Phase <scp>I</scp> study of escalating doses of carfilzomib with <scp>HyperCVAD</scp> in patients with newly diagnosed acute lymphoblastic leukemia

Jonas, Brian A.; Fisch, Samantha C; Rosenberg, Aaron S; Hoeg, Rasmus T; Tuscano, Joseph M.; Abedi, Mehrdad

doi:10.1002/ajh.26105

Cited by 6 publications

(3 citation statements)

References 15 publications

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“…The treatment was well-tolerated and resulted in a complete response (CR) rate of 90% after the first cycle; the last patient achieved CR after the fourth cycle. Moreover, MRD negativity was achieved in seven (70%) patients [ 165 ].…”

Section: Methods Of Enhancing the Results Of Glucocorticoid Therapy I...mentioning

confidence: 99%

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Kośmider

Karska

Kozakiewicz

et al. 2022

IJMS

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Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 109 blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.

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Section: Methods Of Enhancing the Results Of Glucocorticoid Therapy I...mentioning

confidence: 99%

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Kośmider

Karska

Kozakiewicz

et al. 2022

IJMS

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“…They achieved 80% of MRD negativity rate, compared with 53% when treated with hyper-CVAD alone. None of them had cardiac events ( 70 ).…”

Section: Clinical Studies Of Various Proteasome Inhibitorsmentioning

confidence: 99%

The Role of Proteasome Inhibitors in Treating Acute Lymphoblastic Leukaemia

Sin

Man

2021

Front. Oncol.

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Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy. The prognosis of ALL is excellent in paediatric population, however the outcome of relapse/refractory disease is dismal. Adult ALL has less favourable prognosis and relapse/refractory disease is not uncommonly encountered. Bortezomib is the first generation proteasome inhibitor licensed to treat plasma cell myeloma and mantle cell lymphoma with favourable side effect profile. Efficacy of bortezomib had been proven in other solid tumors. Clinical studies showed promising response for proteasome inhibitors in treating relapse/refractory ALL. Thus, proteasome inhibitors are attractive alternative agents for research in treating ALL. In the review article, we will introduce different proteasome inhibitors and their difference in pharmacological properties. Moreover, the mechanism of action of proteasome inhibitors on ALL will be highlighted. Finally, results of various clinical studies on proteasome inhibitors in both paediatric and adult ALL will be discussed. This review article provides the insights on the use of proteasome inhibitors in treating ALL with a summary of mechanism of action in ALL which facilitates future research on its use to improve the outcome of ALL.

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“…It was in fact seen that Carfilzomib showed relevant activity in the majority of ALL cell lines except for the P-glycoproteinpositive t (17, 19) ALL cell lines, and the knockout of the IKZF1 gene was associated with a favorable response to Carfilzomib treatment (136), making the association of Carfilzomib with the current chemotherapy protocols a new therapeutic option for refractory ALL with P-glycoproteinnegative leukemia cells. In a Phase I study, increasing doses of Carfilzomib were associated with Hyper CVAD in Patients with Newly Diagnosed ALL, showing promising results, also in terms of safety, feasibility and Minimal Residue Disease (MRD) response improvement (137).…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies

et al. 2021

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The microenvironment that surrounds a tumor, in addition to the tumor itself, plays an important role in the onset of resistance to molecularly targeted therapies. Cancer cells and their microenvironment interact closely between them by means of a molecular communication that mutually influences their biological characteristics and behavior. Leukemia cells regulate the recruitment, activation and program of the cells of the surrounding microenvironment, including those of the immune system. Studies on the interactions between the bone marrow (BM) microenvironment and Acute Lymphoblastic Leukemia (ALL) cells have opened a scenario of potential therapeutic targets which include cytokines and their receptors, signal transduction networks, and hypoxia-related proteins. Hypoxia also enhances the formation of new blood vessels, and several studies show how angiogenesis could have a key role in the pathogenesis of ALL. Knowledge of the molecular mechanisms underlying tumor-microenvironment communication and angiogenesis could contribute to the early diagnosis of leukemia and to personalized molecular therapies. This article is part of a Special Issue entitled: Innovative Multi-Disciplinary Approaches for Precision Studies in Leukemia edited by Sandra Marmiroli (University of Modena and Reggio Emilia, Modena, Italy) and Xu Huang (University of Glasgow, Glasgow, United Kingdom).

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Phase I study of escalating doses of carfilzomib with HyperCVAD in patients with newly diagnosed acute lymphoblastic leukemia

Abstract: First-in man, phase 1 study of CSL362 (anti-IL3Rα/anti-CD123 monoclonal antibody) in patients with CD123+ acute myeloid leukemia (AML) in CR at high risk for early relapse.

Cited by 6 publications

References 15 publications

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

The Role of Proteasome Inhibitors in Treating Acute Lymphoblastic Leukaemia

The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies

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