The potential prognostic value of quantitative real-time reverse transcriptionpolymerase chain reaction (RT-PCR [qrt-PCR]) measurements of PML-RAR␣ mRNA in acute promyelocytic leukemia was retrospectively assessed before treatment and at 3 posttreatment intervals in 123 patients on intergroup protocol 0129. The primary measure was the PML-RAR␣ GAPDH normalized quotient (NQ), that is, PML-RAR␣ mRNA copies divided by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA copies. Only samples with more than 2.5 ؋ 10 5 copies of the housekeeping gene GAPDH mRNA (detection sensitivity exceeding 10 4 ) were considered NQ evaluable. With RNA from low-density selected cells, paired peripheral blood (PB) and bone marrow samples (n ؍ 140) had comparable NQs (P < .001). Before treatment, high NQ was associated with short-form PML-RAR␣ (P < .001), but not with white blood cell count or clinical outcome. Following treatment, NQ was lower in all-trans retinoic acidinduced complete remission (CR) than chemotherapy-induced CR (P ؍ .018) and at first test after consolidation chemotherapy (P ؍ .037). After consolidation chemotherapy, patients with NQ exceeding 10 ؊5 had 4.1-fold increased relapse risk (P ؍ .008); however, 73% of patients who experienced relapse had NQ lower than 10 ؊5 . In the follow-up period (FUP), any NQ exceeding 10 ؊5 and 10 ؊6 had 17.5-fold and 7.6-fold increased relapse risk, respectively (P < .001), while no gradation of relapse risk (approximately 18%) could be identified at NQ lower than 10 ؊6 , including NQ ؊ .
Relapse of acute promyelocytic leukemia (APL) following alltrans retinoic acid (ATRA) therapy has been associated with the acquisition of mutations in the high-affinity ATRA binding site in PML-RARa, but little information is available about the selection dynamics of the mutation-harboring subclones. In this study, 6/18 patients treated with sequential ATRA and chemotherapy on protocol INT0129 relapsed with complete replacement of the nonmutant pretreatment APL cell population by a PML-RARa mutant subclone. Two patients relapsed in proximity of ATRA treatment; however, in four patients there was a 6-48 month hiatus between the last ATRA treatment and relapse. The mutant subclones were not detectable in samples tested X3 months before relapse at X1 in 10 2 (10 À2 ) sensitivity. In one patient, a functionally weak mutation was detected at 10 À4 sensitivity before therapy but only limited pre-relapse enrichment of the mutant subclone was observed on subsequent ATRA therapy. These results indicate that proximate ATRA selection pressure is frequently not the main determinant for the emergence of strongly dominant PML-RARa mutant subclones and suggest that APL subclones harboring PMLRARa mutations are predisposed to the acquisition of secondary genetic/epigenetic alterations that result in a growth/ survival advantage.
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