Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to the age of 60 years with Philadelphia chromosome-negative acute lymphoblastic leukemia

摘要

Administration of pediatric-inspired chemotherapy to adults up to age 60 with acute lymphoblastic leukemia (ALL) is challenging in part due to toxicities of asparaginase as well as myelosuppression. We conducted a multi-center phase II clinical trial (clinicaltrials gov. Identifier: NCT01920737) investigating a pediatric-inspired regimen, based on the augmented arm of the Children’s Cancer Group 1882 protocol, incorporating six doses of pegaspargase 2,000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents. We treated 39 adults aged 20-60 years (median age 38 years) with newly-diagnosed ALL (n=31) or lymphoblastic lymphoma (n=8). Grade 3-4 hyperbilirubinemia occurred frequently and at higher rates in patients aged 40-60 years (n=18) versus 18-39 years (n=21) (44% vs . 10%, P =0.025). However, eight of nine patients rechallenged with pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. Grade 3-4 hypertriglyceridemia and hypofibrinogenemia were common (each 59%). Asparaginase activity at 7 days post-infusion reflected levels associated with adequate asparagine depletion, even among those with antibodies to pegaspargase. Complete response (CR)/CR with incomplete hematologic recovery was observed post-induction in 38 of 39 (97%) patients. Among patients with ALL, rates of minimal residual disease negativity by multi-parameter flow cytometry were 33% and 83% following induction phase I and phase II, respectively. Event-free and overall survival at 3 years (67.8% and 76.4%) compare favorably to outcomes observed in other series. These results demonstrate pegaspargase can be administered in the context of intensive multi-agent chemotherapy to adults aged ≤60 years with manageable toxicity. This regimen may serve as an effective backbone into which novel agents may be incorporated in future frontline studies. Trial registration: https://clinicaltrials. gov/ct2/show/NCT01920737