Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations, GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3 months with a loading dose. Pharmacokinetics were performed on day 1 and 8. Trough and peak concentrations of DCA were measured monthly. GSTZ1 genotypes were correlated with drug concentrations, tolerability, and disease outcomes. One patient responded and two patients showed a partial response after one month of DCA treatment, which included the loading dose. The initial half‐life of DCA was shorter in two patients, correlating with heterozygosity for GSTZ1*A genotype, a high enzyme activity variant. Over 3 months, one patient maintained DCA trough concentrations approximately threefold higher than other patients, which correlated with a low activity promoter genotype (−1002A, rs7160195) for GSTZ1. This patient displayed the strongest response, but also the strongest neuropathy. Overall, serum concentrations of DCA were sufficient to inhibit the constitutive target PDK2, but unlikely to inhibit targets induced in cancer. Promoter GSTZ1 polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. Novel dosing regimens may be necessary to achieve effective DCA concentrations in most cancer patients while avoiding neuropathy.

For the treatment of mature B cell malignancies including chronic lymphocytic leukemia (CLL), the last 5 years has brought major advances in the application of targeted therapies. Whilst monoclonal anti-CD20 agents such as rituximab have a central role in combination with traditional cytotoxic therapy, their combination with novel agents that target the B cell receptor signaling pathway and other intracellular mechanisms of B cell proliferation is a new approach to treatment. Venetoclax is a highly specific novel agent inhibiting the bcl-2 anti-apoptotic pathway and has potent activity in CLL. Its combination with rituximab results in deeper and more durable responses and this regimen is a valuable option in the treatment of relapsed or refractory CLL including adverse prognostic variants such as cases that are fludarabine refractory or harbor the 17p chromosomal deletion. This review centers on the use of venetoclax and rituximab in relapsed or refractory CLL.

No abstract

Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPD) particularly low-grade B-LPD However, this diagnosis may be challenging. A recent study reported a median diagnostic delay of 1.1 (0.5-2.6) years from onset of angioedema. Possible reasons are lack of awareness of the condition, misdiagnosis of the angioedema symptoms as part of the hematologic disorder.

No abstract

No abstract