General AML

The clinical impact of SAMHD1 in patients with acute myeloid leukemia receiving consolidation chemotherapy with high-dose cytarabine regimens

Response to high-dose cytarabine (ara-C) correlates with the tendency of acute myeloid leukemia (AML) blasts to efficiently accumulate ara-CTP (a major determinant of ara-C efficacy). Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), is a key negative factor limiting ara-CTP accumulation. Moreover, high SAMHD1 mRNA expression levels at diagnosis in patients with AML have been shown to correlate with poor survival. However, it is not known whether SAMHD1 limits the efficacy of ara-C at induction or consolidation.

Researchers at the MD Anderson Cancer Center (MDACC) analyzed two independent and clinically different cohorts of patients with de novo AML to assess whether SAMHD1 protein expression in blasts at the time of diagnosis correlates with clinical endpoints, including complete remission (CR), event-free survival (EFS) and overall survival (OS) as well as the type of ara-C treatment (low or high). The results of the study were published in Blood Cancer Journal.

Two-hundred and twenty-two de novo AML patients who were diagnosed and treated at the MDACC between 1 June 2007 and 31 December 2015 (n = 98) or at the National University Hospital of Singapore between 1 February 2001 and 31 December 2011 and had available diagnostic samples, were included in this study. SAMHD1 data was available in 189 patients. Among these, 144 patients were treated with ara-C-based induction regimen, four received non-ara-C-based induction regimen and 41 had no clinical data. Consolidation treatment consisted of high-dose Ara-C (HDAC) or other.

Key findings:
  • Optimized double immunochemistry assay was used to assess the expression of SAMHD1 on normal bone marrow and AML blasts
    • No SAMHDI expression was detected on normal hematopoietic stem cells and progenitors
    • SAMHD1 expression was positive on AML blasts and ranged from 1 to 100%
    • A cut-off of 25% was chosen for low SAMHD1 and 75% for high SAMHD1 levels
  • There was no correlation between the percentage of SAMHD1-positive blasts at diagnosis and the administered ara-C dose
  • SAMHD1 expression levels did not correlate with response to induction therapy in all patients, P = 0.7583
  • Data below is representative of survival in evaluable patients (n = 143) with low and high SAMHD1 levels respectively, who were treated with ara-C contacting regimens
    • 5-year EFS: 37% vs 19%, P = 0.0896
    • 5-year OS: 54% vs 29%, P = 0.107
    • 5-year EFS in patients receiving HDAC as a consolidation therapy: 47% vs 20%, P = 0.0085
    • 5-year OS in patients receiving HDAC as a consolidation therapy: 44% vs 34%, P = 0.0085

In summary, “low-level SMAHD1 expression in AML blasts at diagnosis identifies a sizeable patient subset with favorable EFS and OS upon treatment with HDAC-containing consolidation regimens.”

The researchers concluded that SAMHD1 expression which can be assessed by immunohistochemistry may represent a novel predictor of outcome in patients with AML.

References
  1. Rassidakis G. Z. et al. Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens. Blood Cancer J. 2018 Oct 19; 8(11): 98. DOI: 10.1038/s41408-018-0134-z.
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