Klinik fur Hamatologie

Hannover, Germany

Klinik fur Hamatologie

Hannover, Germany
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Kramer A.,German Cancer Research Center | Heuser M.,Klinik fur Hamatologie
Onkologe | Year: 2017

Background: Somatic mutations in isocitrate dehydrogenase (IDH) 1 and IDH2 have been identified in multiple human cancers, including glioma, chondrosarcoma, cholangiocellular carcinoma, angioimmunoblastic T cell lymphoma, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Objective: This review article summarizes the current data on the use of IDH inhibitors for tumors with IDH1 and 2 mutations. A description of the mutation diagnostics, which ultimately lead to a decision on therapy is also given. Methods: Clinical data on the treatment of patients with mutation-specific IDH inhibitors are currently available for one IDH1 inhibitor and two IDH2 inhibitors for patients with AML and MDS as well as one IDH1 inhibitor for glioma patients. Results: Overall response rates of AML and MDS patients to the different inhibitors are approximately 35–40%. Additionally, the majority of patients profit from an increase in the numbers of functionally active neutrophilic granulocytes, which is associated with a reduction in infection rates. The most frequent side effects are mild hyperbilirubinemia, elevated transaminase levels and nausea. Conclusion: As several studies with mutation-specific IDH1 and IDH2 inhibitors are currently recruiting, all patients with AML, MDS and gliomas should be tested for mutations in IDH1 and IDH2 and included in studies. In the future these studies will investigate not only monotherapy but also combination therapies with, e.g. azacitidine or intensive chemotherapy and include previously treated as well as newly diagnosed patients. Currently, IDH inhibitors represent an important new development in the treatment of AML and MDS patients. © 2017 Springer Medizin Verlag GmbH

Schott G.,Charité - Medical University of Berlin | Dunnweber C.,Institute For Pharmakologie | Muhlbauer B.,Albert Ludwigs University of Freiburg | Niebling W.,Klinik fur Hamatologie | And 2 more authors.
Deutsches Arzteblatt International | Year: 2013

Background: The recommendations in clinical guidelines are based on clinical trial findings and expert opinion. The influence of drug companies on these two factors is illustrated with two examples. Methods: A judicially ordered expert review revealed that the market authorization holder (MAH) of gabapentin manipulated study data. Gabapentin was, therefore, chosen as an example for this article to analyze whether manipulated data serve as a basis for recommendations in German clinical guidelines. A search was carried out for manipulated publications on gabapentin that found their way into guidelines published by the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesell schaften, AWMF). To analyze the possible effects of financial ties between guideline authors and drug companies, the S3 guideline on the treatment of psoriasis vulgaris with efalizumab was compared with guidelines whose authors had no conflicts of interest. One of the authors of this article had noted variable prescribing practices for psoriasis among dermatologists while carrying out an economic assessment for a German state Association of Statutory Health Insurance Physicians. Results: The data that had been manipulated by the MAH of gabapentin served as a basis for recommendations to prescribe gabapentin in guidelines that were published by the AWMF. Efalizumab was judged more favorably in the S3 guideline than in a guideline issued by the National Institute of Health and Care Excellence: for example, the evidence for it was judged as good, the use of efalizumab for induction and combination therapy in psoriasis vulgaris was recommended, and efalizumab was said to improve patients' health-related quality of life. Conclusion: Public access to all trial data must be ensured so that independent evaluations are possible. We take the view that the responsibility for creating guidelines should be borne by authors and organizations that do not have any conflicts of interest.

Reimer P.,Klinik fur Hamatologie | Chawla S.,Spectrum Pharmaceuticals
Journal of Hematology and Oncology | Year: 2013

Peripheral T/NK-cell lymphomas (PTCL) are rare malignancies with a poor prognosis. Due to the lack of randomised studies, standard therapy has not been established. First-line treatment with anthracycline-based polychemotherapy followed by consolidation with high-dose therapy and autologous stem cell transplant in responding patients has demonstrated good feasibility with low toxicity in prospective studies and is widely used in eligible patients. In relapsed and refractory patients, who are not candidates for transplant approaches, therapeutic options are limited and are usually palliative. Several new agents are currently under investigation to improve the outcome of PTCL in the first line and salvage settings. Belinostat, a histone deacetylase (HDAC) inhibitor, has demonstrated broad antineoplastic activity in preclinical studies, and promising results in advanced relapsed/refractory lymphomas. Here, we report the case of a 73 year old patient with heavily pre-treated refractory PTCL in complete remission with belinostat for 39 months. © 2013 Reimer and Chawla; licensee BioMed Central Ltd.

Discussion: Most recommendations rely on anecdotal data from specialized centers. The field of supportive therapy lacks a sufficient number of prospective studies which could give answers on the optimal approach to therapy management in the era of molecular therapies.Background: Molecular therapies are a landmark in the landscape of cancer treatment. The often long-term intake and clinical activity comes at the expense of chronic toxicity and renders therapy management a key ingredient for successful application.Aim: This article depicts different aspects of selected adverse events (AE) of molecular therapies and gives guidance for therapy management when using these novel class of agents.Material and methods: A selective literature search was performed in the Pubmed database.Results: Hand-foot syndrome and arterial hypertension are key AEs of vascular endothelial growth factor receptor (VEGFR) inhibitors, whereas oral mucositis and metabolic AEs remain the main aspects during treatment with mTOR inhibitors. Both therapeutic classes require specific therapy management in order to monitor and treat specific AEs. © 2015, Springer-Verlag Berlin Heidelberg.

Grunwald V.,Klinik fur Hamatologie | Rickmann M.,Klinik fur Hamatologie
Internist | Year: 2014

Recent years have seen dramatic changes in the biological understanding and treatment of solid tumors. Based on the tumor biology, targeting agents have been developed which directly affect the underlying genetic or immunological changes found in specific tumor entities. Significant increases in survival have delivered the functional proof of the concept of targeted and immunological tumor therapy. The management and adherence of the patient as well as optimized cooperation with clinicians are decisive for the results of therapy and disease control.Several solid tumors are currently under investigation in clinical studies evaluating the (sequential) therapy with targeting and immunologically active agents, e.g. tyrosine kinase and mTOR inhibitors, targeting antibodies, such as bevacizumab, specific antagonists, such as enzalutamide and immunological checkpoint inhibitors via PD(L)1 and/or CTLA 4 antibodies.Currently approved agents have dramatically changed the landscape of treatment options especially for prostate cancer. Such agents include hormone therapy with enzalutamide and abiraterone, radiotherapy with cabazitaxel and xofigo (radium 223), metastatic breast cancer (eribulin and everolimus), renal cell carcinoma (sunitinib, sorafenib, axitinib, everolimus and temsirolimus), non-small cell lung cancer (crizotinib and afatinib), colorectal cancer and gastrointestinal stromal tumor (regorafenib) and melanoma (ipilimumab and vemurafenib). The treatment of rarer tumors, such as pancreatic and hepatocellular cancer and soft tissue sarcoma has entered the stage of targeted therapy with the approval of nanoparticle albumin-bound (nab)-paclitaxel, sorafenib, and eribulin/pazopanib. Current clinical trials are focusing on the best time point and sequence of therapy and also improvement in the management of these promising agents. © 2014, Springer-Verlag Berlin Heidelberg.

Reimer P.,Klinik fur Hamatologie
European journal of Clinical and Medical Oncology | Year: 2010

Peripheral T/NK-cell lymphomas (PTCL) comprise a rare and heterogeneous group of malignancies that are characterized by an aggressive course. So far, no standard therapy has been defined. With the exception of anaplastic large cell lymphoma (ALCL) expressing the anaplastic lymphoma kinase (ALK), conventional (anthracycline-based) polychemotherapy leads to dismal outcome, with sustaining complete remissions achievable in only a minority of patients. High-dose therapy supported by autologous stem cell transplantation (HDT-ASCT) is a well-defined and widely used therapeutic approach in different hematological malignancies (e.g., relapsed aggressive B-cell lymphomas, relapsed Hodgkin's disease, multiple myeloma), and has also shown efficacy in relapsed PTCL. However, on account of the lack of randomized PTCL-restricted studies, the impact of HDT-ASCT as first-line therapy in PTCL is unclear. Retrospective studies in this setting have shown good feasibility with a low therapy-associated morbidity and mortality not exceeding toxicity in high-dose studies on aggressive B-cell lymphomas. To date, five larger prospective PTCL-restricted trials have addressed this strategy, varying in terms of inclusion criteria, induction therapy, high-dose protocols, etc. The outcome shows promising results with an overall survival of about 50% at 3 years. Patients achieving complete remission (CR) at transplantation seem to benefit most from this strategy. Therefore, induction therapy needs to be further improved to increase the transplantation rate. With the limited data available, upfront HDT-ASCT seems a reasonable approach in eligible patients, especially in patients achieving CR after induction therapy. This approach should be urgently evaluated in randomized trials, as planned by the German High-Grade Non-Hodgkin Lymphoma Study Group.

Bergmann M.,Klinik fur Hamatologie | Wendtner C.-M.,Klinik fur Hamatologie | Wendtner C.-M.,University of Cologne
Deutsche Medizinische Wochenschrift | Year: 2015

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/μl need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17p deletion and/or TP53-mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL is the BH3-mimetic inhibitor of the Bcl-2 family of pro-survival proteins, ABT-199. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.

Bast F.,Klinik fur Hals | Fuss H.,Klinik fur Hamatologie | Schrom T.,Klinik fur Hals
HNO | Year: 2012

Osteonecrosis of the mandible is a well-known and dreaded complication after the administration of bisphosphonates. Only a few cases of bisphosphonate-associated osteonecrosis of the external ear canal have been described. Especially after long-lasting bisphosphonate therapy, for example in patients with multiple myeloma, an ulceration of the floor of the bony external auditory canal should be treated surgically and be distinguished from radioosteonecrosis, malignant external otitis, or carcinoma of the external ear. © Springer-Verlag Berlin Heidelberg 2012.

The market authorisation or extension of indication for all oncology drugs in Europe is now based on Regulation (EC) No. 726/2004, a centralised procedure of the European Medicines Agency (EMA). Studies in recent years have highlighted deficiencies in pivotal studies. For example, the requirements of the EMA are not always consistently followed and studies are stopped prematurely after only interim analysis that at this time point shows improved efficacy with regard to the comparator arm. Our current analysis of the European Assessment Reports (reporting period: 01/01/2009 to 08/13/2012) on 29 drugs for 39 oncology indications shows that the quality of the trials for market authorisation has improved in several respects. Primary endpoints recommended by the EMA and the Food and Drug Administration (FDA) such as overall survival and progression-free survival are used, and only one study was conducted as a phase II trial with no comparator arm. In contrast, oncology drugs that are approved for the treatment of rare diseases (orphan drugs) are based on small studies which are often carried out without blinding, are not randomised and investigate surrogate endpoints. To answer patient-relevant issues following market authorisation, it is necessary to conduct independent clinical studies. Increased public funding needs to be provided and bureaucratic hurdles have to be reduced. Only this will permit a more efficient use of limited health care resources and allow to improve the quality of care for cancer patients. Copyright © 2013 S. Karger AG, Basel.

Success medical treatment of lung cancer relies on the sensitivity of the individual cancer and on customizing drug doses to the individual patient. This paper describes typical toxicities of single drugs and drug combinations used in the treatment of lung cancer. It discusses the impact on the patients, prophylaxis and criteria for individual dosing. Detailed information on single drugs is given in other chapters of this series. © 2016 Dustri-Verlag Dr. Karl Feistle.

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