A case of therapy-related acute myeloid leukemia with a normal karyotype after sustained molecular complete remission of acute promyelocytic leukemia.

Dear editor,

Given that the current therapeutic regimen for acute promyelocytic leukemia (APL) includes idarubicin (a topoisomerase II inhibitor) and methotrexate (an alkylating agent), therapy-related acute myeloid leukemia (t-AML) can develop after APL treatment, and several cases have been reported to date [1-13]. Most of these cases involved the development of secondary clonal cytogenetic abnormalities following successful treatment of APL, and, to our knowledge, only 2 cases involving a normal karyotype at t-AML diagnosis have been reported [5, 12]. We report a rare case of t-AML with a normal karyotype after sustained molecular complete remission of APL.

A 58-yr-old man was admitted in January 2010 because of gingival bleeding and thrombocytopenia. His hemogram results were as follows: White blood cell (WBC) count, 11.4×109/L; Hb, 12.3 g/dL; and platelets, at 51×109/L. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were within the reference range (12.5 sec for PT and 25.8 sec for aPTT). The fibrinogen level was decreased (156 mg/dL), and the levels of both D-dimer and fibrinogen degradation product were increased (23.0 µg/mL and 43.9 µg/mL, respectively). A peripheral blood smear showed a large number of blasts (60%) with abundant cytoplasmic granules, and bone marrow (BM) aspiration revealed a scattered distribution of blasts (60%) and abnormal promyelocytes (16%) with occasional Auer rods. The patient's karyotype was 46,XY,t(15;17;19)(q22;q21q13.3)[20], consistent with APL with a t(15;17) variant clone. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect a breakpoint cluster region 1 (bcr1) isoform of the PML-RARα fusion transcript. The PML-RARα fusion transcript was quantified in the BM sample, using the Real-Q PML-RARα Quantification kit (BioSewoom, Seoul, Korea), showing a PML-RARα/ABL ratio of 0.91. On the basis of these results, the patient was diagnosed as having APL, and induction chemotherapy with idarubicin (10 mg/m2 for 4 days) and ATRA (200 mg/m2 for 7 days) was administered. After 4 weeks of treatment, the patient acquired complete remission (CR) and his PML-RARα/ABL quantification ratio reduced to 0.006. He was finally assessed as negative in April 2010. Maintenance chemotherapy with methotrexate (15 mg/m2 per week) and 6-mercaptopurine (90 mg/m2 per day) was administered for 20 months, and the PML-RARα fusion transcript was not detected for 32 months.

In March 2013, the patient was re-admitted because of the presence of blasts in the blood. The morphology of blasts in the peripheral blood (37%) and BM (23.2%) (large amount of cytoplasm without azurophilic granules) was different from that noted at diagnosis of APL. The HemaVision (DNA Technology, Aarhus, Denmark) result was negative for all detectable fusion transcripts. The patient's karyotype had changed to 46,XY[20], indicating a loss of the APL clone, and the assay for PML-RARα in both peripheral blood and BM samples was also negative. On the basis of these findings, the patient was diagnosed as having t-AML with a normal karyotype, relapsed as the FAB M2 subtype. Comparison of the characteristics of two previously reported t-AML cases with a normal karyotype after sustained molecular CR of APL and our case is summarized in Table 1.

Table 1

Comparison of the characteristics of two previously reported t-AML cases with a normal karyotype after sustained molecular complete remission of acute promyelocytic leukemia and the present case

Abbreviations: APL, acute promyelocytic leukemia; t-AML, therapy-related acute myeloid leukemia; F, female; M, male; CR, complete remission; SCT, stem cell transplantation.

The median time from molecular CR of APL to the development of t-AML has been reported to be 43 months (range, 17-68 months) [13], and the latency period (32 months) from the achievement of molecular CR to the development of t-AML was similar in the present case. Patients who developed t-AML have been reported to show partial or complete deletion of chromosome 5 or 7, which is associated with prior alkylating agent therapy in most cases [4, 5, 12, 14]. Balanced translocations involving MLL/11q23 regions, which are associated with prior topoisomerase II inhibitor therapy, have been observed in some cases [12]. Most cytogenetic abnormalities described in reported cases of t-AML derived after APL treatment are high-risk abnormalities (e.g., monosomy 5, monosomy 7, and complex karyotype) [6-13]. Therefore, cases of t-AML with a normal karyotype after sustained molecular CR of APL are thought to be extremely rare, and only 2 such cases have been reported to date [5, 12]. In conclusion, we report a rare case of t-AML with a normal karyotype after sustained molecular CR of APL.