Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Abstract

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

“…We also found that patients relapsing after ATRA-ATO treatment are characterized by a higher number of mutations in other genes, including ASXL1, DNMT3A, JAK2, SRSF2, TET2, and TP53 [70]. Similarly, Madan et al [71] found FLT3-ITD, WT1, RUNX1, and ARID1B mutations as recurrent in relapsing APL cases.…”

“…2). These types of mutations, as well as those observed in the RARA gene, which impair response to ATRA, mostly emerge under the selective pressure of ATO treatment [68][69][70].…”

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

“…More recently, point mutations in the PML-RARA fusion gene have been described in up to 30% of the relapsed cases [136] (Figure 1). These studies suggested that mutations occurred in the two moieties of PML-RARA could contribute to 10-15% of patients who relapse or those eventually resistant to treatment by targeted therapy with ATRA and ATO [136,138]. PML mutations are thought to inhibit ATO binding whereas RARA mutations could reduce the affinity to ATRA binding [136,138].…”

“…However, this average is greater at relapse, with a mean of three additional somatic mutations (range 0-61), mostly acquired through the disease course [115,116,123,128,135]. These mutations are mainly localized in NRAS, RUNX1 and ARID1B, and rarely found in newly diagnosed APL, suggesting their possible role as predictive markers of relapse [136,137]. More recently, point mutations in the PML-RARA fusion gene have been described in up to 30% of the relapsed cases [136] (Figure 1).…”

“…These mutations are mainly localized in NRAS, RUNX1 and ARID1B, and rarely found in newly diagnosed APL, suggesting their possible role as predictive markers of relapse [136,137]. More recently, point mutations in the PML-RARA fusion gene have been described in up to 30% of the relapsed cases [136] (Figure 1). These studies suggested that mutations occurred in the two moieties of PML-RARA could contribute to 10-15% of patients who relapse or those eventually resistant to treatment by targeted therapy with ATRA and ATO [136,138].…”