Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of all trans-retinoic acid and combination chemotherapy has made acute promyelocytic leukemia (APL) a potentially curable leukemia. Late sequelae of the treatment of APL have therefore become an important consideration in the overall treatment strategy. We report a patient with APL who achieved complete clinical and molecular remission after treatment with the topoisomerase II inhibitors daunorubicin, mitoxantrone, etoposide, and the anti-metabolite cytosine arabinoside. Seven years later, she developed therapy-related myelodysplastic syndrome (t-MDS) without any evidence of relapse of the APL clone. Karyotypic and molecular cytogenetic analysis showed complex cytogenetic aberrations, including deletion of the long arm of chromosome 5, monosomy 7, but without rearrangement of the MLL gene/11q23. Interestingly, this case would be classified clinically as "epipodophyllotoxin related MDS," but pathologically as "alkylating-agent related MDS" according to the recently proposed World Health Organization (WHO) classification system for MDS. This case of t-MDS in an APL patient in durable remission highlights the importance of avoiding long-term treatment related toxicities, as APL is a potentially curable leukemia.
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PMID:Therapy-related myelodysplastic syndrome after eradication of acute promyelocytic leukemia: cytogenetic and molecular features. 1117 6

Therapy-related MDS and AML are complications of intensive chemotherapy regimens. Traditionally, patients exposed to topoisomerase II inhibitors are reported to develop secondary AML with abnormalities of chromosome 11q23. We evaluated the long-term hematologic toxicity of topoisomerase II-intensive high-dose mitoxantrone-based chemotherapy in 163 newly diagnosed acute leukemia patients treated over an 8 year period. Nine (5.5%) patients developed new cytogenetic abnormalities. Four patients developed MDS with progression to AML, three patients developed new abnormalities at the time of relapse, and three patients (including one of the former patients) had changes that were not associated with hematologic disease. The abnormalities most frequently involved chromosomes 7q, 20q, 1q, and 13q. Despite the use of topoisomerase II-intensive treatment, no patient developed an abnormality involving chromosome 11q23. Spontaneous resolution of some changes and prolonged persistence of others in the absence of hematologic disease indicates that some cytogenetic changes are not sufficient to promote leukemogenesis.
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PMID:Secondary acute myelogenous leukemia and myelodysplasia without abnormalities of chromosome 11q23 following treatment of acute leukemia with topoisomerase II-based chemotherapy. 1141 84

The AML1 (CBFA2) gene is the most frequent target of chromosomal rearrangements observed in human acute leukemia. These rearrangements include the commonly reported t(8;21)(q22;q22) or AML1/ETO fusion in AML-M2, the t(3;21)(q26;q22) or AML1 fusion with one of three genes, MDS1, EAP or EVI1, in therapy-related AML and MDS, as well as in blast crisis in CML and the t(12;21)(p13;q22) or TEL/AML1 fusion in B-cell ALL. In addition to the t(3;21), other AML1 translocations have also been reported in therapy-related MDS and AML, particularly after treatment with topoisomerase II inhibitors. AML1 gene rearrangements have also been observed less frequently with numerous other chromosomal partners. Here, we describe a patient with AML-M4 and a previously unreported rearrangement involving the AML1 locus and an unknown locus on the short arm of chromosome 1 at 1p32.
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PMID:A unique AML1 (CBF2A) rearrangement, t(1;21)(p32;q22), observed in a patient with acute myelomonocytic leukemia. 1156 47

Among 511 patients with therapy-related myelodysplastic syndrome or acute leukemia (t-MDS/t-AL) and balanced chromosome aberrations, 162 (32%) had translocations involving 11q23. The recurring translocation partners were 9p22 (48%), 19p13.3 (11%), 19p13.1 (10%), 4q21 (9%), 6q27 (6%), 1p32 (2%), 16p13.1 (2%), 10p13 (1%), and 17q25 (1%); in 9%, the translocations were seen only once. The remaining 349 patients were divided into five subgroups based on the balanced aberration: 21q22, inv(16), t(15;17), Rare, and Unique aberrations. Patients in the 11q23 subgroup had a sole cytogenetic abnormality more often than those in the 21q22, inv(16), Rare, and Unique subgroups, and a complex karyotype or -5/del(5q) and/or -7/del(7q) less often than patients in the 21q22, Rare, and Unique subgroups. Clinically, 11q23 patients had acute lymphoblastic leukemia (ALL) more often as their primary disease and a shorter latency from start of treatment for the primary disease to their t-MDS/t-AL diagnosis, except when compared with the inv(16) subgroup. The 11q23 subgroup demonstrated a younger age at t-MDS/t-AL diagnosis, but this finding was not significant when patients with AL as their primary diagnosis were excluded. Survival from the time of diagnosis of t-MDS/t-AL was significantly shorter for the 11q23 subgroup compared with that of the 21q22, inv(16), and t(15;17) subgroups (median 8 vs. 14, 28, and 29 months, respectively). Inferior survival occurred even though 11q23 patients were younger and more often received blood or marrow transplantation (BMT). Even among patients receiving BMT, 11q23 patients had a shorter median survival (9 vs. 12-31 months for the other subgroups). However, among 11q23 patients, those receiving BMT survived longer, with 1- and 5-year survivals of 43% and 18% compared with 23% and 7% for patients not transplanted. With regard to prior therapy, 11q23 patients, compared with other patients, received radiotherapy less often as their sole therapy and chemotherapy more often. They had received VP16, methotrexate, 6MP/6TG, L-asparaginase, daunorubicin, cytarabine, and VM26 more often, likely attributed to the high frequency of AL as their primary disease. More patients in the 11q23 subgroup had received doxorubicin, except in comparison with the 21q22 subgroup; more vincristine, except in comparison with the Rare and Unique subgroups; and more prednisone, except in comparison with the Unique subgroup. Patients in the 11q23 subgroup more often received alkylating agents (AAs) (86% vs. 59-82% for the other subgroups), and topoisomerase II inhibitors (TIs) (84% vs. 49-75%), and they more often reported exposure to AAs plus TIs without radiotherapy (33% vs. 12-21%), except in comparison with the 21q22 subgroup (36%). We performed a multivariate analysis to determine whether the adverse survival of 11q23 patients compared to other Workshop patients was explained by factors other than the presence of the 11q23 abnormality. Covariates in the final model were the five cytogenetic subgroup indicators, where the 11q23 subgroup was the referent (P < 0.0001); age at t-MDS/t-AL (P = 0.0036); previous exposure to lomustine (P < 0.0001) and mitoxantrone (P = 0.0225); BMT for t-MDS/t-AL (P = 0.0006); and karyotype complexity (P = 0.0114). The risk of death for 11q23 patients relative to patients in the 21q22, inv(16), t(15;17), and Unique subgroups was significant, even after adjustment for other risk factors (relative risks 2.3, 3.6, 3.1, and 1.5, respectively; P < 0.0001 for the first three comparisons and P = 0.0125 for the last). When a multivariable model was constructed, excluding patients with AL or MDS as their primary diagnosis, the relative risk of death for 11q23 patients was significantly higher than that of all five other cytogenetic subgroups. We conclude that among t-MDS/t-AL patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor. Although BMT is the current therapy of choice, new treatment is required.
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PMID:11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 71

The International Workshop on the relationship between prior therapy and balanced chromosome aberrations in therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute leukemia (t-AL) identified 79 of 511 (15.5%) patients with balanced 21q22 translocations. Patients were treated for their primary disease, including solid tumors (56%), hematologic malignancy (43%), and juvenile rheumatoid arthritis (single case), by radiation therapy (5 patients), chemotherapy (36 patients), or combined-modality therapy (38 patients). 21q translocations involved common partner chromosomes in 81% of cases: t(8;21) (n = 44; 56%), t(3;21) (n = 16; 20%), and t(16;21) (n = 4; 5%). Translocations involving 15 other partner chromosomes were also documented with involvement of AML1(CBFA2/RUNX1), identifying a total of 23 different 21q22/AML1 translocations. The data analysis was carried out on the basis of five subsets of 21q22 cases, that is, t(8;21) with and without additional aberrations, t(3;21), t(16;21), and other 21q22 translocations. Dysplastic features were present in all 21q22 cases. Therapy-related acute myeloid leukemia (t-AML) at presentation was highest in t(8;21) (82%) and lowest in t(3;21) (37.5%) patients. Cumulative drug dose exposure scores for alkylating agents (AAs) and topoisomerase II inhibitors indicated that t(3;21) patients received the most intensive therapy among the five 21q22 subsets, and the median AA score for patients with secondary chromosome 7 aberrations was double the AA score for the entire 21q22 group. All five patients who received only radiation therapy had t(8;21) t-AML. The median latency and overall survival (OS) for 21q22 patients were 39 and 14 months (mo), compared to 26 and 8 mo for 11q23 patients, 22 and 28 mo for inv(16), 69 and 7 mo for Rare recurring aberrations, and 59 and 7 mo for Unique (nonrecurring) balanced aberration (latency P < or = 0.016 for all pairwise comparisons; OS, P < or = 0.018 for all pairwise comparisons). The percentages of 21q22 patients surviving 1 year, 2 years, and 5 years were 58%, 33%, and 18%, respectively. Noticeable differences were observed in median OS between 21q22 patients (n = 7) receiving transplant (BMT) (31 mo) compared to 21q22 patients who received intensive non-BMT therapy (n = 46) (17 mo); however, this was nonsignificant because of the small sample size (log-rank, P = 0.33). t-MDS/t-AML with balanced 21q22 aberrations was associated with prior exposure to radiation, epipodophyllotoxins, and anthracyclines, dysplastic morphologic features, multiple partner chromosomes, and longer latency periods when compared to 11q23 and inv(16) t-MDS/AML Workshop subgroups. In general, patients could be divided into two prognostic risk groups, those with t(8;21) (median OS, 19 mo) and those without t(8;21) (median OS, 7 mo) leukemia (log-rank, P = 0.0007).
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PMID:21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. 1192 Dec 72

The Workshop identified 48 unselected patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML) and inv(16), and 41 patients with t(15;17) after chemotherapy (CT) and/or radiotherapy (RT) for a malignant or nonmalignant disease. The primary diseases were: breast cancer, 33 patients; lymphomas, 24 patients; various other solid tumors, 30 patients; and nonmalignant diseases, 2 patients. The general type of previous therapy was RT only in 10 patients with an inv(16) and in 12 patients with a t(15;17), alkylating agents plus topoisomerase II inhibitors in 24 patients with an inv(16) and in 18 patients with a t(15;17), topoisomerase II inhibitors only in 5 patients with an inv(16) and in 2 patients with a t(15;17), alkylating agents only in 6 patients in each subgroup, and other types of chemotherapy in 3 patients in each subgroup. Most CT-treated patients (69%) also received RT. The latency period to development of t-MDS/t-AML was short: a median of 22 months in patients with inv(16) and 29 months in patients with t(15;17). Twenty-six patients (54%) with an inv(16) and 17 patients (41%) with a t(15;17) had additional cytogenetic abnormalities, which were unrelated to age and survival in both subgroups. Trisomy of chromosomes 8, 21, and 22 and del(7q) were the most frequent additional abnormalities in the inv(16) subgroup, whereas +8, -5, and del(16q) were most frequent in the t(15;17) subgroup. The disease was overt t-AML in 38/48 patients (79%) with an inv(16) and in 38/41 patients (93%) with a t(15;17). Thirty-three of 39 intensively treated patients (85%) with an inv(16) obtained a complete remission, whereas 24 of 35 intensively treated patients (69%) with a t(15;17) obtained a complete remission. The median overall survival of intensively treated patients was 29 months in both cytogenetic subgroups. In the inv(16) subgroup, patients younger than 55 years of age had a longer survival when compared with older patients (P = 0.006). The study supports the observation that t-MDS/t-AML with inv(16) and t(15;17) is often associated with prior therapy with topoisomerase II inhibitors; however, a notable finding was the high frequency of treatment with only radiotherapy, 29% of t(15;17) and 21% of inv(16). Response rates to intensive chemotherapy in this study were comparable to those of de novo disease.
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PMID:Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 73

Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities.
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PMID:Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 74

Two main forms of therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) have been recognized. The most frequent type, occurring after treatment with alkylating agents, is characterized by abnormalities of chromosomes 5 and/or 7 and t-MDS/AML following treatment with topoisomerase II inhibitors and is associated with molecular aberrations of MLL (11q23) and AML-1 (21q22). Individuals with certain polymorphisms associated with impaired detoxification of cytotoxic agents have an increased risk of developing MDS or AML after treatment of unrelated cancers. Multidrug chemotherapy is less effective for patients with MDS, or AML following MDS, or t-MDS/AML when compared with primary AML, and results in lower complete remission (CR) rates and lower long-term survival. Patients with good risk cytogenetic features, such as t(15; 17), t(8; 21) and inversion 16 are an exception as their treatment outcome is comparable with primary AML patients. Patients who attain a polyclonal and/or a cytogenetic CR may be candidates for autologous stem cell transplantation. For the remaining patients, the only curative option is allogeneic stem cell transplantation with stem cells from a histocompatible sibling or an alternative donor. Reduced intensity conditioning regimens may be considered for patients older than 50 years or patients with comorbidities. The advice is to treat patients early after diagnosis and preferably before progression as these patients have the highest chance of a favorable outcome.
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PMID:Stem cell transplantation for leukemias following myelodysplastic syndromes or secondary to cytotoxic therapy. 1206 Apr 85

There has not been a reported series of children with therapy-induced myelodysplastic syndrome/acute myeloid leukemia (tMDS/tAML) who were treated systematically. This paper describes 24 children with tMDS/tAML who were assigned randomly to standard- or intensive-timing induction on protocol CCG 2891. Presenting features and outcomes of those children were compared with those of 960 patients with de novo MDS (62 patients) or AML (898 patients). Children with tMDS/tAML were older at presentation (P =.015), had lower white blood cell counts (P =.01), and were more likely to have MDS (21% vs 7%) (P =.02) and trisomy 8 (P =.06). Fewer had hepatomegaly (P =.02), splenomegaly (P =.03), hepatosplenomegaly (P =.02), or classic AML translocations [t(8;21), t(15;17), 16q22; P =.02]. They had a poorer induction rate (50% vs 72%, P =.016), overall survival (26% vs 47% at 3 years, P =.007), and event-free survival (21% vs 39% at 3 years, P =.023). Disease-free survival after achieving remission was similar (45% vs 53%, P =.868). Children with tMDS/tAML who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%, P =.54). In this study, the latency period to development of tMDS/tAML was the same for presumed alkylator-induced as for topoisomerase-induced myeloid leukemia. The findings of this study confirm that most children with tMDS/tAML have disease resistant to current therapies. Standard-timing induction appears less effective for this population.
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PMID:Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. 1209 32

Treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (t-AML) are now well established as complications of cytotoxic chemotherapy. We experienced a 28-yr-old female patient who developed t-MDS/t-AML with characteristic chromosomal abnormalities including 11q23 chromosomal rearrangement following high-dose chemotherapy with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma. The patient was admitted with bulky abdominal masses of B cell lineage non-Hodgkin's lymphoma. After 2 cycles of systemic chemotherapy of the Vanderbilt regimen, the patient underwent ASCT with high dose chemotherapy of the BEAC regimen. She also received radiation of 48 Gy for the residual periportal lymphadenopathy. The initial cytogenetic analysis of the infused mononuclear cells revealed a normal karyotype. Twenty two months after the ASCT, pancytopenia was noted and her bone marrow aspirate showed dysplastic hemopoiesis with myeloblasts up to 12% of nonerythroid nucleated cells. The patient was diagnosed as t-MDS (refractory anemia with an excess of blasts). Cytogenetic analysis showed complex chromosomal abnormalities including 11q23 rearrangement, which is frequently found in topoisomerase II inhibitor-related hematologic malignancies. Four months later, it was noted that the t-MDS had evolved into an overt t-AML. Cytogenetic analysis showed an evolving pattern with more complex abnormalities. The patient was treated with combination chemotherapy, but her leukemic cells were resistant to the therapy.
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PMID:A case of treatment-related myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemotherapy with autologous stem cell transplantation for non-Hodgkin's lymphoma. 1217 56


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