Therapy Related Leukemias: Susceptibility, Prevention and Treatment

Abstract

Acute leukemia is the most frequent therapy-related malignancy. Together with the increasing use of chemo- and radiotherapy, individual predisposing factors play a key role. Most of secondary leukemias can be divided in two well-defined groups: those secondary to the use of alkylating agents and those associated to topoisomerase inhibitors. Leukemias induced by alkylating agents usually follow a long period of latency from the primary tumour and present as myelodysplasia with unbalanced chromosomal aberrations. These frequently include deletions of chromosome 13 and loss of the entire or of part of chomosomes 5 or 7. The loss of the coding regions for tumor suppressor genes from hematopoietic progenitor cells is a particularly unfavourable event, since the remaining allele becomes susceptible to inactivating mutations leading to the leukemic transformation. The tumorigenic action of topoisomerase inhibitors is on the other hand due to the formation of multiple DNA strand breaks, resolved by chromosomal translocations. Among these, chromosome 11, band q23, where the myeloid-lymphoid leukemia (MLL) gene is located, is often involved. Frequent partners are chromosomes 9, 19 and 4 in the t(9;11), t(19;11) and t(4;11) translocations. Younger age, a mean period of latency of 2 years and monocytic subtypes are characteristic features of this type of leukemia. Among patients at risk for secondary leukemia, those with Hodgkin's disease are the most extensively studied, with the major impact of alkylating agents included in the chemotherapy schedule. The same is true for non-Hodgkin's lymphoma, while in multiple myeloma and acute lymphoblastic leukemia determinants are the dose of melphalan and of epypodophyllotoxin, respectively. Patients with breast, ovarian and testicular neoplasms are also at risk, in particular if trated with the association of alkylating agents and topoisomerase II inhibitors. According to the EBMT registry, in patients with lymphoma treated with high-dose therapy and autologous stem cell transplantation the cumulative risk of inducing leukemia at 5 years is 2.6%. Among treatment options, supportive therapy is indicated in older patients, while allogeneic stem cell transplantation, related or matched-unrelated, is feasible in younger patients. These data indicate the need for the identification of predisposing factors for secondary leukemia. In particular, frequent follow-up of patients at high-risk should be performed and any peripheral blood cytopenia should be considered suspicious. Whenever possible, the exclusion of drugs known to be leukemogenic from the treatment schedules should be considered, especially in young patients.

Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ

“…A variety of important anticancer drugs, such as etoposide and doxorubicin, kill cells by acting as topoisomerase II poisons (37,(63)(64)(65)(66)(67). Despite the importance of these compounds in cancer chemotherapy, ∼2-3% of patients that are treated with regimens that include topoisomerase II-targeted agents eventually develop secondary leukemias (58,61,66,(68)(69)(70)(71). Like the infant leukemias, these drug-related malignancies are characterized by rearrangements in the MLL gene (58,61,(68)(69)(70)(71).…”

“…Despite the importance of these compounds in cancer chemotherapy, ∼2-3% of patients that are treated with regimens that include topoisomerase II-targeted agents eventually develop secondary leukemias (58,61,66,(68)(69)(70)(71). Like the infant leukemias, these drug-related malignancies are characterized by rearrangements in the MLL gene (58,61,(68)(69)(70)(71). Agents such as etoposide display potent activity against both topoisomerase IIR and topoisomerase II in vitro and in human cells (72)(73)(74), but the relative contributions of the two enzyme isoforms to either the therapeutic or leukemogenic properties of these drugs are not known.…”

Loss of response to azacitidine is associated with deletion 12p13 in a patient with myelodysplastic syndrome with unique translocation t(13;17)(q12;q25) after prior breast cancer and acute promyelocytic leukemia

“…With increasingly successful treatment of malignancies, therapy-related leukemia (TRL) and myelodysplastic syndrome (MDS) are increasingly observed, especially in association with prior radiotherapy, use of alkylating agents or topoisomerase-II inhibitors [1,2]. They are characterized by lesions of chromosomes 5 and 7 and poor survival (median 7-10 months) [3,4].…”

Double Therapy-related Leukemia: Coincidental Occurrence or Susceptibility for Leukemia?

“…This benefit, however, may unfortunately result in the unpredicted devastating complication of therapy-related leukemia (t-AML) or myelodysplasia (t-MDS) within longterm survivors. Although the reported actuarial incidences of t-AML/MDS development widely vary (2-20% of long-term survivors), they depend mainly on the treatment regimen for the previous malignancy, in addition to individual factors including genetic predisposition, ethnicity, age and gender (1).…”

“…Molecular pathogenesis of chromosomal translocations in t-AML/MDS mediated by topoisomerase II inhibitors is relatively well defined. These inhibitors leave the DNA strands with a permanent break as their pharmacological effect per se, and subsequent chromosomal breakage leads to leukemogenic translocation with a breakpoint within the MLL, AML1 and other genes (1). Meanwhile, molecular mechanisms in the development of chromosomal deletion-type t-AML/MDS are still not clearly defined.…”