General AML

Secondary AML: Biology and therapy- Educational session at the 2017 ASCO Annual Meeting

An Educational Session took place during the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting on Tuesday 6th June 2017. During this session,  emerging treatment options for Acute Myeloid Leukemia (AML) subsets were discussed. This enthralling session chaired by Richard M. Stone, MD, from the Dana-Farber Cancer Institute, USA.  

The final talk in this educational session was given by Bruno C. Medeiros, M.D., Stanford School of Medicine, in which the biology and therapy of Secondary AML (sAML) was discussed.1

According to the revised 2016 World Health Organization Classification of myeloid neoplasms, sAML is categorized as AML with myelodysplasia related changes and it is defined as AML diagnosed after a history of antecedent Myelodysplastic Syndrome (MDS)/Myeloproliferative Neoplasms (MPN).

sAML accounts for 20–30% of AML, occurring mostly in older patients (median age at diagnosis = 73 years). Genetic evolution studies of sAML has revealed evidence of sub-clonal disease progression, with persistence of the founding MDS clone. This is characterized by serial acquisition of new AML defining driver gene mutational events. Interestingly, there was no single genomic event that consistently occurs during transformation to sAML. However, a number of diverse somatic mutations can contribute to the transformation to sAML including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2.

The talk was then focused on therapy for sAML. Recent analysis of survival of sAML patients was compared with patients with de novo AML and stratified according to treatment intensity including intensive, non-intensive, and low-intensive therapy. Results of the study showed that patients with sAML have a worse 1-year survival compared to patients with de novo AML. Additionally, sAML can be grouped further into two prognostic groups, including those whose AML follows antecedent MDS, and those with prior MPN. Conversely, age and cytogenetic risk classification retained independent prognostic value in sAML.

Furthermore, in order to incorporate all the prognostic variables that are present in patients with sAML, the Study Alliance Leukemia Study Group developed and validated a prognostic model in sAML patients following treatment with intensive induction therapy. Platelets at diagnosis (HR = 1.95, P < 0.001), NPM1 mutation at diagnosis (HR = 1.75, P = 0.03), age (HR = 1.37, P = 0.025), and cytogenetic risk group (HR = 1.15, P = 0.04) were independently associated with worse outcomes for sAML patients. Using a scoring system, sAML patients were split into three cohorts: favorable-, intermediate-, and high-risk groups. Patients in the high-risk group had a significantly worse OS compared to favorable- and intermediate-risk groups.

The speaker then discussed a phase III randomized study of CPX-351 in older AML patients. In total, 309 newly diagnosed AML patients (60–75 years) were randomized to receive either CPX-351 (n = 153) or 7+3 (cytarabine and daunorubicin, n = 156) induction therapy. The key results of the study were:

  • Median Overall Survival (OS) in patients receiving CPX-351 and 7+3; 9.56 vs 5.95 months, HR = 0.69, P = 0.005

CPX-351 improved the survival in older patients with AML. Additionally, there was a significant benefit for CPX-351 observed in patients who underwent allogenic stem cell transplantation.

Bruno C. Medeiros concluded by highlighting that preclinical results have led to unprecedented advances in understanding the biology and the development of novel therapies for sAML. However, the speaker suggested that future studies should be focused on understanding the role of minimal residual disease in sAML.

References
  1. Medeiros B.C. Biology and Therapy of Secondary Acute Myeloid Leukemia: Any Progress?. 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.