Manfred Hensel

Quality of life during maintenance therapy with the anti-CD20 antibody rituximab in patients with B cell non-Hodgkin’s lymphoma: results of a prospective randomized controlled trial

The introduction of rituximab into the primary treatment of malignant lymphomas of the B cell lineage has had a major impact on the management of these diseases. In addition, prolonged exposure to rituximab as maintenance therapy has been beneficial in patients with follicular lymphoma and mantle cell lymphoma. For the individual patient, the effect of any prolonged antitumor therapy on the quality of life (QoL) is a very important question. However, so far, the question whether rituximab maintenance therapy may impair QoL in patients with non-Hodgkin’s lymphoma remains unanswered. To investigate this subject, we have performed a prospective randomized trial of rituximab maintenance therapy (8 cycles rituximab 375xa0mg/m2 every 3xa0months) versus observation in patients with CD20+B cell non-Hodgkin’s lymphoma in our institution. Between July 2002 and December 2005, 122 patients were included into the trial. QoL was assessed with the standardized questionnaires EORTC-QLQ-C30, EuroQol-5D, and EuroQol-5D (VAS) in 91 patients. After statistical analysis with the exact Wilcoxon rank sum test, we found no significant differences of the QoL between the rituximab treatment group and the observation group. We conclude that rituximab maintenance therapy seems to be safe and does not impair quality of life in this patient population.

Less intense conditioning with fludarabine, cyclophosphamide, idarubicin and etoposide (FCIE) followed by allogeneic unselected peripheral blood stem cell transplantation in elderly patients with leukemia

The objective of this study was to assess toxicity and feasibility of achieving engraftment of allogeneic blood progenitor cells following nonmyeloablative conditioning according to the FCIE protocol (fludarabine 25 mg/m2/day, days −7 to −3; cyclophosphamide 200 mg/m2/day, days −7 to −3; idarubicin 12 mg/m2/day, days −7 to −5; etoposide 250 mg/m2/day, days −4 to −3) in elderly patients with leukemia. Eleven patients were included in the study: six patients with acute myeloid leukemia (AML) in complete remission (CR); three patients with refractory or relapsed AML; one patient with chronic myeloid leukemia; one patient with acute lymphoblastic leukemia. The median age of the patients was 62 years. All patients received blood progenitor cells from an HLA-identical sibling with 8.8 × 106 CD34+ cells/kg (median; range 4.7 to 26.2 × 106/kg) and 5.5 × 108 CD3+cells/kg (median; range 4.5 to 7.9 × 108/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and three courses of methotrexate. The median duration of white blood cell counts <1 × 109/l was 17 days and of platelet counts <50 × 109/l 20 days. In two patients acute GVHD grade I occurred. Nine of 10 patients analyzed developed mixed chimerism. Of seven patients transplanted in CR, three remained in CR 19 to 31 months after transplantation. Three patients with refractory leukemia did not achieve CR, while the patient with relapsed AML achieved a 3rd CR. After a median follow-up time of 22 months, chronic GVHD was mild and limited. The data from this pilot study in elderly patients with leukemia show that the combination of primarily immunosuppressive (FC) and antileukemic (IE) drugs for nonmyeloablative conditioning has moderate nonhematological toxicity and allows engraftment of allogeneic blood progenitor cells.

HIV and cancer in Germany.

BACKGROUNDnCancer is now the leading cause of death in persons with HIV. In this study, we gathered current epidemiological data on Aids-defining (AD) and non-Aids-defining (NAD) malignancies among HIV-positive patients in Germany.nnnMETHODSnFrom 2000 to 2007, all 35 specialized HIV outpatient clinics and 189 HIV ambulatory care centers in Germany were contacted and asked to fill out a structured questionnaire on the incidence of malignancies in HIV-positive patients during multiple periods of observation.nnnRESULTSn552 evaluable data sets were reported. 253 (45.8%) of the reported malignancies were AD. Among the 299 cases (54.2%) of NAD malignancies, there were 214 solid tumors, including 71 anal carcinomas (23.7% of all NAD malignancies), and 85 hematopoietic malignancies, including 29 cases of Hodgkin`s lymphoma (9.7% of all NAD malignancies). The high percentage of NAD malignancy remained constant throughout the entire period of the study. Only a single case of primary cerebral lymphoma was reported after 2001. The number of patients with Hodgkin`s lymphoma rose steadily from 2000 to 2007.nnnCONCLUSIONnThe spectrum of HIV-associated malignancies has changed since the early days of the HIV epidemic. In Germany, NAD malignancies have become more common than AD malignancies. In particular, anal carcinoma and Hodgkins lymphoma are much more common among persons with HIV than in the general population. Persons with HIV need more intensive preventive care for cancer than non-infected persons do.

Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma. Results of the HD2002 prospective multicentre randomized phase III trial

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m2 every 3 months for 2 years) versus observation was evaluated for CD20+ B‐cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5‐year relapse‐free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B‐cell lymphoma (DLBCL) subgroup (n = 152), 5‐year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5‐year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00–1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05–0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.

Treatment of limited stage follicular lymphoma with Rituximab immunotherapy and involved field radiotherapy in a prospective multicenter Phase II trial-MIR trial

BackgroundThe optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy.Methods/designThe MIR (Mabthera® and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combinations efficacy and safety with an accrual of 85 patients.Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life.DiscussionThe trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only).Trial RegistrationClinicalTrials (NCT): NCT00509184

Treatment of Neurological Autoimmune Diseases with Immunoglobulins: First Insights from the Prospective SIGNS Registry

PurposeSeveral immunoglobulin (IG) preparations have been approved for the immunomodulatory treatment of the neurological autoimmune diseases (AID) Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). Although efficacy has been proven in randomised clinical trials, long-term outcome data on drug utilization, effectiveness, tolerability, health related quality of life, and economic variables are lacking.MethodsIn the prospective, observational internet-based SIGNS registry, patients of all age groups are eligible if they have received or are scheduled for IG therapy for neurological AID or primary or severe secondary immunodeficiency.ResultsOf the 306 patients currently included in the database (1 November 2011), 51 have neurological AID (27 males; mean age 56u2009±u200915xa0years): 21 CIDP, 7 MMN, 11 multiple sclerosis (MS), 6 myasthenia gravis, 2 myositis, 4 others (no cases of GBS). Mean duration of disease since first symptoms was 7.8xa0years, and disease duration since diagnosis was 5.9xa0years. Eight different IG preparations have been reported as current therapy. According to SF-36, patients’ quality of life is substantially impaired.ConclusionsPresent data indicate some off-label use of IG (e.g. in MS) in patients with neurological AID. Quality of life in these patients is substantially compromised. Increasing patient numbers and extended follow-up periods will provide data on treatment concepts and disease development in AID patients.

Excellent long-term survival of 170 patients with Waldenström’s macroglobulinemia treated in private oncology practices and a university hospital

The purpose of this study was to compare treatment and outcome of patients with Waldenström’s macroglobulinemia (WM) in four private oncology practices (PP) and a university hospital (UH) in southwest Germany. We retrospectively reviewed the charts of all patients with WM of the last two decades of four PP in Mannheim, Heidelberg, Karlsruhe, and Speyer and the Department of Hematology of the University of Heidelberg. One hundred seventy patients could be identified, 74 from PP, 96 from the UH. Median age was 63.3xa0years. Patients from PP were older (median 65.3 vs. 62.5xa0years, pu2009=u20090.01). Only 54xa0% of patients from PP have received treatment during the observation time, as compared to 78.1xa0% of the UH (pu2009<u20090.001). In PP, 35xa0% of treated patients have received rituximab, as compared to 62.6xa0% of the patients of the UH (pu2009<u20090.001). Sixty percent of treated patients of PP have received bendamustine, as compared to only 8xa0% of the patients of the UH (pu2009<u20090.001). Time to first treatment was significantly shorter in patients from the UH compared to PP (median 13.7 vs. 52.9xa0months, pu2009=u20090.05). A trend towards a better overall survival was observed for patients treated with a rituximab-containing first-line regimen. The International Prognostic Scoring System for WM had significant prognostic value. Median overall survival was 25.0xa0years and did not differ between PP and UH. Despite different treatment strategies between PP and UH today overall survival of patients with WM is excellent, and better than previously reported.

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.

[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.

HIV-associated lung cancer: Survival in an unselected cohort

Abstract Background: Lung cancer is one of the most common non-AIDS-defining malignancies in HIV-infected patients. However, data on clinical outcome and prognostic factors are scarce. Methods: This was a national German multicentre, retrospective cohort analysis of all cases of lung cancer seen in HIV-infected individuals from 2000 through 2010. Survival was analyzed with respect to the use of antiretroviral therapy (ART), specific lung cancer therapies, and other potential prognostic factors. Results: A total of 72 patients (mean age 55.5 y, CD4 T-cells 383/μl) were evaluated in this analysis. At time of lung cancer diagnosis, 86% were on ART. Of these, 79% had undetectable HIV-1 RNA (< 50 copies/ml) for a mean duration of 4.0 y. All but 1 patient were current or former heavy smokers (mean 42 package y). The median estimated overall survival was 1.08 y, with a 2-y overall survival of 24%. The prognosis did not improve during the observation time. A limited lung cancer stage of I–IIIA was associated with better overall survival when compared with the advanced stages IIIb/IV (p = 0.0003). Other factors predictive of improved overall survival were better performance status, CD4 T-cells > 200/μl, and a non-intravenous drug use transmission risk for HIV. Conclusions: Currently, most cases of lung cancer occur in the setting of limited immune deficiency and a long-lasting viral suppression. As in HIV-negative cases, the clinical stage of lung cancer is highly predictive of survival, and long-term overall survival can only be achieved at the limited stages. The still high mortality underscores the importance of smoking cessation strategies in HIV-infected patients.