Impact of individualized treatment on recovery from fatigue and return to work in survivors of advanced-stage Hodgkin's lymphoma: results from the randomized international GHSG HD18 trial.

BACKGROUND: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W). PATIENTS AND METHODS: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables. RESULTS: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL. CONCLUSIONS: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma.

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial.

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

Nelfinavir and lenalidomide/dexamethasone in patients with lenalidomide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10).

The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding nelfinavir to lenalidomide-dexamethasone can overcome lenalidomide resistance in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide-bortezomib double-refractory 34%). Twenty-four patients (83%) had prior bortezomib and 10 (34%) were lenalidomide-bortezomib double-refractory. They received four cycles of nelfinavir 2500 mg/day with standard-dose lenalidomide (25 mg days 1-21) and dexamethasone (40/20 mg days 1, 8, 15, 22). Minor response or better was achieved in 16 patients (55%; 95% CI 36-74%), including 40% of those who were lenalidomide-bortezomib double-refractory, and partial response or better in nine patients (31%; 95% CI 15-51%). Median progression-free survival was 3.4 (95% CI 2.0-4.9) months and median overall survival 21.6 (13.0-50.1) months. Lenalidomide-related pneumonitis, pneumonia, and neutropenic fever occurred, but there were no unexpected adverse events. Peripheral blood mononuclear cells showed a 45% (95% CI 40-51%) reduction in total proteasome activity from baseline and significant induction of unfolded protein response and autophagy. Thus, nelfinavir-lenalidomide-dexamethasone is an active oral combination in lenalidomide-refractory MM.

Hairy cell leukemia: short review, today's recommendations and outlook.

Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately 2% of all leukemias. Treatment with splenectomy and interferon-α historically belonged to the first steps of therapeutic options, achieving partial responses/remissions (PR) in most cases with a median survival between 4 and 6 years in the 1980s. The introduction of the purine analogs (PA) pentostatin and cladribine made HCL a well-treatable disease: overall complete response rates (CRR) range from 76 to 98%, with a median disease-free survival (DFS) of 16 years a normal lifespan can be reached and HCL-related deaths are rare. However, insufficient response to PA with poorer prognosis and relapse rates of 30-40% after 5-10 years of follow-up may require alternative strategies. Minimal residual disease can be detected by additional examinations of bone marrow specimens after treatment with PA. The use of immunotherapeutic monoclonal antibodies (mAB) like rituximab as a single agent or in combination with a PA or more recently clinical trials with recombinant immunotoxins (RIT) show promising results to restrict these problems. Recently, the identification of the possible disease-defining BRAF V600E mutation may allow the development of new therapeutic targets.

[Persistent Eosinophilia--differential diagnosis and work-up]. / Persistierende Eosinophilie - Differenzialdiagnose und diagnostischer Algorithmus.

The differential diagnosis of eosinophilia is broad and constitutes a major challenge for both, the general practitioner and the hematologist. Whereas in developing countries secondary eosinophilia is commonly caused by parasitic infections, in Western and European countries eosinophilia is more often associated with atopic diseases or drug-related. This case-report presents an asymptomatic patient with marked persisting eosinophilia caused by Strongyloidiasis in whom parasitic stool examinations were repeatedly negative and infection could only be established by serologic testing.

Integrating novel agents into multiple myeloma treatment - current status in Switzerland and treatment recommendations.

The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.

[Immunotherapy of cancer--status and perspectives]. / Immuntherapie des Krebses--Stand und Perspektive.

Already since more than 80 years in medicine a cancer control by means of immunological methods has been tried again and again. In the last decennium above all the possibilities of the immunostimulation and the immunopotentiation as therapeutical principle were investigated. But neither the influence on the macrophages and the NK-cells perhaps by BCG, MDP, interferons or similar things nor the application of a tumour vaccine, e.g. blasts stimulated with neuraminidase, nor the T-lymphocyte stimulation, e.g. by thymus factors or levamisol, nor the activation of the specific tumour defence possibly by interleukins or clonic killer-cells brought a decisive breaking forth. Only in some certain malignant diseases, such as in virus-induced leukaemias or non-Hodgkin lymphomas of the B-cell series, by means of interferon and monoclonal anti-idiotype-antibodies, respectively, principal possibilities of an immunotherapy could be revealed. The question arises, whether the concept of an immunological tumour control underlying the previous therapeutic efforts really proves right or whether or not the recent knowledge about the principle of the oncogenes should give rise to a change of therapeutic thoughts.

[Viewpoints on the problem of subspecialization in internal medicine]. / Betrachtungen zum Problem der Subspezialisierung in der Inneren Medizin.

There is no doubt that the specialisations which were performed during the last two to three decades in the field of internal medicine decisively furthered the scientific progress also in this subject. From the more and more detailed insights into the pathological process connected with this and the opening of more and more far-reaching therapeutic possibilities, however, resulted also with regard to the patients' care an increasingly organ-related medicine, which lost sight of the patient as a subject and personality. It has been omitted that the purely natural-scientifically orientated way of consideration is only one side of medical activity and that for recognition of all aspects of the homo patients internal medicine has to make use also of comprehensions and experiences of arts and social sciences. The synthesis of the two roots, connected with a subspecialization restricted to the necessary measure and its integration into a patient-orientated total concept of internal medicine should be able to reasonably coordinate scientifically explored facts, technical achievements, ethical things and things expected by the patient.

[Immunology and oncology of paraproteins]. / Betrachtungen zur Immunologie und Onkologie der Paraproteine.

Since the first description by Apitz paraproteins were for a long time regarded as biologically abnormal proteins which normally do not appear in the human plasma. According to the modern biochemical knowledge this determination of the notion can no more be acknowledged, since analyses of amino acids did not reveal any differences in the composition of the complete paraproteins and the immune globulins. Apart from the complete paraproteins which consist either of gamma, my, delta, alpha or epsilon heavy chains on the one hand and of kappa or lambda easy chains on the other hand, also molecule fragments and isolated heavy or easy chains, respectively, appear. Like immune proteins paraproteins are formed by B-lymphocytes and their transformation forms, respectively, in which case the monoclonality represents their specific characteristic. Thus exist close relations to malignant changes of the B-lymphocyte system, in particular to the non-Hodgkin-lymphomas. Several functional peculiarities of the paraproteins, such as autoantibody effect, lymphocytotoxicity, aggregation ability and binding affinity to blood cells lead to multiform clinical phenomena. To this belong immune defects, nephropathies, haemocytopenias, amyloidoses and haemorrhagic diatheses. As evoking cause of the alteration of B-lymphocyte system with activation of one or several cell clones (e.g. in double paraproteinaemia) tumour viruses are taken into consideration. After an infection with oncogenic herpes viruses irreversible cell transformations in the lymphatic system have been proved. Thus it is doubtful, whether there are indeed true benign paraproteinaemias. One has rather to speak only of relatively benign forms of the course.

[The spleen--still a puzzling organ?]. / Die Milz--noch immer ein rätselvolles Organ?

The model of animal experiments developed in the sixties by the Erfurt investigation team of A. Sundermann, according to which autoimmunisation phenomena may be evoked in the rabbit by the application of warmth-alterated autologous blood cells, undergoes a repeated critical consideration on the basis of the modern knowledge of the nature of the autoimmunisation process. In this case must be stated that the importance of the spleen for the development of such processes is finally still unclear. The favourable therapeutical effects of a splenectomy observed in the model and also in clinical routine work cannot be explained sufficiently theoretically, particularly on the basis of the recent results of research concerning the cellular immune mechanisms. No doubt, it seems to be clear that the spleen is authoritatively responsible for the primary immune response, however it remains questionable, whether an isolated primary response is really existing, since on its part it already depends on T-lymphocytes which stimulate the secondary response. However, a splenectomy might be suitable theoretically--if at all--for the interruption of the immune process only in the stage of the primary reaction. In the complex process within the immune response with the various implications between B- and T-lymphocytes and the increasing knowledge of the counter-regulating humoral and cellular control mechanisms the picture of the importance of the spleen seeming to be more distinct in the intervening time becomes again more indistinct. Thus the spleen for the time being remains the enigmatical organ, as it was characterized by Sundermann already for more than ten years ago.