L-Asparaginase Allergic Patients Treated with L-Asparaginase Loaded into Red Blood Cells in an Expanded Access Program. Report of Four Cases
Authors: Contet Audrey , Lissandre Severine , Berthon Céline , Godfrin Yann , Bertrand Yves 
Published: October 2019

Abstract

L-asparaginase (L-ASP) is an important drug in the treatment of acute lymphoblastic leukemia (ALL) demonstrating efficacy in a broad range of patients. However the toxicity profile, including allergy, has been a major drawback. There is an unmet medical need for patients who cannot receive L-ASP current formulations, especially due to allergy.
E-Coli L-Asparaginase encapsulated into red blood cells (RBC/L-ASP) is a new product under development with the aim of improving the tolerability of this enzyme. Asparagine is actively transported through the membrane of red blood cells (RBC) where it is hydrolyzed by the encapsulated L-ASP, the erythrocytes acting as “bioreactors”. In addition, the RBC membrane shields against the anti-L-ASP antibody then avoiding binding to encapsulated L-ASP. Clinical trials have demonstrated a reduction in allergy with encapsulated L-ASP, and the enzyme activity is sustained even in presence of anti-L-ASP antibodies.
Four patients, who were not able to receive any current L-ASP due to allergy, were enrolled in an Expanded Access Program (# NCT02197650) allowing to receive RBC/L-ASP:
Patient 1: 48 year old, female, with T-cell ALL Ph-, normal karyotype, without neuro-meningeal infiltration, without extra-medullar localization. Treated according to GRAALL-2005 protocol. In complete remission (CR) after induction therapy, with negative MRD. During consolidation therapy, a grade 3 allergy (anaphylaxis) was observed after 6 injections of native E-Coli L-ASP. For late intensification, the patient was switched to Erwinia and after 3 injections a grade 3 allergy occurred. This patient was switched to RBC/L-ASP (150IU/Kg) receiving 2 injections to complete the late intensification phase with no occurrence of allergy. To date this patient is treated by radiotherapy which will be followed by the maintenance therapy.
Patient 2: 30 year old, male, with T-cell ALL Ph-, normal karyotype, without neuro-meningeal infiltration, with extra-medullar localization (cutaneous and renal involvement). Treated according to GRAALL-2005 protocol, corticosensitive and chemosensitive. In CR after induction therapy, with negative MRD after 35 and 70 days. During consolidation phase, a grade 3 allergy (anaphylaxis) was observed after 8 injections of native E.Coli L-ASP. The patient was switched to Erwinia and after 2 injections a grade 2 allergy was observed. For late intensification this patient received RBC/L-ASP (150IU/Kg) at day 2 and at day 15. No allergy occurred. The patient remains in CR and has initiated maintenance therapy.
Patient 3: 9 year old, male, with relapsing B-cell ALL Ph-, with hyperdipliody, without neuro-meningeal infiltration, with no extra-medullar localization. Treated according to INTREALL 2010 protocol UKALL R3 arm. In CR after re-induction therapy, with negative MRD on day 35. Grade 1 L-ASP related allergy was observed after 17 injections of native E-coli L-ASP. Erwinia was initiated and a grade 1 allergy observed after 5 injections. Peg-ASP then resulted in a grade 1 allergy after 1 injection. This patient received RBC/L-ASP (150IU/Kg) at day 6 and at day 41 of the consolidation phase. A grade 1 allergy was observed in hours following the first administration. One dose of hydrocortisone and an anti histamine treatment for 2 days resulted in full resolution. 35 days later, the patient received a second injection with prophylactic anti allergic treatment. No allergy occurred. 21 days later the patient died due to bacterial infection with ARDS.
Patient 4: 3 year old, male, with T-cell ALL Ph-, with no extramedullary localization, treated in the VHR group of EORTC 58081 protocol (poor prednisone response to the prephase). In CR at the end of induction (Ia), with negative MRD after induction and consolidation (<10-4). Grade 3 allergy to native E Coli L-ASP occurred during the first injection of the consolidation phase and the patient received 6 injections of Erwinase . During the subsequent phase (VANDA) a grade 3 allergy occurred at the first Erwinase injection. The patient was switched to RBC/L-ASP (150IU/Kg) for the re-induction phase. No allergy occurred. The second re-induction phase is scheduled in 3 months.
Circulating L-ASP activity was sustained over 100 IU/L for at least 14 days.
In conclusion, for patients allergic to the native E-Coli and/or Erwinia L-ASP, RBC/L-ASP seems to strongly reduce the risk of allergy in maintaining L-ASP activity.

Disclosures
Godfrin: ERYTECH: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.