A prospective study reveals feasibility and merits of drug profiling-guided precision therapy for children with high-risk leukemias

Abstract Introduction Children with relapsed or refractory acute leukemias have limited treatment options and portend a dismal prognosis. Functional precision medicine (FPM), which applies treatment based on the results of ex vivo drug sensitivity profiling on tumor samples, has shown benefits in adults with aggressive hematologic malignancies but there is a scarcity of pediatric trials. We previously showed the preliminary feasibility and merits of FPM in two children with refractory myeloid leukemias (Wang et al, Blood Cancer Discovery, 2022). In this study, we further extends this initiative to a case series of high-risk pediatric leukemias and evaluate the technical feasibility of implementing FPM and the resulting clinical outcomes. Methods We conducted a prospective study at the Hong Kong Children's Hospital from 1 July 2020 to 10 December 2024. Children with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL) were enrolled to the study. Bone marrow samples were tested for their sensitivity to 44 FDA approved drugs using MTT-based or flow cytometry-based protocols for myeloid and lymphoid leukemias, respectively. Half maximal inhibitory concentration (IC50) values were calculated and ranked for drug sensitivity. All enrolled patients received parallel genomic profiling by RNA-sequencing, targeted sequencing, whole-exome sequencing or whole-genome sequencing. The tumor board reviewed clinical data, drug profiling results and genomic analyses to make treatment decisions. The primary objective was to evaluate the objective response rate (ORR) of patients who received FPM-guided therapies. The secondary objective was to evaluate the actionability and turnaround time (TAT) of reporting drug profiling results to the FPM tumour board and compared with those by genomic profiling. The trial was registered at the ClinicalTrials.gov (NCT04478006). Results Thirty patients had drug profiling been successfully performed. The median TAT of drug profiling for myeloid leukemias was 5 days (range: 4 to 6 days), while that for lymphoid leukemias was 6 days (range: 5 to 7 days). Twelve patients received standard therapies and achieved complete remission. FPM-guided therapies were given to 18 patients. The responses of 4 patients were unevaluable due to worsening of clinical conditions or toxicities. The evaluable cohort consisted of 14 patients (7 with AML, 3 with T-ALL, 3 with B-ALL and 1 with MPAL), comprising high-risk leukemia subjects (very early first relapse, relapse post-HSCT, second relapse or above, or refractory disease) whom had received a median of two prior lines of therapy. The 14 evaluable patients received a total of 17 FPM-guided therapies. Frequently used drug combinations included chemotherapy plus venetoclax, homoharringtonine, or bortezomib. According to the best response per patient, 4 patients achieved complete remission (CR) and 3 achieved partial remission (PR) while 5 patients had stable disease (SD), and 2 patients had progressive disease (PD). The ORR was 50%. Six patients (42.9%) were bridged to HSCT or CAR T therapy. By genomic profiling, we were able to identify a wide range of genomic alterations within our cohort. Four patients (28.6%) had actionable targets, including JAK2 in 2 patients, KIT in 1 patient, and FLT3-ITD in 1 patient, and only the patient with FLT3-ITD received sorafenib as a matched therapy. This proportion of actionability was significantly less than recommendations guided by drug profiling, which identified treatment options in 14 of 14 patients (100%). In addition, the median TAT for returning genomic profiling results to the tumor board was 30 days, which was significantly longer than that of drug profiling. Conclusions This study represents the largest case series with a pure cohort of pediatric acute leukemias to evaluate the feasibility and merits of FPM, and demonstrated that FPM-guided therapy could achieve favorable responses in pediatric patients with very high-risk leukemias, with a short TAT and high actionabiliby to enable timely treatment decisions. Given the limited number of eligible subjects for FPM in the context of childhood leukemias, a prospective, multi-center trial is neccesary to better inform its utility and real benefits.