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)

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation.
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PMID:FLT3-TKD mutation in childhood acute myeloid leukemia. 1275 Jul 1

Point mutations of D835/I836 of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). FLT3-D835/I836 mutations were found in 6 (5.4%) of 112 children with ALL older than 1 year and in 8 (16.0%) of 50 infants with ALL. Missense mutations were found in 11 patients, 3-base pair deletions in 2 patients, and a deletion/insertion in 1 patient. Remarkably, FLT3-D835/I836 mutations were found in 8 (18.2%) of 44 infants with ALL with MLL rearrangements and in 4 (21.5%) of 19 patients with hyperdiploid ALL, but they were not found in any patients older than 1 year who had TEL-AML1 (n = 11), E2APBX1 (n = 4), or BCR-ABL (n = 6) fusion genes. Although infant ALL patients with mutations had poorer prognoses than did those without mutations, pediatric ALL patients with mutations who were older than 1 year had good prognoses. We also found FLT3-D835 mutations in 2 of 11 leukemic cell lines with MLL rearrangements. FLT3 was highly phosphorylated in these cell lines with FLT3-D835 mutations, leading to constitutive activation of downstream targets such as signal transducer and activator of transcription 5 (STAT5) without FLT3 ligand stimulation. These results suggested that FLT3-D835/I836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy.
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PMID:FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. 1450 97

t(X;11)(q24;q23) is a recurring chromosomal translocation in pediatric acute myeloid leukemia. The rearrangement results in fusion of MLL at 11q23 with SEPT6 at Xq24. Here, we report the identification of an MLL-SEPT6 fusion transcript in an infant with acute myeloid leukemia (AML)-M4. Reverse transcription-polymerase chain reaction confirmed the presence of an MLL-SEPT6 fusion transcript composed of exon 8 of MLL and exon 2 of SEPT6, but the absence of the reciprocal SEPT6-MLL fusion transcript. Sequence analysis of the genomic break junctions in MLL and SEPT6 suggested that the rearrangement in this case was the result of an insertion of the inverted Xq24 segment, which contained the 3' region of SEPT6 intron 1 and up to 950 kb centromeric to SEPT6, into MLL intron 8. This is a novel type of chromosomal rearrangement leading to the MLL-SEPT6 fusion. The presence of deletions, duplications, and non-template DNA sequence at the break junctions suggested that the DNA damage-repair machinery is likely to be involved in the translocation events.
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PMID:Molecular analysis of t(X;11)(q24;q23) in an infant with AML-M4. 1450

Acute myelocytic leukemia (AML) is a heterogeneous disease that accounts for nearly a quarter of the pediatric leukemias. Despite near myeloablative therapy, half of patients relapse and die from their disease. Identification of patients at high risk of relapse early in the course of treatment may allow for treatment modification to improve their outcome. In addition, patients at lower risk of relapse may benefit from treatment de-escalation, sparing them adverse side effects. This review describes prognostic factors that play a major role in the outcome of children with AML and their potential use for treatment stratification in pediatric AML trials.
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PMID:Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia. 1452 8

To determine the clinical significance of central nervous system (CNS) involvement at the time of diagnosis of pediatric acute myeloid leukemia (AML), we analyzed clinical features and outcomes of 290 patients treated consecutively on four institutional trials (AML80, AML83, AML87, and AML91). CNS status was classified as CNS1 (no blast cells in CSF; n=205), CNS2 (<5 WBC/mul CSF with blast cells; n=37), or CNS3 (>/=5 WBC/mul CSF with blast cells, or signs of CNS involvement; n=48). Patients with CNS3 status were significantly younger than others (P=0.016) and significantly more likely to have the favorable cytogenetic features t(9;11), t(8;21), or inv(16) (P<0.001). The CNS3 group had a significantly greater probability (+/-s.e.) of 5-year event-free survival (43.7+/-7.0%) than did the CNS1 (27.8+/-3.2%, P=0.015) and CNS2 (24.3+/-7.5%, P=0.032) groups. However, after adjustment for favorable genetic features, there was no significant difference in EFS between the CNS3 and the combined CNS1+CNS2 groups (P=0.075). In all, 10 of 151 patients treated on AML80 and AML83, but none of 139 treated on AML87 and AML91, had primary CNS relapse. CNS involvement had no adverse prognostic significance, and patients with CNS2 status had similar outcome to CNS1 patients in this large group of pediatric patients with AML, treated at a single institution.
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PMID:Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: a single institution's experience. 1452 77

To explore the potential efficacy of l-asparaginase treatment in acute myeloid leukaemia (AML) patients, we studied the in vitro resistance of French-American-British (FAB) subtypes of childhood AML to l-asparaginase using a methyl-thiazol-tetrazolium assay. We tested leukaemic cells obtained from 177 common acute lymphoblastic leukaemia (cALL) and 228 AML children at diagnosis. The median 70% lethal dose of l-asparaginase (LD70asp) (U/ml) was 0.46 in the cALL and 6.70 in the AML samples. The median LD70asp among each FAB subtype of AML was 0.76 (M0), 0.46 (M1), 10.00 (M2), 10.00 (M3), 1.18 (M4), 1.35 (M5) and 10.00 (M7). Type M3 samples had the highest LD70asp. The LD70asp of the M2 samples was significantly higher than that of the M1, M4 and M5 samples. When the LD70asp values were classified as low (0.016-0.159), intermediate (0.16-1.59) or high (1.6-10.00), the frequency of low, intermediate or high LD70asp among the M1 samples were similar to those among the cALL samples. In conclusion, cells from AML types M1, M4 and M5 were relatively sensitive to l-asparaginase, and M1 cells were as sensitive as those of cALL, suggesting that l-asparaginase treatment may be effective for these subtypes of AML.
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PMID:In vitro efficacy of l-asparaginase in childhood acute myeloid leukaemia. 1463 70

Autologous peripheral blood stem cell transplantation (APBSCT) after intensifying conditioning is one of the post-remission therapeutic options in childhood acute myeloid leukemia (AML) patients without a matched family donor, but the optimal conditioning regimen has not been defined. This study was performed to evaluate the efficacy of a novel conditioning regimen without busulfan or total body irradiation. In total, 28 children with AML underwent APBSCT with BCVAC (BCNU, etoposide, cytosine arabinoside and cyclophosphamide) conditioning regimen during first remission. The event-free survival rate was 71.43% for all patients and the only cause of treatment failure was relapse. Eight male patients recurred at 1-11 months (median 5 months) after APBSCT. One patient remains alive with salvage therapy after relapse. With the exception of fever, mucositis and diarrhea, no serious complications occurred during APBSCT, including veno-occlusive disease (VOD), and there was no transplantation-related mortality. One patient developed secondary MDS after APBSCT but recovered hematologically on medication. APBSCT with BCVAC conditioning was found to be a safe and effective alternative option for patients with childhood AML in first remission, without a matched family donor.
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PMID:Autologous peripheral blood stem cell transplantation with BCVAC conditioning in childhood acute myeloid leukemia. 1471 39

Relapsed pediatric patients with acute myeloid leukemia (AML) have a poor clinical prognosis. The aim of this study was the analysis of the ex vivo drug resistance profile on relapse in childhood AML in comparison to newly diagnosed AML. The results of 98 pediatric AML samples tested by the MTT assay were analyzed. Eighteen samples (18%) were excluded from the further analysis due to spontaneous apoptosis of blasts in 4-days culture, low percentage of myeloblasts in the sample either in the beginning or at the end of the assay, infection, or formation of clots in the sample. Finally, ex vivo drug resistance of 20 relapsed samples were compared with that of 60 de novo AML, including 9 matched pairs. Up to 18 drugs were tested for each patient. No significant differences between drug resistance at diagnosis and at relapse in AML was found, neither for the whole groups of patients, nor for matched pairs only. Possibly, relatively good sensitivity of myeloblasts on relapse was found against melphalan, thiotepa, 4-HOO-ifosfamide, and cladribine. In summary, cellular drug resistance in childhood AML at relapse is not higher than at first diagnosis. These observations suggest that other, than cellular drug resistance, factors play a key role in therapy failure of relapsed childhood AML.
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PMID:Ex vivo drug resistance in childhood acute myeloid leukemia on relapse is not higher than at first diagnosis. 1475 87

Treatment of acute leukemia relapse following an allogeneic transplantation is a challenge. We reinduced three pediatric patients with acute myeloid leukemia (AML) relapsing after a marrow transplantation from a sibling donor into remission with chemotherapy and used donor lymphocyte infusions (DLIs) as consolidation. In two of the cases, the allogeneic recognition was enhanced through the use of interferon in the absence of clinical graft vs. host disease (GVHD). Subsequently, all the three developed (acute grade III-IV or chronic extensive) GVHD and remain in remission with a good quality of life 19, 15 and 14 months post-relapse. We consider an active approach in the treatment of pediatric AML relapsing post-transplant justified.
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PMID:Adoptive immunotherapy as consolidation of remission in pediatric AML relapsing post-transplant. 1487 Aug 87

Children with leukemias and increasing mixed chimerism (increasing MC) after allogeneic stem cell transplantation have the highest risk to relapse. Early immunological intervention was found to be effective in these cases. To substantiate this on a defined group of pediatric acute myelogenous leukemia (AML) patients, we performed serial analysis of post transplant chimerism and pre-emptive immunotherapy in patients with increasing MC. In total, 81 children were monitored, 62 patients revealed complete chimerism (CC), low-level MC or decreasing MC. Increasing MC was detected in 19 cases. Despite early immunological intervention relapse was still significantly more frequent in patients with increasing MC (9/19) than in patients with CC, low-level or decreasing MC (8/62, P<0.005). The probability of 3-year event-free survival (EFS) was 52% for all patients (n=81), 59% for patients with CC, low-level MC, 60% for patients with decreasing MC (n=62), and 28% for patients with increasing MC (n=19, P<0.005). Patients with increasing MC who received early immunological intervention showed a significantly enhanced probability for event-free survival (pEFS 36%, n=15) compared to patients with increasing MC without intervention (pEFS 0%, n=4, P<0.05). These results prove that pediatric AML patients with increasing MC are at highest risk for relapse and that early immunological intervention can prevent relapse in these patients.
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PMID:Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective. 1499 Sep 84


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