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Pediatric Blood & Cancer Jan 2024The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is...
BACKGROUND
The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted.
PROCEDURE
We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches, and selecting those reporting at least 3 years of follow-up.
RESULTS
We identified eight pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from eight publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with nonmalignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with sickle cell disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12 years.
CONCLUSION
The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for nonmalignant conditions other than SCD.
Topics: Adult; Humans; Child; Busulfan; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Leukemia, Myeloid, Acute; Neoplasms, Second Primary; Risk Assessment; Vidarabine; Graft vs Host Disease
PubMed: 37856098
DOI: 10.1002/pbc.30738 -
British Journal of Haematology Jan 2024How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by...
Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties.
How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in paediatric patients with SCD from the EBMT registry. In 2010-2020, 251 patients aged <18 years underwent a first matched sibling donor (MSD) HSCT with conditioning based on busulfan-fludarabine (bu-flu; n = 89) or treosulfan-fludarabine (treo-flu; n = 162). In the bu-flu and treo-flu groups, 51.7% and 99.4% of patients, respectively, received thiotepa. Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu (p = 0.63). Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively (p = 0.25). The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu (p = 0.057). These multinational data confirm the excellent curative capacity of MSD HSCT with myeloablative conditioning. Both conditioning regimens yielded excellent OS, low rates of acute and chronic GVHD, and low rates of graft failure.
Topics: Humans; Child; Busulfan; Siblings; Hematopoietic Stem Cell Transplantation; Vidarabine; Graft vs Host Disease; Transplantation Conditioning; Anemia, Sickle Cell; Retrospective Studies
PubMed: 37795523
DOI: 10.1111/bjh.19122 -
Leukemia Nov 2023Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal...
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal abnormality (del(8p), deletion of the short arm of chromosome 8) in the context of CLL. By comparing the largest cohort of del(8p) CLL to date (n = 57) with a non-del(8p) cohort (n = 155), del(8p) was significantly associated with a poor prognosis, a shorter time to first treatment, worse overall survival (OS), and a higher risk of Richter transformation. For patients treated with fludarabine-based regimens, the next-treatment-free survival and the OS were shorter in del(8p) cases (including those with mutated IGHV). One copy of the TNFRSF10B gene (coding a pro-apoptotic receptor activated by TRAIL) was lost in 91% of del(8p) CLL. TNFRSF10B was haploinsufficient in del(8p) CLL, and was involved in the modulation of fludarabine-induced cell death - as confirmed by our experiments in primary cells and in CRISPR-edited TNFRSF10B knock-out CLL cell lines. Lastly, del(8p) abrogated the synergy between fludarabine and TRAIL-induced apoptosis. Our results highlight del(8p)'s value as a prognostic marker and suggest that fit CLL patients (i.e. with mutated IGHV and no TP53 disruption) should be screened for del(8p) before the initiation of fludarabine-based treatment.
Topics: Humans; Chromosome Aberrations; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Prognosis; Receptors, TNF-Related Apoptosis-Inducing Ligand; Vidarabine
PubMed: 37752286
DOI: 10.1038/s41375-023-02035-3 -
Pediatric Blood & Cancer Dec 2023Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat...
BACKGROUND
Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.
PROCEDURE
We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza-FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1-21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy-related AML (n = 1).
RESULTS
Overall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) C , V , T , and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m , 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m , respectively. T , V , and C , but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi).
CONCLUSIONS
Pevonedistat 20 mg/m combined with Aza-FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza-FLA combination demonstrated significant anti-leukemic activity.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Chronic Disease; Cyclopentanes; Cytarabine; Feasibility Studies; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Pyrimidines; Vidarabine
PubMed: 37710306
DOI: 10.1002/pbc.30672 -
Frontiers in Pharmacology 2023var. angustifolia Thw. (Annonaceae), is a famous traditional medicinal plant in Asia. Ample data specifies that the medicinal plant has anticancer activity; however,...
var. angustifolia Thw. (Annonaceae), is a famous traditional medicinal plant in Asia. Ample data specifies that the medicinal plant has anticancer activity; however, the detailed mechanisms of action still need to be well studied. Recent studies have revealed the cytotoxicity potential of leaf against HeLa cells. Therefore, the current study was conducted to examine the regulation of miRNAs in HeLa cancer cells treated with the standardized methanolic leaf extract (PLME). The regulation of miRNAs in HeLa cancer cells treated with the standardized PLME extract was studied through Illumina, Hi-Seq. 2000 platform of Next-Generation Sequencing (NGS) and various bioinformatics tools. The PLME treatment regulated a subset of miRNAs in HeLa cells. Interestingly, the PLME treatment against HeLa cancer cells identified 10 upregulated and 43 downregulated ( < 0.05) miRNAs associated with apoptosis induction. Gene ontology (GO) term analysis indicated that PLME induces cell death in HeLa cells by inducing the pro-apoptotic genes. Moreover, the downregulated oncomiRs modulated by PLME treatment in HeLa cells were identified, targeting apoptosis-related genes through gene ontology and pathway analysis. The LC-ESI-MS/MS analysis identified the presence of Vidarabine and Anandamide compounds that were previously reported to exhibit anticancer activity. The findings of this study obviously linked the cell cytotoxicity effect of PLME treatment against the HeLa cells with regulating various miRNAs expression related to apoptosis induction in the HeLa cells. PLME treatment induced apoptotic HeLa cell death mechanism by regulating multiple miRNAs. The identified miRNAs regulated by PLME may provide further insight into the mechanisms that play a critical role in cervical cancer, as well as novel ideas regarding gene therapeutic strategies.
PubMed: 37693900
DOI: 10.3389/fphar.2023.1198425 -
Blood Nov 2023Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in...
Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in patients with mutated immunoglobulin heavy chain variable gene (IGHV-M). We updated long-term follow-up results from the original 300-patient FCR study initiated at MD Anderson in 1999. The current median follow-up is 19.0 years. With this extended follow-up, the median PFS for patients with IGHV-M was 14.6 years vs 4.2 years for patients with unmutated IGHV (IGHV-UM). Disease progression beyond 10 years was uncommon. In total, 16 of 94 (17%) patients in remission at 10 years subsequently progressed with the additional follow-up compared with the patients in our prior report in 2015. Only 4 of 45 patients (9%) with IGHV-M progressed beyond 10 years. Excluding Richter transformation, 96 of 300 patients (32%) developed 106 other malignancies, with 19 of 300 (6.3%) developing therapy-related myeloid neoplasms (tMNs), which were fatal in 16 of 19 (84%). No pretreatment patient characteristics predicted the risk of tMNs. In summary, FCR remains an option for patients with IGHV-M chronic lymphocytic leukemia (CLL), with a significant fraction achieving functional cure of CLL. A risk-benefit assessment is warranted when counseling patients, balancing potential functional cure with the risk of late relapses and serious secondary malignancies.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Follow-Up Studies; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Vidarabine
PubMed: 37595283
DOI: 10.1182/blood.2023020158 -
The Journal of Physiological Sciences :... Aug 2023In this work, we examined the involvement of type 5 adenylyl cyclase (AC5) in cardiac dysfunction induced in mice given Porphyromonas gingivalis lipopolysaccharide...
In this work, we examined the involvement of type 5 adenylyl cyclase (AC5) in cardiac dysfunction induced in mice given Porphyromonas gingivalis lipopolysaccharide (PG-LPS) at a dose equivalent to the circulating levels in periodontitis (PD) patients. Cardiac function was significantly decreased in mice given PG-LPS compared to the control, but treatment for 1 week with the AC5 inhibitor vidarabine ameliorated the dysfunction. Cardiac fibrosis and myocyte apoptosis were significantly increased in the PG-LPS group, but vidarabine blocked these changes. The PG-LPS-induced cardiac dysfunction was associated with activation of cyclic AMP/Ca-calmodulin-dependent protein kinase II signaling and increased phospholamban phosphorylation at threonine 17. These results suggest that pharmacological AC5 inhibition may be a promising approach to treat PD-associated cardiovascular disease.
Topics: Mice; Animals; Vidarabine; Lipopolysaccharides; Porphyromonas gingivalis; Heart; Cardiomyopathies
PubMed: 37558983
DOI: 10.1186/s12576-023-00873-5 -
Blood Cancer Journal Aug 2023
Ibrutinib plus fludarabine, cyclophosphamide and rituximab (iFCR) as initial treatment in chronic lymphocytic leukemia/ small lymphocytic leukemia with or without TP53 aberrations: a prospective real-world study in Chinese cohort.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; East Asian People; Prospective Studies; Cyclophosphamide; Vidarabine; Antineoplastic Combined Chemotherapy Protocols; Tumor Suppressor Protein p53
PubMed: 37558684
DOI: 10.1038/s41408-023-00890-y -
Journal of Oncology Pharmacy Practice :... Jul 2024Fludarabine, a purine analog, is getting more attention with the increasing use of reduced intensive conditioning regimens in allogeneic hematopoietic stem cell...
INTRODUCTION
Fludarabine, a purine analog, is getting more attention with the increasing use of reduced intensive conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The side effect of bradycardia was observed in only a few cases reported in the literature. In clinical practice, bradycardia can be asymptomatic or cause syncope and cardiac arrest. This study aimed to evaluate the bradycardia side effect of fludarabine used in the conditioning regimen in allo-HSCT recipients and to increase awareness of this issue.
METHODS
This retrospective study included 73 patients who received fludarabine in the allo-HSCT conditioning regimen between January 2015 and January 2021. Patients with and without bradycardia were compared regarding demographic data, allo-HSCT characteristics, electrolyte values, fludarabine administration dose and duration, and survival. Univariate and multivariate analyzes were performed to evaluate independent predictors for fludarabine-induced bradycardia.
RESULTS
Fludarabine administration doses and days were higher in the bradycardia group, but no statistically significant difference was observed. In the multivariate analysis, age was the only independent predictor of fludarabine-induced bradycardia (odds ratio (OR) 0.93, 95% confidence interval (CI): 0.89-0.98, p = 0.007). The median age in the group with bradycardia was 19 years younger than those without bradycardia (34 (19-49) vs 53 (19-69), p = 0.005). In 11 (84.6%) of the patients who had bradycardia, bradycardia improved with the discontinuation of fludarabine alone, but atropine was administered in 2 (15.4%) patients.
CONCLUSION
Age was the only independent predictor of fludarabine-induced bradycardia; therefore, close heart rate monitoring is recommended during fludarabine administration, especially in younger patients.
Topics: Humans; Vidarabine; Bradycardia; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Male; Female; Adult; Middle Aged; Transplantation Conditioning; Transplantation, Homologous; Young Adult; Aged
PubMed: 37475474
DOI: 10.1177/10781552231189868 -
Haematologica Jan 2024Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of...
Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) without or with venetoclax (FLAVIDA) in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLAIDA- treated patients (78% vs. 47%; P=0.001), while measurable residual disease was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eighty-one percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation or donor lymphocyte infusion after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA- and FLA-IDA-treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing measurable residual disease-negative remission in a high proportion of R/R AML patients.
Topics: Humans; Idarubicin; Cytarabine; Retrospective Studies; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Vidarabine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37470150
DOI: 10.3324/haematol.2023.282912