Among all the leukemias that occur in adults, acute lymphoblastic leukemia (ALL) is the second most prevalent type. Even though 80% of ALL cases are reported in younger age, it is a fatal disease when it affects adults. A bimodal distribution describes the incidence of ALL, with the first peak occurring in childhood and the second peak appearing at the age of 50 years. Chromosomal abnormalities and genetic changes affecting lymphoid precursor cell development and proliferation are the distinguishing features of ALL. In adults, 75% of cases are caused by B-cell lineage precursors, while the remaining instances are caused by malignant T-cell progenitors. Despite improvements in the treatment regimens, allogenic stem cell transplantation combined with multi-agent chemotherapy, including vincristine, corticosteroids, and anthracycline, remains the cornerstone of therapy for these patients. But due to the relapses associated with these treatment regimens, there is a continuous search for advanced treatment options.
What is the role of asparaginase in all?
L-asparaginase is an enzyme that is not found in humans, and it depletes the serum levels of L-asparagine(an amino acid essential for cell growth). Inadequate levels of this amino acid leads to cell death due to reduced DNA.
L-asparaginase is widely used to treat childhood acute lymphoblastic leukemia. In the year 1966, Dolowy et al. published the first report of complete remission in a case of refractory pediatric acute lymphoblastic leukemia (ALL) treated with guinea pig-derived L-ASNase.
L-ASNase was frequently utilized to treat ALL in the ensuing decades. According to the literature, the survival rate is about 90% when additional chemotherapeutic agents are used in combination with this drug in ALL patients.
L-asparaginase treatment is occasionally used for other hematological malignancies because not all patients can benefit from this drug due to its immunogenicity and drug resistance.
To overcome this resistance, variants of L-ASNases were introduced. The three L-ASNases now employed in clinical settings are E. coli-ASNase, Erwinia-ASNase, and PEG-ASNase, with PEG-ASNase having the lowest immunogenicity and longest half-life. However, 3-33% of patients still experience adverse reactions when Erwinia-ASNase is used, thereby decreasing its effectiveness .
What is JZP-458?
A new Pseudomonas fluorescens expression platform(a platform commonly used to develop recombinant proteins) was used to create JZP-458. This is a recombinant Erwinia asparaginase drug that has no immunological cross-reactivity to Escherichia coli (E.coli). Viral DNA or RNA genetic codes are inserted in to living organisms to produce these recombinant vaccines.
It is available under the trade name Rylaze® and is being used for the treatment of pediatric and adult patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who are hypersensitive to asparaginase products generated from E. coli.
It will be given as part of a multi-agent chemotherapy regimen. In October 2019, the U.S. Food and Drug Administration approved JZP-458 as fast track designation for the treatment of ALL patients.It acts by reducing the levels of asparagine, which in turn effects the DNA synthesis in leukemic cells leading to cell death..
What is the clinical efficacy of JZP-458 in all?
A study was conducted to determine the efficacy of JZP-458. In this phase III randomized controlled open study (ClinicalTrials.gov identifier - NCT04145531), Rylaze was administered intramuscularly in a range of dosages to patients who were hypersensitive to asparaginase produced from E. coli to assess its efficacy.
The effectiveness of this drug was evaluated by evaluating the level of serum asparaginase activity, which was above the level of 0.1 U/mL. The study results further revealed that with a dosage of 25 mg/m2 given intramuscularly every 48 hours, an average of 93.6% patients maintained this enzyme level at 0.1 U/mL indicating its efficacy .
Take home message!
Although EZP-458 is effective in ALL and LBL patients who were sensitive to asparaginase, it is associated with various adverse effects like recurrent infections, rise in blood glucose levels, increased neutrophil count and bleeding. So further studies are required to improve its efficacy and reduce its side effects.
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2. L. Maese et al., “Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study,”Blood, vol. 141, no. 7, pp. 704–712, Feb. 2023, doi: 10.1182/blood.2022016923.
3. C. for D. E. and Research, “FDA approves asparaginase erwinia chrysanthemi (recombinant) for leukemia and lymphoma,”FDA, Jul. 2021, Accessed: Jul. 29, 2023. [Online]. Available: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asparaginase-erwinia-chrysanthemi-recombinant-leukemia-and-lymphoma
4. “Study Aims to Evaluate JZP-458 in ALL/Lymphoblastic Lymphoma Subgroup.” https://www.cancernetwork.com/view/study-aims-to-evaluate-jzp-458-in-all-lymphoblastic-lymphoma-subgroup (accessed Jul. 29, 2023).