Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001

Abstract

PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( P = .65). CONCLUSION Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.

Hyperglycemia during induction therapy for acute lymphoblastic leukemia is temporally linked to pegaspargase administration

“…Patients received one dose of IV pegaspargase (2500 IU/m 2 ) on day 6 (DFCI 16‐001) or day 7 (DFCI 05‐001 and 11‐001) of induction. Other chemotherapy administered during induction included four weekly doses of vincristine (days 4, 11, 18, and 25) and 2 consecutive days of doxorubicin (days 4 and 5), as well as intrathecal chemotherapy, as previously described 11,12 . On DFCI 16‐001, only high‐risk patients received doxorubicin.…”

Asparaginase in the Treatment of Acute Lymphoblastic Leukemia in Adults: Current Evidence and Place in Therapy

“…27 The use of a succinimidyl carbonate linker to covalently bind E. coli L-asparaginase and PEG, results in increased stability and longer half-life allowing for every-third-week dosing. 23 …”

“…Calaspargase pegol (Asparlas TM - Servier Pharmaceuticals) was FDA approved in 2018, with data from the DCFI 11–001 Phase III trial 23 noting similar outcomes, SAA, and toxicity profile to pegaspargase in patients (ages 1–21) with newly diagnosed ALL or LBL randomized to receive either IV pegaspargase or calaspargase pegol. Given these findings in this population, a multicenter, open-label, single-arm phase 2/3 trial (NCT04817761) is underway, incorporating calaspargase pegol into a COG backbone for adults (ages 22–65) with newly diagnosed Ph-negative ALL.…”

Does anticoagulation prophylaxis reduce the rate of venous thromboembolism in adult acute lymphoblastic leukaemia treated with asparaginase‐based therapy?

“…1 This asparaginase-related toxicity has been described extensively. [2][3][4][5][6][7][8][9][10] Sibai et al found that low-molecular-weight heparin (LMWH) prophylaxis reduced the incidence of symptomatic venous thromboembolism (VTE) in adult patients with acute lymphoblastic leukaemia (ALL) during intensified asparaginase therapy. They included the largest adult cohort of 225 ALL patients.…”

“…The prevalence of symptomatic (venous) thrombosis has been reported to range from 0% to 36%, depending on the chemotherapy protocols containing asparaginase alone or in combination with corticosteroids 1 . This asparaginase‐related toxicity has been described extensively 2–10 …”