Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients

Abstract

Summary:The incidence of secondary myelodysplasia/acute myeloid leukemia (AML) was retrospectively assessed in an international joint study in 305 node-positive breast cancer patients, who received mitoxantrone-based high-dose chemotherapy (HDCT) followed by autologous stem cell support as adjuvant therapy. The median age of the patients was 57 years (range 22-67). In all, 268 patients received peripheral blood stem cells, and 47 patients received autologous bone marrow. After a median followup of 57 months (range 10-125), three cases of secondary AML (sAML) were observed, resulting in a cumulative incidence of 0.94%. One case of sAML developed 18 months after HDCT (FAB M3) The karyotype was translocation 15;17 and, after induction therapy, the patient underwent autologous stem cell transplantation, and is in complete remission (CR) of both breast cancer and AML. The second patient developed AML (FAB M4eo with inversion 16) 5 months after HDCT. This patient achieved CR after induction therapy, but died of infectious complication. A third patient developed AML (FAB M4) 6 months after HDCT. She achieved CR after induction therapy, but relapsed and expired 28 months after diagnosis of AML. sAML after mitoxantrone-based HDCT is a possible, but rare complication in breast cancer patients. Bone Marrow Transplantation (2003) 32, 1153-1157. doi:10.1038/sj.bmt.1704291 Keywords: high-dose chemotherapy; adjuvant therapy; breast cancer; mitoxantrone; secondary AML Secondary myelodysplasia (MDS) or acute myeloid leukemia (AML) in breast cancer patients is a rare but wellknown long-term complication of prior chemotherapy or radiation therapy as adjuvant therapy. 1-3 Specific risk factors are the combinations of chemotherapy and radiation therapy, the cumulative dose of alkylating agents and the duration of therapy. 2 Two different types of treatmentrelated leukemia can be distinguished. The first type results from prior therapy with alkylating agents or radiation therapy, and occurs after a latency period of 5-7 years. This type of AML is often preceded by a preleukemic period of MDS. Nearly 90% of the patients with alkylating agentrelated MDS or AML show clonal chromosome aberrations including monosomy or deletions on chromosomes 5 and/or 7 or complex aberrations involving chromosomes 3, 12, 17, and 21. 4 The second type of therapy-related leukemia is induced by topoisomerase II-targeted drugs like etoposide, anthracyclines or, recently, anthracenediones. [5][6][7] This type of AML usually occurs after a median of 2 years and is not preceded by a myelodysplastic syndrome. According to the French-American-British (FAB) classification, more frequently, M4 or M5 subtype is observed and cytogenetic analysis showed a high frequency of rearrangements of the chromosome band as 11q23, translocation (t)(8;21), t(15;17), inversion 16 (inv(16)) or t(8;16), as in de novo AML. 5,8 Recently, several studies indicated that adjuvant chemotherapy consisting of the anthracenedione mitoxantrone, a topoisomerase II-targeted drug, may induce sec...

Aberrations in chromosomes associated with lymphoma and therapy‐related leukemia in benzene‐exposed workers

“…Alternatively, benzene metabolites may act more like dioxopiperazine and quinone topoisomerase II inhibitors than epipodophylotoxin inhibitors such as etoposide [Eastmond et al, 2005]. The former tend to induce leukemias with translocations t(8;21), inv(16), and t(15;17), and rarely t(11q23) [Xue et al, 1992;Zhang et al, 1993;Bhavnani and Wolstenholme, 1987;Kroger et al, 2003;Mistry et al, 2005]. Our previous finding of higher levels of t(8;21) in benzene-exposed workers ] is in agreement with this hypothesis, and the idea that benzene metabolites may induce leukemia in a manner similar to piperazine and quinone drugs warrants further exploration.…”

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

“…2 On the other hand, clinical and experimental data collected over the past decades suggest that MM could be successfully treated through (cellular) immunotherapy. 3,4 The curative potential of cellular immunotherapy in MM is illustrated by the induction of long-term sustained remissions after allogeneic stem cell transplantation or donor lymphocyte infusions in a subset of patients. 5,6 A highly appealing and more specific immunotherapy strategy for cancer is the adoptive transfer of cytotoxic T cells that are genetically engineered to express chimeric antigen receptors (CAR).…”

Does autologous transplantation directly increase the risk of secondary leukemia in lymphoma patients?

“…Despite differences in how these incidences were calculated (actuarial versus cumulative incidences), a risk of up to 10% for t-AML/MDS in patients who underwent ASCT for NHL was found when all studies through 1999 were considered together in a recent meta-analysis. 48 An increased risk of t-AML/MDS has also been seen in patients following ASCT performed for other indications such as breast cancer, 49,50 multiple myeloma 51 and germ cell tumors. 52 In general, the rate of t-AML/MDS seen after ASCT for these disorders is substantially lower than that observed in lymphoma patients who have undergone ASCT.…”

“…55 This again suggests that pre-ASCT lymphoma therapy leads to genotoxic damage, which then causes the emergence of abnormal hematopoietic clones associated with t-AML/MDS. MDS and AML have been reported after transplantation for other malignancies, such as breast cancer, 49,50 multiple myeloma 51 and germ cell tumors. 52 The University of Arkansas group reported seven cases of MDS among 188 patients who underwent ASCT for myeloma.…”