Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: Result of the randomized MRC trial

All-trans retinoic acid (ATRA) is an essential component of the treatment o f acute promyelocytic leukemia (APL), but the optimal timing and duration r emain to be determined. Molecular characterization of this disease can refi ne the diagnosis and could be potentially useful in monitoring response to treatment. Patients defined morphologically to have APL were randomized to receive a 5-day course of ATRA before commencing chemotherapy or to receive daily ATRA commencing with chemotherapy and continuing until complete remi ssion (CR). The chemotherapy was that used in current MRC Leukaemia Trials. Outcome comparisons were by intention to treat with additional analysis fo r relevant risk factors. Patients were characterized by molecular technique s for the fusion products of the t(15;17) and monitored by reverse transcri ptase-polymerase chain reaction (RT-PCR) during and after treatment, Two hu ndred thirty-nine patients were randomized. Treatment with extended ATRA re sulted in a superior remission rate (87% v 70%, P < .001), due to fewer ear ly and induction deaths (12% v 23%, P = .02), and less resistant disease (2 % v 7%, P = .03), which was associated with a significantly more rapid reco very of neutrophils and platelets. Extended ATRA reduced relapse risk (20% v 36% at 4 years, P = .04) and resulted in superior survival (71% v 52% at 4 years, P = .005). Presenting white blood cell count (WBC) was a key deter minant of outcome. The 70% of patients who presented with a WBC less than 1 0 x 10(9)/L had a better CR (85% v 62%, P = .0001) and reduced relapse risk (22% v 42%, P = .002) and superior survival (69% v 43%, P < .0001). Within the low count group, extended ATRA resulted in a better CR (94% v 76%, P = .001), reduced relapse risk (13% v 35%, P = .04), and improved survival (8 0% v 57%, P = .0009), There was no evidence of benefit in patients presenti ng with a higher WBC (>10 x 109/L). Molecular monitoring after the third ch emotherapy course had a correlation with risk of relapse. The relapse risk was 57% if the RT-PCR was positive versus 27% if the PT-POP was negative (P = .006). APL patients who present with a low WBC derive substantial benefi t from combining ATRA with induction chemotherapy until remission is achiev ed, whereas patients with a higher WBC did not benefit. Molecular character ization of disease can improve diagnostic precision and a positive RT-PCR a fter consolidation identifies patients at a higher risk of relapse. (C) 199 9 by The American Society of Hematology.