Combined with intensive chemotherapy, the next-generation inhibitor provided excellent results in pediatric patients with Philadelphia chromosome-positive ALL, leading to changes in how this population is treated.
Intensive chemotherapy combined with dasatinib (Sprycel) yielded superior results in the treatment of pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) compared with imatinib mesylate (Gleevec), according to a study published in JAMA Oncology.1
Moreover, dasatinib therapy provided excellent control of central nervous system (CNS) leukemia, without using prophylactic cranial irradiation. These results, identified by researchers from St. Jude Children’s Research Hospital and the Chinese Children’s Cancer Group, collectively led to changes in the way this leukemia is treated.
“This was a very fruitful collaboration,” corresponding and co-senior author Ching-Hon Pui, MD, St. Jude Department of Oncology Chair, said in a press release.2 “No single institution could enroll enough patients to do this kind of randomized clinical trial. By working with the Chinese Children’s Cancer Group, we were able to answer which targeted therapy provides the most benefit.”
Patients in this phase III study, conducted at 20 hospitals in China, were randomized to receive either daily dasatinib (n = 92) at a dosage of 80 mg/m2 per day or imatinib (n = 97) at a dosage of 300 mg/m2 per day. In this cohort of 189 participants, the 4-year event-free survival and overall survival rates in the dasatinib group were 71% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, and 48.9% (95% CI, 32%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of an relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test).
There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Approximately 5% of the participants in each arm died of fatal infections, which accounted for 23% and 42% of the treatment failures in the imatinib and dasatinib groups, respectively. Additionally, approximately 7% of the patients in each treatment arm had disseminated fungal infections, suggesting that the intensity of chemotherapy should by reduced in future studies or that prophylactic antimicrobial treatment could be initiated.
“This study demonstrates the importance of global medicine,” Carlos Rodriguez-Galindo, MD, St. Jude Department of Global Pediatric Medicine chair, said in a press release. “Results from studies run in one country can save the lives of children around the world by informing changes in the standard of care.”
Comparing results observed in previous trials, achievement of improved disease control in the dasatinib group was attributed to the use of a higher drug dose than generally specified by other protocols. Researchers suggested that by employing this modification, they may have overcome the relative drug resistance of some patients by increasing systemic drug exposure, possibly eradicating leukemia in the CNS by reaching a therapeutic level in the cerebrospinal fluid.
According to an accompanying editorial published in JAMA Oncology, Philadelphia chromosome-positive ALL makes up 3% to 5% of childhood ALL, with historically dismal outcomes.3 And though the present study provides promising early data, it also highlights the challenges that persist in the management of this cancer type. “Further studies are needed to address remaining questions relating to the optimal choice of tyrosine kinase inhibitors (TKI) (both agent and dose), chemotherapy backbone, as well as the role of hematopoietic stem cell transplants (HSCT), immunotherapies, and non-TKI targeted therapies,” Karen R. Rabin, MD, PhD, director of the leukemia program at Texas Children’s Hospital, wrote in the editorial.
Findings from this clinical trial were reported at the European Society for Paediatric Oncology and American Society of Hematology annual meetings in 2019.
1. Shen S, Chen X, Cai Z, et al. Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. JAMA Oncology. doi:10.1001/jamaoncol.2019.5868.
2. Partnership with China Prompts Change in Care for High-Risk Type of Leukemia [news release]. St. Jude’s Children’s Research Hospital. Published January 14, 2020. newswise.com/articles/partnership-with-china-prompts-change-in-care-for-high-risk-type-of-leukemia?sc=mwhp. Accessed January 20, 2020.
3. Rabin KR. Optimizing Targeted Therapy for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. JAMA Oncology. doi:10.1001/jamaoncol.2019.5849.