The Role of β-Elimination for the Clinical Activity of Hypomethylating Agents and Cyclophosphamide Analogues

A beta-elimination reaction generally involves the cleavage of a sigma (σ) bond at the position beta (β) to a pair of electrons that departs a molecule via a nucleophilic leaving group, subsequently leading to the formation of a new pi (π) bond. We describe the importance of β-elimination reactions in the mechanisms of action of two classes of chemotherapeutic agents. First, we evaluate the chemical steps resulting in formation of 5-methyl-cytosine and its disassociation from DNA methytransferase (DNMT) by b­-elimination reaction. When carbon 5 (C5) of cytosine is substituted with a nitrogen atom (N) in 5-aza-cytosine analogues, the critical β-elimination reaction cannot proceed, which results in the permanent attachment of 5-aza-cytosine to DNMT. The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of β-elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing β-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical β-elimination reaction. This ultimately culminates in a selective cytotoxic effect of these agents against lymphocytes, but not against hematopoietic and other stem cells with high aldehyde dehydrogenase content

Case Report Reverse Pseudohyperkalemia: An Important Clinical Entity in Chronic Lymphocytic Leukemia

Hyperkalemia is a potentially lethal electrolyte derangement commonly seen in patients with hematologic neoplasms with or without renal failure. Pseudohyperkalemia and reverse pseudohyperkalemia also can be seen in this patient population and early recognition and diagnosis of these conditions are vital. Here, we report a case of reverse pseudohyperkalemia in a patient with chronic lymphocytic leukemia (CLL) and provide recommendations regarding diagnostic and therapeutic strategies for management of such patients. Further, we discuss the pathogenesis of this condition and its potential role as a surrogate of favorable prognostic features in patients with CLL

Reverse Pseudohyperkalemia: An Important Clinical Entity in Chronic Lymphocytic Leukemia

Hyperkalemia is a potentially lethal electrolyte derangement commonly seen in patients with hematologic neoplasms with or without renal failure. Pseudohyperkalemia and reverse pseudohyperkalemia also can be seen in this patient population and early recognition and diagnosis of these conditions are vital. Here, we report a case of reverse pseudohyperkalemia in a patient with chronic lymphocytic leukemia (CLL) and provide recommendations regarding diagnostic and therapeutic strategies for management of such patients. Further, we discuss the pathogenesis of this condition and its potential role as a surrogate of favorable prognostic features in patients with CLL

Increased body mass index is a risk factor for acute promyelocytic leukemia

Abstract Introduction Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non‐APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. Methods Multicenter, retrospective analysis of 71 196 patients: APL (n = 200), AML (n = 437), ALL (n = 103), nonleukemia hospitalized (n = 70 456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. Results Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 and 30.3 kg/m2) than those with AML (28.3 and 27.1 kg/m2), ALL (29.3 and 27.7 kg/m2), and others (29.3 and 27.7 kg/m2) (P < .001). Log‐transformed BMI multivariable models demonstrated that APL patients had a significantly higher adjusted mean BMI by 3.7 kg/m2 (P < .001) or approximately 10% (P < .01) compared to the other groups, when controlled for sex, race, and age. Conclusions This study confirms that when controlled for sex, age, and race there is an independent association of higher BMI among patients with APL compared to patients with ALL, AML, and hospitalized individuals without leukemia in the same community