Secondary cytogenetic changes in acute promyelocytic leukemia - Prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: A Cancer and Leukemia Group B study

Purpose: To examine, in newly diagnosed patients with acute promyelocytic leukemia (APL), the prognostic significance of secondary cytogenetic changes and the relationship between such changes and the two major promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) mRNA types. Patients and Methods: One hundred sixty-one patients with t(15; 17)(q22;q11-12) enrolled onto Cancer and Leukemia Group B (CALGB) protocol 8461, a prospective study of cytogenetics in acute myeloid leukemia (AML), were studied. Eighty of these 161 patients were treated solely with chemotherapy and evaluated for response to treatment and survival. PML- RARα, mRNA type was determined using reverse transcriptase polymerase chain reaction (RT-PCR) in 56 patients. Results: The incidence of secondary cytogenetic abnormalities was 32%. Among 80 patients treated with chemotherapy, the presence of a secondary chromosome abnormality was associated with longer complete remission (CR) duration (median, 29.9 v 15.7 months; P = .03) and longer event-free survival (EFS) duration (median, 17.0 v 12.2 months; P = .03). There was no difference in overall survival (P = .28). In a separate group of 56 patients with both cytogenetic and molecular data, 32 had the type L PML-RARα transcript (intron 6 PML breakpoint). Of these 32 patients, four (12.5%) had chromosome changes in addition to t(15; 17), whereas 12 of 20 patients (60%) with the type S PML-RARα transcript (intron 3 PML breakpoint) had secondary cytogenetic changes (P < .001). Conclusion: (1) Secondary cytogenetic changes do not confer a poor prognosis in APL patients treated with anthracycline/cytarabine (Ara-C)-based chemotherapy; and (2) A highly significant relationship exists between the PML-RARα S isoform (intron 3 PML genomic breakpoint) and secondary cytogenetic changes in APL.