Risk of secondary leukemia after treatment with etoposide VP-16) for Langerhans cell histiocytosis in Italian and Austrian-German populations

Abstract

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 G4,000 mg/m 2 . Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17. Int. J. Cancer, 71:9-13, 1997.r 1997 Wiley-Liss, Inc.

Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience

“…As to the pathogenetic role of previous treatments, the importance of chemotherapy including topoisomerase II inhibitors has been reported by several authors. [6][7][8][9][10][11][12] These drugs had been employed for the treatment of PMs in 11 (22%) of our patients. A high proportion of patients in our study (53%) had previously been treated with radiotherapy (alone or combined with chemotherapy) for their PMs.…”

“…[1][2][3] For example, consistent karyotypic changes are reported in AL-st patients receiving alkylating or topoisomerase II inhibitors for their PM. [4][5][6][7][8][9][10][11] In addition, a significant fraction of AL-st's develop in patients who had previously received radiotherapy with or without chemotherapy. Together, these AL-st's are also referred to as therapy-related ALs.…”

Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification

“…It was not possible to distinguish between disease-induced and therapy-related hematopoietic and hepatic toxicity. One patient developed an atypical acute myeloid leukemia with monosomy 7 at 11 months after diagnosis and a relatively low cumulative dose of 1350 mg/m 2 VP-16, raising the question as to whether the leukemia was treatment related 29,30 or a separate process. 31 …”

Etoposide-related acute promyelocytic leukemia

“…23 Clinical profiles of 17 cases with etoposide-related APL reported in the literature are given in Table 1. 20,21,[24][25][26][27][28][29][30][31][32] The close association was demonstrated between the treatment with etoposide for Langerhans cell histiocytosis (LCH) and the development of t-APL. The primary tumor was a LCH in nine cases; in three of four Japanese patients and four of five Italian patients, no therapeutic agents other than prednisolone and vinblastin had been used in addition to etoposide.…”