Isocitrate dehydrogenase inhibitor-driven differentiation may resemble secondary graft failure in post-allogeneic haematopoietic cell transplantation relapsed acute myeloid leukaemia.
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ABSTRACT:
SUBMITTER: Rasche A
PROVIDER: S-EPMC8936480 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Isocitrate dehydrogenase inhibitor-driven differentiation may resemble secondary graft failure in post-allogeneic haematopoietic cell transplantation relapsed acute myeloid leukaemia.
Rasche Adrianne A Mason Emily F EF Strickland Stephen A SA Byrne Michael M Ferrell P Brent PB
British journal of haematology 20210607 5
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Project description:BackgroundMutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown.Patients and methodsWe report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control).ResultsNo statistical significance was detected in patient's overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model.ConclusionOur results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.
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Project description:Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for blood cancers and other haematological disorders. However, allo-HSCT leads to graft-versus-host disease (GVHD), a severe and often lethal immunological response, in the majority of transplant recipients. Current therapies for GVHD are limited and often reduce the effectiveness of allo-HSCT. Therefore, pro- and anti-inflammatory factors contributing to disease need to be explored in order to identify new treatment targets. Purinergic signalling plays important roles in haematopoiesis, inflammation and immunity, and recent evidence suggests that it can also affect haematopoietic stem cell transplantation and GVHD development. This review provides a detailed assessment of the emerging roles of purinergic receptors, most notably P2X7, P2Y2 and A2A receptors, and ectoenzymes, CD39 and CD73, in GVHD.
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Project description:A 17-gene stemness (LSC17) score determines risk in acute myeloid leukaemia patients treated with standard chemotherapy regimens. The present study further analysed the impact of the LSC17 score at diagnosis on outcomes following allogeneic haematopoietic cell transplantation (HCT). Out of 452 patients with available LSC17 score, 123 patients received allogeneic HCT. Transplant outcomes, including overall (OS), leukaemia-free survival (LFS), relapse incidence (RI) and non-relapse mortality (NRM), were compared according to the LSC17 scored group. The patients with a low LSC17 score had higher OS (56.2%) and LFS (54.4%) at 2 years compared to patients with high LSC17 score (47.2%, p = 0.0237 for OS and 46.0%, p = 0.0181 for LFS). The low LSC17 score group also had a lower relapse rate at 2 years (12.7%) compared to 25.3% in the high LSC17 score group (p = 0.017), but no difference in NRM (p = 0.674). Worse outcomes in the high LSC17 score group for OS, LFS and relapse were consistently observed across all stratified sub-groups. The use of more intensive conditioning did not improve outcomes for either group. In contrast, chronic graft-versus-host-disease was associated with more favourable outcomes in both groups. The 17-gene stemness score is highly prognostic for survival and relapse risk following allogeneic HCT.
| S-EPMC9422016 | biostudies-literature
Project description:Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery.
| S-EPMC4926758 | biostudies-other
Project description:Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.
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Project description: Not available
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Project description:Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those from a donor1,2. Here, to quantify dynamics of long-term stem cell engraftment, we sequenced genomes from 2,824 single-cell-derived haematopoietic colonies of ten donor-recipient pairs taken 9-31 years after HLA-matched sibling HCT3. With younger donors (18-47 years at transplant), 5,000-30,000 stem cells had engrafted and were still contributing to haematopoiesis at the time of sampling; estimates were tenfold lower with older donors (50-66 years). Engrafted cells made multilineage contributions to myeloid, B lymphoid and T lymphoid populations, although individual clones often showed biases towards one or other mature cell type. Recipients had lower clonal diversity than matched donors, equivalent to around 10-15 years of additional ageing, arising from up to 25-fold greater expansion of stem cell clones. A transplant-related population bottleneck could not explain these differences; instead, phylogenetic trees evinced two distinct modes of HCT-specific selection. In pruning selection, cell divisions underpinning recipient-enriched clonal expansions had occurred in the donor, preceding transplant-their selective advantage derived from preferential mobilization, collection, survival ex vivo or initial homing. In growth selection, cell divisions underpinning clonal expansion occurred in the recipient's marrow after engraftment, most pronounced in clones with multiple driver mutations. Uprooting stem cells from their native environment and transplanting them to foreign soil exaggerates selective pressures, distorting and accelerating the loss of clonal diversity compared to the unperturbed haematopoiesis of donors.
| S-EPMC11602715 | biostudies-literature
Project description:Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.
| S-EPMC6806510 | biostudies-literature
Project description:Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.
| S-EPMC11191922 | biostudies-literature
Project description:Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered to be the strongest curative immunotherapy for various malignancies (primarily, but not limited to, haematologic malignancies). However, application of allo-HSCT is limited owing to its life-threatening major complications, such as graft-versus-host disease (GVHD), relapse and infections. Recent advances in large-scale DNA sequencing technology have facilitated rapid identification of the microorganisms that make up the microbiota and evaluation of their interactions with host immunity in various diseases, including cancer. This has resulted in renewed interest regarding the role of the intestinal flora in patients with haematopoietic malignancies who have received an allo-HSCT and in whether the microbiota affects clinical outcomes, including GVHD, relapse, infections and transplant-related mortality. In this Review, we discuss the potential role of intestinal microbiota in these major complications after allo-HSCT, summarize clinical trials evaluating the microbiota in patients who have received allo-HSCT and discuss how further studies of the microbiota could inform the development of strategies that improve outcomes of allo-HSCT.
| S-EPMC7485905 | biostudies-literature