Outcomes of Children and Adolescents with Acute Myeloid Leukemia and KIT Mutations Treated with Low- or Standard-Dose Chemotherapy Plus Dasatinib on the CALSⅢ-AML18 Trial

Introduction:

Acute myeloid leukemia (AML) with KIT mutations is associated with poor prognosis. Dasatinib, a tyrosine kinase with KIT inhibitory properties, represents an additional therapeutic approach for this subset of AML. However, its efficacy for pediatric patients with AML and KIT mutations has yet to be determined.

Methods:

Patients enrolled in the CALSⅢ-AML18 clinical trial (NO. ChiCTR1900024325) received dasatinib (80 mg/m², daily) in combination with either low-dose (LDC) or standard-dose (SDC) chemotherapy upon detection of a KIT mutation. Dasatinib administration was temporarily halted in cases of infection or severe neutropenia (<0.5 x 10⁹/L). Treatment with dasatinib continued until one year after the completion of chemotherapy or from recovery of hematopoietic stem cell transplantation (HSCT).

Results:

In our cohort, 133 of 497 (26.8%) patients had AML with KIT mutations. Of these , 90 (67.7%) patients received dasatinib in combination with either LDC or SDC chemotherapy. Among the patients in the dasatinib group, 35 (38.9%) received during induction I, 76 (84.4%) during induction II, and 88 (97.8%) during consolidation. The remaining one-third of patients (43/133, 32.3%) did not receive dasatinib because of physician preference.

There were no significant differences between the two groups regarding white blood cell counts (WBC) at diagnosis, age, sex, risk group, treatment arms (LDC or SDC), or the receving HSCT in first complete remission (CR). Cases that did not receive dasatinib had significantly more KIT exon 17 mutations (79.0%) and fewer KIT exon 8 mutations (7.0%). Additionally, this group exhibited a higher prevalence of RUNX1-RUNX1T1 transcript fusions (83.7%) and a lower prevalence of CBFβ-MYH11 transcript fusions (7.0%) when compared with those in the dasatinib group.

After induction II, in 76 patients treated with dasatinib, 96.0% attained CR or CR with incomplete blood cell recovery (CRi), while the CR/CRi rate was 94.6% in patients who did not receive dasatinib. The death rate was similar between both groups (15.6% versus 18.6%, P=0.658). However, there were more relapses among patients who received dasatinib than among those who did not receive dasatinib (26.7% versus 16.3%, respectively; P=0.185).

The 5-year overall survival (OS) rates for patients who received dasatinib were similar to those who did not receive it (77.4±6.1% and 79.1±6.7%, respectively; P=0.786). The 5-year event-free survival (EFS) rates were 59.5±5.4% and 66.5±7.3% for those who received and those who did not receive dasatinib, respectively, (P=0.617). The 5-year relapse-free survival (RFS) rates were 67.5±5.4% for recipients of dasatinib and 74.4±7.0% for the others (P=0.628). Univariable and multivariable analyses for OS, EFS, and RFS revealed that the treatment arm, risk classification, and HSCT in the first CR were independent prognostic factors for EFS and RFS but not for OS. Dasatinib showed no significant impact on OS, EFS, or RFS. There were no significant differences in toxicities between the groups receiving dasatinib or not. The median duration of neutropenia after induction II was 13 days for those in the dasatinib group and 12 days for those in the other group (P=0.286). The median duration for platelet recovery was 5 days for patients in the dasatinib group and 4 days for those in the other group (P=0.151). During consolidation therapy, there were more grade 3 and 4 adverse events, such as infection and febrile neutropenia episodes, pneumonia, and sepsis, in the dasatinib group. Gastrointestinal hemorrhage was only observed in the dasatinib group (4.6%) during consolidation.

Conclusions:

Dasatinib combined with LDC or SDC regimen was well tolerated. While dasatinib combined with SDC is associated with improved EFS and RFS, these must be carefully weighed against the increased risk of toxicities.

No relevant conflicts of interest to declare.

Dasatinib Treatment Schedule: IndicationsTarget therapy with Dasatinib is suggested to start immediately when C-KIT mutation is determined. Considering the effect of bone marrow suppression, Dasatinib should be used when C-KIT mutation is determined as well as ANC≥0.5Ö109/L and PLT≥50×109/L in peripheral blood. Dose and Duration: ＞10kg, 80mg/m2, po, qd; ≤10kg, 2.66mg/kg, po, qd, continued as single-agent maintenance for 0.5-1 year after the end of the whole chemotherapy or after transplantation. Withdrawal: bone marrow suppression (neutrophil＜0.5×109/L or platelet＜50×109/L), obvious organ bleeding, hypoproteinemia, fluid retention, diarrhea, rash, headache, fatigue, skeletal and muscle soreness which cannot be tolerant. Drug modifications: Dasatinib will be restarted from half the dose (40mg/m2 po qd) when bone marrow is in recovery with neutrophil≥0.5Ö109/L and platelet≥50×109/L and will be added to full dose (80mg/m2 po qd) if PB is stable for one week. Dasatinib will be restarted from half the dose (40mg/m2 po qd) when organ bleeding is controlled or when the symptoms like fluid retention, diarrhea, rash, headache, fatigue, skeletal and muscle soreness have subsided.