A Pediatric-Inspired Regimen Containing Multiple Doses of Intravenous Pegylated Asparaginase Appears Safe and Effective in Newly Diagnosed Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia in Adults up to Age 60: Results of a Multi-Center Phase II Clinical Trial

Background: The U.S. Intergroup C10403 trial has demonstrated that treating acute lymphoblastic leukemia (ALL) in adolescents and young adults up to age 39 using a pediatric regimen improves event-free and overall survival compared with adult regimens (Stock W et al. ASH 2014). However, the safety and efficacy in implementing pediatric regimens in older adults above age 40 have not been well studied. Herein, we report the results from a phase II multicenter study of pediatric-inspired regimen in newly diagnosed adult patients (pts) with ALL up to age 60 (NCT01920737).

Methods: Newly diagnosed adult pts aged 18 to 60 with ALL were eligible. Burkitt type and Ph+ ALL were excluded. The treatment regimen consisted of induction 1 (I1), induction 2 (I2) followed by several cycles of intensifications and re-inductions and 3 years of maintenance therapy. The treatment contained a total of 6 doses of 2,000 IU/m² pegylated asparaginase (Peg-ASP), administered IV at various intervals of ³4 weeks based on our previous pharmacokinetics (PK) data (Douer D et al. Blood 2007). Minimal residual disease (MRD) was assessed after I1 and I2 by multiparameter flow cytometry. Serum asparaginase enzymatic activity and presence of anti-asparaginase antibody (Ab) were assessed on day 7 after each Peg-ASP dose.

Results: 27 pts were enrolled between 4/2014 and 4/2016. The median age at diagnosis was 43.6 (range, 20-60) years: 52% were 40-60 years. The majority had precursor B-ALL (70%) and rest T-ALL. Four pts (15%) had extramedullary disease only (mediastinal mass, lymph nodes, bone). Of the 27 pts, 26 pts (96%) achieved complete remission (CR) after I1. MRD was assessed in 20 pts; 8 (40%) and 15 (75%) pts achieved MRD neg CR after I1 and after I2, respectively. Six pts proceed to allogeneic HSCT. With a median follow-up of 7.8 months (range, 0.9-22.5), 3 patients (12%) relapsed: 2 occurred among the 12 MRD+CR group (17%) after I1 at 4.5 and 8.8 months, and 1 occurred among the 8 MRD negative CR group (13%) after I1 at 7 months from I1 completion. No relapses occurred among the 6 MRD unknown pts. No pt died on study. Grade 3-4 Peg-ASP-related toxicities (Table 1) included hypertriglyceridemia (59%), transaminitis (52%), hyperglycemia (41%), hyperbilirubinemia (30%), and pancreatitis (4%). Notably, all cases of hyperbilirubinemia occurred during I1 but despite continued use of Peg-ASP, grade 3-4 hyperbilirubinemia did not recur. Four pts (15%) developed hypersensitivity reactions to Peg-ASP and subsequently received Erwinia asparaginase without reaction and completed the full intended doses of Peg-Asp treatments. Three pts (11%) discontinued Peg-ASP due to toxicity (n=2; hyperbilirubinemia, transaminitis) and physician preference (n=1). Asparaginase PK and anti-ASP Ab data were available in 16 pts. In pts without hypersensitivity to Peg-ASP, a median asparaginase enzymatic activity was 0.58 IU/ml (range, 0.30-0.88) and 0.73 IU/ml (range, 0.53-0.88) on day 7 of Peg-ASP during I1 and I2, respectively. One pt developed silent inactivation after I1 with the activity level <0.01 IU/ml during I2 but without detectable anti-ASP Ab; 3 pts with hypersensitivity reactions had no or lowest activity levels, ranging from <0.01-0.1 IU/ml. Four pts (15%) had pre-existing anti-ASP Ab at pre-treatment; none of these was neutralizing and all 4 pts had adequate enzymatic activity.

Conclusions: This phase 2 study suggests that a pediatric-inspired regimen containing rationally synchronized 6 doses of 2,000 IU/m² IV Peg-ASP is safe and effective in older adults with newly diagnosed Ph-negative ALL up to age 60. Although follow-up remains short, we have observed high CR rates and few relapses. Hypertriglyceridemia, hyperglycemia, transaminitis and hyperbilirubinemia occurred frequently but few discontinued treatment due to toxicities. The rate of silent inactivation of asparaginase was low (6%), and almost all pts without hypersensitivity had adequate activity on day 7. Further results of asparaginase PK analysis and silent inactivation will inform the appropriate dosing of Peg-ASP and utility of PK/Ab tests in future adult ALL trials.

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