Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.Results: The group was 69% male, 96% had relapsed/ refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

A significant barrier to effective cancer therapy is the development of resistance to the drugs utilised. Standard chemotherapeutic regimens typically contain genotoxic agents, designed to damage DNA of existing tumour cells as well as prevent the synthesis of new DNA during proliferation. DNA damage in normal cells can be repaired efficiently or tolerated to preserve cellular and organ functionality. The mechanisms of DNA repair and tolerance are distinct for different types of lesion, but can be predicted if the mechanism of interaction of the drug with the DNA is known. There is now evidence in solid tumours to suggest that increased repair or tolerance of DNA lesions may contribute to the ability of the cancer cell to survive in high genotoxic stress environments afforded by the therapy. This review will explore the current understanding of drug resistance mechanisms to chemotherapy, but will focus on the new evidence for tolerance and repair, including some new data from the authors' laboratory on the haematological malignancy multiple myeloma. The review will focus particularly on the role of the 'specialised polymerases' which have flexible active sites capable of accommodating DNA lesions, allowing replication past the lesion by translesion synthesis and tolerance of the damage, which ultimately results in a phenotype of drug resistance.

Growing evidence suggests that the flavonoid epigallocatechin-3-gallate (EGCG), notably abundant in green tea, has health-promoting properties. We examined the effect of EGCG on cell survival and apoptosis in the prostate cancer cell line PC3. Cell survival was reduced and apoptosis increased significantly with a low dose of 1 µM EGCG. The ability of the anticancer drug cisplatin to promote apoptosis was enhanced by EGCG. Furthermore, EGCG, both alone and in combination with cisplatin, promoted the expression of the pro-apoptotic splice isoform of caspase 9.

Multiple myeloma is the most common haematological malignancy yet currently it remains incurable. For decades the mainstay in therapy has been non-targeted approaches including genotoxic agents and immunosuppressants. With myeloma predominantly affecting an elderly population, who are vulnerable to aggressive therapy, these non-specific approaches have resulted in poor survival. However, in recent years an explosion of collaborative research into myeloma has identified molecular interactions between myeloma cells and the bone marrow microenvironment as promoting myeloma development and associated complications such as bone lesions due to osteolysis. At the same time, a better understanding of the adhesion molecules, cytokines and signalling pathways involved in myeloma has led to the development of new targeted therapies, which are improving the quality of life for patients and significantly extending median patient survival. This review explores the current understanding of molecular pathways that promote myeloma progression and lead to bone destruction, with particular reference to the influence of interactions with the bone marrow microenvironment. It describes molecular targets for therapy with reference to the new therapeutics and their improved efficacy. While the outlook for myeloma patients has improved in recent years as a result of these new approaches, drug resistance remains a problem and future therapies will also need to address the molecular mechanisms of resistance in order to improve further the outcome for patients with this disease.

Prior to introduction to the clinic, pharmaceuticals must undergo rigorous toxicity testing to ensure their safety. Traditionally, this has been achieved using in vivo animal models. However, besides ethical reasons, there is a continual drive to reduce the number of animals used for this purpose due to concerns such as the lack of concordance seen between animal models and toxic effects in humans. Adequate testing to ensure any toxic metabolites are detected can be further complicated if the agent is administered in a prodrug form, requiring a source of cytochrome P450 enzymes for metabolism. A number of sources of metabolic enzymes have been utilised in in vitro models, including cell lines, primary human tissue and liver extracts such as S9. This review examines current and new in vitro models for toxicity testing, including a new model developed within the authors' laboratory utilising HepG2 liver spheroids within a co-culture system to examine the effects of chemotherapeutic agents on other cell types.