Idarubicin and ATRA Is as Effective as MRC Chemotherapy in Patients with Acute Promyelocytic Leukaemia with Lower Toxicity and Resource Usage: Preliminary Results of the MRC AML15 Trial.

The UK MRC AML12 Trial in Acute Promyelocytic Leukaemia was conducted between 1994 and 2002 and involved the simultaneous administration of ATRA with standard chemotherapy (Daunorubicin/Etoposide/Ara-C) until complete remission. This approach resulted in an overall survival at 5 years of 80% for patients given long ATRA; however it was associated with prolonged periods of neutropenia, days on antibiotics and hospitalisation. In the successor trial, AML15, which recruited 291 patients between May 2002 and June 2007 from 90 treatment centres, the same treatment was compared with the Idarubicin/ATRA approach developed by the Spanish PETHEMA Group. Patients under 60 years of age were randomised to receive either the MRC Arm (four treatment courses ADE/ADE/MACE and MidAC with ATRA given for the first 60 days of treatment) or the Spanish Arm (two courses of Idarubicin/ATRA followed by two courses of Mitoxantrone/ATRA, and then 18 months of maintenance. In course 3 of each arm patients are randomised to receive, or not, Gemtuzumab Ozogamicin (GO) on day 1. Since it was considered unlikely that sufficient patients would be available to demonstrate any effectiveness difference the primary endpoints were toxicity, neutropenic days, days on antibiotics, hospitalisation, supportive care requirements and Quality of Life which was measured at baseline, and 3, 6, 12 and 24 months from entry using the EORTC QLQ30, plus leukaemia module, and Hospital Anxiety and Depression Score.

Results: No difference in CR was seen (91% MRC vs 93% Spanish; OR 0.73, 95%CI 0.30–1.77, p=0.5); 10 vs 8 patients died during induction and 1 patient in each arm had resistant disease. Five (MRC) vs 6 (Spanish) patients have relapsed. More patients (n=11) in the MRC arm died in CR than in the Spanish arm (n=2) (p=0.009). Overall survival, with a median follow up of 24 months, was not significantly different (85% Spanish vs 81% MRC at 4 years; HR 0.57 95% CI 0.29–1.11, p=0.10). The MRC treatment was significantly more myelosuppressive which resulted in significantly greater need for blood product support, days on antibiotics and hospitalisation, particularly in the second course (p<0.0001). The randomisation to GO in course 3 continues. Preliminary analysis of the quality of life data suggests a benefit for Spanish therapy during the induction/consolidation phase, but with some adverse impact during the maintenance phase.

Conclusion: We confirm that the Spanish combination of Idarubicin and ATRA is as effective as the more intensive MRC chemotherapy based approach. The extra chemotherapy involved in the MRC approach increased supportive care requirements and resulted in an excess of deaths in CR and an adverse impact on quality of life. We will now compare the Idarubicin/ ATRA treatment with the chemotherapy free combination of ATRA/ Arsenic Trioxide.