Background: Infants with -rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with -rearranged ALL.
Methods: Eight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine efficacy.
Results: Carfilzomib demonstrated low IC concentrations within the nanomolar range (6.0-15.8 nm) across the panel of cell lines. Combination drug testing indicated synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase.
Conclusions: Our study highlights that efficacy does not necessarily translate to benefit and emphasizes the importance of validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of -rearranged infant ALL in the clinical setting.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082024 | PMC |
| http://dx.doi.org/10.3389/fonc.2021.631594 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Evaluation of anticancer efficacy of survivin si-RNA functionalized combined drug-loaded mesoporous silica nanoparticles in a lung cancer mouse model.
Naunyn Schmiedebergs Arch Pharmacol
January 2025
Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.
Lung cancer continues to be the leading cause of mortality globally. Nanotechnology-mediated targeted drug delivery approach is one of the promising strategies for the treatment of lung cancer. Due to their multifactorial role, mesoporous silica nanoparticles (MSNs), have attracted a lot of attention for drug delivery.
View Article and Find Full Text PDFEvolution of frontline treatment for multiple myeloma: clinical investigation of quadruplets containing carfilzomib and anti-CD38 monoclonal antibodies.
Ann Hematol
January 2025
Department of Oncology, Hematology and BMT, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Although survival rates for patients with newly diagnosed multiple myeloma (NDMM) have improved over recent decades, multiple myeloma (MM) remains without a cure for most. There is increasing consensus that achievement of deep remissions, especially minimal residual disease negativity (MRD -), in frontline treatment is crucial and translates into improved survival. The standard of care (SOC) for NDMM consists at minimum of a triplet regimen of therapies, with or without an autologous stem cell transplant, or a doublet regimen for certain ineligible, particularly frail patients who may have specific limitations.
View Article and Find Full Text PDFDelayed Onset of Thrombotic Microangiopathy (TMA) upon Prolonged Carfilzomib Therapy in Multiple Myeloma: A Case Report and Comprehensive Review.
Pharmaceuticals (Basel)
December 2024
Department of Hematology and Stem Cell Transplantation, South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, 1097 Budapest, Hungary.
Background: Thrombotic microangiopathy (TMA) is a potentially life-threatening complication associated with carfilzomib, a proteasome inhibitor approved for treating multiple myeloma. TMA typically presents within the initial months of treatment; however, delayed onset is rare and poses significant diagnostic challenges.
Methods: We conducted a retrospective analysis of the medical records of a 47-year-old Caucasian woman diagnosed with IgA kappa myeloma who developed signs and symptoms consistent with TMA eleven months after the initiation of carfilzomib therapy and already in ongoing very good partial remission.
Proteasome Inhibitors Induce Apoptosis in Ex Vivo Cells of T-Cell Prolymphocytic Leukemia.
Int J Mol Sci
December 2024
Hematology Section, Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, 35122 Padova, Italy.
Finding an effective treatment for T-PLL patients remains a significant challenge. Alemtuzumab, currently the gold standard, is insufficient in managing the aggressiveness of the disease in the long term. Consequently, numerous efforts are underway to address this unmet clinical need.
View Article and Find Full Text PDFOutcomes of Standard-Risk Multiple Myeloma Patients Who Undergo Upfront Autologous Hematopoietic Stem Cell Transplantation.
Transplant Cell Ther
December 2024
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:
Patients with multiple myeloma (MM) without high-risk cytogenetic abnormalities are classified as having standard-risk MM (SRMM), and data focusing on their outcomes after autologous hematopoietic stem cell transplantation (autoHCT) are limited. To evaluate survival outcomes for patients with SRMM receiving autoHCT, and to elucidate factors that impact these outcomes. Single-center retrospective analysis that included consecutive MM patients who received upfront autoHCT between 2013 and 2021, had available cytogenetic information and had no high-risk chromosomal abnormalities on fluorescence in situ hybridization, defined as t(4;14), t(14;16), del(17p) or 1q21 gain or amplification.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!