[Chronic Lymphocytic Leukemia]. / Chronische Lymphatische Leukämie (CLL).

Chronic Lymphocytic Leukemia Abstract. CLL is an indolent B-cell lymphoma characterized by a leukemic course. It is clinically and biologically very heterogeneous. The disease is preceded by a condition called monoclonal B lymphocytosis (MBL). The treatment of CLL has changed dramatically in recent years. Chemoimmunotherapy is being replaced by new molecularly targeted therapeutic modalities like B cell receptor inhibitors and BCL-2 regulators of programmed cell death. When to initiate therapy and what "new" drug combinations to use in which line of treatment are issues currently addressed in clinical trials.

[Myelodysplastic Syndromes]. / Myelodysplastische Syndrome.

Myelodysplastic Syndromes Abstract. Myelodysplastic Syndromes are a heterogenous group of myeloid neoplasias with differing prognosis. Diagnostics include morphology of blood and marrow and cytogenetic analysis. Risk scores, such as the IPSS or IPSS-R allow for prognostication of survival and the probability of transforming to acute myeloid leukemia. Most patients are elderly and may present with co-morbidities that need to be taken into account. Treatment measures include supportive care as well as low dose chemotherapy and up to hematopoetic cell transplantation and are therefore equally heterogenous in intensity. Supportive measures consist of transfusion of red cells but also platelets, erythropoiesis stimulating agents (ESA) and if transfused, iron chelation. In older patients with advanced MDS, who are not candidates for hematopoetic cell transplantation, low-dose chemotherapy such as with hypomethylating agents, e. g. azacyitinde is reasonably effective and well tolerated.

Long-term outcome of dasatinib first-line treatment in gastrointestinal stromal tumor: A multicenter, 2-stage phase 2 trial (Swiss Group for Clinical Cancer Research 56/07).

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS: This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS: Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS: Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54. © 2018 American Cancer Society.

Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial.

The combination of lenalidomide (Revlimid® , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46-83]) and were treated with B 75 mg/m2  days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.

Lymphodepletion chemotherapy followed by donor leukocytes for post-transplantation relapse of myelofibrosis after previous donor leukocyte infusion failure.

Treatment of relapse after allogenic stem cell transplantation (allo-SCT) is challenging. The efficacy of donor leukocyte infusions (DLI) is excellent in chronic phase chronic myeloid leukaemia but limited in other disorders. We present a patient who relapsed 10 months after reduced intensity conditioning allo-SCT for a myelodysplastic/ myeloproliferative neoplasm with myelofibrosis despite receiving escalating doses of DLI for incomplete chimerism. He finally achieved complete remission with full whole blood and T-cell donor chimerism after DLI preceded by lymphodepletion chemotherapy. This case demonstrates that chemotherapy prior to DLI is a useful approach for treating relapses of relatively slowly progressive diseases, such as myeloproliferative diseases or myelodysplastic syndromes.

Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis.

Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer. However, a comprehensive evaluation of BRAF and K-RAS mutations and their specific clinicopathological features, histomorphological presentation and effect on protein expression have not been systematically analyzed. The aim of this study was to characterize the clinicopathological, histomorphological and protein expression profiles of BRAF- and K-RAS-mutated colorectal cancers and determine their impact on patient survival. Molecular analysis for microsatellite instability (MSI), K-RAS and BRAF was carried out on paraffin-embedded samples from 404 patients with primary colorectal cancer. Using tissue microarrays, 36 tumor-associated and 14 lymphocyte/inflammatory-associated markers were evaluated by immunohistochemistry. BRAF mutation was associated with right-sided tumor location (p < 0.001), higher tumor grade (p = 0.029), absence of peritumoral lymphocytic inflammation (p = 0.026) and MSI-H (p < 0.001). In right-sided tumors, loss of CDX2 expression was observed in 23 of 24 cases (95.8%). BRAF mutation was a poor prognostic indicator in patients with right-sided disease (p = 0.01). This result was maintained in multivariable analysis (p < 0.001; HR = 2.82; 95% CI: 1.5-5.5) with pT, pN and vascular invasion and independent of CDX2 expression. K-RAS mutation, in contrast, was not associated with any of the features analyzed. BRAF gene mutation is an adverse prognostic factor in right-sided colon cancer patients independent of MSI status and, moreover, in patients with lymph node-negative disease. These results indicate that molecular analysis for BRAF may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.

New Direct Oral Anticoagulants (DOAC) and Their Use Today.

The ideal anticoagulant is oral, has a wide therapeutic range, predictable pharmacokinetics and pharmacodynamics, a rapid onset of action, an available antidote, minimal side effects and minimal interactions with other drugs or food. With the development of the novel direct oral anticoagulants (DOAC), we now have an alternative to the traditional vitamin K antagonists (VKA) for the prevention and treatment of thrombosis. DOACs have limited monitoring requirements and very predictable pharmacokinetic profiles. They were shown to be non-inferior or superior to VKA in the prophylaxis or treatment of thromboembolic events. Particularly in terms of safety they were associated with less major bleeding, including intracranial bleeding, thus providing a superior benefit for the prevention of stroke in patients with atrial fibrillation. Despite these advantages, there are remaining limitations with DOACs: their dependence on renal and hepatic function for clearance and the lack of an approved reversal agent, whereas such antidotes are successively being made available. DOACs do not need regular monitoring to assess the treatment effect but, on the other hand, they interact with other drugs and interfere with functional coagulation assays. From a practical point of view, the properties of oral administration, simple dosing without monitoring, a short half-life allowing for the possibility of uncomplicated switching or bridging, and proven safety overwhelm the disadvantages, making them an attractive option for short- or long-term anticoagulation.