Baseline TP53 mutations in adults with SCD developing myeloid malignancy following hematopoietic cell transplantation.
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ABSTRACT:
SUBMITTER: Ghannam JY
PROVIDER: S-EPMC7118814 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) offers a potential cure for high-risk hematological malignancy; however, long-term survivors experience increased cardiovascular morbidity and mortality. It is unclear how allo-HCT impacts cardiovascular function in the short-term. Thus, this 3-month prospective study sought to evaluate the short-term cardiovascular impact of allo-HCT in hematological cancer patients, compared to an age-matched non-cancer control group.MethodsBefore and ~3-months following allo-HCT, 17 hematological cancer patients (45 ± 18 years) underwent cardiopulmonary exercise testing to quantify peak oxygen uptake (VO2peak)-a measure of integrative cardiovascular function. Then, to determine the degree to which changes in VO2peak are mediated by cardiac vs. non-cardiac factors, participants underwent exercise cardiac MRI (cardiac reserve), resting echocardiography (left-ventricular ejection fraction [LVEF], global longitudinal strain [GLS]), dual-energy x-ray absorptiometry (lean [LM] and fat mass [FM]), blood pressure (BP) assessment, hemoglobin sampling, and arteriovenous oxygen difference (a-vO2diff) estimation via the Fick equation. Twelve controls (43 ± 13 years) underwent identical testing at equivalent baseline and 3-month time intervals.ResultsSignificant group-by-time interactions were observed for absolute VO2peak (p = 0.006), bodyweight-indexed VO2peak (p = 0.015), LM (p = 0.001) and cardiac reserve (p = 0.019), which were driven by 26, 24, 6, and 26% reductions in the allo-HCT group (all p ≤ 0.001), respectively, as no significant changes were observed in the age-matched control group. No significant group-by-time interactions were observed for LVEF, GLS, FM, hemoglobin, BP or a-vO2diff, though a-vO2diff declined 12% in allo-HCT (p = 0.028).ConclusionIn summary, allo-HCT severely impairs VO2peak, reflecting central and peripheral dysfunction. These results indicate allo-HCT rapidly accelerates cardiovascular aging and reinforces the need for early preventive cardiovascular intervention in this high-risk group.
| S-EPMC9797839 | biostudies-literature
Project description:Allogeneic hematopoietic cell transplantation, gene therapy, and gene editing offer a potential cure for sickle cell disease (SCD). Unfortunately, myelodysplastic syndrome and acute myeloid leukemia development have been higher than expected after graft rejection following nonmyeloablative conditioning and lentivirus-based gene therapy employing myeloablative busulfan for SCD. Somatic mutations discovered in 2 of 76 patients who rejected their grafts were identified at baseline at much lower levels. While a whole-genome sequencing analysis reported no difference between patients with SCD and controls, a study including whole-exome sequencing revealed a higher prevalence of clonal hematopoiesis in individuals with SCD compared with controls. Genetic risk factors for myeloid malignancy development after curative therapy for SCD are currently being explored. Once discovered, decisions could be made about whether gene therapy may be feasible vs allogeneic hematopoietic cell transplant, which results in full donor chimerism. In the meantime, care should be taken to perform a benefit/risk assessment to help patients identify the best curative approach for them. Long-term follow-up is necessary to monitor for myeloid malignancies and other adverse effects of curative therapies for SCD.
| S-EPMC9820448 | biostudies-literature
Project description:IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).
| S-EPMC9649991 | biostudies-literature
Project description:There is increasing recognition of the risk of developing therapy-related myeloid malignancy, including after cellular therapy. While retrospective studies have implicated pre-existing TP53 mutated hematopoietic clones as a common causative mechanism, no prospective screening to identify those patients at greatest risk is currently possible. We demonstrate that ultradeep DNA-sequencing prior to therapy may be used for discovery of TP53 mutations that are subsequently associated with malignancy.
| S-EPMC10896414 | biostudies-literature
Project description:PurposeThis study assessed and compared preferences for treatment attributes of maintenance therapies post-hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and in physicians who treat these patients.Patients and methodsPatients with AML post HSCT and physicians from the United States, United Kingdom, Canada, and Australia (physicians only) completed a web-based discrete choice experiment (DCE). The DCE used inputs identified via a targeted literature review and qualitative interviews to ascertain relevant treatment attributes and associated levels. Six treatment attributes were selected (chance of 2-year relapse-free survival, quality of life [QoL], risk of serious infections, risk of nausea, chance of achieving transfusion independence, and duration of hospitalization annually), each with three or four levels. The experimental design included 36 choice tasks that presented a pair of hypothetical treatment profiles with varying attribute levels; participants chose a preferred treatment for each choice task. Choice tasks were divided into three blocks of 12 tasks each in the patient survey and 4 blocks of 9 tasks each in the physician survey; survey participants were randomly assigned to one of the blocks. Random parameter logit regression models were used to assess the impact of stated attributes on preferences for maintenance treatment post HSCT.ResultsSurveys from 84 patients and 149 physicians were assessed. For patients, QoL was the most important attribute, followed by duration of hospitalization and chance of 2-year relapse-free survival. For physicians, chance of 2-year relapse-free survival was the most important attribute, followed by QoL and risk of serious infections.ConclusionDifferences in how patients and physicians valued post-HSCT maintenance treatment attributes were identified. These differences suggest that patient-centered decision-making may help physicians choose maintenance treatments for patients with AML post HSCT that better meet their treatment needs and improve their treatment satisfaction.
| S-EPMC10637189 | biostudies-literature
Project description:Access to allogenic hematopoietic cell transplantation (HCT), a potentially curative treatment for chemotherapy-resistant hematologic malignancies, can be limited if no human leukocyte antigen (HLA) identical related or unrelated donor is available. Alternative donors include Cord Blood as well as HLA-mismatched unrelated or related donors. If the goal is to minimize the number of HLA disparities, partially matched unrelated donors are more likely to share 8 or 9 of 10 HLA alleles with the recipient. However, over the last decade, there has been success with haploidentical HCT performed using the stem cells from HLA half-matched related donors. As the majority of patients have at least one eligible and motivated haploidentical donor, recruitment of haploidentical related donors is frequently more rapid than of unrelated donors. This advantage in the accessibility has historically been offset by the increased risks of graft rejection, graft-versus-host disease and delayed immune reconstitution. Various ex vivo T-cell depletion (TCD) methods have been investigated to overcome the immunological barrier and facilitate immune reconstitution after a haploidentical HCT. This review summarizes historical and contemporary clinical trials of haploidentical TCD-HCT, mainly in pediatric malignancy, and describes the evolution of these approaches with a focus on serial improvements in the kinetics of immune reconstitution. Methods of TCD discussed include in vivo as well as ex vivo positive and negative selection. In addition, haploidentical TCD as a platform for post-HCT cellular therapies is discussed. The present review highlights that, as a result of the remarkable progress over half a century, haploidentical TCD-HCT can now be considered as a preferred alternative donor option for children with hematological malignancy in need of allogeneic HCT.
| S-EPMC9614427 | biostudies-literature
Project description:We aimed to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation with targeted oral busulfan (BU) and cyclophosphamide (CY) in a phase II study. Busulfan (1.0 mg/kg) was given initially in six doses. Based on the estimated concentration at steady state after the first dose of BU, subsequent (7th-16th) doses were adjusted to obtain a targeted overall concentration at steady state of 700-900 ng/mL. The primary endpoint was 1-year overall survival (OS). Fifty patients were registered and 46 (median age, 53 years; range, 18-62 years) received planned transplant, including 24 with AML, 16 with myelodysplastic syndrome, and six with CML. Fourteen patients were categorized as standard risk. Nineteen patients received transplant from human leukocyte antigen-identical siblings, 27 from unrelated donors. The BU dose required reduction in 32 patients and escalation in six patients. One-year OS was 65% (95% confidence interval, 50-77%). Cumulative incidence of hepatic sinusoidal obstruction syndrome was 11%. One-year transplant-related mortality was 18%. Both OS and transplant-related mortality were favorable in this study, including patients of older age and with high risk diseases. Individual dose adjustment based on BU pharmacokinetics was feasible and effective in the current phase II study. This trial is registered in the University Hospital Medical Information Network Clinical Trial Registry System (UMIN-CTR, ID:C000000156).
| S-EPMC7659230 | biostudies-literature
Project description:Granulocyte colony-stimulating factor is a cytokine able to stimulate both myelopoiesis and hematopoietic stem cell mobilization, which has seen it used extensively in the clinic to aid hematopoietic recovery. It acts specifically via the homodimeric granulocyte colony-stimulating factor receptor (G-CSFR), which is principally expressed on the surface of myeloid and hematopoietic progenitor cells. A number of pathogenic mutations have now been identified in CSF3R, the gene encoding G-CSFR. These fall into distinct classes, each of which is associated with a particular spectrum of myeloid disorders, including malignancy. This review details the various CSF3R mutations, their mechanisms of action, and contribution to disease, as well as discussing the clinical implications of such mutations.
| S-EPMC4013473 | biostudies-other
Project description:BackgroundPediatric CML is very rare. Before the introduction of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (HSCT) from a donor -if available- was the standard cure attempt. Data on the long-term outcome and health-related quality of life (HRQOL) in former pediatric CML patients undergoing HSCT are lacking.Study questionWe investigated long-term survivors' self-reporting to a questionnaire sent out to patients formerly enrolled in pediatric CML-HSCT trials.MethodsIndividuals with CML transplanted at age <18 years were identified from the German Childhood Cancer Registry database. Long-term survivors received a questionnaire based on the SF-36 and FACT-BMT asking them to self-report HRQOL issues. (Ethical vote #541_20 B, Medical Faculty, University of Erlangen-Nürnberg).Results111/171 (64.9%) individuals survived HSCT long-term and 86/111 (77.5%) fulfilled all inclusion criteria and received the questionnaire. 37/86 (43%) participants (24 female, 13 male, median age at HSCT 12 years [range 2-18], median age at the time of the survey 29 years [range 18-43]) responded after a median follow-up period of 19 years (range 4-27) after HSCT. 10/37 (27%) participants underwent no regular medical follow-up examinations. Self-reported symptoms like chronic graft-versus-host disease (cGvHD)-associated organ impairments and conditioning regimen consequences could causatively not sharply be separated in each case. Complains comprised hypothyroidism (N=11, 30%), infertility (N=9, 24%), lung problems, dry eyes (each N=7, 19%), skin alterations (N=6, 17%), hair problems (N=4, 11%), and sexual dysfunction (N=3, 9%). 10 (27%) participants experienced 13 CML relapses after a median interval from HSCT of 31 months (range 2-93). Only one patient underwent 2nd SCT after failure of relapse treatment with TKIs. Six secondary malignancies (dysplastic melanocytic nevus and ALL, basal cell carcinoma (N=2), rhabdomyosarcoma, and thyroid carcinoma developed in 5 (13%) participants. As assessed by the SF-36 questionnaire, impaired physical health was mainly associated with cGvHD. The mental component summary score showed that also participants without cGvHD scored significantly lower than the general population. When assessed by the FACT-BMT, participants with cGvHD scored significantly lower while participants without cGvHD scored even 5 points higher than the data from controls. 18 (49%) participants considered the sequelae of HSCT an obstacle to education. Out of the total cohort, N=20 (54%), N=7 (19%), N=5 (14%), and N=4 (11%) participants worked full time, part-time, were unemployed, or had not yet finalized their education, respectively. 20 (54%) participants lived as singles, 8 (22%) lived in a partnership, 6 (16%) were married, and 3 (8%) had been divorced. Four (11%) participants reported a total number of 7 children.ConclusionThis first assessment of HRQOL in former pediatric patients with CML surviving HSCT for more than two decades demonstrates self-reported satisfactory well-being only in the absence of cGvHD. Research-based on self-reported outcomes sheds light on former patients' perspectives and provides an additional layer of valuable knowledge for pediatric and adult hematologists. Regular follow-up examinations are mandatory helping to avoid that late secondary neoplasias, CML-relapse, and disorders forming the broad range of possible long-term consequences of HSCT are not detected too late.
| S-EPMC9580018 | biostudies-literature
Project description:Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15-4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06-3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.
| S-EPMC7139772 | biostudies-literature