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.

P1, N=19, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; Administratively Complete

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

Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.

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.

P1, N=12, Withdrawn, Porton Biopharma Limited | Not yet recruiting --> Withdrawn

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

P1, N=12, Terminated, Jazz Pharmaceuticals | Trial completion date: Nov 2024 --> Apr 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2024 --> Apr 2024; The study was terminated based on a business decision by the Sponsor.

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

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.

P1, N=12, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting | N=88 --> 12 | Trial completion date: Nov 2027 --> Nov 2024 | Trial primary completion date: Nov 2027 --> Nov 2024

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

P1, N=19, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=62 --> 19

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

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.

In this high-risk, heavily treated population, the combination of fludarabine, cytarabine, and PegC is feasible. Responding patients included 2 AML and 1 ALL. Further exploratory analysis about the relation between response and asparagine depletion as well as specific sensitive subsets could clarify which patients might benefit the most from this combination.

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.

We reported in vitro and in vivo depletion of Gln induced by long-acting Erwinia asparaginase, PegC, inhibited proliferation of complex karyotype (CK) AML and synergistically enhanced the antiapoptotic activity of Ven-mediated antagonism of Bcl-2 by decreasing the expression of proteins such as Mcl-1, whose translation is cap-dependent...Pt 31 (post-alloHSCT relapsed AML with FLT3-ITD) who had persistent disease after gilteritinib achieved an MRD-negative CRi, pending 2nd alloHSCT... VenPegC is a novel regimen that can induce complete remission in some heavily pretreated R/R AML patients, even with previous exposure to Ven. Pts with RUNX1 mutation, whose translation depends on pheIF4E, may benefit further from this regimen.

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

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.

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

P1, N=12, Not yet recruiting, Porton Biopharma Limited

P1, N=27, Active, not recruiting, University of Maryland, Baltimore | Recruiting --> Active, not recruiting