded to rituximab‐containing induction and were scheduled for rituximab maintenance, were observed for 24 months. Effectiveness was measured by response and Kaplan‐Meier survival analysis. In addition, treatment patterns of induction and maintenance, as well as adverse events, were documented. The evaluable study population consisted of 310 first‐line patients and 173 relapsed/refractory patients, including 116 patients with initial Ann‐Arbor stage I/II and 20 patients with FL grade 3B. Regarding first‐line induction, a shift from R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to R‐bendamustine was observed over time, as well as a decline in radiotherapy. 2‐year progression‐free survival rates were 88.3% (95% confidence interval [CI] 84.0‐92.6) for first‐line patients and 76.0% (95% CI: 68.8‐83.3) for relapsed/refractory patients. Conversion from partial to complete remission (PR, CR) occurred in 53.4% of analyzed first‐line patients with PR, resulting in 69.4% CRs at study end (relapsed/refractory: conversion in 42.9%, final CRs 57.9%). Safety results were consistent with the known safety profile of rituximab in this setting. Both treatment‐naïve and relapsed/refractory patients with FL show favorable 2‐year PFS rates and improvements in the remission status with postinduction rituximab monotherapy as maintenance and consolidation therapy.

Prospektive Versorgungsforschungsstudie zur Therapie mit Immunglobulinen (SIGNS)

Non-modified human immunoglobulins (IgG) are standard of care for replacement therapy with primary (inherited) immunodeficiencies, and secondary immunodeficiencies due to multiple myeloma (MM) or chronic lymphocytic leukemia (CLL). Further, they have effectively been used as immunomodulation in neurological autoimmune diseases such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). A variety of IgG preparations for intravenous and subcutaneous use are available. In view of the broad range of indications, data on the utilization of the IgG preparations in everyday clinical care are of high clinical interest. Furthermore, data on the outcomes of IgG therapy outside the setting of controlled clinical trials are needed. Therefore, the SIGNS study (Assessment of Immunoglobulins in a Long-Term Non-Interventional Study) was set up as a non-interventional prospective open-label cohort study and was approved by the ethics committee. Led by an interdisciplinary steering board, hospital- and office-based investigators in 30-40 centers throughout Germany (neurologists, pediatricians, oncologists, other) will document approximately 300 patients, and will follow them for at least 2 years. Patients of both genders and any age are eligible if they have received, or are scheduled for, IgG therapy for primary or severe secondary immunodeficiency or neurological autoimmune diseases, and have provided written informed consent. No exclusion criteria have been defined in order to minimize selection bias. Long-term outcome data will be collected on patient characteristics in the various indications, drug utilization (e.g., treatment and dosing patterns), effectiveness (i.e., number of infections), tolerability, health-related quality of life, and economic variables (number of hospitalizations, sick-leave days, etc.) with the possibility to estimate direct costs. For the neurological autoimmune diseases, detailed data will be gathered, among others, on neurological function, muscular function, physical function (grip strength, INCAT disability scale, etc.) and stabilization or progression of symptoms over time. Data collection in SIGNS is performed using a secure internet site and an MySQL database. A number of quality measures are routinely performed including automated plausibility checks at data entry, queries, and on-site monitoring with source data verification. It is expected that SIGNS will contribute to optimization of therapy in this diverse patient population.ZusammenfassungNichtmodifizierte humane Immunglobuline (IgG) sind der Standard für die Substitutionstherapie von Patienten mit primären (angeborenen) Immundefekten (PID) sowie sekundären Immundefekten (SID) aufgrund von multiplem Myelom (MM) oder chronischer lymphatischer Leukämie (CLL). Außerdem werden sie zur Immunmodulation bei neurologischen Autoimmunerkrankungen wie Guillain-Barré-Syndrom (GBS), chronisch-inflammatorischer demyelinisierender Polyneuropathie (CIDP) und multifokaler motorischer Neuropathie (MMN) eingesetzt. Eine Vielzahl von IgG-Produkten steht für die intravenöse und subkutane Anwendung zur Verfügung. Hinsichtlich des breiten Indikations- und Produktspektrums sind Daten zur Anwendung in der täglichen Praxis von großem Interesse. Außerdem werden Daten zu den Therapieergebnissen außerhalb kontrollierter klinischer Studien benötigt.Die SIGNS-Studie (Assessment of Immunoglobulins in a Long-Term Non- Interventional Study) wurde durch ein interdisziplinäres klinisches Expertengremium als nichtinterventionelle, prospektive, offene Kohortenstudie (Versorgungsforschungsstudie) konzipiert. Neurologen, Pädiater, Onkologen und weitere Fachgruppen schließen in 30–40 Zentren in ganz Deutschland ca. 300 Patienten ein und werden sie über mindestens 2 Jahre beobachten. Patienten beiderlei Geschlechts und aller Altersgruppen sind für die Dokumentation geeignet, wenn sie zur Behandlung von PID, SID oder neurologischen Autoimmunerkrankungen IgG-Präparate erstmals oder zum wiederholten Mal erhalten und ihr schriftliches Einverständnis erklären. Um Selektionsbias zu minimieren, wurden keine Ausschlusskriterien definiert. Dokumentierte Parameter im Langzeitverlauf umfassen Patientencharakteristika, Anwendungsmuster (u.a. Dosierungen, Präparatewechsel), Wirksamkeit (z.B. Zahl und Schwere der Infektionen bei PID und SID), Verträglichkeit und ökonomische Variablen, um direkte Kosten erfassen zu können (Fehltage in Beruf und Schule, Arztbesuche). Besonderes Augenmerk liegt auf der detaillierten Erfassung der gesundheitsbezogenen Lebensqualität und Krankheitsbelastung (u.a. bei Erwachsenen mittels SF-36, EQ-5D und WHO-5 bzw. bei Kindern mittels EQ-5D-Y, CHQ-PF-50, Kidscreen-27 und Disabkids- 37). Bei neurologischen Autoimmunerkrankungen werden u.a. Daten zur neurologischen Funktion, muskulären und physischen Funktion (Greifkraft, INCAT-Behinderungsskala etc.) und Stabilisierung/Krankheitsprogression gesammelt. Die Datenerfassung erfolgt über eine SSL- und passwortgesicherte Internetseite und eine MySQL-Datenbank. Zur Sicherung der Datenqualität werden Plausibilitätsprüfungen bei der Dateneingabe, Rückfragen bei den Zentren (Queries) und Monitoringbesuche durchgeführt. Die SIGNS-Studie soll zur Optimierung der IgG-Therapie in diesen Patientengruppen beitragen.AbstractNeuroimmunologie Non-modified human immunoglobulins (IgG) are standard of care for replacement therapy with primary (inherited) immunodeficiencies, and secondary immunodeficiencies due to multiple myeloma (MM) or chronic lymphocytic leukemia (CLL). Further, they have effectively been used as immunomodulation in neurological autoimmune diseases such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). A variety of IgG preparations for intravenous and subcutaneous use are available. In view of the broad range of indications, data on the utilization of the IgG preparations in everyday clinical care are of high clinical interest. Furthermore, data on the outcomes of IgG therapy outside the setting of controlled clinical trials are needed.Therefore, the SIGNS study (Assessment of Immunoglobulins in a Long-Term Non-Interventional Study) was set up as a non-interventional prospective open-label cohort study and was approved by the ethics committee. Led by an interdisciplinary steering board, hospital- and office-based investigators in 30–40 centers throughout Germany (neurologists, pediatricians, oncologists, other) will document approximately 300 patients, and will follow them for at least 2 years. Patients of both genders and any age are eligible if they have received, or are scheduled for, IgG therapy for primary or severe secondary immunodeficiency or neurological autoimmune diseases, and have provided written informed consent. No exclusion criteria have been defined in order to minimize selection bias. Long-term outcome data will be collected on patient characteristics in the various indications, drug utilization (e.g., treatment and dosing patterns), effectiveness (i.e., number of infections), tolerability, health-related quality of life, and economic variables (number of hospitalizations, sick-leave days, etc.) with the possibility to estimate direct costs. For the neurological autoimmune diseases, detailed data will be gathered, among others, on neurological function, muscular function, physical function (grip strength, INCAT disability scale, etc.) and stabilization or progression of symptoms over time. Data collection in SIGNS is performed using a secure internet site and an MySQL database. A number of quality measures are routinely performed including automated plausibility checks at data entry, queries, and on-site monitoring with source data verification. It is expected that SIGNS will contribute to optimization of therapy in this diverse patient population.