Dasatinib Superior to Imatinib in Pediatric ALL

In a head-to-head phase III trial out of China, dasatinib (Sprycel) outperformed imatinib (Gleevec) for survival in kids with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), and proved superior in other oncologic outcomes.

Among 189 eligible patients undergoing intensive chemotherapy for their newly diagnosed disease, 71% of those randomized to dasatinib were alive and relapse free at 4 years, as compared to 49% of those assigned to imatinib mesylate (P=0.005), Ching-Hon Pui, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee, and colleagues reported.

The trial was stopped early, as described in JAMA Oncology, when an interim analysis revealed better overall survival in the dasatinib arm. At 4 years, 88.4% of patients on dasatinib were alive versus 69.2% of those on imatinib (P=0.04). By that point, nearly twice as many children on imatinib had relapsed (34.4% vs 19.8% with dasatinib, P=0.01).

Roughly 3% to 4% of kids with ALL will have Philadelphia chromosome-positive disease. "Historically, it was associated with a dismal prognosis, with 5-year event-free survival ranging from 28% to 32%, and was an indication for prophylactic cranial irradiation and allogeneic hematopoietic cell transplant," the authors explained.

But this all changed when imatinib came on the scene.

No prophylactic cranial irradiation was used in the trial, and dasatinib provided excellent central nervous system (CNS) control -- fewer than three times as many patients had a CNS relapse (2.7% vs 8.4% with imatinib, P=0.06).

These findings come on the heels of two prior single-arm trials testing a lower dose of dasatinib (60 mg/m²) in pediatric Philadelphia chromosome-positive ALL that failed to demonstrate improved event-free or overall survival over historical controls treated with imatinib.

"We attribute the improved disease control achieved in the dasatinib group to the use of a higher drug dose (80 mg/m²) than typically specified by other protocols," Pui's team wrote. "This modification may overcome the relative drug resistance of some patients by increasing systemic drug exposure and perhaps eradicates leukemia in the CNS by reaching a therapeutic level in the cerebrospinal fluid."

But in an accompanying editorial, Karen Rabin, MD, PhD, of Texas Children's Cancer Center in Houston, noted that the study did not test dasatinib against the higher imatinib dose (340 mg/m²) used in some studies on Philadelphia chromosome-positive ALL. Pui and colleagues said the dose was selected in part "because of the tendency of Asian patients to have higher trough concentrations than white patients."

Nevertheless, Rabin said the study supports the use of the newer tyrosine kinase inhibitor (TKI) for pediatric patients in this setting.

"The second-generation TKI dasatinib was developed because of several potential advantages over imatinib: dual ABL/SRC inhibition; more than 300-fold increased potency in blocking ABL kinase activity; superior [CNS] penetration; and activity in most cases of imatinib resistance," she explained.

From 2015 to 2018, the Chinese Children's Cancer Group study ALL-2015 randomized 92 children with Philadelphia chromosome-positive ALL to daily dasatinib (80 mg/m²) and 97 to daily imatinib (300 mg/m²) across hospitals in China. Median patient age was 7.8 years (range 0 to 18).

In a per-protocol analysis that excluded patients who withdrew from the trial for other treatments (such as hematopoietic stem cell transplant, or HSCT), the 4-year event-free survival rate was 67% versus 40% for the dasatinib and imatinib groups, respectively.

Nearly all of the children in the study had intermediate-risk disease (97.3%), but among the five with high-risk disease, just one remained alive at 4 years post-diagnosis, despite four of them receiving HSCT.

"While the outlook for Philadelphia chromosome-positive ALL is undeniably improved compared with its dismal status in the pre-TKI era, survival remains poorer than for most other ALL subgroups, particularly among the highest-risk patients with Philadelphia chromosome-positive ALL," wrote Rabin. "Even with allocation of high-risk patients to HSCT, their outcomes remain poor."

All patients in ALL-2015 started on an initial 4-day dexamethasone regimen, followed by 24 days of prednisone acetate, vincristine, daunorubicin hydrochloride, and pegaspargase; and then 7 days of cyclophosphamide, cytarabine, and mercaptopurine. Patients started on their respective TKIs following the dexamethasone course (median day 8.0 of treatment).