P2, N=30, Not yet recruiting, University of Washington

Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA)...The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML.

P2/3, N=745, Completed, Universitätsklinikum Hamburg-Eppendorf | Active, not recruiting --> Completed

P3, N=440, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P1, N=15, Recruiting, OHSU Knight Cancer Institute | Trial primary completion date: Dec 2024 --> Dec 2025

HLH can serve as the initial manifestation of ANKL. Leukemia cells of ANKL have significant variations in the morphology and mainly express CD56. Intensive combination chemotherapy based on pegaspargase and anthracyclines may be considered for ANKL.

P=N/A, N=10, Recruiting, Mayo Clinic

P2, N=22, Not yet recruiting, M.D. Anderson Cancer Center

P=N/A, N=89, Recruiting, Ruijin Hospital | Not yet recruiting --> Recruiting

P2/3, N=122, Recruiting, Institut de Recherches Internationales Servier | Trial primary completion date: Dec 2023 --> Feb 2027

P1, N=28, Completed, Chongqing Peg-Bio Biopharm Co., Ltd.

P1, N=20, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Nov 2027 --> May 2027 | Trial primary completion date: Nov 2024 --> May 2025

P2, N=90, Recruiting, Sun Yat-sen University

P3, N=560, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Nov 2028 --> Nov 2034

P2, N=240, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jul 2025 --> Jul 2027

Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML.

P1/2, N=43, Recruiting, Beijing Tongren Hospital

Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.

P2, N=210, Recruiting, Fudan University

P1, N=6, Active, not recruiting, University of Maryland, Baltimore | Recruiting --> Active, not recruiting | N=24 --> 6

In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

P2/3, N=122, Recruiting, Institut de Recherches Internationales Servier | Trial completion date: Aug 2026 --> Feb 2027

P1, N=20, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Phase classification: P1b --> P1 | Trial primary completion date: Sep 2027 --> Nov 2024

P3, N=440, Recruiting, Children's Oncology Group | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2026 --> Dec 2027

P1, N=19, Active, not recruiting, Georgetown University | Trial completion date: Dec 2023 --> Jul 2024

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.

Recently, Xue et al showed that chidamide in combination with cisplatin, etoposide or gemcitabine showed synergistic effect and reversed the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. This study demonstrates that sandwich CP-GEMOX chemoradiotherapy is a safe and promising approach to managing patients with early-stage ENKTL-NT.

One of the main limitations of the frontline pegaspargase (PEG) chemotherapy is the development of hypersensitivity reactions and subsequent development of anti-asparaginase neutralizing antibodies that lead to PEG inactivation...Instead of a single SNP association approach, identifying combinations of variations in pathway specific genes provides a more robust means to predict drug response. Our preliminary results provide a rationale for identification of genome level variations in this cohort and association analysis to establish clinically relevant pharmacogenomics score to optimize PEG treatment.

One of the patients with refractory disease underwent further therapy with blinatumomab, inotuzumab, CAR-T and allogeneic stem cell transplantation and is alive at 16 months from diagnosis...Noteworthy adverse effects include neutropenic fever (65%), liver function tests (LFT) abnormalities (70%), and neuropathy from vincristine (70%). Peg-asparaginase administration was associated with pancreatitis in 12%, thromboembolism in 30% and hypersensitivity reactions in 24% requiring switching to alternative forms of asparaginase products (erwinia and Rylaze)... The pediatric-inspired regimen CALGB 10403 was safe and efficacious in our AYA Ph- ALL population with no deaths due to treatment and a 5-year overall survival of 94%. Toxicities, especially from peg-asparaginase, should be closely monitored. While most patients will attain durable remission/cure, the minority with refractory or relapsed disease can still be successfully salvaged to achieve long term survival.

Despite the introduction of asparaginase/pegaspargase-based chemotherapy, the prognosis of patients with advanced NKTCL needs to be improved, and few salvage treatment options are available for relapsed/refractory patients who fail chemotherapy...Immunotherapy has emerged and shown favorable antitumor activity in NKTCL, including monoclonal antibodies targeting immune checkpoint inhibitors, other receptors on the cellular membrane, and cellular immunotherapy, which could enhance immune cells attack on tumor cells. In this review, we provide an overview of recent immunotherapy in NKTCL, focusing on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), chimeric antigen receptor (CAR) T cells, EBV-specific cytotoxic T lymphocytes, immunomodulatory agents, and other targeted agents, as well as the current progress and challenges in the field.

The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.

P1, N=40, Recruiting, New York Medical College | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations...Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

The incidence of serious clinical toxicities was low in this study, particularly pegaspargase-related venous thromboembolism. This suggests that the practice of capping pegaspargase doses at 3750 units, coupled with vigilant monitoring and prophylaxis for pegaspargase-related adverse events, can allow for the inclusion of this drug in the treatment of older individuals.

Based on the response rate and median disease-free period, treatment with pegylated-l-asparaginase is inferior when compared with historical chemotherapy protocols. However, some cats demonstrated an exceptional long disease-free period. Therefore, pegylated-l-asparaginase could be offered as an alternative to corticosteroid therapy alone. Further studies are needed to evaluate the additional benefit over palliative corticosteroid monotherapy.

P3, N=440, Recruiting, Children's Oncology Group | Not yet recruiting --> Recruiting

P3, N=440, Not yet recruiting, Children's Oncology Group | Initiation date: May 2023 --> Oct 2023

This pegarspargase-containing risk-oriented program was feasible and improved outcome of Ph- ALL/LL patients up to 65 years in a multicenter national setting. ClinicalTrials.gov #NCT02067143.

No abstract available

Bio-similar Pegaspargase in combination with chemotherapy was safe and tolerable in the pediatric ALL patients treated according to ICiCLe ALL-14 protocol. Suspected AEs ranged from mild to moderate and hepatic failure and hyperglycemia being severe.