Treatment-Related Acute Myeloid Leukemia Following Therapy for Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2777-2777
Author(s):  
I. Conradi ◽  
T. Schulz ◽  
B. Woermann ◽  
G. G. Wulf ◽  
L. Truemper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Clonal Evolution ◽  
Alkylating Agents ◽  
Primary Diagnosis ◽  
Initial Diagnosis ◽  
Related Characteristic ◽  
Acute Myeloid

Abstract More than 50% of patients (pts.) who relapse from Acute Myeloid Leukemia (AML) have karyotypes different from those seen at primary diagnosis. This phenomenon might mirror clonal evolution or might result from antecedent therapies. In some cases completely different karyotypes might characterize treatment-related AML (t-AML). t-AML is a well recognized complication following treatment of malignancies with a high cure rate, especially primary breast cancer and Hodgkin’s Disease and, according to a recently increasing number of reports, even in Acute Promyelocytic Leukemia. However, as to our knowledge there are no data from larger series concerning therapy-induced AML following chemotherapy for AML also comprising Non-M3-AML. Furthermore we asked if polymorphisms in phase-II-enzymes like Gluthathione S-Transferase (GST) or N-Acetyl-Transferase (NAT) might be risk factors for t-AML. Cytogenetics of 141 (72 male, 69 female) pts. who were presumed to have relapsed from AML on the basis of cytologic criteria were performed. In 99 of them cytogenetic data from initial diagnosis could be made available and were compared to the corresponding results on relapse. Six classes of cytogenetic sequences (initial diagnosis --> relapse) were defined (normal --> normal: 29 pts; normal --> aberrant: 16 pts.; aberrant --> aberrant with identical aberrations: 22 pts.; aberrant --> aberrant with additional anomalies: 19 pts.; aberrant --> aberrant with completely different anomalies: 7pts.; aberrant --> normal: 6 pts.) to characterize the dynamics of genetics from diagnosis to relapse. Among the 7 pts. who developed completely different anomalies from those seen at initial diagnosis 2 had cytogenetic anomalies characteristic for those seen following treatment with alkylating agents, while the aberrations in the remaining pts. fitted neither those typical for alkylating agents nor those for the topoisomerase-II-inhibitor type of treatment related anomalies. Of the 35 pts. in the second and third group together 3 pts. presented chromosomal changes of alkylating agents’ type, 2 of topoisomerase-II-inhibitors’ type, 1 patient a combination of both and in the remaining pts. such aberrations that could not be related to defined groups of chemotherapeutics so far. As far as available data from bone marrow smears, immunophenotyping, Fluorescence-In-Situ-Hybridization and moleculargenetics were used to differentiate clonal evolution from the development of a chemotherapy induced new clone. We conclude that a small proportion (6,93%) of seemingly relapsed AMLs might be treatment related, thus representing new clonal hematologic disorders completely different from the initial disease. Cytogenetic aberrations characteristic of alkylating drugs arose in pts. some of whom never received alkylating agents and at time intervals shorter than those supposed to be characteristic of t-AML following this class of drugs. Perhaps further types of treatment related characteristic anomalies induced by other components of AML-treatment such as Ara C or Thioguanin could be defined soon that so far cannot directly be related to certain drugs. Furthermore in a substantial proportion of pts. (34,65%) it cannot be excluded, that clonal evolution had been modulated by antecedent antileukemic chemotherapy. Preliminary data suggest that at least in t-AML following breast cancer treatment polymorphisms of GST influence the risk of t-AML.

Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 1909-1912 ◽  
Author(s):  
Jens Pedersen-Bjergaard ◽  
Mette K. Andersen ◽  
Debes H. Christiansen ◽  
Claus Nerlov
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosome Aberrations ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Alkylating Agents ◽  
The Other ◽  
Genetic Pathways ◽  
Topoisomerase Ii Inhibitors ◽  
Acute Myeloid

Abstract Therapy-related acute myeloid leukemia (t-AML) in most cases develops after chemotherapy of other malignancies and shows characteristic chromosome aberrations. Two general types of t-AML have previously been identified. One type is observed after therapy with alkylating agents and characteristically presents as therapy-related myelodysplasia with deletions or loss of the long arms of chromosomes 5 and 7 or loss of the whole chromosomes. The other type is observed after therapy with topoisomerase II inhibitors and characteristically presents as overt t-AML with recurrent balanced chromosome aberrations. Recent research suggests that these 2 general types of t-AML can now be subdivided into at least 8 genetic pathways with a different etiology and different biologic characteristics.

scholarly journals The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2780-2786 ◽  
Author(s):  
J Pedersen-Bjergaard ◽  
JD Rowley
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosome Aberrations ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Alkylating Agents ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Chromosome Material ◽  
Acute Myeloid

Abstract Two general types of clonal chromosome abnormality are observed in de novo acute myeloid leukemia (AML): the unbalanced aberrations with visible gain or loss of chromosome material and the balanced aberrations without such visible gain or loss. AML can be induced by therapy with cytostatic drugs and radiation. The alkylating agents reacting directly with DNA induce AML which often presents as myelodysplasia with unbalanced aberrations, primarily loss of chromosome material. Cytostatic agents targeting DNA-topoisomerase II, frequently administered together with alkylating agents or cisplatin, induce the same type of leukemia. In addition, they often induce another type with a more rapid onset and with specific balanced chromosome aberrations rarely observed after therapy with alkylating agents alone. All of the most important chromosome aberrations found in de novo AML are now also found in therapy-related AML (t-AML); thus, t- AML may serve as a model in the search for mechanisms leading to the development of AML in general. Unbalanced chromosome aberrations with partial deletions or with loss of whole chromosomes may develop as a result of alkylation of DNA or other cellular targets. Balanced chromosome aberrations, on the other hand, may develop as illegitimate recombinations related to the activity of DNA-topoisomerase II. The balanced translocations contribute to malignant transformation by the formation of abnormal chimeric genes, whereas deletions may contribute by the loss of putative tumor suppressor genes. In either situation, the chromosome changes provide the altered cells with a proliferative advantage compared with normal cells.

FLAG ± Idarubicin Compared with 7+3 As Initial Induction for Secondary Acute Myeloid Leukemia: A Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4330-4330
Author(s):  
Jenny Li ◽  
Mandy L Gatesman ◽  
Ashley M Newland ◽  
Roy T Sabo ◽  
Prithviraj Bose
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Alkylating Agents ◽  
Neutrophil Recovery ◽  
Secondary Aml ◽  
Topoisomerase Ii Inhibitors ◽  
Secondary Outcomes ◽  
Acute Myeloid

Abstract Abstract 4330 Objective: Acute myeloid leukemia (AML) that arises from an antecedent hematologic disorder (most often myelodysplastic syndrome, MDS) or that is related to prior chemotherapy (therapy-related AML, t-AML) carries a poor prognosis. Secondary AML occurs in 16–50% of patients with MDS and in <5% of patients previously treated with alkylating agents or topoisomerase II inhibitors. Although 50–70% of patients with de novo AML achieve complete remission (CR) with conventional induction chemotherapy (i.e., cytarabine plus an antracycline, “7+3”), secondary AML is more resistant to such treatment (40–50% CR rate). This has led to the use in some centers of alternative induction regimens such as FLAG (fludarabine, cytarabine, filgrastim) ± idarubicin (Ida) in patients with secondary AML. FLAG ± Ida has been used in patients with relapsed, high-risk MDS and in relapsed/refractory AML, and has an overall CR rate of 33% when used first-line for secondary AML (Clavio M et al. Leuk Lymphoma 2001 Jan; 40(3–4):305-13). There is currently no published data directly comparing 7+3 to FLAG ± Ida in this setting. The present study was undertaken to compare the effectiveness and safety of FLAG ± Ida and 7+3 induction regimens in patients with secondary AML. Methods: A retrospective medical record review was conducted between January 1, 2007 and September 30, 2011 of all patients with AML aged ≥18 years seen at our institution who had either cytogenetic abnormalities commonly associated with MDS or had received prior alkylating agents or topoisomerase II inhibitors, and received either FLAG ± Ida or 7+3 for initial treatment of secondary AML. Patients with chronic myelogenous leukemia in blast crisis were excluded. The primary outcome was the CR rate after induction chemotherapy. Secondary outcomes were 30-day mortality, hospital and intensive care unit (ICU) length of stay (LOS), sources and types of infections, antibiotic usage, and time to neutrophil recovery. Fisher's exact test was used to compare categorical outcomes (CR, documented infections) between groups. Kaplan-Meier curves and corresponding log-rank tests were used for time-to-event outcomes (hospital stay, ICU days, neutrophil recovery). Results: 291 charts were reviewed. 48 patients were found to be eligible and were included in the final analysis. There were no significant differences in baseline demographic characteristics between the two treatment groups, with the exception of AML transformation from MDS being more prevalent in the FLAG ± Ida group (Table I). There were no significant differences in CR rates, 30-day mortality, or hospital LOS between the two groups (Table II). 7+3 was associated with a shorter ICU LOS (0.2 ± 0.7 days vs 2.3 ± 6.8 days, p=0.04) but a greater number of days of antibiotic therapy (56.7 ± 36.3 vs 33.6 ± 31.1, p=0.03), while FLAG ± Ida was associated with a shorter time to neutrophil recovery compared with 7+3 (20.6 ± 4.4 days vs 25.8 ± 7.9 days, p=0.01). Conclusion: In this retrospective study, we found no difference in efficacy between 7+3 and FLAG ± Ida when used as initial induction therapy for patients with secondary AML. Limitations of this study include its retrospective nature, the small sample size and lack of power to detect differences between the groups for both primary and secondary outcomes. A prospectively designed trial is warranted before one regimen can be recommended over the other. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Therapy-related acute myeloid leukemia in a patient with neuroblastoma: case report

2020 ◽  
Vol 19 (3) ◽  
pp. 105-113
Author(s):  
D. T. Utalieva ◽  
I. I. Kalinina ◽  
D. Yu. Kachanov ◽  
D. A. Evseev ◽  
A. P. Shcherbakov ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Alkylating Agents ◽  
Platinum Compounds ◽  
First Line ◽  
Secondary Acute Myeloid Leukemia ◽  
Increased Risk ◽  
Acute Myeloid ◽  
Rule Out

Modern, risk-adapted treatment approaches for intermediate and high-risk neuroblastoma (NB) have led to an increasing numbers of survivors. However, intensive multimodal treatment strategy is associated with a significantly increased risk of secondary malignancies. It is currently known that alkylating agents, topoisomerase II inhibitors, and platinum compounds induce treatment-related leukemia. This article presents a literature review and description of a clinical case of secondary acute myeloid leukemia (s-AML) developed 57 months after the initial diagnosis in a patient with intermediate-risk NB who received intensive first-line and post-relapse chemotherapy. The debut of s-AML required a differential diagnosis to rule out a relapse of NB. Parents gave their consent to use information about the child, including fotos, in the article.

Acute Myeloid Leukemia following Chronic Low-Dose Cyclophosphamide for Metastatic Breast Cancer

2001 ◽  
Vol 87 (2) ◽  
pp. 101-103 ◽  
Author(s):  
Cosimo Sacco ◽  
Franceses Patriarca
Keyword(s):  
Breast Cancer ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Alkylating Agents ◽  
Latency Period ◽  
Metastatic Breast ◽  
Secondary Leukemia ◽  
Acute Myeloid

Unconventional treatments are commonly considered by the scientific community to have unproven efficacy but at least no toxicity. Here we report on the case of a breast cancer patient with lung and liver metastases who developed acute myeloid leukemia after treatment with Di Bella multitherapy, leading rapidly to death due to cerebral hemorrhage. Although an increased susceptibility to malignancy could not be excluded, we considered the possible etiologic role of the treatment received. The drug most likely to be associated with the development of leukemia was the cyclophosphamide contained in the Di Bella multitherapy regimen at a dose of 50 mg daily. The clinical features of this leukemia were therefore compared with those expected for secondary leukemia related to alkylating agents. A preceding myelodysplastic phase and the development of the leukemia after the intake of a cumulative cyclophosphamide dose of 15 g were typical chacteristics of secondary leukemia, but the interval between the start of therapy and the onset of leukemia was only 10 months. We conclude that long-term low-dose cyclophosphamide may have leukemogenic potential and the latency period may be shorter than that commonly reported.

Acquired BCR-ABL1 fusion and IDH1 clonal evolution following BCL2 inhibitor treatment in refractory acute myeloid leukemia

2021 ◽  
Vol 100 ◽  
pp. 106494
Author(s):  
Diego Adrianzen-Herrera ◽  
Ximena Jordan-Bruno ◽  
Katherine A. Devitt ◽  
Joanna L. Conant ◽  
Juli-Anne Gardner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Refractory Acute Myeloid Leukemia ◽  
Inhibitor Treatment ◽  
Acute Myeloid

scholarly journals Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA- topoisomerase II

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3705-3711 ◽  
Author(s):  
HJ Super ◽  
NR McCabe ◽  
MJ Thirman ◽  
RA Larson ◽  
MM Le Beau ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Chromosome Band ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Mll Gene ◽  
Topo Ii ◽  
Acute Myeloid

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II- reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

scholarly journals BCOR Mutations in Acute Myeloid Leukemia: Clonal Evolution and Prognosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Ashley Zhang ◽  
Yuntao Liu ◽  
Shuning Wei ◽  
Benfa Gong ◽  
Chunlin Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Statistical Difference ◽  
Tp53 Mutation ◽  
Clonal Evolution ◽  
Normal Karyotype ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

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