Background Fluorescence in situ hybridization has improved the detection of genomic aberrations in chronic lymphocytic leukemia. We used this method to identify chromosomal abnormalities in patients with chronic lymphocytic leukemia and assessed their prognostic implications. Methods Mononuclear cells from the blood of 325 patients with chronic lymphocytic leukemia were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 6q21, 11q22–23, 13q14, and 17p13; trisomy of bands 3q26, 8q24, and 12q13; and translocations involving band 14q32. Molecular cytogenetic data were correlated with clinical findings. Results Chromosomal aberrations were detected in 268 of 325 cases (82 percent). The most frequent changes were a deletion in 13q (55 percent), a deletion in 11q (18 percent), trisomy of 12q (16 percent), a deletion in 17p (7 percent), and a deletion in 6q (6 percent). Five categories were defined with a statistical model: 17p deletion, 11q deletion, 12q trisomy, normal karyotype, a...

https://www.nejm.org/doi/pdf/10.1056/NEJM200012283432602

Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia

4 CLINICAL PARTICULARS 4.1 Therapeutic Indications Trimetazidine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies. 4.2 Posology and method of administration Oral administration. Posology The dose is one tablet of 35mg of trimetazidine twice daily during meals. Special populations Renal impairment In patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see sections 4.4 and 5.2), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Elderly Elderly patients may have increased trimetazidine exposure due to age-related decrease in renal function (see section 5.2). In patients with moderate renal impairment (creatinine clearance [30-60] ml/min), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Dose titration in elderly patients should be exercised with caution (see section 4.4). Health Products Regulatory Authority

Summary of product characteristics

Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this Review, we discuss strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues. The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in ADC research.

Strategies and challenges for the next generation of antibody–drug conjugates

BACKGROUND Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P = 0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

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Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia

Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.

/pdf/biology-of-bone-tissue-structure-function-and-factors-that-4que250efz.pdf

Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

In this retrospective study we reviewed the clinical course of every patient with multiple myeloma treated from 2006 to 2016 at Vejle Hospital: 303 patients with a median age of 69 years at diagnosis received a median of four (range 1-18) lines of therapy; 149 in a 2006-2010 cohort and 154 in a 2011-2016 cohort. After initiation of treatment, the median decrease in the number of patients per each subsequent line of therapy was 22%. Lenalidomide-dexamethasone (n = 156), bortezomib-dexamethasone (n = 107), and bortezomib-lenalidomide-dexamethasone (n = 84) were the most commonly used regimens. The partial response or better rate was 78%, 58%, 55%, and 44% in lines of therapy one to four, respectively. The median (95% confidence interval [CI]) progression-free survival was 18 (15-22), 10 (8-13), 8 (7-10), and 6 (4-8) months in lines of therapy one to four, respectively. The median (95% CI) overall survival (OS) was 4.1 (3.7-4.8) years. Compared with the 2006-2010 cohort, patients in the 2011-2016 cohort had longer OS; 5.3 (4.7 to not reached) versus 3.4 (2.7-4.0) years, p < 0.0001. This was especially true in patients not treated with high-dose therapy and autologous stem cell transplantation; 4.7 (3.2-5.9) versus 2.6 (2.0-3.3) years, p = 0.0052. Patients in the 2011-2016 cohort were on treatment during a greater part of their life and had higher exposure to high-dose melphalan with autologous stem cell transplantation, lenalidomide, pomalidomide, daratumumab, and carfilzomib.

The clinical course of multiple myeloma in the era of novel agents: a retrospective, single-center, real-world study

An ongoing open-label phase 1/2a study of the safety and efficacy of melphalan-flufenamide (melflufen) and dexamethasone combination for patients with relapsed and relapsed-refractory multiple myeloma

Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-Label, Multicenter, Phase 1b Study (PAVO)

Torben Plesner

Papers

The clinical course of multiple myeloma in the era of novel agents: a retrospective, single-center, real-world study

An ongoing open-label phase 1/2a study of the safety and efficacy of melphalan-flufenamide (melflufen) and dexamethasone combination for patients with relapsed and relapsed-refractory multiple myeloma

Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-Label, Multicenter, Phase 1b Study (PAVO)

consecutive patients with B-cell chronic lymphocytic leukemia Prognostic importance of flow cytometric immunophenotyping of 540

The Contribution of Immunologic Methods to the Classification of Leukemias and Malignant Lymphomas