Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hämorrhagische Diathese Ost (KHDO).

INTRODUCTION: In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years. METHODS: Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records. RESULTS: We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from >70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%. CONCLUSIONS: Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.

Lenalidomide in combination with bendamustine and prednisolone in relapsed/refractory multiple myeloma: results of a phase 2 clinical trial (OSHO-#077).

INTRODUCTION: While lenalidomide monotherapy is established for relapsed and/or refractory multiple myeloma (MM) treatment, combination therapies including lenalidomide are still under investigation in a number of phase 2/3 studies. In the current study, a treatment regime of lenalidomide (Revlimid®), bendamustine and prednisolone (RBP) was tested in patients with relapsed/refractory MM. METHODS: In the previously completed phase 1 study RBP with a dose of 75 mg/m2 bendamustine days 1-2, prednisolone 100 mg days 1-4 and 25 mg lenalidomide days 1-21 was well tolerated. RESULTS: Between July 2011 and September 2013, 25 patients were included in this analysis. The median number of previous treatments was 1 (range 1-2). Twenty-two patients (88%) responded after at least two cycles of RBP (one sCR, five nCR, eight VGPR and eight PR). The median time to first haematological response was 28 days, and median time to best response was 56 days. Due to increased haematological toxicity a dose reduction in most patients required in subsequent cycles of therapy. The median progression-free and overall survival was 22 and 38 months, respectively. In conclusion RBP is a highly effective therapy for patients with relapsed/refractory MM. In contrast to our phase 1 study, dose reduction was necessary in many patients because of haematological toxicity.

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011.

BACKGROUND: Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. METHODS: Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. RESULTS: The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%). CONCLUSIONS: No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

Stem cell mobilization and autologous stem cell transplantation after pretreatment with bendamustine, prednisone and bortezomib (BPV) in newly diagnosed multiple myeloma.

INTRODUCTION: Reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after induction treatment with a combination of bendamustine, prednisone and bortezomib (BPV) is missing. MATERIALS AND METHODS: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 35 patients with MM who had received at least one cycle of a BPV-induction therapy consisting of bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 between October 2008 and May 2014. The mobilization regimen consisted of cyclophosphamide 4 g/m(2) and G-CSF (2 × 5 µg/kg). Apheresis was started as soon as peripheral CD34(+) counts exceeded 20 × 10(6)/L with a harvest target of 8 × 10(6) CD34(+)/kg. The minimal accepted target was 2 × 10(6) CD34(+)/kg. The transplantation conditioning therapy consisted of melphalan 200 mg/m(2). RESULTS: A median number of two (range 1-5) BPV cycles were given. The majority of patients (n = 31, 89 %) responded with two sCR, five nCR, 11 VGPR and 13 PR after BPV induction. Three patients had MR, and one SD. Stem cell mobilization and harvest were successful in all patients. In 19 of 35 patients (54 %), a single apheresis was sufficient to reach the target. The median number of aphereses was one (range 1-4), and the median CD34(+) cell-count/kg was 13.5 (range 3.2-33.1)  × 106. All patients received an autologous SCT. Engraftment was successful in 34 of 35 patients. The median time to a leukocyte count >l × 10(9)/L was 11 days, and the time to untransfused platelet count of >50 × 10(9)/L was 13 days. Thirty-four patients (97 %) responded after the autologous SCT with 11 sCR, two CR, seven nCR, seven VGPR and seven PR. The progression-free survival at 18 months was 87 %, and overall survival was 92 %. CONCLUSION: Stem cell mobilization and autologous SCT are feasible in MM patients who have received BPV-induction therapy .

A retrospective review of diagnosis and treatment modalities of neuroendocrine tumors (excluding primary lung cancer) in 10 oncological institutions of the East German Study Group of Hematology and Oncology (OSHO), 2010-2012.

RATIONALE: There is a paucity of data on the incidence of neuroendocrine tumors (NET) outside pulmonary primaries and on treatment modalities applied to patients with NET in clinical practice. Only very little therapeutic progress has been made with respect to response and overall survival, particularly among patients with poorly differentiated, WHO grade 3 neuroendocrine carcinomas (G3-NEC). We sought to document the incidence and treatment modalities in patients with NET/NEC within a period of 2 years. METHODS: We conducted a retrospective data analysis using a simple documentation file to be completed in written form or electronically, including localization, WHO grading, treatment modalities, and specific therapeutic regimens applied. Primary lung cancer was excluded. The time period to be covered was 2010 through 2012. Individual patient data such as names or age were not documented, so that no ethics committee approval was required. RESULTS: Ten different hospital- or practice-based institutions contributed their data. One to 35 patients were documented per institution, summing up to 149 patients with 154 tumor localizations. Midgut (n = 46), foregut (n = 42), hindgut (n = 17), lung (n = 9), bladder (n = 8), unknown primary (n = 11), and other including prostate and liver (n = 21) were documented as tumor sites. Histological gradings were G1 (n = 71), G2 (n = 27), G3 (n = 34), undifferentiated "G4" (n = 4), and not specified (n = 13). Treatment modalities were surgical resection (n = 102), chemotherapy (n = 49), somatostatin analogs (n = 39), radiotherapy (n = 22), receptor-directed radionuclide therapy (n = 12), and systemic tyrosine kinase inhibition (n = 5). Chemotherapy was given to patients not only with G3-NEC (n = 31), but also with G2 (n = 12) and G1 NET (n = 7). Somatostatin analogs as well as receptor-directed radionuclides were applied to patients throughout all gradings. CONCLUSIONS: NET and NEC are not very rare tumor entities, but are diagnosed with very different frequencies, possibly depending upon the alertness of pathologists and clinicians. Chemotherapy, receptor-directed radionuclide application, and somatostatin analog therapy are applied without a clear correlation to different histologic gradings. Diagnostic and therapeutic progress in the field of NETs/carcinomas is urgently needed.

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma.

INTRODUCTION: Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination in patients with multiple myeloma (MM). In the present protocol, bortezomib was combined with bendamustine and prednisone, in order to assess the efficacy and safety of this combination therapy in patients with newly diagnosed/untreated MM. METHODS: Between June 2006 and October 2013, 49 patients with newly diagnosed/untreated MM were treated with bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 bendamustine, prednisone and bortezomib (BPV) once every 21 days. Patients were divided into three groups: group A (n = 19) consisted of patients with normal renal function or mild dysfunction (eGFR ≥ 60 ml/min), group B (n = 15) patients with moderate or severe renal dysfunction (eGFR 15-59 ml/min) and group C (n = 15) patients with renal failure/dialysis (eGFR <15 ml/min). RESULTS: A median number of two (range 1-5) BPV treatment cycles were given to the patients. The majority of the patients (n = 40, 82 %) responded after at least one cycle of BPV therapy with five stringent complete responses (CRs), nine near complete responses, 12 very good partial responses and 14 partial responses. Five patients had MR, three stable and one progressive disease. After a median observation time of 13 months, progression-free survival (PFS) and overall survival (OS) at 12 months were 92 and 94 %, respectively, for patients with normal renal function or mild renal dysfunction (group A) and 83 and 93 %, respectively, for patients with moderate or severe renal dysfunction (group B). Outcome for these patients was slightly better but not statistically significantly better than that for patients with renal failure/dialysis (group C), who had a PFS, and OS of 66 % (p = 0.08) and 73 % (p = 0.05), respectively. These results indicate that this BPV combination is feasible, effective and well tolerated in patients with newly diagnosed MM and normal or impaired renal function.

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with relapsed or refractory multiple myeloma and light chain-induced renal failure.

INTRODUCTION: Serious renal failure represents a severe complication of multiple myeloma (MM), with an estimated 25-50 % of patients being affected. Both bortezomib and bendamustine have been identified as quickly acting, effective and well-tolerated drugs and might therefore constitute an adequate combination regimen for patients presenting with light chain-induced renal failure. METHODS: Between March 2005 and March 2013, 36 patients with relapsed/refractory MM and light chain-induced renal failure (creatinine clearance <60 ml/min) were treated with bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 (BPV). Patients were divided according to severity of renal impairment into group A (n = 20) with moderate or severe renal dysfunction (eGFR 15-59 ml/min) and group B (n = 16) with renal failure/dialysis (eGFR <15 ml/min). RESULTS: Twenty-four patients (67 %) responded with three CR, three nCR, six VGPR and 12 PR. Six patients had minor response, two stable and four progressive disease. With a median follow-up period of 22 months, median progression-free survival (PFS) and overall survival (OS) for patients of group A were 10 and 25 months, respectively. This outcome was significantly better compared to patients of group B with a median PFS and OS of 3 and 7 months, respectively. Eleven patients showed a CRrenal, five a PRrenal and 15 a MRrenal. These results indicate that this BPV combination is feasible, effective and well tolerated in patients with relapsed/refractory MM and light chain-induced renal failure.

Successful treatment of patients with newly diagnosed/untreated multiple myeloma and advanced renal failure using bortezomib in combination with bendamustine and prednisone.

PURPOSE: Renal failure is a frequent complication of multiple myeloma (MM) and, if present at diagnosis, a considerable risk factor for outcome. Treatment with chemotherapy and/or new agents may result in recovery of renal function in up to 50 % of patients. The window of opportunity to reverse renal impairment is, however, rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as bendamustine has been demonstrated to be potent drugs in the treatment of MM. METHODS: A total of 18 patients with newly diagnosed/untreated MM and renal insufficiency (GFR < 35 ml/min) were treated with bendamustine, prednisone, and bortezomib (BPV). RESULTS: The majority of them (n = 15; 83 %) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow-up of 17 months, PFS at 18 months was 57 % and OS was 61 %. The myeloma protein decreased rapidly, reaching the best response after the first cycle in four and after the second cycle in additional seven patients. Thirteen patients (72 %) improved their renal function after treatment. CONCLUSION: We conclude that the combination of bortezomib, bendamustine, and prednisone is effective and well tolerated in patients with a newly diagnosed MM and renal failure.

Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial.

Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m(2)) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3-4 neutropenia was reported in 12 patients, and grade 3-4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study.