General AML

Acute promyelocytic leukemia with alternative retinoid acid receptor fusions

In the majority of patients with acute promyelocytic leukemia (APL), there is an abnormal translocation involving promyelocytic leukemia (PML) gene at chromosome band 15q24 and the retinoic acid receptor alpha (RARA) gene at 17q2, generating an aberrant PML-RARA fusion gene. However, in some patients with APL, the fusion gene is not known. The molecular landscape of patients lacking the PML-RARA fusion gene is not well understood.

In a Letter to the Editor of Haematologica, a group of Chinese researchers reported results from their study which investigated the clinical and molecular features of patients with APL lacking classic PML-RARA fusion gene.

Cytogenetic and molecular characterization was performed on a total of 1,381 patients with suspected APL. Karyotyping, FISH, RT-PCR, or RNA-seq identified t(15;17)(q24;q21) and/or PML-RARA in 98.6% (n = 1,362) of patients. In 19 patients (1.4%), alternative RARA or RARG fusions (PLZF-RARA fusions [n = 10], STAT5B-RARA [n = 4], STAT3-RARA [n = 2], CPSF6-RARG [n = 2], and TBLR1-RARA [n = 1]) were identified.

Key findings:
  • APL patients with alternative RARA or RARG fusions were found to be resistant to all-trans-retinoic acid (ATRA) and/or arsenic trioxide (ATO)
  • Data below is representative of complete remission (CR) rate, relapse rate and survival in patients with APL with t(15;17)(q24;q21)/PML-RARA and alternative RARA or RARG fusion genes, respectively
    • CR rate in evaluable patients: 94.8% (791/835) vs. 53.3% (8/15), P < 0.001
    • Relapse rate in evaluable patients who achieved CR: 12.3% (58/471) vs. 62.5% (5/8), P < 0.001
    • 3-year overall survival: 92.1% vs. 26.7%, P < 0.0001
    • 3-year leukemia-free survival: 86.5% vs. 20%, P < 0.0001
  • Compared to APL with t(15;17)(q24;q21)/PML-RARA, APL with alternative RARA or RARG presented with more mutations of KMT2C (27.8% vs. 1.5%, P < 0.01), K-RAS (22.2% vs. 1.5%, P < 0.01), GATA2 (16.7% vs. 0%, P < 0.01), and fewer mutations of FLT3-ITD (5.6% vs. 35.4%, P < 0.01).

In summary, compared to APL with t(15;17)(q24;q21)/PML-RARA, poorer outcomes were observed in patients with alternative RARA or RARG fusions.

References
  1. Wen L. et al. Clinical and molecular features of acute promyelocytic leukemia with variant retinoid acid receptor fusions. Haematologica. 2018 Sep 20. DOI: 10.3324/haematol.2018.205369. [Epub ahead of print].
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