Secondary acute leukaemias with 11q23 rearrangement: clinical, cytogenetic, FISH and FICTION studies

Abstract

Three patients with secondary acute leukaemia after treatment with topoisomerase II inhibitor agents are described. Two patients had acute myeloid leukaemia (AML). FAB M5a, one had pro-B-acute lymphoblastic leukaemia (ALL). The interval between initiation of chemotherapy and the onset of secondary acute leukaemia was 19-20 months. 11q23 rearrangements were detected in all cases. They were due to translocations t(11;19) (q23;p13.3), t(11;16)(q23;p13) and t(4;11)(q21;q23), respectively. Fluorescence in situ hybridization (FISH) with Yeast Artificial Chromosome (YAC) probe 13HH4 spanning the ALL-1 gene on 11q23 confirmed that in each case the ALL-1 gene had been disrupted by the translocations. The study underlined the relationship between the development of secondary acute leukaemias with 11q23 rearrangement and previous chemotherapy with topisomerase II inhibitor agents. So far, however, only six adult patients with secondary ALL with t(4;11) after treatment with topoisomerase II inhibitor agents have been reported. All with t(4;11) mostly occurs in infants or young children. Our patient received epirubicin continuously for >19 months. This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL-1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors. Thus they may have a common biological background. This hypothesis was substantiated by means of combined immunophenotyping and FISH (FICTION). In the case of AML M5a with t(11;19), the tumour cells with ALL-1 rearrangement expressed CD34. Moreover, the pro-B-ALL with t(4;11) was CD34 positive. These findings suggest that the cell of origin of secondary AML and ALL with 11q23 rearrangement is an immature haemopoietic progenitor cell.

Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities

“…Showing that treatment may exclude topoisomerase II inhibitors [12][13][14] or may include only an intercalating topo II inhibitor combined with alkylating agents with radiation 15 or alone. 16 The present study suggests that secondary hematological malignancies with 11q23 abnormalities may arise following a wider variety of treatment regimens than initially supposed. In particular, prior treatment with anthracyclines appeared to be at least as important as the use of epipodophyllotoxins.…”

“…In particular, patients treated with topo II inhibitors have been shown to have the shortest latent periods of 2-3 years, 8,16 compared with 5-10 years following treatment with alkylating agents and 6-8 years following radiation treatment. 2,8 Among the Workshop patients, one of the shortest latent periods (10 months) followed treatment with an alkylating agent and antimetabolite for myeloma while the longest latent period (8 years) for patients for whom treatment was known followed treatment of ovarian carcinoma with epipodophyllotoxin, anthracycline, alkylating agents and other drugs.…”

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

“…5 The present finding of treatment-related leukemias in approximately 5% of the cases was also expected, although only a few studies have focused on therapy-associated ALL with 11q23/MLL rearrangements, as opposed to the well-known association between secondary AML and exposure to DNA topoisomerase II inhibitors. 56,57 A review of the literature, however, reveals that all published therapy-associated t(4;11)-positive ALL, in which treatment was specified, had received chemotherapy targeting DNA topoisomerase II, ie etoposide, teniposide, doxorubicin, epidoxorubicin and mitoxantrone. 5 A detailed discussion on therapy-related 11q23 malignancies collected by the Workshop, including the present 10 cases, is found in Secker-Walker et al 58 The majority of the 183 cases of leukemia displayed t(4;11) as the sole change; additional, or secondary, changes were seen in only 30% of the cases (Table 1).…”

Detection of CBP rearrangements in acute myelogenous leukemia with t(8;16)

“…Preliminary results indicated that the MLL gene, on chromosome band 11q23, is one of the two partner genes in the t-AML with t(11;16). [17][18][19] The MLL gene (for mixed lineage leukemia), also known as ALL-1, HRX, or Htrx-1, has been shown to participate in many recurring rearrangements (reviewed in Ref. 20).…”