Tumour lysis syndrome

Tumour lysis syndrome is a consequence of unusually high levels of tumour cell lysis over a short time period. It may be triggered by the initiation of cancer therapy. Laboratory tumour lysis syndrome is defined as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia in response to therapy. Tumour lysis syndrome is unlikely without the previous development of nephropathy (kidney failure) and a consequent inability to excrete solutes quickly enough to cope with the metabolic load. Clinical tumour lysis syndrome also includes increased creatinine level, seizures, cardiac dysrhythmia, or death. Tumour lysis can also release cytokines that cause a systemic inflammatory response syndrome and often multi-organ failure [1].

Cancers with a high potential for cell lysis include high-grade lymphomas, acute leukaemias, and other rapidly proliferating tumours. During cancer drug development an important aspect of phase I trials is dose escalation (patients receive the same drug but some get a higher concentration than others over a relevant step range). This allows monitoring for safety issues associated with dose such as laboratory tumour lysis syndrome. An example of a drug in which tumour lysis syndrome was found to be an issue at certain doses was Venetoclax for treatment of relapsed chronic lymphocytic leukaemia (CLL) [2].

CLL is characterised by long lived lymphocytes that do not undergo apoptosis due their expressing high levels of BCL2. New lymphocytes are constantly generated under normal circumstances but in CLL without apoptosis to eliminate old lymphocytes load increases beyond normal levels. Venetoclax is a BH3 mimetic which binds BCL2 and releases pro-apoptotic signalling pathways from inhibition. In the phase I study clinical tumour lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumour lysis syndrome did not occur in any of the 60 patients in the expansion cohort [2]. This highlights the risk of clinical tumour lysis syndrome in CLL patients treated with the highly effective Venetoclax. Some experts advise that in the clinic the Venetoclax dose should be increased in increments gradually for each individual patient with careful monitoring [3].

Refs

  1. Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. ‘The Tumor Lysis Syndrome’. New England Journal of Medicine 364, no. 19 (12 May 2011): 1844–54. doi:10.1056/NEJMra0904569.
  2. Roberts, Andrew W., Matthew S. Davids, John M. Pagel, Brad S. Kahl, Soham D. Puvvada, John F. Gerecitano, Thomas J. Kipps, et al. ‘Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia’. New England Journal of Medicine, 6 December 2015, 151206090218007. doi:10.1056/NEJMoa1513257.
  3. ‘Episode 10: New Horizons in Hematology’. Novel Targets Podcast, 7 January 2016. http://noveltargets.com/2016/01/episode-10-new-horizons-in-hematology/.
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