Dasatinib Combination Leads to Superior Event-Free Survival Rates in Ph-Positive Pediatric ALL

January 22, 2020

Dasatinib, a second-generation Abl-tyrosine kinase inhibitor, used concurrently with an intensive chemotherapy regimen yields superior outcomes compared with imatinib plus chemotherapy in pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to the results from the first randomized phase III clinical trial comparing the 2 drugs in this patients&nbsp;<a>population</a>.

Dasatinib (Sprycel), a second-generation Abl-tyrosine kinase inhibitor (TKI), used concurrently with an intensive chemotherapy regimen yields superior outcomes compared with imatinib (Gleevec) plus chemotherapy in pediatric patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to the results from the first randomized phase III clinical trial comparing the 2 drugs in this patientspopulation.

“We expect that the event-free survival [EFS] of our dasatinib-treated patients will not only remain superior to that of the imatinib-treated patients, but the gap will be widened with longer follow-up based on a previous observation that more effective treatment would reduce off-therapy relapse in children with ALL, including those withPhiladelphia chromosome-positiveALL,” wrote the study investigators.

The primary end point of the trial was EFS, while secondary end points included relapse, death related to toxicity, and overall survival (OS).A total of 189 patients were included in the trial, and the median follow-up was 26.4 months.

According to data from the intent-to-treat analysis, EFS and OS at 4 years was better with dasatinib compared with imatinib. The 4-year EFS rate in the dasatinib arm was 71.0% versus 48.9% in the imatinib arm (P= .005, log-rank test). The 4-year OS rate was 88.4% versus 69.2% with dasatinib and imatinib, respectively (P= .04, log-rank test).

Investigators also evaluated 4-year cumulative risk of any relapse which was significantly lower in the dasatinib arm at 19.8% versus 34.4% in the imatinib arm (P= .01, Gray test). The 4-year cumulative risk of isolated CNS relapse was 2.7% in the dasatinib arm versus 8.4% in the imatinib arm (P= .60, Gray test). However, cumulative risk of any CNS relapse (10.1% vs 9.4%; P= .20) and the cumulative risk of deaths in remission (5.6% vs 4.3%; P= .67) did not differ significantly in the dasatinib arm and the imatinib arm, respectively.

Inferior EFS in the imatinib arm was associated with select factors, such as patients 10 years or older, having a leukocyte cell count of at least 100 x 103/ μL at diagnosis, T-cell phenotype, and increase minimal residual disease (MRD) on days 19 and 46. In the dasatinib arm, the factors associated with inferior EFS included having a leukocyte cell count of at least 100 × 103/μL at diagnosis, CNS3 status, high-risk classification, and increased MRD on days 19 and 46. However, being at least 10 years old, having a leukocyte count of at least 100 ×103/μL, and T-cell phenotype were all factors associated with poorer EFS with treatment of imatinib.

The most commonly reported adverse events (AEs) did not differ significantly between the dasatinib and imatinib arms, with the most common AE being grade 3/4 infection occurring in 24 patients (25.5%) versus 26 patients (27.4%), respectively (P= .87). Other common AEs included disseminated fungal infection in 7 patients in the dasatinib arm (7.45%) versus 7 patients in the imatinib arm (7.37%;P= .99), pancreatitis in 8 patients each (8.51% vs 8.42%; P= .99), and seizures in 4 each (4.26 vs 4.21%; P= .99), respectively. Grade 5fatal infections occurred in 5 patients in each arm (P= .99).

The prospective multicenter clinical trial was conducted at 20 hospitals and medical centers, which enrolled pediatric patients with a confirmed diagnosis of ALL between the ages of 0 to 18 years old. Patients were assigned to either low-, intermediate-, or high-risk groups based on clinical features and immunophenotype. Overall, 5525 patients were enrolled, of whom 225 (4.1%) had Ph-positive ALL. Thirty-five patients in this group declined randomization, and 1 patient died prior to treatment.

All patients received dexamethasone for 4 days initially followed by induction therapy with prednisone acetate, vincristine, daunorubicin hydrochloride, and pegaspargase from days 5 to 28, then cyclophosphamide, cytarabine, and mercaptopurine from days 29 to 35. All patients with MRD of at least 1% as of day 19 received additional early intensification therapy on days 50 through 57. Patients who presented with Ph-positive ALL received dasatinib at 80 mg/m2per day (n = 92) or imatinib mesylate at 300 mg/m2per day (n = 97) at a median of 8 days after receiving dexamethasone until the end of therapy.

Ph-positive disease occurs in about 3% to 4% of all cases of childhood ALL and is historically associated with a poor prognosis. With the addition of first-generation Abl-TKI imatinib, 5-year EFS improved from the historical rates of 28% to 32% to rates around 57%. This trial demonstrated dasatinib is also an option for these patients and has significantly improved EFS rates compared with imatinib.

Reference:

Shen S, Chen X, Cai J, et al. Effect of dasatinib vs imatinib in the treatment of pediatricPhiladelphia Chromosome-positive acute lymphoblastic leukemia[Published Online January 16, 2020].Jama Oncol.doi: 10.1001/jamaoncol.2019.5868.