Clofarabine

Given the shortage of fludarabine, alternative preparative lymphodepleting regimens for CAR-T-cell therapy need to be identified. We present a case of relapsed/refractory B-cell acute lymphoblastic leukemia requiring multiple lines of salvage therapy with persistent extensive disease, who underwent lymphodepletion with clofarabine and cyclophosphamide before tisagenlecleucel CD19+ CAR-T-cell infusion with eventual remission. We offer evidence of clofarabine's activity against B-cell acute lymphoblastic leukemia in combination with tisagenlecleucel therapy...

Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease. ES cells are selectively sensitive to CD99 inhibition compared to most normal cells and other tumors. Therefore, CD99 is a good molecular target for ES treatment. Clofarabine and cladribine are two FDA approved drugs that are administered for their inhibitory acts on DNA synthesis to treat relapsed or refractory acute lymphoblastic and myeloid leukemia...

Clofarabine (Clo) is an immunosuppressive purine analog that may have better anti-leukemic activity than fludarabine (Flu). The addition of total body irradiation (TBI) to conditioning regimens has been widely investigated. However, the use of single agent Clo in combination with intermediate doses of TBI ranging from 4 to 8 Gy has not been studied yet. This study is a double center, observational, retrospective study of patients with high-risk hematological malignancies diagnosed from 2012 to 2021, treated at the American University of Beirut Medical Center in Beirut (AUBMC), Lebanon, and Saint-Antoine Hospital (SAH) in Paris, France...

BACKGROUND: Despite pronounced improvement in overall survival (OS) in pediatric leukemia, a proportion of patients continue to suffer from lack of response or relapse, and the management of such patients is exceedingly difficult. Immunotherapy and engineered chimeric antigen receptor (CAR) T-cell therapy have shown promising results in the course of relapsed or refractory acute lymphoblastic leukemia (ALL). However, conventional chemotherapy continues to be utilized for re-induction purposes whether independently or in combination with immunotherapy...

INTRODUCTION: Multiple myeloma (MM) is a fatal hematological malignancy and does not have adequate prognostic indicators. Previous studies indicate that CEP72 is closely related to tumorigenesis and tumor progression. However, the expression and function of CEP72 in multiple myeloma have yet to be elucidated. METHODS: In this study, we explored the correlation between CEP72 expression and clinicopathological characteristics as well as the impacts of CEP72 expression on the survival of MM patients...

Aptamers are short single-strand oligonucleotides that can form secondary and tertiary structures, fitting targets with high affinity and specificity. They are so-called "chemical antibodies" and can target specific biomarkers in both diagnostic and therapeutic applications. Systematic evolution of ligands by exponential enrichment (SELEX) is usually used for the enrichment and selection of aptamers, and the targets could be metal ions, small molecules, nucleotides, proteins, cells, or even tissues or organs...

Clofarabine is approved for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in pediatric patients aged 1 to 21 years. Its pharmacokinetic (PK) exposure is strongly related to clinical outcomes and high risk of adverse reactions. PK-guided dosing of nucleoside analogs has the potential to improve survival and reduce toxicity in children. Considering that blood collection is an invasive operation and that the volume of blood collected is usually limited in pediatric ALL patients, a convenient and efficient method for the quantification of clofarabine in human urine and plasma was established with an LC-MS/MS system...

BACKGROUND: Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplant (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and non-relapse mortality. A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been described to exhibit anti-leukemic activity with acceptable toxicity in patients ≤ 70 years old...

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CONTEXT: Clofarabine is an immunosuppressive purine analog that may have better anti-leukemic activity than fludarabine as a conditioning regimen for stem cell transplantation in acute leukemia. The addition of total body irradiation (TBI) to conditioning regimens has been widely investigated. However, the use of single-agent clofarabine in combination with higher doses of TBI ranging from 4 to 8 Gy has not been studied. OBJECTIVE: The aim of this study is to identify the outcome of patients with hematological malignancies who underwent allogeneic stem cell transplantation from full-matched or haploidentical donors and received clofarabine and TBI as a conditioning regimen...

CONTEXT: Lineage switch in acute leukemias (AL) is a rarely described entity. Several hypotheses have been proposed to explain it, notably the expansion of a coexisting subclone after suppression of the leukemic clone apparent at diagnosis by chemotherapy, alterations brought by chemotherapy upon the original clone, by suppressing differentiation programs, thus inducing a shift in phenotypic expression, or high fate plasticity of the hematopoietic progenitor cells, regulated by microenvironmental signals and transcription factors...

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme...

Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of i.v. busulfan (Bu) as part of conditioning chemotherapy has been shown to be effective in controlling disease relapse; however, disease relapse remains a major cause of death following allo-HSCT. This study was conducted to determine the long-term outcomes of vorinostat with i.v. Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT...

Pretransplant conditioning with Fludarabine (Flu)-Busulfan (Bu) is safe, but clofarabine (Clo) has improved antileukemic activity. Hypothesis: Flu+Clo-Bu (FCB) yields superior progression-free survival (PFS) after allogeneic transplantation. We randomized 250 AML/MDS patients aged 3-70, Karnofsky Score ≥80, with matched donors, to FCB (n = 120) or Flu-Bu (n = 130), stratifying complete remission (CR) vs. No CR, (NCR). HCT-CI scores varied, from 0 to 10. All evaluable patients engrafted...

INTRODUCTION: Survival outcomes of children with relapsed/refractory (r/r) acute leukemia remain poor. Novel expensive treatments have been developed to improve their outcomes, yet, limited evidence exists about cost-effectiveness of alternative treatment strategies. AREAS COVERED: A systematic review was conducted to summarize health-economic evidence about costs/cost-effectiveness of treating r/r acute leukemia in children/young adults. We searched Medline, Embase, and Cochrane databases until August 13th, 2021...

Lineage switches in acute leukemia occur rarely, and the underlying mechanisms are poorly understood. Herein, we report the case of an elderly patient with leukemia in which the leukemia started as B-cell acute lymphoblastic leukemia (B-ALL) and later changed to B- and T-cell mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) during consecutive induction chemotherapy treatments. A 65-year-old woman was initially diagnosed with Philadelphia chromosome-negative B-ALL primarily expressing TdT/CD34/HLA-DR; more than 20% of the blasts were positive for CD19/CD20/cytoplasmic CD79a/cytoplasmic CD22/CD13/CD71...

BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized...

The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony-stimulating factor with idarubicin (FLAG-Ida) in 311 patients designated high-risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed...

Owing to the specific and high binding affinity of aptamers to their targets, aptamer-drug conjugates (ApDCs) have emerged as a promising drug delivery system for targeted cancer therapy. However, in a conventional ApDC, the aptamer segment usually just serves as a targeting moiety, and only a limited number of drug molecules are sequentially conjugated to the oligonucleotide, giving a relatively low drug loading capacity. To address this challenge, herein we employ four clinically approved nucleoside analogues, including clofarabine (Clo), ara-guanosine (AraG), gemcitabine (Ge), and floxuridine (FdU), to replace all natural nucleosides in aptamer sequences, generating a series of whole drug-constituted DNA-like oligomers that are termed drugtamers...

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline-based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias...