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Development of Recombinant Immunotoxins for Hairy Cell Leukemia

Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each cou...

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Autores principales: Kreitman, Robert J., Pastan, Ira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464581/
https://www.ncbi.nlm.nih.gov/pubmed/32756468
http://dx.doi.org/10.3390/biom10081140
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author Kreitman, Robert J.
Pastan, Ira
author_facet Kreitman, Robert J.
Pastan, Ira
author_sort Kreitman, Robert J.
collection PubMed
description Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton’s tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR.
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spelling pubmed-74645812020-09-04 Development of Recombinant Immunotoxins for Hairy Cell Leukemia Kreitman, Robert J. Pastan, Ira Biomolecules Review Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton’s tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR. MDPI 2020-08-03 /pmc/articles/PMC7464581/ /pubmed/32756468 http://dx.doi.org/10.3390/biom10081140 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Kreitman, Robert J.
Pastan, Ira
Development of Recombinant Immunotoxins for Hairy Cell Leukemia
title Development of Recombinant Immunotoxins for Hairy Cell Leukemia
title_full Development of Recombinant Immunotoxins for Hairy Cell Leukemia
title_fullStr Development of Recombinant Immunotoxins for Hairy Cell Leukemia
title_full_unstemmed Development of Recombinant Immunotoxins for Hairy Cell Leukemia
title_short Development of Recombinant Immunotoxins for Hairy Cell Leukemia
title_sort development of recombinant immunotoxins for hairy cell leukemia
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464581/
https://www.ncbi.nlm.nih.gov/pubmed/32756468
http://dx.doi.org/10.3390/biom10081140
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