2010

These publications highlight recent findings in t-AML by researchers around the world:

t-AML Diagnosis and Incidence

  • The World Health Organization (WHO) uses the term ‘therapy-related myeloid neoplasms’ (t-MN) to cover a spectrum of therapy-related disorders:

-   Acute myeloid leukemia (t-AML);

-   Myelodysplastic syndromes (t-MDS); and

-   Myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN).

Two distinct groups of t-MN are recognized based on the nature of cytotoxic therapy:

-   Approximately 75% of t-MN cases develop after exposure to alkylating agents (such as cyclophosphamide, cisplatin, and chlorambucil) and/or ionizing radiation.  These patients have a relatively long latency period (5-10 years after exposure) and show geneticabnormalities involving the loss of chromosomes 5 and/or 7.  They are typically diagnosed with t-MDS, and in most cases, rapidly progress to t-AML.

-   The remaining cases of t-MN arise after exposure to topoisomerase II inhibitors (such asetoposide and doxorubicin).  These cases are associated with genetic abnormalities including balanced chromosomal translocations involving 11q23 or 21q22.  Patients in this group show signs of t-AML in a relatively short period of time (1-5 years after exposure).

(Vardiman et al.  (2008d) Therapy-related myeloid neoplasms. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (eds S.H. Swerdlow, E. Campo, N.L. Harris, E.S. Jaffe, S.a. Pileri, H. Stein, J. thiele & J.W. Vardiman), pp. 127-129.  IARC, Lyon.)

(Yin et al.  Recent advances in the diagnosis and classification of myeloid neoplasms–comments on the 2008 WHO classification. Int J Lab Hematol 32:461-467, 2010.)

Editor’s Note:  Dr. James Vardiman, Director of Hematopathology, Department of Pathology, University of Chicago, is the senior author of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.  Dr. Le Beau served as the cancer cytogeneticist for the WHO classification.  The classifications of t-MN were largely based on data generated at the University of Chicago.

  • Fludarabine combination therapy is associated with a moderate risk of t-MDS/t-AML, especially when used with mitoxantrone, a topoisomerase II inhibitor. Carney et al. investigated the incidence of t-MDS/t-AML in 176 patients treated with fludarabine combination chemotherapy for lymphoproliferative disorders.  Fludarabine has been shown to be highly effective for the treatment of chronic lymphocytic leukemia.  After a median follow-up time of 41 months, 19 cases of t-MDS/AML were identified for an overall incidence rate of 10.8%.  The median overall survival rate following diagnosis was 11 months.  (Carney et al.  Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia 24:2056-2062, 2010.)


Genetic Abnormalities in t-AML

  • Molecular networks enriched in cell cycle and DNA repair genes are implicated in t-AML susceptibility. Cahan et al. employed an integrated genomics strategy using inbred strains of mice to identify genetic and transcriptional factors that may contribute to t-AML susceptibility.  Gene expression data including single nucleotide polymorphisms (SNPs) and DNA copy number variants were analyzed.  More than 900 genes were differentially expressed between disease-susceptible and -resistant strains.  A total of 30 t-AML susceptibility networks enriched with genes involved in cell cycle and DNA repair were identified from this data.  Transcriptional regulators, including Parp2, Casp9, and Polr1b are likely to play a role in the development of t-AML.  (Cahan et al.  Integrated genomics of susceptibility to alkylator-induced leukemia in mice. BMC Genomics 11:638, 2010.)
  • The frequency of chromosomal abnormalities do not appear to differ between de novo AML and t-AML using conventional cytogenetic techniques. Priess et al. investigated cytogenetic aberrations in 161 patients with secondary AML compared with age-and sex-matched patients with de novo AML.  Secondary AML patients included patients with a previous diagnosis of MDS, patients with a previous myeloproliferative neoplasm, and patients with t-AML.  No differences were observed in type or number of abnormalities, ploidy levels, normal and abnormal mitoses, or number of centromeric breakages between patients with secondary AML and patients with de novo AML.  (Preiss et al.  Cytogenetic findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse chromosomal aberrations do not differ from adult de novo AML. Cancer Genet Cytogenet. 202:108-122, 2010.)

Editor’s Note: This series includes patients with MDS or MPN progressing to AML, considered to be the natural course of the disease.  These patients may not have been treated with cytotoxic agents and, as such, are not therapy-related AMLs.

  • Use of a high resolution cytogenomics technique leads to the identification of chromosomal abnormalities more frequently found in t-AML than in de novo AML.Itzhar et al. used high resolution array comparative genomic hybridization (CGH) to evaluate gene copy number abnormalities.  Array CGH is a technique used to analyze variations in genomic copy number at a higher resolution level than conventional cytogenetic techniques.  A higher frequency of copy number abnormalities was observed in 30 t-AML (104) compared to 36 de novo AML (69) samples.  Chromosomal abnormalities found more frequently in t-AML included 7q21 or 7q33 deletions and gain of HOX genes, whereas those found more frequently in de novo AML included gain of 11q24 and amplification of ERG and ETS2 genes on 21q22.  (Itzhar et al.  Chromosomal Minimal Critical Regions in Therapy-Related Leukemia Appear Different from Those of De Novo Leukemia by High-Resolution aCGH. PLoS One 6:e16623, 2011.)

  • DAPK1 methylation is more frequently observed in t-MDS/t-AML than de novo MDS and AML. DNA methylation, an epigenetic change that leads to silencing of tumor suppressor genes, plays a role in the development of cancer.  Greco et al. characterized the methylation pattern of E-cadherin, TSP1, and DAPK1 (all genes that are involved inmalignant cell transformation) in patients with de novo MDS (105 cases), de novo AML (208 cases), and t-MDS/t-AML (72 cases).  Patients with t-MDS/t-AML showed more frequent methylation of DAPK1 and also more frequent hypermethylation of 2 or more genes compared with patients with de novo disease.  Patients with previous lymphoproliferative disease had more frequent methylation of DAPK1, while those who received previous radiotherapy showed more frequent methylation of CDH1.  (Greco et al.Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms. Blood Cells Mol Dis 45:181-185, 2010.)


t-AML Treatment and Outcomes

  • Consideration of 4 risk factors may help identify t-MDS/t-AML patients who are most likely to benefit from allogeneic transplantation. Allogeneic hematopoietic cell transplantation (HCT) is a therapeutic option for patients with t-MDS/t-AML, but is typically restricted to younger patients without comorbidities.  Litzow et al. analyzed the clinical outcome of allogeneic HCT for 868 t-MDS/t-AML patients.  Non-relapse mortality was nearly 50% at 5 years following transplantation.   Poor outcome was associated with age older than 35 years, inadequate disease control during HCT, poor-risk cytogenetics, and less well-matched donors.  Having a combination of these risk factors significantly reduced survival rates.  For example, the five-year survival for patients with 1, 2, 3, or 4 of these risk factors was 26%, 21%, 10%, or 4%, respectively. (Litzow et al.  Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia.Blood 115:1850-1857, 2010.)

  • Age and cytogenetic abnormalities at the time of AML diagnosis are the main determinants of disease outcome. Ostgard et al. determined whether therapy-related AML serves as a prognostic factor for survival by analyzing 630 cases of AML from a Danish registry (77 cases of t-MDS, 43 cases of t-MPN, and 37 cases of t-AML).  The presence of t-AML did not have any prognostic significance in overall survival (OS) or disease-free survival (DFS) for patients in complete remission when data was corrected for other clinical variables, such as the influence of age and cytogenetic findings.   Instead, these 2 clinical variables served as prognostic factors for all patients in complete remission.  These findings suggest that patients with t-AML would benefit similarly from treatment for de novo AML.  (Ostgard et al.  Reasons for treating secondary AML as de novo AML. Eur J Haematol. 85:217-226, 2010.)

  • t-AML is an independent adverse prognostic factor for survival. Kayser et al. assessed the clinical endpoints, relapse-free survival (RFS) and overall survival (OS), for induction chemotherapy in 200 patients with t-AML and 2653 patients with de novo AML.  Independent of other clinical variables, t-AML was an adverse prognostic factor for RFS and OS but not for response to chemotherapy.  Specifically, t-AML was an adverse prognostic factor for death in intensively treated younger patients (i.e., those who have received allogeneic transplantation) in complete remission, and relapse in less intensively treated older patients in complete remission.  (Kayser et al.  The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML.  Blood 117:2137-2145, 2011.)