Pediatric-Inspired Pegaspargase Regimen Shows Promise for Treatment of ALL/LBL

A pediatric-inspired treatment regimen incorporating pegaspargase timed to avoid overlapping toxicities was associated with manageable toxicity, high measurable residual disease (MRD) negativity rates, and promising long-term efficacy in adults with newly diagnosed acute lymphocytic leukemia (ALL) and lymphocytic lymphoma (LBL).

According to the study authors, led by Mark Geyer, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, “[incorporating] active novel agents to such a regimen may increase rates of early MRD negativity and reduce rates of relapse [in patients with ALL and LBL].” Corresponding author Jae Park, MD, also of MSKCC, told ASH Clinical News, “This regimen is less myelosuppressive than hyper-CVAD and we have demonstrated that, with proper monitoring and rationally synchronized dosing of pegaspargase, it can be safely used in adults up to age 60.”

Dr. Geyer and colleagues evaluated the regimen in 39 adults with either newly diagnosed and previously untreated Ph-negative precursor B-cell or T-cell ALL (n=31) or LBL (n=8) in this multicenter phase II clinical trial.

Patients received a pediatric-inspired regimen from the augmented arm of the Children’s Cancer Group 1882 protocol. The treatment incorporated 6 doses of pegaspargase 2,000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents.

Modifications included substituting pegaspargase for native E. coli asparaginase and use of high-dose methotrexate (MTX) intensification versus escalating MTX. Six doses of pegaspargase 2,000 IU/m2 were given after the second dose of high-dose MTX in intensification I/II, and only after leucovorin rescue began, to avoid overlapping toxicity with other agents.

Participants also received hydrocortisone 100 mg intravenously before each dose and 1 to 2 weeks of corticosteroids after each dose to prevent hypersensitivity.

“Several retrospective clinical studies and a recent large prospective study reported improved clinical outcome in adolescents and young adults when treated with pediatric chemotherapy regimen containing pegylated asparaginase,” explained Dr. Park. “However, successfully adapting pediatric ALL therapy for adults over age 40 presents additional challenges and the upper age limit of safe administration of pegylated asparaginase is not clearly defined.”

The median age of the cohort was 38.7 years (range = 20-60), and 18 patients (n=46) were between the ages of 40 and 60.

All but one participant (97%) achieved a complete response (CR)/CR with incomplete hematologic recovery (CRi) following induction phase 2. Ten patients in CR/CRi experienced relapse, at a median time of 15.4 months (range = 5.4-40.4 months) from the start of treatment.

MRD assessment was performed in 26 of 31 patients with ALL on day 15 of induction phase 1, at which point 5 patients (19%) had achieved MRD negativity (measured using multiparameter flow cytometry in bone marrow aspirate samples). MRD negativity rates increased following induction phase 1 (33%) and after induction phase 2 (83%).

No patients died during the induction phase. At a median follow up of 38.6 months, the 3-year event-free survival (EFS) rate was 67.8% and the 3-year overall survival (OS) rate was 76.4%. The researchers suggested that both the EFS and OS rates “compare favorably to outcomes observed in other series.” Younger patients (≤39 years) had higher rates of both 3-year OS (88.2% vs. 61.9%; p=0.03) and 3-year EFS (85.0% vs. 48.6%; p=0.05) compared with patients aged 40 to 60 years.

Regarding pegaspargase toxicity, the investigators noted that grade 3-4 hypofibrinogenemia and hypertriglyceridemia were common (TABLE). Patients between 40 and 60 years of age also had higher rates of grade 3/4 hyperbilirubinemia compared with the younger cohort (44% vs. 10%, respectively; p=0.025).

Hyperbilirubinemia and thrombosis were more common during induction but, according to Dr. Park, these events did not recur with subsequent cycles. “It is important to continue with the regimen and not prematurely stop pegylated asparaginase, unless it’s for the reasons of allergic reactions or pancreatitis,” he said.

The authors also observed a nonsignificant trend toward greater risk of grade 3-4 hyperbilirubinemia in patients with a higher body mass index (BMI) at treatment initiation; incidence of other grade 3-4 toxicities did not differ significantly by age, BMI, or sex.

Limitations of the study included its small sample size, the relatively short follow-up period, as well as the number of samples that were unavailable for MRD analysis.

Study authors report relationships with Servier Pharmaceuticals, which sponsored this trial.

Reference

Geyer MB, Ritchie EK, Rao AV, et al. Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. Haematologica. 2020 October 13. [Epub ahead of print]