Asparlas (calaspargase pegol-mknl) / Servier, Takeda, Leadiant Biosci - LARVOL DELTA

A phase I study of venetoclax in combination with multiagent cytotoxic chemotherapy for children and adolescents with relapsed or refractory acute lymphoblastic leukemia or mixed phenotype acute leukemia: Results of the dose determination cohort (ASH 2025) - P1 | "Cohort C is testing VEN in combination with multiagentchemotherapy (dexamethasone, vincristine, doxorubicin, and calaspargase pegol (Cal-peg)) based onDFCI 16-001 high-risk Induction IA (Vrooman et al Blood 2024) in patients (pts) 1-21 years of age withrelapsed/refractory ALL or MPAL. There was excess gastrointestinal toxicity at DL1, likely related to prolonged exposure to VENin combination with dexamethasone, which has not been seen at DL-1. Importantly, overall observedtoxicity is comparable to reported toxicity rates for multiagent reinduction regimens (Hogan et alHaematologica 2025), suggesting that VEN does not further increase toxicity of this regimen."

Clinical • Combination therapy • IO biomarker • P1 data • Acute Lymphocytic Leukemia • Anorexia • Diabetes • Febrile Neutropenia • Gastrointestinal Disorder • Hypertension • Infectious Disease • Mucositis • Neutropenia • Pancreatitis • Septic Shock • BCL2

CalPeg for Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) (clinicaltrials.gov) - P1 | N=7 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

AALL1621: Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Children's Oncology Group | Trial completion date: Mar 2026 ➔ Dec 2026 | Trial primary completion date: Mar 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD22

Evaluation of Prolonged Asparaginase Activity Levels After Calaspargase Pegol Administration (clinicaltrials.gov) - P=N/A | N=20 | Not yet recruiting | Sponsor: Mayo Clinic | Initiation date: Nov 2025 ➔ Feb 2026

Trial initiation date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Long-Acting E. coli-Derived Asparaginase Potentiates the Anti-Leukemic Effect of BCL2 Inhibition, but Not MCL1 Inhibition, in Preclinical Models of Acute Myeloid Leukemia (ASH 2023) - "Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with complex karyotype in vitro and in vivo in a xenograft mouse model... Using a panel of 4 human AML cell lines (MOLM14, MV411, MonoMac6, HL60) as well as primary AML patient samples, weestablished the anti-leukemic activity of the BCL2 inhibitor S55746 and the MCL1 inhibitor S63845 alone and in combination with the long-acting E. coli asparaginase, calaspargase pegol-mknl (CalPegA)... We report that the E. coli asparaginase, CalPegA, enhances the anti-leukemic effect of the BCL2 inhibitor, S55746, but does not impact the activity of the MCL1 inhibitor, S63845, in AML cell lines, patient derived primary AML samples, and in an AML xenograft mouse model. Ongoing studies are further investigating the anti-leukemic mechanism of S55476/S63845 + CalPegA..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4E • EIF4EBP1

Real-World Treatment Patterns Among Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) Who Initiated an Asparaginase Treatment after the Approval of Recombinant Erwinia (Rylaze) (ASH 2023) - "Four asparaginase molecules were included in this study, 2 Erwinia-derived - recombinant Erwinia(Rylaze) and native Erwinia (Erwinaze), and 2 E. coli-derived - pegaspargase (Oncaspar) and calaspargase pegol-mknl (Asparlas). Limitations of this study included the nature of the database used, containing mostly outpatient data, and the relatively short study time frame. Future studies with additional data are needed to fully understand the real-world asparaginase use patterns in these patient populations."

Clinical • HEOR • Real-world • Real-world evidence • Acute Lymphocytic Leukemia • Chronic Obstructive Pulmonary Disease • Diabetes • Genetic Disorders • Hematological Malignancies • Hepatology • Immunology • Leukemia • Lymphoma • Metabolic Disorders • Obesity • Oncology • Pediatrics • Pulmonary Disease • Respiratory Diseases

A Real-World, Single Institution, Post-Market Comparison of Pegaspargase and Calasparagase Pegol-Mknl Therapeutic Drug Monitoring and Toxicity (ASH 2023) - "Introduction: Calaspargase pegol-mknl (CalPEG) was FDA-approved in December 2018 as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia/lymphoma (ALL/LLy) in pediatric patients and adolescent and young adults (AYA)...Patients received either PEGasp, CalPEG, and/or asparaginase Erwinia chrysanthemi recombinant (Rylaze) and had correlative SAA documented by a validated assay (NEXT Molecular Analytics; Chester, VA)... To our knowledge this is the first single-institution post-market retrospective quality and safety analysis comparing CalPEG and PEGasp therapeutic drug monitoring and toxicity. Interestingly, the incidence of pancreatitis and VTE is significantly higher in patients receiving CalPEG and disproportionately higher in T-lineage. Median peak SAA levels were not predictive of toxicity, though GLM may help provide a predictive model."

Clinical • P4 data • Real-world • Real-world evidence • Acute Lymphocytic Leukemia • Cardiovascular • Hematological Malignancies • Hepatology • Immunology • Leukemia • Lymphoma • Oncology • Pancreatitis • Pediatrics • T Acute Lymphoblastic Leukemia • Venous Thromboembolism

Managing Hypersensitivity Reactions after Asparaginase Treatment: A Systematic Literature Review (ASH 2024) - "As patients >1 month to <21.5 years old transitioned from pegaspargase (PEG) to calaspargase pegol (CAL-PEG) beginning December 2022, a limited search of recent congress ABSTRACT s was conducted after the original SLR was completed to capture recent data on CAL-PEG. Likewise, reported usage of desensitization protocols is limited and standardization is lacking, demonstrating variable rates of success. A meta-analysis is being explored to further evaluate HSR rates and premedication effectiveness."

Review • Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Oncology

Economic Burden Associated with Switching to Second Line Asparaginase (Recombinant Erwinia) in Pediatrics, Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL) (ASH 2024) - "Background : Long-acting asparaginases derived from E. coli (pegaspargase [PEG] and calaspargase pegol [CAL-PEG]) are critical components of frontline (1L) chemotherapy regimens in pediatrics, adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL). Mean outpatient costs were $511,810 and $384,396 (p<0.0001) in the non-TDM and TDM groups, respectively.Conclusions : Switch from 1L asparaginase to 2L recombinant Erwinia is relatively common in pediatric and AYA ALL patients which significantly increases treatment costs and HRU, mainly driven by higher outpatient medical costs of recombinant Erwinia. Consideration should be given to performing TDM which may have important implications for mitigating unnecessary switches as well as reducing healthcare burden and achieving substantial cost savings for payers."

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

Pharmacokinetics and Pharmacodynamics of Novel Long-Acting Pegylated Recombinant Asparaginase Comparing with Pegaspargase: A Dose-Escalation, Phase Ia Trial in Chinese Healthy Subjects (ASH 2024) - P1 | "PD5K3, a new generation of long-acting asparaginase, is obtained by site-directed mutagenesis of asparaginase sequence derived from Escherichia coli and subsequent saturation modification with polyethylene glycol (5K-SPA-PEG) to achieve a longer half-life and lower immunogenicity.Preclinical studies have shown that the enzyme activity of PD5K3 is comparable to that of pegaspargase and Asparlas. Previously published reports have concluded that ≥ 0.1 IU/ml is an appropriate target level of asparaginase activity associated with complete asparagine depletion, and considered to be effective in the treatment of ALL/LL.Based on the results of phase Ia, a multicenter, dose-escalation and dose-expansion Phase Ib clinical trial is now planned to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PD5K3 in combined chemotherapy regimen in patients. Eligible patients (aged 12 to 40 years) had newly diagnosed ALL/LL or..."

Clinical • P1 data • PK/PD data • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Anaphylaxis Associated with Calaspargase in Pediatric Patients with Acute Lymphoblastic Leukemia (ASH 2024) - "There have been different types of asparaginase products used in clinical trials over the years including Native or L-asparaginase, Erwinia asparaginase, Pegaspargase (PEG) and Calaspargase pegol-mknl (Cal-PEG)...Patients receiving Cal-PEG were more likely to have a diagnosis of anaphylaxis (2.9 vs 0.7%; OR 4.59, p<0.001), receive Epinephrine (35.5 vs 17.7%; OR 2.55, p <0.001) and had more admissions to the ICU (2.9 vs 1.7%; OR 1.75, p=0.101)...Venous thrombosis and hemorrhage were less associated with Cal-PEG, even though other toxicities remained the same between the two types of asparaginase. Anaphylaxis rates need to be prospectively confirmed in Children's Oncology Group studies, so that preventive strategy guidelines can be developed for these patients."

Clinical • Acute Lymphocytic Leukemia • Cardiovascular • Hematological Malignancies • Hepatology • Immunology • Leukemia • Oncology • Pancreatitis • Pediatrics • Pulmonary Embolism • Respiratory Diseases

Evaluation of Prolonged Asparaginase Activity Levels After Calaspargase Pegol Administration (clinicaltrials.gov) - P=N/A | N=20 | Not yet recruiting | Sponsor: Mayo Clinic

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

RISK FACTORS ASSOCIATED WITH HYPOGLYCEMIA DURING ASPARAGINASE THERAPY AND STRATEGIES FOR MANAGEMENT IN PEDIATRIC PATIENTS WITH LEUKEMIA (SIOP 2025) - " Ninety-four patients received calaspargase pegol (CAL-PEG) or recombinant Erwinia asparaginase, with 19 individuals experiencing at least one episode of AAH...Of these 12 patients, 83.3% had not yet received mercaptopurine, a known risk factor for hypoglycemia... Incidence of AAH was 20% among our cohort with most episodes presenting early in therapy after one dose of CAL-PEG. Identifying patients at an increased risk for AAH allows for enhanced glucose monitoring, aiming to reduce severe hypoglycemic events and hospitalizations in this population."

Clinical • Acute Lymphocytic Leukemia • Diabetes • Genetic Disorders • Hematological Malignancies • Hypoglycemia • Leukemia • Obesity • Pediatrics

CALASPARGASE PEGOL ALGORITHM TO EVALUATE ASPARAGINASE ACTIVITY (SIOP 2025) - "Conclusions These results provide an algorithm to guide the decision to switch to Erwinia asparaginase. Additionally, we are developing an on-line therapeutic monitoring tool to guide dose adjustments for CAL-PEG to maintain activity >0.1 IU/mL for at least 21 days."

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

COLLABORATION WITH CALASPARGASE: A REAL-WORLD MULTICENTER TOXICITY ANALYSIS FOR AT RISK PEDIATRIC AND ADOLESCENT YOUNG ADULT PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (SIOP 2025) - "Conclusions Our multicenter real-world analysis of Cal-PEG demonstrates high rates of AAT. An expansion of the cohort, assessment of risk factors for AAT, and comparisons to historical controls treated with pegaspargase are ongoing."

Adverse events • Clinical • Real-world • Real-world evidence • Acute Lymphocytic Leukemia • Dyslipidemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Hepatology • Hypertriglyceridemia • Immunology • Leukemia • Lymphoma • Obesity • Pancreatitis • Pediatrics • Thrombosis

CASPER: Calaspargase Pegol-Mnkl and Cobimetinib for the Treatment of Locally Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: OHSU Knight Cancer Institute | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Cancer • Solid Tumor

SPARK-ALL: Calaspargase Pegol in Adults With ALL (clinicaltrials.gov) - P2/3 | N=122 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial primary completion date: Feb 2026 ➔ Mar 2025

Trial primary completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Asparagine Synthetase promoter hypermethylation is required, but not sufficient, for sensitivity to Asparlas in patient-derived models of hepatocellular carcinoma. (PubMed, Eur J Pharmacol) - "However, when a panel of patient derived xenograft models representing a range of pASNSmet levels was tested we found that high pASNSmet levels were required but not necessarily sufficient to confer sensitivity to treatment with Asparlas. Collectively, these results are in support of ASNS promoter hypermethylation as a targetable phenotype but indicate that pASNSmet alone is not a viable biomarker of this phenotype, and that significant advancements in our understanding of the underlying biology may be required before asparaginase-depleting therapy can be successfully implemented clinically in HCC."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Hepatocellular Cancer • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • ASNS

A Phase 2 Study to Evaluate Efficacy of Calaspargase Pegol-mknl and Decitabine Combined With Venetoclax in Pediatric, Adolescent, and Young Adult Patients With Relapsed/Refractory T-cell Acute Lymphoblastic Leukemia (T-ALL) and T- Cell Lymphoblastic Lymphoma (T-LLy) (clinicaltrials.gov) - P2 | N=22 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma

Venetoclax Basket Trial for High Risk Hematologic Malignancies (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: Andrew E. Place, MD | Recruiting ➔ Active, not recruiting | N=92 ➔ 13

Enrollment change • Enrollment closed • Pan tumor • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • ABL1 • BCL2 • BCR • FLT3 • IKZF1 • KMT2A

AALL2331: Testing the Addition of Daratumumab to Chemotherapy for Treating Patients With Newly-Diagnosed T-Cell Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LL) (clinicaltrials.gov) - P2/3 | N=1708 | Not yet recruiting | Sponsor: Children's Oncology Group | Initiation date: Sep 2025 ➔ Mar 2026

Trial initiation date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia

Prolonged Therapeutic Serum Asparaginase Activity Levels After Administration of Calaspargase Pegol. (PubMed, Pediatr Blood Cancer) - No abstract available

Journal

Exploring the Effect of Calaspargase Pegol on the Coagulation System in Pediatric Acute Lymphoblastic Leukemia (ALL) Patients: Pilot Study (clinicaltrials.gov) - P=N/A | N=15 | Recruiting | Sponsor: Mayo Clinic | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics

Testing the Addition of Daratumumab to Chemotherapy for Treating Patients With Newly-Diagnosed T-Cell Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LL) (clinicaltrials.gov) - P2/3 | N=1708 | Not yet recruiting | Sponsor: Children's Oncology Group

New P2/3 trial • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia

CalPeg for Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) (clinicaltrials.gov) - P1 | N=7 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology