RESULTS

Patient characteristics

This study enrolled 161 individuals with newly diagnosed AML (median age 43.8 years), among whom 64 and 97, respectively, were treated with the DCAG regimen and IA induction chemotherapy (Table 1). The two groups were similar with respect to gender, risk status, white blood cell (WBC), and performance status.


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The DCAG group received a median of 2 cycles induction therapy of DCAG; 56 (87.5%) received >2 cycles of consolidation therapy, including consolidation chemotherapy or stem cell transplantation (Figure 1). The IA induction chemotherapy group underwent a median of 2 cycles of IA induction chemotherapy; 80 (82.5%) received >2 cycles of other consolidation chemotherapy or stem cell transplantation. All patients underwent molecular testing at baseline using a next-generation sequencing 126-gene panel, comprising genes that are recurrently known to be mutated in acute leukemia.

Response and survival

Of the 64 subjects enrolled in the DCAG group, 43 responded to a single induction cycle. Of these, 32 (50%), 11 (17.2%), and 20 (31.3%) experienced, respectively, a complete (with complete or incomplete count recovery), partial, or no response (Table 1). Forty-five responded to 2 induction cycles; of these, 35 (54.7%), 10 (15.6%), and 13 (20.3%) experienced achieved a complete (with complete or incomplete count recovery), partial, or no response. All subjects with a partial response had a complete hematologic response with a median bone marrow myeloblast count of 13.2% at the beginning of the second induction. One patient withdrew from the DCAG group before a bone marrow biopsy could be performed at the end of the first cycle and therefore could not be clinically evaluated for a response.

Of the 97 subjects in the IA induction chemotherapy group, 76 responded to a single induction cycle. Of these, 57 (58.7%), 19 (19.6%), and 18 (18.6%) showed, respectively, a complete (with complete or incomplete count recovery), partial, or no response (Table 1). Eighty responded to 2 induction cycles; of these, 76 (78.35%), 4 (4.12%), and 12 (12.37%) experienced, respectively, a complete (with complete or incomplete count recovery), partial, or no response.

The DCAG and IA induction chemotherapy groups were statistically similar with regard to complete remission rate after the first cycle (P=0.195), OS (P=0.271), and EFS (P=0.831). Kaplan–Meier estimates for OS for the DCAG group at 1 and 2 years were 66.2% (95% CI 50.3–78.1%) and 60.2% (95% CI 50.3–78.1%). The estimated EFSs of the DCAG group at 1 and 2 years were 61.8% (95% CI 45.8–73.6%) and 58.4% (95% CI 41.9–71.7%). Kaplan–Meier estimates for OS for the IA group at 1 and 2 years were 80.9% (95% CI 7.09–87.7%) and 64.7% (95% CI 52.8–74.3%). The estimated EFSs for the IA group at 1 and 2 years were 73.1% (95% CI 62.5–81.2%) and 62.6% (95% CI 50.9–72.3%).

Among the 15 patients with FLT3-ITD mutation in the DCAG group, after 2 induction cycles, 5 (33.33%), 4 (26.67%), and 6 (40.00%) achieved, respectively, a complete (with complete or incomplete count recovery), partial, or no response. Among 11 patients with FLT3-ITD mutation in the IA induction chemotherapy group, after 2 induction cycles, 8 (72.70%), 1 (9.09%), and 2 (18.17%) achieved, respectively, a complete (with complete or incomplete count recovery), partial, or no response. When considering only the patients with FLT3-ITD mutation, the response of those receiving DCAG was similar to that of the patients who received IA induction chemotherapy (P=0.395). In the present study, 9 FLT3-ITD-positive patients in the DCAG group and 9 FLT3-ITD-positive patients in the DCAG group received allogeneic peripheral blood stem cell transplantation.

Prognostic significance of clinical features and gene mutations in patients receiving DCAG

Several disease and patient characteristics are known to affect survival in AML. These include Eastern Cooperative Oncology Group (ECOG) score ≥3; cytogenetics poor-risk status; NCCN poor-risk status; with or without hematopoietic stem cell transplantation; number of DNA methylation-related mutations; number of overall mutations; lack of response (i.e, no response, NR) after the first induction therapy; NR after the second induction therapy; and without extramedullary infiltration.

The associations of these variables with OS and EFS were investigated. For the patients who underwent DCAG, the following factors were associated with poor OS according to the log-rank test: ECOG score ≥3 (P=0.001); NCCN high-risk status (P=0.004); NR after the second induction therapy (P=0.040); and FLT3-ITD (P=0.0001; Figure 2A). In addition, the following factors were associated with poor EFS for patients who underwent DCAG: ECOG score ≥3 (P=0.0004); NCCN poor-risk status (P=0.008); cytogenetics poor-risk status (P=0.025); NR after the second induction therapy (P=0.046); or FLT3-ITD (P=0.002; Figure 2B).

(To view a larger version of Figure 2, click here.)

Next examined was the HR for death associated with mutations in the 10 genes mutated in >5% of patients in this DCAG cohort (Table 2, Figure 2C and D). In the univariable analysis, FLT3-ITD mutations were also associated with shorter OS (HR 4.69, 95% CI 1.89–11.69, P<0.05) and shorter EFS (HR 3.80, 95% CI 1.49–9.73, P<0.05). No genetic mutations were associated with longer EFS or OS.

(To view a larger version of Table 2, click here.)

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