Therapy-related myeloid leukemia

Abstract

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are thought to be the direct consequence of mutational events induced by chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities, given for a pre-existing condition. The outcomes for these patients have been poor historically compared to people who develop de novo AML. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-AML. Survival varies according to cytogenetic risk group in t-AML patients, with better outcomes being observed in those with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. A deeper understanding of the factors that predispose patients to the development of therapy-related myeloid leukemia would help clinicians monitor patients more carefully after treatment for a primary condition. Ultimately, this knowledge could influence initial treatment strategies with the goal of decreasing the incidence of this serious complication.

Figure 1. Characteristic but non-specific cytologic changes are observed in therapy-related myeloid leukemias

Trilineage dysplasia seen in the peripheral blood and bone marrow from a 38 year old male survivor of Hodgkin disease, who had been treated with chemotherapy, radiation, and an autologous stem cell transplant. The patient was asymptomatic until presentation with a macrocytic anemia and thrombocytopenia, five years after his diagnosis of Hodgkin lymphoma and three years after autologous stem cell transplant. A bone marrow biopsy revealed trilineage dysplasia and fewer than 5% myeloblasts, consistent with a diagnosis of therapy-related myelodysplasia. Karyotype analysis revealed a loss of chromosome 7, consistent with alkylating agent-induced disease. (A–C) Dysplasia in the peripheral blood. (A–B) Dysplastic neutrophils have hypolobated, hypercondensed chromatin and hypogranular cytoplasm. The cell shown in A has a pseudo-Pelger Huet nucleus. (C) A multinucleated abnormal erythroid precursor in the peripheral blood. (D–G) Dysplasia in the bone marrow. (D) An abnormal multinucleated erythroid cell with basophilic stippling (arrowheads). (E–F) Micromegakaryocytes with abnormal separation of nuclear lobes. Photomicrographs courtesy of Dr. Ozden Ozer, The University of Chicago Department of Pathology.

Figure 2. Genetic pathways identified in 140 cases of t-MDS and t-AML by Pedersen-Bjergaard et al

At least eight genetic pathways could be distinguished among 140 cases of therapy-related myeloid malignancies. Pathways I and II are characteristic of patients who had been treated previously with alkylating agents. Mutations of AML1, p53, and RAS are common in patients with abnormalities of 7q or –7. Pathways III–VI are often seen in patients who had received topoisomerase II inhibitors. By definition, any myeloid leukemia arising after prior chemo- or radiotherapy is considered therapy-related. However, because there are few characteristic chromosomal changes or genetic mutations seen in leukemias described by Pathways VII and VIII, these may actually represent de novo cases, or cases in which the underlying genetic defect has not yet been elucidated. RAS mutations are commonly seen in the transition to t-AML within Pathway I, in t-AMLs with MLL rearrangements (Pathway III), and in t-AMLs with a normal karyotype (Pathway VII). Reprinted with permission.

Figure 3. Decision tree for the management of t-AML