Allogeneic stem cell transplantation for acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Peccatori J
PROVIDER: S-EPMC2878779 | biostudies-literature | 2010 Jun
REPOSITORIES: biostudies-literature
Publications
Allogeneic stem cell transplantation for acute myeloid leukemia.
Peccatori Jacopo J Ciceri Fabio F
Haematologica 20100601 6
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Project description:The number of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has increased constantly over the last years due to advances in transplant technology development, supportive care, transplant safety, and donor availability. Currently, acute myeloid leukemia (AML) is the most frequent indication for alloHCT. However, disease relapse remains the main cause of therapy failure. Therefore, concepts of maintaining and, if necessary, reinforcing a strong graft-versus-leukemia (GvL) effect is crucial for the prognosis and long-term survival of the patients. Over the last decades, it has become evident that effective immunosurveillance after alloHCT is an entangled complex of donor-specific characteristics, leukemia-associated geno- and phenotypes, and acquired resistance mechanisms. Furthermore, adoption of effector cells such as natural killer (NK) cells, alloreactive and regulatory T-cells with their accompanying receptor repertoire, and cell-cell interactions driven by messenger molecules within the stem cell and the bone marrow niche have important impact. In this review of pre- and posttransplant elements and mechanisms of immunosurveillance, we highlight the most important mechanisms after alloHCT.
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Project description:Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.
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Project description:Relapse remains the main cause of treatment failure in acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Emerging evidence has demonstrated that AML patients might benefit from maintenance therapy post-transplantation, especially for high-risk AML patients. In this mini-review, we will summarize targeted drugs, such as hypomethylating agents, FLT3 inhibitors and isocitrate dehydrogenase inhibitors, as maintenance therapy post-transplantation in AML patients undergoing allo-HSCT.
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Project description:Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT.
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Project description:Low intake of magnesium has been associated with the occurrence of lymphomas and decreased magnesium levels suppress the cytotoxic function of T cells and natural killer cells in patients with "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia" (XMEN) syndrome. These cell types are also important mediators of immune-mediated effects after allogeneic hematopoietic stem cell transplantation. Here, we show that high posttransplant magnesium levels independently associate with a lower incidence of relapse, a higher risk of acute graft-versus-host disease, and a higher non-relapse mortality in 368 patients with acute myeloid leukemia from our center. Magnesium serum levels might impact on donor-cell-mediated immune responses in acute myeloid leukemia.
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Project description:Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML.
| S-EPMC7667262 | biostudies-literature
Project description:There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.
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Project description:Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p < 10-5), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p < 10-5) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p < 10-4) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p < 10-4) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p < 10-3). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.
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Project description:In acute leukemia, advances have been made in therapeutic strategies centered on allogeneic hematopoietic stem cell transplantation (allo-SCT), three of which are presented here. The indication of allo-SCT for acute myeloid leukemia (AML) in 1st complete remission (CR1) has been debated. Genomic medicine has helped us gain a deeper understanding of this disease, some of which may serve as prognostic factors. Such genetic abnormalities could also help measure minimal residual disease (MRD) and provide additional clues to estimate the efficacy of chemotherapy. Combined with existing prognostic factors, these data can be used to construct a more accurate prognostic model, providing an optimal indication of allo-SCT for AML in CR1. Furthermore, overall treatment algorithms for high-risk AML after allo-SCT should include prophylactic and pre-emptive treatment to prevent relapse. These include immunotherapy using donor lymphocyte infusion (DLI), FLT3 inhibitors in FLT3-mutated AML, hypomethylating agents, or a combination of DLI with these agents. Clinical trials are currently ongoing to elucidate the role of these strategies, which will lead to a risk-adapted treatment for preventing relapse in high-risk AML. CD19-targeted chimeric antigen receptor (CAR) T-cell therapy induces a remarkable response in B-acute lymphoid leukemia (B-ALL); however, relapse remains a major problem. In this regard, allo-SCT as a consolidation treatment after CAR-T cell therapy for B-ALL is recommended for pediatric and adult patients. Achieving complete remission (CR) with CAR-T cell therapy is considered a promising bridging therapy to allo-SCT. Novel CAR-T treatment techniques are being developed to change their role as a pre-transplant treatment.
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