Curing acute promyelocytic leukaemia: ‘Blunderbuss, vitamins, and a poison chaser’

Blood cancers

By Tony James

17 Nov 2016

Professor Harry Iland, from Royal Prince Alfred Hospital in Sydney, told the HAA meeting how the treatment of acute promyelocytic leukaemia (APL) has evolved from non-selective ‘blunderbuss’ therapy anthracyclines through the addition of vitamin A-based retinoids and most recently, arsenic.

Delivering the Carl de Gruchy Oration, Professor Iland explained how the cytogenetic and molecular abnormalities causing this highly lethal form of leukaemia had been identified through more than three decades of research.

“APL causes an extraordinarily high rate of early haemorrhagic deaths, and relapse after achieving complete remission can occur,” he said.

Although the early death rate has fallen significantly with modern treatments including haemostatic supportive care, early haemorrhagic death remains an unresolved problem.

“In contrast, the risk of leukaemic relapse has been dramatically reduced through the application of highly effective treatment targeted at the underlying pathophysiological molecular abnormality,” he said.

APL arises from rearrangements of the retinoic acid receptor alpha (RARA) gene, leading to a range of defects in the control of cell differentiation.

The initial approach to treatment was anthracycline-based chemotherapy, especially daunorubicin, using similar protocols to those for acute myeloid leukaemia. Although this improved clinical response rates to about 80%, the death rate during induction was 20-40%, mainly from cerebral or pulmonary haemorrhage.

Bleeding resulted from a combination of thrombocytopenia, a consumptive coagulopathy and primary hyperfibrinolysis.

The addition of all-trans retinoic acid (ATRA) to chemotherapy helped to address the coagulopathy and became established as an essential component of treatment protocols. ‘Retinoic acid syndrome’ caused by ATRA led to complications of capillary leakage including renal failure, but could be controlled by steroids.

The Australasian Leukaemia and Lymphoma Group conducted the series of APML trials which have now influenced clinical practice worldwide. Most recently in APML4 they explored the use of arsenic trioxide, first reported as a potentially effective agent by Chinese medicine practitioners in the 1990s.

APNL4 showed that ATRA, arsenic and reduced-dose idarubicin were effective and well tolerated, and the regimen has been adopted in a number of international APL protocols. Current trials are assessing ATRA plus arsenic alone, with no chemotherapy.

Professor Iland is also involved in developing an oral form of arsenic, to reduce the need for very burdensome regimens of intravenous infusion.

“The remaining challenges in the management of APL primarily involve the development of strategies to reduce early deaths, and the reconfiguration of consolidation protocols to reduce resource use and improve the overall patient experience without sacrificing efficacy,” Professor Iland concluded.

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