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Pediatric Transplantation Mar 2022Short telomere syndrome (STS) in children may result in phenotypically heterogenous clinical spectrum ranging from completely asymptomatic to typical dyskeratosis...
BACKGROUND
Short telomere syndrome (STS) in children may result in phenotypically heterogenous clinical spectrum ranging from completely asymptomatic to typical dyskeratosis congenita (DC). Patients with this cancer predisposition syndrome may have multiple organ dysfunctions including pulmonary fibrosis, liver cirrhosis, and bone marrow failure. Not all mutations in telomerase or telomere genes have been identified, and STS may pose a diagnostic and management challenge.
METHODS
A retrospective chart review and literature search were done for this report.
RESULTS
Here, we report a case of atypical DC with a heterozygous germline missense mutation in the postmeiotic segregation increased 2 (PMS2) gene, exon 5, (c.466A>G (p. Thr156Ala)). The PMS2 (a mismatch repair protein) gene is known to be an important mediator of telomere-induced aging. The patient was transfusion dependent and underwent successful umbilical cord blood transplant using a non-myeloablative regimen with alemtuzumab, fludarabine, cyclophosphamide, and total body irradiation.
CONCLUSION
In this case of atypical DC with a previously unreported germline missense mutation in PMS2, the patient was successfully treated with an umbilical cord blood transplant with a non-myeloablative regimen.
Topics: Alemtuzumab; Antineoplastic Agents; Child, Preschool; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Dyskeratosis Congenita; Female; Germ-Line Mutation; Humans; Mismatch Repair Endonuclease PMS2; Vidarabine; Whole-Body Irradiation
PubMed: 34626046
DOI: 10.1111/petr.14157 -
Nucleosides, Nucleotides & Nucleic Acids 2022Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin's...
Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cyclophosphamide; Humans; Neoplasms; Nucleosides; Tumor Suppressor Protein p53; Vidarabine
PubMed: 34886743
DOI: 10.1080/15257770.2021.2013500 -
Biology of Blood and Marrow... Jun 2018We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between...
We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34 cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.
Topics: Adolescent; Busulfan; Child; Child, Preschool; Female; Graft Rejection; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Infant; Italy; Lymphohistiocytosis, Hemophagocytic; Male; Recurrence; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine
PubMed: 29410181
DOI: 10.1016/j.bbmt.2018.01.022 -
Biology of Blood and Marrow... Nov 2014Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3α [REG3α], elafin, tumor necrosis factor receptor 1 [TNFR1], and...
Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3α [REG3α], elafin, tumor necrosis factor receptor 1 [TNFR1], and soluble IL-2 receptor-alpha [sIL2Rα]) were measured at specific time points after cyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft-versus-host disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21, and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset at day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-statistic = .72, P = .03), day +14 (c-statistic = .74, P = .02), and day +21 (c-statistic = .75, P = .02); elevated plasma REG3α concentrations at day +14 (c-statistic = .73, P = .03), day +21 (c-statistic = .76, P = .01), and day +30 (c-statistic = .73, P = .03); and elevated elafin at day +14 (c-statistic = .71, P = .04). Plasma concentrations of TNFR1 and sIL2Rα were not associated with aGVHD risk at any of the time points studied. This study identified ST2, REG3α, and elafin as prognostic biomarkers to evaluate risk of aGVHD after cyclophosphamide/fludarabine-based NMAT. These results need to be confirmed in an independent validation cohort.
Topics: Acute Disease; Biomarkers, Tumor; Cyclophosphamide; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Prognosis; Risk Factors; Survival Analysis; Transplantation Conditioning; Vidarabine
PubMed: 25017764
DOI: 10.1016/j.bbmt.2014.06.039 -
Clinical Epigenetics Dec 2019In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined...
BACKGROUND
In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen.
RESULTS
The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology.
CONCLUSIONS
Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.
Topics: Adult; Aged; Cyclophosphamide; DNA Methylation; Disease Progression; Epigenesis, Genetic; Female; Gene Regulatory Networks; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Longitudinal Studies; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Rituximab; Treatment Outcome; Vidarabine
PubMed: 31791414
DOI: 10.1186/s13148-019-0783-1 -
Internal Medicine (Tokyo, Japan) Jun 2022Objective Graft failure (GF) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). A standardized conditioning regimen and an appropriate...
Objective Graft failure (GF) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). A standardized conditioning regimen and an appropriate graft source of salvage HSCT for GF have not yet been established. Some case series have shown good hematopoietic recoveries after salvage HSCT using a short-term reduced-intensity preparative regimen consisting of fludarabine (30-90 mg/m), cyclophosphamide (2 g/m), and total-body irradiation (2 Gy). However, the dose of fludarabine has varied in these reports based on the clinical condition of the patients, resulting in very limited experiences with each dose of fludarabine. Methods We retrospectively analyzed 10 patients who developed GF after allogeneic HSCT and underwent salvage cord blood transplantation (CBT) using the above-mentioned conditioning regimen with a fixed dose (90 mg/m) of fludarabine. Results Eight patients (80.0%) achieved neutrophil engraftment within 30 days from salvage HSCT with a median of 21 (range, 17-23) days. The 1-year overall survival (OS) rate after the salvage HSCT was 50.0%, and the median OS was 281 (range, 23-1,638) days. Cumulative incidences of non-relapse mortality and relapse at 1 year were 50.0% and 10.0%, respectively. Conclusion CBT using this short-term reduced-intensity conditioning regimen may be a promising salvage therapy for GF.
Topics: Cord Blood Stem Cell Transplantation; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Salvage Therapy; Transplantation Conditioning; Vidarabine
PubMed: 34803091
DOI: 10.2169/internalmedicine.7836-21 -
The British Journal of Dermatology Aug 2021Linked Article: Vanden Oever et al. Br J Dermatol 2021; 185:380-390. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder. Patients with RDEB...
Linked Article: Vanden Oever et al. Br J Dermatol 2021; 185:380-390. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder. Patients with RDEB experience severe painful blistering and skin fragility due to separation of two layers of the skin: the dermis and epidermis. This occurs because type VII collagen (C7) is deficient or absent in the skin. C7 is a major component responsible for tethering the epidermis to the dermis. The skin heals with disfiguring scarring, and patients are at risk of secondary infection and an aggressive form of squamous carcinoma, a type of skin cancer. There is currently no cure but there are encouraging results from some experimental treatments. One treatment is haematopoietic stem cell transplantion, where the engrafted cells appear to increase the amount of C7 (a process called deposition) over the long-term. Unfortunately, this treatment requires long term immunosuppression and this is particularly risky in patients with RDEB, who are prone to infections. The authors, based in Minneapolis, USA, explored whether any of the drugs used in chemotherapy treatment used before transplant might have an effect on C7 deposition. They found that fludarabine influences the production of C7 in affected cells in RDEB. They describe various mechanisms for this effect. They stress the need to determine how much the increased C7 deposition following haematopoietic stem cell transplantation is because of the engrafted cells, and how much is from the patient's own cells stimulated by drugs such as fludarabine. They caution that drugs may cause deposition of non-functional C7, which could be harmful. Unfortunately, fludarabine is generally too toxic to use in patients with RDEB, but there is the possibility of less toxic analogues that could have the same desirable effect on C7 deposition and have clinical benefit.
Topics: Collagen Type VII; Epidermolysis Bullosa Dystrophica; Humans; Skin; Vidarabine
PubMed: 34396502
DOI: 10.1111/bjd.20528 -
Leukemia Research Oct 2018
Topics: Anthracyclines; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Vidarabine
PubMed: 30212655
DOI: 10.1016/j.leukres.2018.08.018 -
The Lancet. Haematology Nov 2018
Randomized Controlled Trial
Topics: Area Under Curve; Busulfan; Cyclophosphamide; Female; Graft Rejection; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Randomized Controlled Trials as Topic; Survival Analysis; Transplantation Conditioning; Vidarabine; Young Adult
PubMed: 30389031
DOI: 10.1016/S2352-3026(18)30171-6 -
ACS Chemical Biology Sep 2019Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of...
Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin's lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of their targets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for arabinose nucleotide-mediated inhibition of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of fludarabine could be modified to improve its specificity and affinity toward primase, possibly leading to less toxic and more effective therapeutic agents.
Topics: Adenosine Triphosphate; Antineoplastic Agents; Antiviral Agents; Catalytic Domain; Crystallography, X-Ray; DNA Primase; Enzyme Assays; Humans; Protein Binding; Vidarabine
PubMed: 31479243
DOI: 10.1021/acschembio.9b00367