Current Use of Asparaginase in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Abstract

Pediatric Acute Lymphoblastic Leukemia (ALL) cure rates have improved exponentially over the past five decades with now over 90% of children achieving long-term survival. A direct contributor to this remarkable feat is the development and expanded understanding of combination chemotherapy. Asparaginase is the most recent addition to the ALL chemotherapy backbone and has now become a hallmark of therapy. It is generally accepted that the therapeutic effects of asparaginase is due to depletion of the essential amino acid asparagine, thus occupying a unique space within the therapeutic landscape of ALL. Pharmacokinetic and pharmacodynamic profiling have allowed a detailed and accessible insight into the biochemical effects of asparaginase resulting in regular clinical use of therapeutic drug monitoring (TDM). Asparaginase's derivation from bacteria, and in some cases conjugation with a polyethylene glycol (PEG) moiety, have contributed to a unique toxicity profile with hypersensitivity reactions being the most salient. Hypersensitivity, along with several other toxicities, has limited the use of asparaginase in some populations of ALL patients. Both TDM and toxicities have contributed to the variety of approaches to the incorporation of asparaginase into the treatment of ALL. Regardless of the approach to asparagine depletion, it has continually demonstrated to be among the most important components of ALL therapy. Despite regular use over the past 50 years, and its incorporation into the standard of care treatment for ALL, there remains much yet to be discovered and ample room for improvement within the utilization of asparaginase therapy.

PEGylated recombinantAplysia punctataink toxin depletes arginine and lysine and inhibits growth of tumor xenografts

“…(3) A prime example of amino acid depletion cancer therapy is the treatment of leukemias asparaginase curing more than 90% of pediatric acute lymphoblastic leukemia patients. (4)…”

“…(3) A prime example of amino acid depletion cancer therapy is the treatment of leukemias asparaginase curing more than 90% of pediatric acute lymphoblastic leukemia patients. (4) Since APIT depletes the essential amino acid lysine and the semi-essential amino acid arginine (26), both activities interfere with tumor cell amino acid metabolism. Besides increased need of proliferating cells for lysine, the enzymes involved in de novo synthesis of arginine, argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL) are frequently deregulated in cancer cells (5,6), leading to arginine auxotrophies in many different tumor cells (for review see ( 9)) This metabolic Achilles heel of tumor cells can be used for therapeutic approaches based on the activities of APIT.…”

“…Treatment with asparaginase cures more than 90% of pediatric acute lymphoblastic leukemia patients. (3,4) Another highly discussed therapeutic approach is the depletion of arginine in arginine auxotroph tumors. Auxotrophy to the semi-essential amino acid arginine occurs through epigenetic silencing of arginosuccinate synthetase 1 (ASS1) or arginine lyase (AL) genes, preventing the synthesis of arginine through citrulline in the urea cycle.…”

“…Treatment with asparaginase cures more than 90% of pediatric acute lymphoblastic leukemia patients. (3, 4)…”

Case report: Hyperosmolar hyperglycemic syndrome secondary to PEG-asparaginase-induced hypertriglyceridemia and pancreatitis

“…While asparaginase use has improved survival outcomes in adults, its expanded use also introduced the risk of unique toxicities such as AAP, endocrine dysfunction, and coagulopathy, as well as more common toxicities such as hyperglycemia and hepatotoxicity ( 15 , 16 ). Asparaginase exhibits a similar toxicity profile in AYA/adult patients as in pediatric patients; however, pediatric patients experience lower rates of toxicity than their adult counterparts ( Table 2 ) ( 17 , 18 ).…”