Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemtuzumab ozogamicin (GO), a monoclonal antibody used in the treatment of acute myelogenous leukemia (AML) has been linked to the development of venoocclusive disease (VOD). We conducted a retrospective study of 62 patients with previously treated AML/MDS (myelodysplastic syndrome) who underwent allogeneic stem cell (SC) transplantation at our institution from December 2000 to October 2002 to determine whether GO exposure prior to allogeneic SC transplantation increases the risk of developing VOD. Fourteen patients received GO prior to SC transplantation. Of 62 patients, 13 (21%) developed VOD; 9 (64%) of 14 with prior GO exposure developed VOD compared with 4 (8%) of 48 without prior GO exposure (P <.0001). Logistic regression controlling for sex, disease status, donor type, and graft-versus-host disease prophylaxis identified prior treatment with GO as a significant risk factor for VOD (odds ratio [OR], 21.6; 95% confidence interval [CI], 4.2-112.2]. Nine of 10 patients who underwent SC transplantation 3.5 months or less following GO developed VOD compared with none of 4 patients who underwent SC transplantation more than 3.5 months from GO administration. Three of 14 patients who received GO prior to SC transplantation died of VOD. We conclude that patients undergoing SC transplantation within a short interval from GO administration are at increased risk of developing VOD.
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PMID:Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. 1497 63

The application of allogeneic hematopoietic stem cell transplantation (HSCT) has been limited to younger patients without organ dysfunctions due to transplant-related toxicities. Recently, non-myeloablative stem cell transplantation(NST) or reduced-intensity stem cell transplantation(RIST) has been developed as a less toxic HSCT, which enables the application of HSCT to patients of advanced age or with organ dysfunction by the use of mild conditioning regimen. The anti-leukemia effect mainly depends on the graft-versus-leukemia (GVL) effect. Several studies showed promising results of NST/RIST for acute myeloblastic leukemia(AML) and myelodysplastic syndrome(MDS). However, this novel treatment is still very toxic compared to conventional chemotherapy. We should continue clinical trials of NST/RIST to evaluate its efficacy and toxicity in patients with AML/MDS.
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PMID:[Mini-transplant for acute myeloblastic leukemia and myelodysplastic syndrome]. 1451 25

Regimens of adjuvant chemotherapy for early-stage breast cancer commonly include alkylating agents and anthracyclines. These agents have been associated with treatment-related acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS). This article reviews the medical literature concerning the incidence, causes, and natural history of treatment-related AML/MDS, with emphasis on the association of these factors with alkylating agents, topoisomerase inhibitors, growth factors, and radiation treatment. Data from 6 completed adjuvant National Surgical Adjuvant Breast and Bowel Project trials that tested regimens containing doxorubicin and cyclophosphamide were reviewed to characterize the incidence of treatment-related AML/MDS. The regimens differed in cyclophosphamide intensity, cumulative cyclophosphamide dose, and the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. Rates were compared across regimens, by patient age, and by treatment with or without adjuvant in-breast radiation therapy (RT). The relative risk (RR) for the development of treatment-related AML/MDS was greater for patients undergoing the more-intense regimens than for those undergoing standard AC (doxorubicin/cyclophosphamide) regimens (RR, 6.16; P<0.0001). Risk correlated more closely with dose intensity than with cumulative dose, and the data suggested that granulocyte colony-stimulating factor (G-CSF) dose may also be independently correlated with increased risk. Patients who received in-breast RT experienced more secondary AML/MDS than those who did not (RR, 2.38; P=0.006). Patients treated with AC with intensified doses of cyclophosphamide requiring G-CSF support had increased rates of treatment-related AML/MDS, even though the incidence was slight relative to breast cancer relapse. In-breast RT appeared to be associated with an increased risk of AML/MDS.
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PMID:Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome among patients with breast cancer: review of the literature and the National Surgical Adjuvant Breast and Bowel Project experience. 1465 72

DNA mismatch repair (MMR) is an important replication error avoidance mechanism that prevents mutation. The association of defective MMR with familial and sporadic gastrointestinal and endometrial cancer has been acknowledged for some years. More recently, it has become apparent that MMR defects are common in acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS) that follows successful chemotherapy for a primary malignancy. Therapy-related haematological malignancies are often associated with treatment with alkylating agents. Their frequency is increasing and they now account for at least 10% of all AML cases. There is also evidence for an association between MMR deficient AML/MDS and immunosuppressive treatment with thiopurine drugs. Here we review how MMR interacts with alkylating agent and thiopurine-induced DNA damage and suggest possible ways in which MMR defects may arise in therapy-related AML/MDS.
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PMID:Human mismatch repair, drug-induced DNA damage, and secondary cancer. 1472 20

We scored oral mucositis and gut toxicity and measured sugar permeability testing among 56 recipients of a haematopoietic stem cell transplant (HSCT) given myeloablative conditioning with idarubicin, cyclophosphamide and TBI, and a group of 18 patients given cytotoxic chemotherapy for newly diagnosed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Gut integrity was already disturbed in the AML/MDS group as measured by the lactulose/rhamnose ratio (L/R ratio=0.09) before therapy and was severely perturbed (L/R ratio >0.13) for a month after HSCT. Oral mucositis and to a lesser extent gut toxicity was only significantly correlated with disturbed permeability in the transplant group. The data suggest that sugar permeability, oral mucositis and gut toxicity measure different features of mucosal damage after intensive cytotoxic therapy.
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PMID:Measuring mucosal damage induced by cytotoxic therapy. 1475 25

Amplification within chromosome arm 11q involving the mixed-lineage leukemia gene (MLL) locus is a rare but recurrent aberration in acute myeloid leukemia and myelodysplastic syndrome (AML/MDS). We and others have observed that 11q amplifications in most AML/MDS cases have not been restricted to the chromosomal region surrounding the MLL gene. Therefore, we implemented a strategy to characterize comprehensively 11q amplicons in a series of 13 AML/MDS patients with MLL amplification. Analysis of 4 of the 13 cases by restriction landmark genomic scanning in combination with virtual genome scan and by matrix-based comparative genomic hybridization demonstrated that the 11q amplicon in these four cases consisted of at least three discontinuous sequences derived from different regions of the long arm of chromosome 11. We defined a maximally 700-kb sequence around the MLL gene that was amplified in all cases. Apart from the core MLL amplicon, we detected two additional 11q regions that were coamplified. Using fluorescence in situ hybridization (FISH) analysis, we demonstrated that sequences in 11q13.5 and 11q23-24 were amplified in 8 of 13 and 10 of 12 AML/MDS cases, respectively. Both regions harbor a number of potentially oncogenic genes. In all 13 cases, either one or both of these regions were coamplified with the MLL amplicon. Thus, we demonstrated that 11q amplicons in AML/MDS patients display a complex organization and have provided evidence for coamplification of two additional regions on the long arm of chromosome 11 that may harbor candidate target genes.
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PMID:Distinct sequences on 11q13.5 and 11q23-24 are frequently coamplified with MLL in complexly organized 11q amplicons in AML/MDS patients. 1497 88

FLT3 gene internal tandem duplication (ITD) and activating loop mutations (D835) were determined in 22 cases of therapy-related acute myelocytic leukemia/myelodysplastic syndrome (t-AML/MDS) and 102 cases of de novo AML/MDS. In t-AML/MDS, FLT3 ITD was absent, and D835 was found in only one case of therapy-related acute promyelocytic leukemia (APL). In de novo AML/MDS, however, FLT3 ITD and D835 were significantly more frequent (28 of 102 cases, P=0.024) and were associated with high peripheral blood and marrow blast counts. Our results suggest that different pathogenetic pathways might be involved in t-AML/MDS and de novo AML/MDS.
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PMID:Low frequency of FLT3 gene internal tandem duplication and activating loop mutation in therapy-related acute myelocyticleukemia and myelodysplastic syndrome. 1503 94

Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.
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PMID:Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation. 1509 Apr 54

The molecular pathogenesis of therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/MDS) remains uncertain. However, clonal haemopoiesis may develop following stem cell transplantation and precede the development of t-AML/MDS. Moreover, accelerated telomere shortening may be induced by replicative stress or oxidative damage, leading to genomic instability, and inactivating polymorphisms of the gene encoding NADPH-quinone oxidoreductase (NQO1) are more frequently observed in patients with t-AML. We studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients receiving conventional chemotherapy for non-myeloid malignancies. Clonal haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was reduced in patients following chemotherapy (n = 52) compared with controls (n = 42) (P < 0.001), particularly in those with clonal haemopoiesis (P < 0.002). Whilst there was a trend towards telomere shortening in control subjects polymorphic for NQO1-187Ser (n = 12), chemotherapy-exposed patients polymorphic for the NQO1-187Ser allele (n = 29) had significantly shorter telomeres (P < 0.001). Furthermore, chemotherapy-treated patients with the NQO1-187Ser, polymorphism were more likely to develop clonal haemopoiesis than patients with wild type NQO1 (odds ratio = 7; 1.16-42.6). We conclude that a switch to clonal haemopoiesis may occur after conventional chemotherapy and lead to accelerated telomere shortening. Patients with the NQO1-187Ser polymorphism have an increased risk of developing both clonal haemopoiesis and telomere shortening, which may partly explain the predisposition to t-AML in NQO1-187Ser null individuals.
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PMID:Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS. 1519 33

Progression to acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) is a possible evolution of polycythemia vera (PV), but whether some patients are at increased natural risk for this complication and how much the contribution of pharmacologic cytoreduction can affect the natural course of the disease remain uncertain. The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) prospective project included 1638 patients with PV. AML/MDS was diagnosed in 22 patients after a median of 2.5 years from recruitment in the study and a median of 8.4 years from the diagnosis of PV. Variables associated with progression to AML/MDS were assessed using different models of multivariate analysis. Older age was confirmed as the main independent risk factor (hazard ratio [HR], 4.30; 95% confidence interval [95% CI], 1.16-15.94; P = .0294), whereas overall disease duration failed to reach statistical significance (more than 10 years: HR, 1.91; 95% CI, 0.64-5.69; P = .2466). Exposure to P32, busulphan, and pipobroman (HR, 5.46; 95% CI, 1.84-16.25; P = .0023), but not to hydroxyurea (HU) alone (HR, 0.86; 95% CI, 0.26-2.88; P = .8021), had an independent role in producing an excess risk for progression to AML/MDS compared with treatment with phlebotomy or interferon.
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PMID:Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. 1586 73


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