Acute Promyelocytic Leukaemia APML4 Protocol

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia that is characterized by distinct clinical and laboratory abnormalities. It is associated with a striking risk of early death due to bleeding. Fortunately, the outcome for patients with APL has improved dramatically following the introduction of all-trans retinoic acid (ATRA) and its combination with chemotherapeutic drugs such as idarubicin. Patients with a white cell count > 10 x 109/L at diagnosis are at particularly increased risk of early death and of relapse (disease recurrence). Arsenic trioxide (ATO) has proved to be even more effective than ATRA as a single agent, and is now routinely used for the treatment of the 20%–30% of patients who relapse after initial treatment with ATRA and chemotherapy. ATO has a side-effect profile that is substantially different from both ATRA and chemotherapy. In the APML4 trial, members of the Australasian Leukaemia and Lymphoma Group (ALLG) combined the 3 most active drugs used for APL (ATRA, idarubicin, and ATO) in induction, and then consolidated the responses with 2 cycles of ATRA and ATO without chemotherapy. This strategy helped reduce the total amount of chemotherapy compared with many other protocols available, in the hope of reducing long-term side effects such as bone marrow damage and heart damage. Two years of maintenance was used as per the ALLG standard practice for APL. The results were very impressive. One hundred and twenty-four evaluable patients were enrolled between Nov 2004 and Sep 2009, and the outcomes were reported in 2 publications (Blood 2012, Lancet Haematology 2015). The early death rate was 3%, and 95% of patients achieved complete remission after induction with ATRA, ATO and idarubicin. All 112 patients who started consolidation achieved molecular remission (no detectable leukaemia by a very sensitive molecular assay). The long term results that were reported in Lancet Haematology showed that the relapse rate at 5 years was only 5%. Patients traditionally regarded as at very high risk of relapse had the same low relapse rate as patients who were in the standard risk category, and this was a major achievement of the APML4 treatment plan. Overall, 94% of patients were still alive at 5 years. When the results were compared with the ALLG’s previous APML3 trial (which did not include ATO), the results were substantially better with less relapses and better overall survival. Although side effects occurred, as in every clinical trial for leukaemia, the overall side effect profile was widely acknowledged as acceptable (ie. not excessive).