Prognostic Significance of bcr-1 and bcr-3 Isoforms of PML-RARA and FLT3-ITD in Patients With Acute Promyelocytic Leukemia

Abstract

Background: Acute promyelocytic leukemia (APL) has a characteristic peculiar morphologic and genetic features as well as a more favorable outcome. We studied the differential effect of bcr-1 and bcr-3 isoforms of the promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) transcript together with FLT3 internal tandem duplication (FLT3-ITD) mutation status on the outcome of newly diagnosed de novo APL patients.

Patients and methods: This cohort study included all patients diagnosed with APL at outpatient medical and pediatric oncology clinics of the National Cancer Institute, Cairo University, Cairo, Egypt, from May 2012 to January 2018.

Results: The study included 118 patients with APL, 71 adults (60.2%) and 47 children (39.8%). Median (range) age was 25 (1.5-70) years. Children had significantly higher total leukocyte count (≥10 × 10⁹/L), disseminated intravascular coagulation (DIC), and thrombocytopenia (< 40 × 10⁹/L) than adults (P = .04, .03, and .04, respectively), while the latter group had significantly higher hemorrhage than children (P = .04). FLT3-ITD mutation was detected in the whole group, children, and adults in 23.7%, 30.6%, and 24.6%, respectively. FLT3-ITD mutation was significantly associated with leukocytosis in the whole group (P = .039). bcr-3 was significantly associated with FLT3-ITD mutation in the whole APL cohort and in adults (P = .011, P = .022). All children (both bcr-1 and bcr-3) and all adult patients with bcr-3 experienced CR, while 22 (78.5%) of 28 patients with bcr-1 experienced CR (P = .04). APL patients with DIC and hemorrhage had significantly lower overall survival (P = .002 and < .001, respectively). Overall survival for APL in children was significantly better than in adults (P = .005). Multivariate analysis indicated that age was an independent prognostic variable affecting survival (hazard ratio = 2.6; 95% confidence interval, 1.3-5.3; P = .007) (adults had hazard ratio of death 2.6 times higher than children). DIC and FLT3-ITD were independent prognostic variables affecting survival in children with APL (hazard ratio = 12.3; 95% confidence interval, 1.46-104.61; P = .021; and hazard ratio = 5.2; 95% confidence interval, 1.01-26.95; P = .048, respectively).

Conclusion: Age is an independent prognostic factor for APL. bcr-3 is significantly associated with FLT3-ITD in adults with APL. DIC and FLT3-ITD are adverse prognostic factors in children with APL. Despite children being at higher risk, outcome is better than in adults.

Keywords: APL; FLT3-ITD; Prognosis; bcr-1; bcr-3.