Erwinase (erwinia asparaginase) / Jazz, Bioprofarma, Ohara Pharma - LARVOL DELTA

Beyond approval: Lymphoma drugs and real-world representation (2015–2025) (ASH 2025) - "Our findings reveal that between 2015 and 2025, 6 out of 53 clinical trials associated withFDA approvals met the minimum criteria for clinical trial excellence. These trials are/were: acalabrutinibwith bendamustine and rituximab, lisocabragene maraleucel, axicabtagene ciloleucel, mosunetuzumab,asparaginase erwinia chrysanthemi, and tisagenlecleucel. While these drugs have received FDA approval,88.7% do not accurately represent the intended patient populations."

Clinical • Real-world • Real-world evidence • Hematological Malignancies • Lymphoma

Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report (ASH 2023) - P | "In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration...For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7RALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3KALT)...Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%)...A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ASXL1 • ATM • BCL2 • DNMT3A • IDH1 • IDH2 • IL7R • PHF6 • SRSF2 • TET2 • TP53

APR-246 Overcomes Resistance to Asparaginase in Lymphoid Malignancies By Targeting Metabolic Cell Vulnerabilities (ASH 2024) - "KHYG-1 cells were treated with Erwinase associated with a ferroptosis inducer (RSL3) and/or a ferroptosis inhibitor (ferrostatin-1). In our work, APR-246/Erwinase combination effectively disrupts the balance between ROS generation and antioxidation dependent on glutamine/GSH metabolism in ASNase-R cells and leads to cell death by ferroptosis. Prospective phase I/II studies are now required to confirm the clinical efficacy of APR-246/Erwinase combination in ASNase-R ENKTL and ALL patients."

Acute Lymphocytic Leukemia • CNS Disorders • Extranodal Natural Killer/T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • Psychiatry • T Cell Non-Hodgkin Lymphoma • ANXA5 • TP53

Unveiling Putative Pathway Enrichment Following Crisantaspase Treatment in AML through RNA Sequencing Analysis (ASH 2023) - " We utilized Rylaze, an FDA-approved Erwinia crisantaspase, to deplete exogenous Gln. This study represents a significant contribution towards advancing our understanding of amino acid-regulated metabolic pathways in AML, with potential implications for other Gln metabolism-dependent cancers as well."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CHAC1 • S100P

Switch of Asparaginase Formulation Based on Antibody Monitoring in Adults with Philadelphia-Negative Adult Lymphoblastic Leukemia. Results of the Graall-2014 Trial (ASH 2024) - "Those exhibiting low activity, any clinical allergy to ASPA, or the presence of anti-ASPA antibodies were considered for switching to Erwinase (ERW) during LI...In contrast to prior observation, the presence of Abs did not predict ASPA inactivation. Pts who switched to ERW during LI had a higher risk of relapse, possibly due the different pharmacology profile between both asparaginases."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • T Acute Lymphoblastic Leukemia

Asparaginase Erwinia Chrysanthemi With Chemotherapy for the Treatment of High-Risk Adults With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (clinicaltrials.gov) - P2 | N=53 | Recruiting | Sponsor: City of Hope Medical Center | Not yet recruiting ➔ Recruiting | Trial completion date: Apr 2028 ➔ Mar 2029 | Trial primary completion date: Apr 2028 ➔ Mar 2029

Enrollment open • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics

PRECISION MEDICINE FOR RELAPSED/REFRACTORY T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA : A FRENCH ALL-TARGET OBSERVATORY REPORT (EHA 2025) - P | "TTOs included Tofacitinib or Ruxolitinib-Venetoclax (Tofa or Ruxo/Ven) in case of IL7R(CD127) expression or IL7R-pathway alterations (IL7RALT), 5-azacytidine-Venetoclax (Aza/Ven) in case of epigenetic regulators alterations, or Temsirolimus-Erwinase-Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3KALT)...Of note, 1 patient received a triplet with Aza/Ven/Tofa and 2 pts Trametinib/Ven plus Tofa or Aza.Sixteen of 25 pts responded after Aza/Ven (ORR 64%), with 14 CR/CRi (56%)... Our results demonstrate that a better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With an ORR above 60%, TTOs appear to be a promising approach in R/R T-ALL."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ATM • BCL2 • DNMT3A • IL7R • JAK1 • TP53

Peptide hydrogels as slow-release formulations of protein therapeutics: case study of asparaginase-loaded hydrogels. (PubMed, Biomater Sci) - "For the first time, our peptide hydrogels were used to develop an injectable sustained release formulation of a therapeutic enzyme, namely Erwinase®, an FDA-approved asparaginase for the treatment of acute lymphoblastic leukemia. We show that the current hexamer peptide-based hydrogels allow sufficient protein loading and sustained release of the fully active asparaginase enzyme both in vitro and in vivo. Altogether, this study describes how peptide hydrogels can be exploited to provide injectable slow-release formulations of biologics, including enzyme therapeutics, to enhance their clinical applicability."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Evaluation of Calaspargase Pegol Reactions and Asparaginase Activity Level Monitoring (ASPHO 2025) - "Patients with severe reactions to calaspargase are transitioned to asparaginase Erwinia chrysanthemi (ERW), which is associated with lower incidence of reactions. Implementation of routine premedications and intravenous hydration for pediatric patients receiving calaspargase led to a decreased incidence of hypersensitivity reactions."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Pediatrics

Optimizing Asparaginase Therapy: Navigating Evolving Clinical Challenges in Pediatric and AYA ALL for Improved Outcomes (ASPHO 2025) - "Notably, the recent the FDA approval and updated safety labeling for asparaginase erwinia chrysanthemi offers clinical benefits of novel dosing regimens, and provides a reliable treatment option for affected patients faced not only with the barrier of hypersensitivity but also with the manufacturing issues that have plagued native asparaginase E chrysanthemi (Erwinaze/Erwinase) and led to global shortages...Lastly, in an evolving treatment landscape of ALL, updated therapeutic regimens and treatment guidelines including the emergence of immune-targeted therapies, pose challenges in treatment sequencing and understanding the place in therapy for asparaginase therapies. Learning Objectives: Discuss current efficacy evidence and unmet needs related to the optimized use of asparaginase in pediatric ALL, including the role of novel Erwinia asparaginase compounds Devise strategies to address therapeutically relevant considerations related to asparaginase use for pediatric ALL..."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • Pediatrics

Asparaginase Erwinia Chrysanthemi With Chemotherapy for the Treatment of High-Risk Adults With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (clinicaltrials.gov) - P2 | N=53 | Not yet recruiting | Sponsor: City of Hope Medical Center

New P2 trial • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics

Forecasting Asparaginase Need and Cost for Childhood Cancer Using ACCESS FORxECAST. (PubMed, JCO Glob Oncol) - "Treatment intensification requires a cost increase that should be accessible for most LMICs, but PEG utilization is substantially more costly, suggesting that prioritizing investment in intensifying treatment using native E. coli is the least costly approach to maximize treatment availability. Cost savings associated with native E. coli utilization may liberate funds for Erwinase procurement for patients with ASN hypersensitivity. Future analyses needed include an evaluation of costs associated with preventing abandonment due to compliance complexity with native E. coli given increased administration frequency compared with PEG."

Journal • Immunology • Oncology • Pediatrics

Aifa: in September the Board of Directors approves 9 new drugs, three of which are anti-tumor drugs [Google translation] (AboutPharma) - "The AIFA Board of Directors examined and approved 38 dossiers in the session of Wednesday 11 September 2024 for which the Scientific and Economic Commission for Medicine (CSE) completed the evaluation process...The orphan drugs authorised and eligible for reimbursement by the NHS are for the treatment of the following pathological conditions...Tepkinly (epcoritamab), as monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy; Finlee...in combination with trametinib for the treatment of low-grade and high-grade glioma in pediatric patients; Spexotras...in combination with dabrafenib for the treatment of low-grade and high-grade glioma in pediatric patients...Erwinase...to treat patients, mainly children, with acute lymphoblastic leukemia; Jaypirca....indicated as monotherapy for the treatment of adult patients with mantle cell lymphoma."

Reimbursement • Acute Lymphocytic Leukemia • Brain Cancer • CNS Tumor • Diffuse Large B Cell Lymphoma • Glioma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Phase 1, Single Centre, Open Label, Single Dose, Pharmacokinetic Study of Erwinaze in Healthy Adult Volunteers (ANZCTR) - P1 | N=12 | Withdrawn | Sponsor: Porton Biopharma Limited | Not yet recruiting ➔ Withdrawn

Trial withdrawal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

ACTIVINA PROMOTES CHEMORESISTANCE IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) (EHA 2024) - "Our preliminary data demonstrated that ActA significantlyincreases the viability of 697 cells in vitro after 72 hours of Dexamethasone- (Dex) and Erwinase Asparaginase-based (ASNase) chemotherapy. Our results suggest that ActA could improve chemoresistance also in the context of B-ALL, modulating severalmediators of chemotherapy-induced death and intracellular oxidative stress. In the future we will investigatewhether ActA is able to exert a chemoprotective role also in an in vivo xenograft mouse model to evaluatewhether the combined targeting of B-ALL and its corrupted microenvironment could improve diseasemanagement."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • CASP3

Desensitization using pegaspargase in the era of commercially available Erwinia: A single-institution report on efficacy, cost, and resource utilization. (PubMed, Pediatr Blood Cancer) - "Performing desensitization to pegaspargase in the pediatric acute lymphoblastic leukemia population is feasible, safe, and effective. It is financially advantageous over available alternative approaches, and requires fewer injections and presentations to care."

HEOR • Journal • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Critical care • Hematological Malignancies • Immunology • Leukemia • Oncology • Pediatrics • Transplantation

PEGylation versus glycosylation: effect on the thermodynamics and thermostability of crisantaspase. (PubMed, Prep Biochem Biotechnol) - "The activation energy of denaturation of PEG-crisantaspase (307.1 kJ mol) was higher than for crisantaspase (218.1 kJ mol) and Glyco-crisantaspase (120.0 kJ mol), which means that more energy is required to overcome the energy barrier of the unfolding process. According to our results, PEG-crisantaspase is more thermostable than its native form, while Glyco-crisantaspase is more thermosensitive."

Journal

A Phase 1, Single Centre, Open Label, Single Dose, Pharmacokinetic Study of Erwinaze in Healthy Adult Volunteers (ANZCTR) - P1 | N=12 | Not yet recruiting | Sponsor: Porton Biopharma Limited

New P1 trial • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Our Experiences with Asparaginase Activity Measurements in Children with Lymphoblastic Diseases. (PubMed, Children (Basel)) - "Monitoring of AEA can help to identify patients with 'silent inactivation' and their asparaginase therapy can thus be optimized."

Journal • Hematological Disorders • Oncology • Pediatrics

Back to the future: the amazing journey of the therapeutic antileukemia enzyme asparaginase Erwinia chrysanthemi. (PubMed, Haematologica) - "An asparaginase product displaying the same characteristics of the Erwinia chrysanthemi asparaginase recently has been produced by use of recombinant technology, thus securing a preparation available for use as an alternative, or as a back-up in case of shortages, for the non-recombinant product. The long journey of the Erwinia chrysanthemi asparaginase product as it has developed throughout the last several decades has made it possible for almost every child and adult with ALL to complete the asparaginase-based protocol treatment when an immunological reaction has occurred to any Escherichia coli asparaginase product."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

METABOLIC PLASTICITY REVEALS A TARGETABLE VULNERABILITY IN LEUKEMIA (EHA 2023) - "R/R T-ALL/LL have dismal prognosis and outcomes, in part due to chemoresistance acquisition and limited therapeutic options. We propose a promising treatment combining an asparagine and glutamine degrader(Erwinase) with a PI3KS inhibitor (Torisel) that should be considered as a therapeutic option in a bridge-to- transplant approach for R/R T-ALL/LL with PI3KS deregulation. We show that metabolic plasticity conveys a unique and targetable vulnerability in PI3KS-driven leukemia that show promising results in pre-clinical and clinical settings."

Acute Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • T Acute Lymphoblastic Leukemia • Transplantation

Monitoring of treatment with L-asparaginase in children with acute lymphoblastic leukaemia, with a focus on silent inactivation and its influence on the treatment outcome. (PubMed, Contemp Oncol (Pozn)) - "Eight children continued therapy with Erwinase, and 4 did not switch to Erwinase after inactivation of PEG-ASP...Due to regular monitoring and switching to other ASP preparations after allergy or silent inactivation, therapeutic activity was ensured in almost all patients. Monitoring of ASP activity is crucial to recognize silent inactivation and to guarantee treatment effectiveness by switching to other ASP preparations."

Journal • Acute Lymphocytic Leukemia • Allergy • Hematological Malignancies • Immunology • Leukemia • Oncology

AALL1521: A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P2 | N=171 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • CRLF2 • EPOR • IL7R • JAK1 • JAK2 • SH2B3

Asparaginase therapy in patients with acute lymphoblastic leukemia: expert opinion on use and toxicity management. (PubMed, Leuk Lymphoma) - "Due to its favorable pharmacokinetic profile and reduced immunogenicity compared to native E. coli preparations, pegaspargase is the first-line asparaginase therapeutic option. Previous global shortages of asparaginase Erwinia chrysanthemi necessitated conversion mitigation strategies such as premedication protocols, desensitization, and asparaginase activity level monitoring. Here, we discuss the efficacy, safety, pharmacokinetics, current use, and administration of asparaginase therapies for pediatric and adolescent patients with ALL/LBL."

Adverse events • Journal • Acute Lymphocytic Leukemia • Allergy • Dermatology • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Oncology • Pediatrics

Erwinia asparaginase (crisantaspase) increases plasma levels of serine and glycine. (PubMed, Front Oncol) - P1 | "To the best of our knowledge, we are the first to report comprehensive plasma amino acid changes in mice and humans treated with asparaginase. As dysregulated serine metabolism has been implicated in tumor development, our findings offer insights into how leukemia/cancer cells may potentially overcome glutamine/asparagine restriction, which can be used to design future synergistic therapeutic approaches."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma