Summer 2011

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

[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).]

t-AML Diagnosis and Incidence

  • The presence of ring sideroblasts in the post-therapy setting is not a reliable indication of t-MDS. Ring sideroblasts (RS), a morphological manifestation of abnormal iron metabolism, is a common feature of MDS and is often used to support the diagnosis of t-MDS.  Ok et al. assessed the clinical significance of RS (>15%) in bone marrow as an indicator of t-MDS in the absence of cytogenetic abnormalities or increased myeloblasts (<5%) in a retrospective study of 19 patients who fit this criteria.  Although most patients with a significant level of RS had t-MDS, RS was reversible in approximately one third of the patients, possibly because of exposure to RS-causing medications.  (Ok, et al.  Transient/reversible ring sideroblasts in bone marrow of patients post cytotoxic therapies for primary malignanciesLeukemia Res 35:1605-10, 2011.)
  • Myeloablative conditioning with radioimmunotherapy does not increase the risk of t-MDS/t-AML compared to chemotherapy-based conditioning. The long-term toxicity of myeloablative radioimmunotherapy is unknown.  Guidetti et al. evaluated the hematopoietic damage and incidence of t-MDS/t-AML in a prospective study of 53 elderly patients with non-Hodgkin lymphoma (NHL) who received high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with 90Y-ibritunomab tiuxetan.  Accelerated telomere length shortening and limited toxicity on hematopoietic progenitors were observed after a median follow-up time of 49 months.  Four cases of t-MDS/t-AML were identified for a 5-year cumulative incidence of 8.3%, a rate comparable to the incidence observed (8.05%) in a matched group of patients who received analogous treatment without HD-RIT.  (Guidetti, et al.  Myeloablative doses of yttrium-90-ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia. Cancer 117:5074-84, 2011.)

Genetic Abnormalities in t-AML

  • Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct pattern of gene expression in secondary AML. Ten-eleven translocation (TET) proteins catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is thought to play a role in epigenetic gene regulation.  Mutations and deletions of TET2 are found in a wide range of myeloid malignancies, including secondary AML.  In a small series of 30 patients with secondary AML, Konstandin et al. observed that patients who had TET2 mutations had low 5hmC levels, and patients with low 5hmC levels had a lower degree of gene deregulation compared to patients with high 5hmC levels.  These observations suggest that 5hmC levels may be useful for identifying t-AML subtypes. Editor’s Note: This series included 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.  (Konstandin et al.  Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia. Leukemia 25:1649-52, 2011.)
  • TET2 mutational status does not influence the prognosis of secondary AML. The impact of ten-eleven translocation 2 (TET2) mutations on therapeutic response in t-AML is unknown.  Kosmider et al. analyzed TET2 mutations in a retrospective study of 247 cases of secondary AML, consisting of patients with MDS or MPN progressing to AML (considered a natural progression of the disease) and patients with t-AML.  TET2 mutations were detected in 19.8% of patients and found less frequently in patients with t-AML (8.7%) compared to patients with MDS/MPN progressing to AML (22.3%). Remission and overall survival rates were not influenced by TET2 mutational status.  (Kosmider et al.  TET2 mutations in secondary acute myeloid leukemias: a French retrospective study. Haematologica 96:1059-63, 2011.)

t-AML Treatment and Outcomes

  • A new prognostic scoring system for secondary AML may facilitate differential therapeutic strategies. General prognostic factors such as age and cytogenetic pattern are well-established for AML, but not for secondary AML.  Stolzel et al. evaluated factors influencing overall survival and event-free survival in a retrospective study of secondary AML, which included 233 patients with MDS progressing to AML (considered a natural progression of the disease) and 72 patients with t-AML.  Absolute platelet count and nucelophosmin 1 mutational status at diagnosis were identified as prognostic factors and used to develop a scoring system that divided patients into high-, intermediate-, and low-risk subgroups.  The prognostic scoring system was validated in an independent series of secondary AML patients.  (Stolzel et al.  Risk stratification using a new prognostic score for patients with secondary acute myeloid leukemia: results of the prospective AML96 tria. Leukemia 25: 420-428, 2011.)