Academia.eduAcademia.edu

Treatment related myeloid malignancies in childhood

Incidence of treatment related AML/MDS (t-AML/MDS) in children is extremely low. Consequently assessment of data from adults and to some extent extrapolation from adults is needed. Epipodophyllotoxin induced t-AML/MDS is more common, which is likely to be related to the shorter latency period, FAB-M4, FAB-M5, APL, balanced karyotypes, 11q23 and 21q22 anomalies, inv(16) and t(15;17) are noted more often. Duration and short interval between administrations of epipodophyllotoxins results in higher incidence of t-AML/MDS. Genetic (karyotypic) make up influence duration of remission, although the relation with overall-survival is less clear. Choice of therapy should be based on co-morbidity and the likelihood to undergo intensive therapy. The majority of children with t-AML/MDS should have a transplantation. A minority of children with t-AML with inv(16), t(8;21) and t(15;19) should be considered for chemotherapy according to de-novo protocols. Monitoring of early response criteria for detection of primary resistance is advised.

Hematology and Leukemia ISSN 2052-434X Review Open Access Treatment related myeloid malignancies in childhood Henk van den Berg Correspondence: [email protected] CrossMark ← Click for updates Department of Pediatric Oncology, Emma Children Hospital Academic Medical Centre, University of Amsterdam, The Netherlands. Abstract Incidence of treatment related AML/MDS (t-AML/MDS) in children is extremely low. Consequently assessment of data from adults and to some extent extrapolation from adults is needed. Epipodophyllotoxin induced t-AML/MDS is more common, which is likely to be related to the shorter latency period, FAB-M4, FAB-M5, APL, balanced karyotypes, 11q23 and 21q22 anomalies, inv(16) and t(15;17) are noted more oten. Duration and short interval between administrations of epipodophyllotoxins results in higher incidence of t-AML/MDS. Genetic (karyotypic) make up inluence duration of remission, although the relation with overall-survival is less clear. Choice of therapy should be based on co-morbidity and the likelihood to undergo intensive therapy. he majority of children with t-AML/MDS should have a transplantation. A minority of children with t-AML with inv(16), t(8;21) and t(15;19) should be considered for chemotherapy according to de-novo protocols. Monitoring of early response criteria for detection of primary resistance is advised. Keywords: Leukemia, aml, children, secondary, alkylating agents, epipodophyllotoxins, etoposide Introduction Myeloid malignancies represent a number of clonal hematopoietic disorders with extensive production of non-differentiating myeloid precursors cells. Due to infiltration in the bone marrow limiting production of normal cells, anemia, thrombocytopenia and neutropenia are often the first signs of the disease. Myeloid malignancies are mostly denominated as leukemias and myelodysplasia (MDS) and are delineated by the percentage and characteristics of the malignant cells and are classified in the same WHO category. Most patients with myeloid malignancies have no preceding disease. For those patients with a preceding disease, which is related to the development of a myeloid malignancy, a separate entity exists and is defined as “Acute myeloid leukemia and myelodysplastic syndromes, therapy related”. A subclassification was based on major related inducing factors; i.e.,1. Alkylating agent/radiation–related type, 2. Topoisomerase II inhibitor–related type; 3. Others [1]. This remaining subclassification; i.e., “others”, includes cases related to e.g., fludarabine, chlorambucil and radiotherapy/radioactive isotopes [2-6]. An additional cause of t-AML is immune suppression; e.g., due to azathioprine [7]. Since most patients had combinations of inducing agents this WHO subclassification is currently not seen as relevant [8]. Generally both therapyrelated AML of secondary-AML terms are used. Review Incidence Incidence of acute myeloid leukemia in children is low. Based on SEER data an incidence rate of 0.7 cases of AML per 100,000 children in the age group <20 years is noted. No epidemiological data exist on the incidence of t-AML/MDS. St. Jude’s Hospital reports on 36 (1%) out of 3,696 children over a 12 year period [9]. Literature data indicate that around 6 to 13% of AML cases, irrespective of age, can be designated as t-AML/MDS [10,11]. In a study on 642 children who had suffered from ALL and who developed a secondary malignancy t-AML/MDS was seen in 255 children; i.e., AML in 186, MDS in 69 children [12]. After a prolonged follow-up after being cured of their primary malignancy, an increment in incidence in secondary malignancies is noted, with a total ratio of observed versus expected cases of 6603 for MDS and 226 for AML [13]. In a followup study on 14359 5-year survivors of childhood cancer 1402 patients developed 2703 neoplasms, among them 24 t-AML and 11 undefined non-ALL leukemia, resulting in a standardized increased risk (SIR) of 9.3 for all treatment related malignancies and specific for t-AML/MDS a SIR of 6.0 [14]. In a long follow-up study on 1378 patients surviving pediatric cancer, the standardized mortality rates (SMR) from secondary cancers tend to decrease from 38.1 to 6.19, after follow-up from the first decade to >25 years follow-up after initial diagnosis, respectively. A similar reduction was seen calculating the absolute excess risk (AER; decrease from 1.75 to 1.05 per 1,000 patient years). Only 16% were t-AML/MDS. Explanatory for the lowering of AER and SMR is the increase due to other cancers at older age in the normal population. A factor influencing the observed decrease in incidence rate in more recently treated children is © 2014 Henk Van Den Berg; licensee Herbert Publications Ltd. his is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). his permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf the striving to reduce the alkylator dose as well as the trend to irradiate less often, reducing irradiation dosages and limiting irradiation fields [15-17]. Diagnosis Clinical symptoms and physical findings of t-AML/MDS are to some extent similar to de-novo AML/MDS. Signs of leukemia are more often linked to hyperleukocytosis and cytopenias of normal cells, whereas MDS results in most cases in cytopenias; leading to tiredness, infections and bruises. The primary diagnosis is based on morphology and histochemical staining. Subtyping is done similar to de-novo AML/MDS and based on the FAB-classification. Epiphyllotoxins and anthracyclines/ mitoxantrone related secondary myeloid malignancies are mainly FAB-M4 (among them M4eo~inv (16)), M5 and acute promyelocytic leukemia (APL–FAB- M3~t(15;17)) presenting as acute onset disease. Alkylating agent related t-AML/MDS more often present as FAB-M6 and -M7 subtypes. Secondary myeloid malignancies related to alkylating agents have (in contrast to epipodophyllotoxins related mali-gnancies) a more protracted course presenting initially in many cases as MDS [15]. It was shown that the dominant clone in t-AML as seen after preceding t-MDS is derived by further evolution from the MDS clone [18]. In adults there is a relation on incidence with type of alkylating agent and occurrence of t-AML/MDS. It is claimed that melphalan induced more often secondary AML as compared to cyclophosphamide. Dose relationships were noted for cyclophosphamide [19-21]. Similar to de-novo AML in M4 and M5 subtypes a high frequency of rearrangements of 11q23 anomalies, t(8;21), inv(16) and t(8;16) are noted [22]. Compared to de-novo AML, the incidence of polyclonality is higher in t-AML/MDS. Secondary APL forms a peculiar exception; it has been found to be similar to de-novo APL in respect to morphology, immunology and cytogenetics [23]. doi: 10.7243/2052-434X-2-3 topoisomerase induced myeloid leukaemia [26]. This might in part be related to the age limits restricting the standard follow-up period by paediatricians and is in contrast to findings in adults. The number of patients included in the cited document was also low (n=24) and low-risk t-AML/ MDS related to epipodophyllotoxin cases are absent in the report. In adults epipodophyllotoxins related AML tends to present between 1-4.5 years, and a preceding MDS phase is often lacking, whereas alkyting agents induced-AML often occurs after 1-20 years [10,21,27]. As a result reports on only children may have missed a part of alkylator induced t-AML/ MDS and/or the epipodophyllotoxin related low-risk patients. Cytogenetics Distribution of karyotype aberrations is different from de-novo AML since more 11q23 and complex karyotypes are noted [10]. T-AML patients more often have a balanced karyotype as compared to patients with t-MDS [27]. Also in relation to the preceding therapy differences are noted. Alkylating agents are linked more frequently with cytogenetic anomalies involving chromosomes 5 and 7. The latter anomalies were noted in 76% cases in a series of 306 patients, which is substantially higher as compared to de-novo AML [28,29]. Affymetrix mapping confirmed the occurrence of single nucleoside polymorphism (SNP) in a subset of patients with loss of chromosomes 5 and/ or 7, which was associated in that study with prior treatment with alkylating agents [30]. In topoisomerase II inhibitor related secondary AML more balanced translocations are noted; more often involving 11q23 and 21q22. Translocations related with epipodophyllotoxins involving 21q22, inv(16) and t(15;17) have received more often anthracyclines as well [25,31-39]. These findings were also confirmed for children in a study on 20 patients [40]. However, 11q23 and 21q23 abnormalities have been identified in non-anthracycline treated patients as well [9]. Further DNA analysis revealed in epipodophyllotoxin related t-AML/MDS MLL-rearrangements, EML1-1, CBFβ-MYH11and Adults PML-RARα. Whereas in alkylating agent specific genetic In adults often an initial phase compatible with MDS evolving aberrations are less specific [15]. It is hypothesized that the in to AML is common. In children this is not as usual. In adults differences between alkylator induced and epipodophyllotoxin the percentage of patients presenting with a t-MDS (in contrast induced t-AML/MDS in respect both to latency to develop a to t-AML) is substantially higher as compared to adults [24]. t-AML and chromosomal findings are related to differences Higher rates of uncommon AML subtypes such as FAB-M6 in oncogene alterations. In alkylating agent induced t-AML/ and M7, i.e., erythroblastic and megakaryoblastic AML, are MDS multiple tumor suppressor or oncogenes are needed noted in t-AML in contrast to de-novo AML. In adults a peak to induce a malignancy, resulting in imbalanced karyotypes. incidence is noted 4-6 years after cytotoxic therapy given Epipodophyllotoxins result in balanced karyotypes related for the first malignancy. Occurrence after a latency period to an activation of an oncogene in a dominant fashion [21]. as short as 12 months but even ranging to 15-20 years are Several pathways more or less specific for either alkylator- or not uncommon. epipodophyllotoxins have been constructed; it is beyond this review to discuss these hypotheses [41]. Children It is stated that in children the occurrence of t-AML is negligible 6-years after treatment cessation of the primary disease [25]. Also the latency period to development of t-AML/ MDS was found to be the same for alkylator-induced as for Risk factors Secondary myeloid malignancies are in the majority of cases related to cytotoxic chemotherapy and organic compounds such as benzene [42]. Earliest reports date from Hodgkin pat- 2 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf ients receiving mechlorethamine, vincristine, procarbazine and prednisone (MOPP) courses. In patients treated before the age of 16 years, the relative risk of leukemia was about 80 times higher than the control population (relative risk of 321.3). After replacing mechlorethamine by cyclophosphamide a lower SIR of 122 was found. After introducing doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) another reduction was noted [15,43-46]. Cytostatic drugs most commonly linked with secondary malignancies are topoisomerase II inhibitors (epipodophyllotoxins, anthracyclines and anthracenediones) and alkylating agents. Topoismerase inhibitors interfere with the enzymes involved in uncoiling the DNA in order to form single strands. This results in deletions, insertions, inversions and translocations [8]. Additional risk factors related to the use of medication are duration of exposure and cumulative dosage [47]. Cyclophosphamide has been mentioned earlier. In respect to cumulative and duration of administration of epipodophyllotoxins several reports mention the link of a higher cumulative dosage and a higher risk [48,49]. Others do not confirm such a finding, but link the risk to the dosing schedule. They noted that higher cumulative dosages did not result in increased incidence rates, but prolonged administration had a more pronounced effect [50]. Being the most prominent factor of secondary malignancies noted in children; pediatric data are available on the increase related to the dosing interval. Prolonged administration of epipodophyllotoxin twice weekly or weekly was independently associated with the development of secondary AML. The overall cumulative risk of AML at six years was 3.8 percent; but in subgroups treated twice weekly or weekly, the risks were 12.3 percent and 12.4 percent [51]. Alkylating agents act by transferring alkylgroups to oxygen or nitrogen atoms of DNA bases. Alkylating agents with two active sites are additionally capable of cross linking DNA strands. Effects of alkylating agents on SIR are less clearly reported. In most cases they are used in combination with other chemotherapy. As a result the exact effect on induction of t-AML/MDS is less elucidated. It is claimed that anthracenediones (mitoxantrone e.g.,) induce more frequently secondary t-AML as compared to anthracyclines. However, data are mainly based on adults [52-55]. The effects of other agents may be clarified in the future. For instance campthotecans are potential candidates since the mode of action, i.e., blocking topoisomerase I, is quite similar to topoisomerase II inhibitors. It is probable that due to the low number of patients treated with these compounds (in most cases in combination with other drugs) the leukemia inducing effect is still unnoticed [56]. High levels of irradiation and radioactive isotopes are reported to induce secondary myeloid malignancies [6,9,57]. Ionizing irradiation induces the formation of reactive oxygen species through radiolysis of water molecules, which oxidize or deaminate DNA bases and induces DNA strand breakage. Proton irradiation leads to DNA strand breaks as well. It was described that radiotherapy as such is not related to t-AML/ doi: 10.7243/2052-434X-2-3 MDS. However in combination with chemotherapy there was a clear relation [33,58]. The findings reported by others do not support the finding that radiotherapy given as single treatment modality is not related to induction of t-AML/MDS [27]. Synergy in respect to the induction of second malignancies in relation to other cytostatic drugs and host factors are well known as based on findings in Fanconi anemia, neurofibromatosis type 1 and gluthatione transferase polymorphisms [59-61]. An increase of risk of epipodophyllotoxin induced t-AML/MDS was related to the combination with other anticancer drugs. For asparaginase and alkylating agents, cisplatin and antimetabolites this has been reported as well. In respect to the effects of asparaginase a decrease of protein levels and as consequence a decrease in recombinogenesis activity is relevant in epipodophyllotoxin treatment. Which is explanatory for the increase of t-AML/MDS occurrence if asparaginase is given immediately before epipodophyllotoxin administration [9,15,25,33,37,48,62,63]. Co-medication has been debated to play a role in induction of secondary malignancies. Especially the use of growth factors (G-CSF) and dexrazoxane have been under focus. In adults data on G-CSF are contradictory. An increased risk was found in breast cancer patients diagnosed at a younger age as compared with older patients [52,64,65]. In children with Ewing sarcoma no relation was noted, whereas in ALL patients a relation was suggested [66,67]. In a study by Relling et al., on 412 children treated for ALL receiving etoposide and anthracyclines, 99 had received G-CSF, 284 cyclophosphamide, 58 of these 284 also received cranial irradiation. There were 20 children who developed t-AML/MDS after median interval of 2.3 years (range, 1.0-6.0 years; 16 AML, 3 MDS, and 1 chronic myeloid leukemia). The 6-year cumulative incidence of t-AML was 12.3% (5.3%) Excluding children receiving irradiation, the incidence rate was higher in those receiving G-CSF (P=0.019) [67]. Although G-CSF is mentioned to be linked with the development of secondary malignancy, especially AML, this is at least in adults minimal with an absolute risk increase of 0.43%. In contrast its use resulted in reduction of death (3.4%) probably due to the possibly to give more intensive treatment schedule [68]. Dexrazoxane is used as agent giving cardioprotection to prevent side effects of anthracyclines. The induction of secondary malignancies is claimed by some. Others question such a side effect. As a result the product is only marketed for adults. The debate in children in respect to risk-benefit has not been finalized yet [69-71]. For both G-CSF and dexrazoxane the setting of this drug administered in relation to other carcinogenetic medication is probably of major importance in inducing t-AML/MDS. Immune-suppression is related with secondary malignancies. Lymphomas are quite common, but AML is relatively scarce. In heart-lung recipients and kidney recipients relative risks of 5.5 and 2.1 for t-AML were reported. Non-DNA as well as DNA damaging immune-suppressants (e.g., azathioprine) are noted to be related with t-AML [7]. In hematopoietic stem 3 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf cell transplantation patients a higher incidence as compared to patients treated without transplantation was reported in several manuscripts. However, administered cytostatic drugs and total body irradiation administered to these patients may be even more important in comparison with the resulting immune deficient state and the extensive cellular proliferation in these procedures [27,72-75]. In a study on 1487 paediatric autologous hematopoietic cell transplantation 35 secondary malignancies were noted; among them 6 cases with t-AML and 7 with t-MDS. For all secondary malignancies these children had a 24 times higher risk for developing a secondary malignancy, for AML and MDS the observed versus expected ratios were 266 and 6603 respectively. Analysis for specific risk factors did not reveal any significances [13]. Some inborn metabolic host factors are also linked with an increased susceptibility for t-AML/MDS. Low thiopurine-methyltransferase activity and polymorphism of a CYP3A4 enzyme results in as DNA-damaging metabolite of epipodophyllotoxins [38,76,77]. Also glutathione-S-transferase, NAD(P)H: quinine oxireductase and polymorphisms of DNA repair genes are linked with an increased occurrence of t-AML/MDS [28,36,78-87]. Extensive reviews on genetic susceptibility and biological pathogenesis were published [21,56,66,82]. Some (often inheritable) anomalies attribute to the development of AML/MDS and AML/MDS without the need for prior therapy. In principle the term secondary AML/MDS is more applicable instead of treatment related AML/MDS. Based on similarities in disease characteristics some reports on t-AML/MDS deal with these anomalies, as well. Examples of genetic predisposition are Down syndrome, Fanconi anemia, Li-Fraumeni syndrome, Leopard syndrome, Noonan syndrome and Costello syndrome. Several of them are related to RAS-MAPK pathways [8,88-94]. The higher incidence of malignancies in relatives of patients with t-AML then in relatives of patients with de-novo AML and the occurrence of new malignancies in cancer patients treated with only surgery can be put forward for existence of yet unidentified factors [91]. As such it is assumed that at least some patients have an inheritable susceptibility to develop t-AML [7]. Patients with specific primary malignancies run an additional risk for t-AML/MDS; e.g., pediatric Hodgkin’s lymphoma, osteosarcoma and APL after breast carcinoma [49,95]. The percentage of patients suffering from a specific secondary malignancy is not only related to former therapy; the primary disease itself is related to the distribution of type of malignancy as well. For instance t-AML is rare in chemotherapy treated patients with retinoblastoma treated who are prone to develop second malignancies. It is hypothesized that this is related to the fact that the underlying mutation of the Rb1 gene does not play a role in hematopoietic stem cells [96]. Prognosis Since AML is more frequent in adults and t-AML/MDS only occurs after a preceding oncogenic exposure t-AML/MDS has doi: 10.7243/2052-434X-2-3 a very low incidence in children. As a consequence many data have to be extrapolated from adults. In adults the prognosis of secondary AML is dismal in comparison with de-novo AML. However, remission rates reported range in a single report up to 82%. But in an analysis of 13 different studies an overall CR rate was calculated to be 27%. Survival at 5 years was reported to be less than 10%. The recent study reported by Godley et al., states an overall survival at 1 year of 51%. Overall survival at 1 year was 74% for patients who had achieved a CR, but only 20% for patients who had achieved only a partial remission after induction. After allogeneic stem cell transplantation median survival was 673 days, compared to 399 days for those who had an autologous transplant and 93 days in case no transplantation was done. Overall survival at 1 year was 72%, 75%, and 17% for patients respectively [27,97-101]. The number of children suffering from t-AML/MDS reported in literature is very low [12,102-105]. Tabori et al., reported on 21children with t-AML and 2 with t-MDS. Both event free survival and overall survival were 14%. Leahey et al., report on 11 children. Only 3 survived, resulting in a 3-years survival of 24%. Causes of death were recurrence of primary disease and new malignancies [103]. Sandler reported on 16 children, 9 out of 13 children who achieved complete remission were transplanted. Two transplanted children survived over 2 years, whereas one not transplanted patient survived at least 8 months [104]. One of the larger studies reports on 62 children. Compared to de-novo AML they had a poorer induction rate (50% vs 72%), overall survival (26% vs 47% at 3 years, and event-free survival (21% vs 39% at 3 years) [15]. Children with t-AML/MDS who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%) [26]. In a study on 642 children who had suffered from ALL and later developed a secondary malignancy t-AML/MDS 5-year survival estimates for AML were 11.2% for 125 patients diagnosed before 2000 and 34.1% for 61 patients diagnosed after 2000 (P<0.001); 5-year survival estimates for MDS were 17.1% for 36 patients and 48.2% for 33 patients, respectively. Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation [12]. Prognostic factors Adults Dismal prognosis is related to age, and co-morbid conditions and restrictions in treatment due to preceding treatments [106-109]. In many cases t-AML/MDS is a fatal condition. Additionally factors are organ and vascular supply injury. Bone marrow function may be severely hampered due to cytostatic use and extensive irradiation [108,110]. In respect to the preceding treatment alkylator related t- AML has a dismal prognosis, due to the more frequent harboring of anomalies of chromosomes 5 and 7. Remission rates of 24 and 26% were noted in t-AML versus 52 and 42% in de-novo 4 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf doi: 10.7243/2052-434X-2-3 AML. Long-term survival rates approximate 10% [108,111,112]. On the other hand patients with t-AML due to epipodophyllotoxins are reported to have a better prognosis. In epipodophyllotoxins related cases remission rates are as high as 81%, but ultimate outcome is still low; i.e., 8% at 2-years [104]. In t-AML the expression rate of MDR1 is high. But in contrast to adults expression of the multidrug resistance gene MDR1 in children is expected to be (at least in de-novo AML) non-relevant [113]. Relevance in pediatric t-AML/MDS is undetermined. matching for these anomalies of secondary versus de-novo patients. It was concluded that karyotypes were influencing survival duration, however ultimate prognosis irrespective of cytogenetic findings was very poor [10]. Similar findings for adults were reported from Chicago, 29 patients with t-AML with favorable cytogenetics had a median survival time of 27 months; those with intermediate cytogenetics had a survival time of 12 months which contrasted with 16 months for denovo AML. This was however not significant (p=0.19). For t-AML and de-novo AML patients with unfavorable cytogenetics Genetics survival was 6 and 7 months, respectively [29,118]. In another Prognosis in adults is related to the karyotype observed. Several report on adult patients from Germany a shorter survival time classifications delineating prognostic groups exist (Table 1) was noted in t-AML versus de-novo AML. In a later update of [114-116]. A relative old report mentions that patients with their study it was shown that karyotype is a factor in respect t(8;21) (n=26), inv (16) (n=16) and t(15;17) (n=6) have similar to duration of survival, but also in the favorable group 5-years outcomes as compared to de-novo AML [117]. Schoch et al., overall survival is below 25% and a plateau is not reached defined, based on data of 93 patients that unfavorable anomalies [10,119]. Smith et al., reported similar data, however not all were 3q21q26, 5q-/-5, 7q-/-7, 11q23, 12p 17p, >2 abnormalities, patients had received intensive remission induction chemointermediate anomalies (normal karyotype and other abnorma- therapy. Even patients responding to therapy and patients lities) and favorable (i.e., t(15;17), t(8;21) and inv (16)) karyotypes. with favorable karyotypes died either from t-AML or from Unfavorable karyotypes are more frequently noted in t-AML; their primary malignancy. The incidence of unfavorable karyoi.e., favorable , intermediate and unfavorable karyotypes 26%, types was over two-third, the worst prognosis was noted in 28% and 46% respectively. Rates in de-novo patients are 22, patients with anomalies of chromosome 5 and 7 [27]. In a 57 and 20% (p<0.001). Matching de-novo with therapy related Korean report on outcome in 48 patients multivariate analysis cases only in patients with secondary AML with t(8;21), inv (16) showed that only APL and presence of non-complex karyotypes and t(15;17) a shorter overall survival was noted; higher relapse were related with a more profitable outcome [120]. For APL rate but similar CR rate were noted. Among these karyotypes no differences as compared to de-novo AML were reported t(8;21) was found to have the poorest prognosis. Unfavorable [121]. Which once again suggests, similar to the findings in and intermediate karyotypes had a similar outcome after morphological and immunological cell characteristics, that Table 1. Risk groupings according to cytogenetics in literature. Stölzel et al., 2011 Kröger et al., 2009 AML Low (Stölzel/Kröger) Favorable (Armand) Intermediate (Stölzel/Kröger) Standard (Armand) High (Stölzel/Kröger) Adverse (Armand) Poor (Litzow) Litzow et al., 2011 MDS AML t(8;21) or inv(16) normal and t(8;21), ns inv 16 or t(15;17 ns patients not harboring high- or low-risk aberrations one or two abnormalities not mentioned under low or high risk ns ns del(5q)/25, 27/del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) and complex karyotypes (≥3 unrelated abn) complex (ie, ≥3 Complex anomalies) or t(9;22) chromosome 7 t(6;9) abnormalities -5/del(5q); -7/del (7q); 11q; t(6;9); -7; monosomies of other del(7q); del 5q or chromosomes (with complex ( ≥3) exception for the loss of chromosomes X or Y); inv(3q); abn12p; abn11q;+11; +13; +21; +22; t(6;9); t(9;22); t(3; 3); complex aberrant karyotype (≥ three independent abnormalities) Armand et al., 2007 MDS or AML arising from MDS t(8;21) alone inv(16/t(16;16)/del(16q22) with M4 t(15 ;17) Normal Del(9q) t(8 ;21)+del(9q) or complex Trisomy 8 Abnormal 5 or 7 Abnormal 11q23 All others Normal Abnormal 3q Abnormal 5 Trisomy 8 All others Abnormal 7 Complex ns=not speciied *=restricted to post-hematopoietic transplantation patients 5 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf doi: 10.7243/2052-434X-2-3 t-APL is similar to the de-novo APL). inclusive the therapy for the first malignancy may therefore be important factors in the poor outcome of t-AML patients in the early phase of treatment [10,119,122,125]. In a report from FTL3 In respect to FLT3 internal tandem duplications (FLT3-ITD) it was Seattle outcome was noted after correction for risk factors in shown that the percentage expressing cells was significantly HLA-identical or partially mismatched family hematopoietic lower in t-AML, indicating that t-AML leukemogenesis in most transplantation. Relapse probability and relapse-free survival cases follows mechanisms different from those seen in de- correlated significantly with disease stage and karyotypes. novo AML. For de-novo AML FTL3-ITD was found to be a risk Relapse incidence was lower and relapse-free survival superior factor, for t-AML such conclusion was not made [122]. Also (P=0.02) with unrelated donor transplants. Their data also nucleophosmin-1 mutations were found to be less frequent in suggest that inferior outcome in patients with t-AML/MDS t-AML as compared to de-novo AML and presence was found was related to the frequency of high-risk cytogenetics [126]. to be a risk factor in patients below the age of 60 years [116]. Similar findings were reported from the Dana Faber Cancer Institute [114]. A Danish report on 157 adults with t-AML and Transplantation 473 de-novo AML patients showed in univariate analysis a In adults undergoing transplantation for t-AML/MDS 2-year better outcome for patients not reaching a complete remission. survival rates of 30%, relapse rates of 42% and treatment Differences were not significant after correction for age, cytorelated mortality of 49% were reported in a French study genetic anomalies, performance status and WBC [127]. [123]. In a series of 46 patients undergoing transplantation 5-years disease-free survival was 24%, relapse and non-relapse Children mortality was 31% and 44% respectively. In this cohort no As already mentioned the data in children are scarce. A major statistical differences existed for patients treated with chemo- difference is the more frequent relation with epipodophyllotherapy before conditioning for stem cell transplantation ver- toxins in children as compared with adults. Remission rates sus those who were not pretreated [124]. are as high as 81%, but ultimate outcome is still low, i.e., 18% Patients after hematopoietic stem cell transplantation for at 2-years [104]. In a study on 20 children only 3 children were their primary malignancy are at high risk since they have in alive after 1, 12 and 68 months; no correlation was found the majority of cases a history with high dose irradiation and with chromosomal abnormalities [40]. Hale et al., reported cytostatic use. In a report from the European Society for Blood on epipodophyllotoxin induced t-AML in 19 children. Ten and Marrow Transplantation t-AML and t-MDS multivariate patients died from a relapse, and only 4 were alive 3 years analysis revealed a better prognosis in case of an age <40 after allogeneic transplant [102]. In a report on 38 allogeneic years, normal cytogenetics and a status of CR at the moment transplanted patients from St Judes Hospital 3-year overall and of transplantation; overall survival rates were 62%, 33% and event free survival were both 15%, the non-relapse mortality 24% at 2 years, respectively. Cytogenetic anomalies were rel- was found to be 60% at 3-years. Severe (grade III–IV) acute evant, but sub-analysis on specific anomalies seemed not to graft-versus-host disease and relapse rate were 24% and 19%, be relevant in their prognostic scoring system (Table 2) [22]. respectively [128]. A report from the MD Anderson Hospital In multivariable analyses on 2853 adults t-AML was an describes 22 patients from a group of 2589 children treated adverse prognostic factor for death in complete remission for a malignancy 2-year survival rates of 20%, 40%, and 25% but not relapse as compared to de-novo AML. In contrast to in children who underwent stem cell transplantation without older patients the younger patients were more intensively induction, children transplanted in remission after induction treated and did not show higher induction failures, but more therapy and receiving a stem cell transplantation as salvage relapse in complete remission. As a result it is suggested therapy, differences were not significant. Risk factors identified that co-morbidity, cumulative toxicity of cancer treatment, were poor/intermediate-risk cytogenetics (p=0.01), lower hemoglobin level (P=0.0001), and t-MDS/AML (vs. de-novo) (p=0.003) [129]. Barnard et al., describe 24 children with t-AML/ Table 2. European society for blood and marrow transplantation MDS who were assigned randomly to standard- or intensiverisk scoring for t-AML/MDS (Kröger et al.,). timing induction. A comparison was done with 62 de-novo Risk factor Number of points MDS and 898 de-novo AML children. T-AML/MDS children Age >40 years +2 were older, had lower white blood cell counts and more often Not in complete remission +2 MDS (21% vs 7%) and trisomy. None of the patients had the Abnormal cytogenetics +1 classic t(8;21), t(15;17) and 16q22 anomalies. Patients were Risk group Overall Relapse free Non-relapse Relapse randomized for time- and G-CSF- intensification of therapy. survival survival mortality rate Induction rate comparing t-AML/MDS with de-novo AML (2 year) (2 year) (2 year) (2 years) was lower 50% vs 72%, overall survival was 26% vs 47% at Low (0-1 factors) 96% 58% 22% 20% 3 years), and event-free survival was 21% vs 39% at 3 years. Moderate (2-3 factors) 33% 32% 37% 31% T-AML/MDS children who received intensive-timing induction High-risk (4-5 factors) 24% 20% 38% 42% 6 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf had a trend for a better outcomes than those who received standard-timing induction, but this was not significant (overall survival 32% vs 0%, P=0.54). The authors state that most chil-dren with t-AML/MDS have disease resistant to current therapies. Unfortunately they only did univariate analysis and did not correct for specific risk factors [26]. doi: 10.7243/2052-434X-2-3 Table 4. German alliance leukemia study group (Stölzel et al.,). Risk factor Number of points Age >60 years 1 High risk karyotype 1 NPM1 wild-type in bone marrow 1 9 Platelet count <50x10 /l in peripheral blood herapy Risk group 1 Overall survival (2 year) Event free Patients with t-AML have generally a poor tolerance for survival (2 year) standard chemotherapy. Generally it is stated that patients Favorable (0-1 factors) 58% 40% with t-AML who have a good performance status should intermediate (2 factors) be treated similar as patients with de-novo AML. For those 28% 21% patients who have favorable cytogenetic abnormalities, High-risk (3-4 factors) 9% 7% such as t(15;17), inv(16), and t(8;21); intensive chemotherapy is advocated. Hematopoietic stem cell transplantation is advised for unfavorable karyotypes. Supportive care alone in childhood. For the cases expressing 11q and 22p anomalies may be warranted for those with poor performance status this statement is in line with data from adults. However, for [21,29,98,99]. Recently the European Group for Bone Marrow those with APL and inv(16) such an advise cannot be given Transplantation and the Center for International Bone Marrow since no or very low numbers of APL and inv(16) cases were Transplantation Research devised scores to predict outcome among the patients with t-AML/MDS and the advice is not in including age, cytogenetics, disease status at transplantation line with recommendations in adults. In children the general and donor characteristics (Tables 2 and 3) [22,115]. The German rule not to transplant patients with APL can be adopted, as it Alliance Leukemia Study Group devised a similar scoring, but is based on the finding that cell characteristics and outcome incorporated NPM1 as additional factor and platelet count in this subgroup is similar to de-novo APL [21,95,130]. For (Table 4) [116]. EFS and OS were, however, quite different non-APL patients with low-risk t-AML/MDS pediatric patients applying these scores. Based on these scoring the treatment treatment advises could align with advices in adults. As such advises per subgroup can be formulated as mentioned above. the presented algorithm can be applied in choosing treatment However, whether these scorings are useful in children is (Figure 1). Those with unfavorable karyotypes should be doubtful considering the better tolerance of chemotherapy transplanted; preferably (if feasible) after bringing them in and less co-morbidity in children as compared to adults and remission. Those with favorable karyotypes (e.g., t(15:17), t(8;21) the inclusion of age as risk factor in these scorings It is has and inv (16)) could be treated according protocols similar to been stated that most children with t-AML/MDS have disease de-novo AML protocols. Current new protocols use minimal resistant to current therapies and all should be classified as residual disease (MRD) as surrogate marker for resistant high-risk patients. This might not be fully appropriate as disease and adapt treatment accordingly. As a result some the advised is based on univariate analysis only and did not children with t-AML/MDS with good risk characteristics will correct for specific risk factors [26]. Since epipodophyllotoxin be transplanted in the end. For some transplantation can be induced t-AML/MDS is the most common form of t-AML/MDS withheld. Only a few patients will be sorted in the supportive care category, since physical condition in children is usually better as compared to adults. Table 3. Center for International Bone Marrow Transplantation Research risk scoring for t-AML/MDS (Litzow et al.,). Risk factor Age Poor risk cytogenetics Disease state Donor type Risk group No risk factors 1 factor 2 factors 3 factors 4 factors Each valid 1 point >35 year AML: del(5q)/25, 27/del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) and complex karyotypes (≥3 unrelated abn) MDS: complex (ie, ≥3 anomalies) or chromosome 7 abnormalities Not in remission at moment of grating Non-sibling related donor and mismatched donor Overall survival (5 year) 50% 26% 21% 10% 5% Conclusion The incidence of treatment related AML/MDS (t-AML/MDS) in children is extremely low. Consequently assessment of data from adults and to some extent extrapolation from adults is needed. Epipodophyllotoxin induced t-AML/MDS is more common in children, which is likely to be related to the shorter latency period to develop this condition. I FAB-M4, FAB-M5, APL, balanced karyotypes, 11q23 and 21q22 anomalies, inv (16) and t(15;17) are noted more often. Duration and short interval between administrations of epipodophyllotoxins in children results in a higher incidence of t-AML/MDS. Genetic (karyotypic) make up is influencing duration of remission, although the relation with overall-survival is less clear. Choice of therapy should be based on co-morbidity and the 7 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf doi: 10.7243/2052-434X-2-3 Diagnosis of t-AML/MDS Good performance Poor performance T-APL favorable karyotype i.e. Inv(16) and t(8;21) Unfavorable karyotype Chemotherapy+ ATRA Treat as de novo AML according to protocol with or without stem cell transplantation Allogeneic stem cel transplantation; preferably in complete remission Supportive care Figure 1. Algorithm for choice of treatment in t-AML/MDS in children. likelihood to undergo intensive therapy. The majority of children with t-AML/MDS should have hematopoietic stem cell transplantation. A minority of children with t-AML with inv(16), t(8;21) and t(15;19) translocation should be considered for chemotherapy according to de-novo AML protocols. Monitoring of early response criteria for detection of primary resistance is advised. Competing interests The author declares that he has no competing interests. Publication history Editor: Mingjiang Xu, Indiana University School of Medicine, USA. EIC: Evangelos Terpos, University of Athens School of Medicine, UK. Received: 20-Mar-2014 Final Revised: 19-Apr-2014 Accepted: 25-Apr-2014 Published: 09-May-2014 References 1. 2. 3. 4. Vardiman JW, Harris NL and Brunning RD. The World Health Organizaion (WHO) classiicaion of the myeloid neoplasms. Blood. 2002; 100:2292-302. | Aricle | PubMed Coso D, Costello R, Cohen-Valensi R, Sainty D, Nezri M, Gastaut JA and Bouabdallah R. Acute myeloid leukemia and myelodysplasia in paients with chronic lymphocyic leukemia receiving ludarabine as iniial therapy. Ann Oncol. 1999; 10:362-3. | Aricle | PubMed Marin-Salces M, Canales MA, de Paz R and Hernandez-Navarro F. Treatment-related acute myeloid leukemia with 11q23 translocaion following treatment with ludarabine, cyclophosphamide and rituximab. Leuk Res. 2008; 32:199-200. | Aricle | PubMed McLaughlin P, Estey E, Glassman A, Romaguera J, Samaniego F, Ayala A, Hayes K, Maddox AM, Prei HA and Hagemeister FB. Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with ludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood. 2005; 105:4573-5. | Aricle | PubMed Abstract | PubMed Full Text Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Larson RA and Schifer CA. Therapyrelated myeloid leukemias are observed in paients with chronic lymphocyic leukemia ater treatment with ludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol. 2002; 20:3878-84. | Aricle | PubMed 6. Schroeder T, Kuendgen A, Kayser S, Kroger N, Braulke F, Platzbecker U, Klarner V, Zohren F, Haase D, Stadler M, Schlenk R, Czibere AG, Bruns I, Fenk R, Gatermann N, Haas R, Kobbe G and Germing U. Therapyrelated myeloid neoplasms following treatment with radioiodine. Haematologica. 2012; 97:206-12. | Aricle | PubMed Abstract | PubMed Full Text 7. Ofman J, Opelz G, Doehler B, Cummins D, Halil O, Banner NR, Burke MM, Sullivan D, Macpherson P and Karran P. Defecive DNA mismatch repair in acute myeloid leukemia/myelodysplasic syndrome ater organ transplantaion. Blood. 2004; 104:822-8. | Aricle | PubMed 8. Sill H, Olipitz W, Zebisch A, Schulz E and Woller A. Therapy-related myeloid neoplasms: pathobiology and clinical characterisics. Br J Pharmacol. 2011; 162:792-805. | Aricle | PubMed Abstract | PubMed Full Text 9. Sandoval C, Pui CH, Bowman LC, Heaton D, Hurwitz CA, Raimondi SC, Behm FG and Head DR. Secondary acute myeloid leukemia in children previously treated with alkylaing agents, intercalaing topoisomerase II inhibitors, and irradiaion. J Clin Oncol. 1993; 11:1039-45. | Aricle | PubMed 10. Schoch C, Kern W, Schnitger S, Hiddemann W and Haferlach T. Karyotype is an independent prognosic parameter in therapyrelated acute myeloid leukemia (t-AML): an analysis of 93 paients with t-AML in comparison to 1091 paients with de novo AML. Leukemia. 2004; 18:120-5. | Aricle | PubMed 11. Mauritzson N, Albin M, Rylander L, Billstrom R, Ahlgren T, Mikoczy Z, Bjork J, Stromberg U, Nilsson PG, Mitelman F, Hagmar L and Johansson B. Pooled analysis of clinical and cytogeneic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplasic syndromes based on a consecuive series of 761 paients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia. 2002; 16:2366-78. | Aricle | PubMed 12. Schmiegelow K, Levinsen MF, Atarbaschi A, Baruchel A, Devidas 5. 8 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. M, Escherich G, Gibson B, Heydrich C, Horibe K, Ishida Y, Liang DC, Locatelli F, Michel G, Pieters R, Piete C, Pui CH, Raimondi S, Silverman L, Stanulla M, Stark B, Winick N and Valsecchi MG. Second malignant neoplasms ater treatment of childhood acute lymphoblasic leukemia. J Clin Oncol. 2013; 31:2469-76. | Aricle | PubMed Danner-Kopik KE, Majhail NS, Brazauskas R, Wang Z, Buchbinder D, Cahn JY, Dilley KJ, Frangoul HA, Gross TG, Hale GA, Hayashi RJ, Hijiya N, Kamble RT, Lazarus HM, Marks DI, Reddy V, Savani BN, Warwick AB, Wingard JR, Wood WA, Sorror ML and Jacobsohn DA. Second malignancies ater autologous hematopoieic cell transplantaion in children. Bone Marrow Transplant. 2013; 48:363-8. | Aricle | PubMed Abstract | PubMed Full Text Friedman DL, Whiton J, Leisenring W, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadows AT, Robison LL and Neglia JP. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010; 102:1083-95. | Aricle | PubMed Abstract | PubMed Full Text Hijiya N, Ness KK, Ribeiro RC and Hudson MM. Acute leukemia as a secondary malignancy in children and adolescents: current indings and issues. Cancer. 2009; 115:23-35. | Aricle | PubMed Abstract | PubMed Full Text Cardous-Ubbink MC, Heinen RC, Langeveld NE, Bakker PJ, Voute PA, Caron HN and van Leeuwen FE. Long-term cause-speciic mortality among ive-year survivors of childhood cancer. Pediatr Blood Cancer. 2004; 42:563-73. | Aricle | PubMed Cardous-Ubbink MC, Heinen RC, Bakker PJ, van den Berg H, Oldenburger F, Caron HN, Voute PA and van Leeuwen FE. Risk of second malignancies in long-term survivors of childhood cancer. Eur J Cancer. 2007; 43:351-62. | Aricle | PubMed Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K, Larson DE, McLellan MD, Dooling D, Abbot R, Fulton R, Magrini V, Schmidt H, Kalicki-Veizer J, O’Laughlin M, Fan X, Grillot M, Witowski S, Heath S, Frater JL, Eades W, Tomasson M, Westervelt P, DiPersio JF, Link DC, Mardis ER, Ley TJ, Wilson RK and Graubert TA. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med. 2012; 366:1090-8. | Aricle | PubMed Abstract | PubMed Full Text Greene MH, Harris EL, Gershenson DM, Malkasian GD, Jr., Melton LJ, 3rd, Dembo AJ, Bennet JM, Moloney WC and Boice JD, Jr. Melphalan may be a more potent leukemogen than cyclophosphamide. Ann Intern Med. 1986; 105:360-7. | Aricle | PubMed Curis RE, Boice JD, Jr., Stovall M, Bernstein L, Greenberg RS, Flannery JT, Schwartz AG, Weyer P, Moloney WC and Hoover RN. Risk of leukemia ater chemotherapy and radiaion treatment for breast cancer. N Engl J Med. 1992; 326:1745-51. | Aricle | PubMed Godley LA and Larson RA. Therapy-related myeloid leukemia. Semin Oncol. 2008; 35:418-29. | Aricle | PubMed Abstract | PubMed Full Text Kroger N, Brand R, van Biezen A, Zander A, Dierlamm J, Niederwieser D, Devergie A, Ruutu T, Cornish J, Ljungman P, Gratwohl A, Cordonnier C, Beelen D, Deconinck E, Symeonidis A and de Wite T. Risk factors for therapy-related myelodysplasic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantaion. Haematologica. 2009; 94:542-9. | Aricle | PubMed Abstract | PubMed Full Text Duield AS, Aoki J, Levis M, Cowan K, Gocke CD, Burns KH, Borowitz MJ and Vuica-Ross M. Clinical and pathologic features of secondary acute promyelocyic leukemia. Am J Clin Pathol. 2012; 137:395-402. | Aricle | PubMed Abstract | PubMed Full Text Huh HJ, Lee SH, Yoo KH, Sung KW, Koo HH, Kim K, Jang JH, Jung C, Kim SH and Kim HJ. Therapy-related myeloid neoplasms in 39 Korean paients: a single insituion experience. Ann Lab Med. 2013; 33:97104. | Aricle | PubMed Abstract | PubMed Full Text 25. Pui CH, Relling MV, Rivera GK, Hancock ML, Raimondi SC, Heslop HE, Santana VM, Ribeiro RC, Sandlund JT, Mahmoud HH and et al. Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia. 1995; 9:1990-6. | Aricle | PubMed 26. Barnard DR, Lange B, Alonzo TA, Buckley J, Kobrinsky JN, Gold S, Neudorf S, Sanders J, Burden L and Woods WG. Acute myeloid leukemia and myelodysplasic syndrome in children treated for cancer: comparison with primary presentaion. Blood. 2002; 100:427- doi: 10.7243/2052-434X-2-3 34. | Aricle | PubMed 27. Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, Vardiman JW, Rowley JD and Larson RA. Clinical-cytogeneic associaions in 306 paients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 2003; 102:43-52. | Aricle | PubMed 28. Larson RA, Wang Y, Banerjee M, Wiemels J, Harford C, Le Beau MM and Smith MT. Prevalence of the inacivaing 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in paients with primary and therapy-related myeloid leukemia. Blood. 1999; 94:803-7. | Aricle | PubMed 29. Larson RA. Eiology and management of therapy-related myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2007; 453-9. | Aricle | PubMed 30. Knight JA, Skol AD, Shinde A, Hasings D, Walgren RA, Shao J, Tennant TR, Banerjee M, Allan JM, Le Beau MM, Larson RA, Graubert TA, Cox NJ and Onel K. Genome-wide associaion study to idenify novel loci associated with therapy-related myeloid leukemia suscepibility. Blood. 2009; 113:5575-82. | Aricle | PubMed Abstract | PubMed Full Text 31. Pedersen-Bjergaard J, Andersen MK and Johansson B. Balanced chromosome aberraions in leukemias following chemotherapy with DNA-topoisomerase II inhibitors. J Clin Oncol. 1998; 16:1897-8. | Aricle | PubMed 32. Pedersen-Bjergaard J and Rowley JD. The balanced and the unbalanced chromosome aberraions of acute myeloid leukemia may develop in diferent ways and may contribute diferently to malignant transformaion. Blood. 1994; 83:2780-6. | Aricle | PubMed 33. Pedersen-Bjergaard J, Philip P, Larsen SO, Andersson M, Daugaard G, Ersboll J, Hansen SW, Hou-Jensen K, Nielsen D, Sigsgaard TC and et al. Therapy-related myelodysplasia and acute myeloid leukemia. Cytogeneic characterisics of 115 consecuive cases and risk in seven cohorts of paients treated intensively for malignant diseases in the Copenhagen series. Leukemia. 1993; 7:1975-86. | Aricle | PubMed 34. Pedersen-Bjergaard J, Pedersen M, Roulston D and Philip P. Diferent geneic pathways in leukemogenesis for paients presening with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood. 1995; 86:3542-52. | Aricle | PubMed 35. Secker-Walker LM, Moorman AV, Bain BJ and Mehta AB. Secondary acute leukemia and myelodysplasic syndrome with 11q23 abnormaliies. EU Concerted Acion 11q23 Workshop. Leukemia. 1998; 12:840-4. | PubMed 36. Leone G, Mele L, Pulsoni A, Equitani F and Pagano L. The incidence of secondary leukemias. Haematologica. 1999; 84:937-45. | Aricle | PubMed 37. Pui CH, Relling MV, Behm FG, Hancock ML, Boyet JM, Raimondi SC, Krance RA, Mahmoud HH, Ribeiro RC, Sandlund JT and et al. L-asparaginase may poteniate the leukemogenic efect of the epipodophyllotoxins. Leukemia. 1995; 9:1680-4. | Aricle | PubMed 38. Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta. 1998; 1400:233-55. | Aricle | PubMed 39. Ellis M, Ravid M and Lishner M. A comparaive analysis of alkylaing agent and epipodophyllotoxin-related leukemias. Leuk Lymphoma. 1993; 11:9-13. | Aricle | PubMed 40. Rubin CM, Arthur DC, Woods WG, Lange BJ, Nowell PC, Rowley JD, Nachman J, Bostrom B, Baum ES, Suarez CR and et al. Therapy-related myelodysplasic syndrome and acute myeloid leukemia in children: correlaion between chromosomal abnormaliies and prior therapy. Blood. 1991; 78:2982-8. | Aricle | PubMed 41. Pedersen-Bjergaard J, Chrisiansen DH, Desta F and Andersen MK. Alternaive geneic pathways and cooperaing geneic abnormaliies in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2006; 20:1943-9. | Aricle | PubMed 42. Rinsky RA. Benzene and leukemia: an epidemiologic risk assessment. Environ Health Perspect. 1989; 82:189-91. | PubMed Abstract | PubMed Full Text 43. Bhaia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossai-Bellani F and Meadows AT. Breast cancer and other second neoplasms ater childhood Hodgkin’s disease. N Engl J Med. 1996; 334:745-51. | Aricle | PubMed 9 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf 44. Schellong G, Riepenhausen M, Creutzig U, Riter J, Harbot J, Mann G and Gadner H. Low risk of secondary leukemias ater chemotherapy without mechlorethamine in childhood Hodgkin’s disease. GermanAustrian Pediatric Hodgkin’s Disease Group. J Clin Oncol. 1997; 15:2247-53. | Aricle | PubMed 45. Cimino G, Papa G, Tura S, Mazza P, Rossi Ferrini PL, Bosi A, Amadori S, Lo Coco F, D’Arcangelo E, Giannarelli D and et al. Second primary cancer following Hodgkin’s disease: updated results of an Italian mulicentric study. J Clin Oncol. 1991; 9:432-7. | Aricle | PubMed 46. Brusamolino E, Goi M and Fiaccadori V. The Risk of Therapy-Related Myelodysplasia/Acute Myeloid Leukemia in Hodgkin Lymphoma has Substanially Decreased in the ABVD Era Abolishing Mechlorethamine and Procarbazine and Limiing Volumes and Doses of Radiotherapy. Mediterr J Hematol Infect Dis. 2012; 4:e2012022. | Aricle | PubMed Abstract | PubMed Full Text 47. Koontz MZ, Horning SJ, Balise R, Greenberg PL, Rosenberg SA, Hoppe RT and Advani RH. Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generaions of clinical trials. J Clin Oncol. 2013; 31:592-8. | Aricle | PubMed Abstract | PubMed Full Text 48. Ratain MJ, Kaminer LS, Bitran JD, Larson RA, Le Beau MM, Skosey C, Purl S, Hofman PC, Wade J, Vardiman JW and et al. Acute nonlymphocyic leukemia following etoposide and cisplain combinaion chemotherapy for advanced non-small-cell carcinoma of the lung. Blood. 1987; 70:1412-7. | Aricle | PubMed 49. Le Deley MC, Leblanc T, Shamsaldin A, Raquin MA, Lacour B, Sommelet D, Chompret A, Cayuela JM, Bayle C, Bernheim A, de Vathaire F, Vassal G and Hill C. Risk of secondary leukemia ater a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol. 2003; 21:1074-81. | Aricle | PubMed 50. Smith MA, Rubinstein L, Anderson JR, Arthur D, Catalano PJ, Freidlin B, Heyn R, Khayat A, Krailo M, Land VJ, Miser J, Shuster J and Vena D. Secondary leukemia or myelodysplasic syndrome ater treatment with epipodophyllotoxins. J Clin Oncol. 1999; 17:569-77. | Aricle | PubMed 51. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC, Head DR, Behm FG, Mahmoud MH, Sandlund JT and et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblasic leukemia. N Engl J Med. 1991; 325:1682-7. | Aricle | PubMed 52. Le Deley MC, Suzan F, Cutuli B, Delaloge S, Shamsaldin A, Linassier C, Clisant S, de Vathaire F, Fenaux P and Hill C. Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-simulaing factor: risk factors for leukemia and myelodysplasic syndrome ater breast cancer. J Clin Oncol. 2007; 25:292-300. | Aricle | PubMed 53. Saso R, Kulkarni S, Mitchell P, Treleaven J, Swansbury GJ, Mehta J, Powles R, Ashley S, Kuan A and Powles T. Secondary myelodysplasic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma. Br J Cancer. 2000; 83:91-4. | Aricle | PubMed Abstract | PubMed Full Text 54. Linassier C, Barin C, Calais G, Letortorec S, Bremond JL, Delain M, Peit A, Georget MT, Cartron G, Raban N, Benboubker L, Leloup R, Binet C, Lamagnere JP and Colombat P. Early secondary acute myelogenous leukemia in breast cancer paients ater treatment with mitoxantrone, cyclophosphamide, luorouracil and radiaion therapy. Ann Oncol. 2000; 11:1289-94. | Aricle | PubMed 55. Chaplain G, Milan C, Sgro C, Carli PM and Bonithon-Kopp C. Increased risk of acute leukemia ater adjuvant chemotherapy for breast cancer: a populaion-based study. J Clin Oncol. 2000; 18:2836-42. | Aricle | PubMed 56. Smith MA, McCafrey RP and Karp JE. The secondary leukemias: challenges and research direcions. J Natl Cancer Inst. 1996; 88:40718. | Aricle | PubMed 57. Samet JM. Epidemiologic studies of ionizing radiaion and cancer: past successes and future challenges. Environ Health Perspect. 1997; 105 Suppl 4:883-9. | PubMed Abstract | PubMed Full Text 58. Kantarjian HM, Keaing MJ, Walters RS, Smith TL, Cork A, McCredie doi: 10.7243/2052-434X-2-3 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. KB and Freireich EJ. Therapy-related leukemia and myelodysplasic syndrome: clinical, cytogeneic, and prognosic features. J Clin Oncol. 1986; 4:1748-57. | Aricle | PubMed Davies SM. Therapy-related leukemia associated with alkylaing agents. Med Pediatr Oncol. 2001; 36:536-40. | Aricle | PubMed Mahgoub N, Taylor BR, Le Beau MM, Graiot M, Carlson KM, Atwater SK, Jacks T and Shannon KM. Myeloid malignancies induced by alkylaing agents in Nf1 mice. Blood. 1999; 93:3617-23. | Aricle | PubMed Chen H, Sandler DP, Taylor JA, Shore DL, Liu E, Bloomield CD and Bell DA. Increased risk for myelodysplasic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet. 1996; 347:295-7. | Aricle | PubMed Amylon MD, Shuster J, Pullen J, Berard C, Link MP, Wharam M, Katz J, Yu A, Laver J, Ravindranath Y, Kurtzberg J, Desai S, Camita B and Murphy SB. Intensive high-dose asparaginase consolidaion improves survival for pediatric paients with T cell acute lymphoblasic leukemia and advanced stage lymphoblasic lymphoma: a Pediatric Oncology Group study. Leukemia. 1999; 13:335-42. | Aricle | PubMed Kushner BH, Cheung NK, Kramer K, Heller G and Jhanwar SC. Neuroblastoma and treatment-related myelodysplasia/leukemia: the Memorial Sloan-Ketering experience and a literature review. J Clin Oncol. 1998; 16:3880-9. | Aricle | PubMed Hershman D, Neugut AI, Jacobson JS, Wang J, Tsai WY, McBride R, Bennet CL and Grann VR. Acute myeloid leukemia or myelodysplasic syndrome following use of granulocyte colony-simulaing factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst. 2007; 99:196-205. | Aricle | PubMed Pat DA, Duan Z, Fang S, Hortobagyi GN and Giordano SH. Acute myeloid leukemia ater adjuvant breast cancer therapy in older women: understanding risk. J Clin Oncol. 2007; 25:3871-6. | Aricle | PubMed Bhaia S. Role of geneic suscepibility in development of treatmentrelated adverse outcomes in cancer survivors. Cancer Epidemiol Biomarkers Prev. 2011; 20:2048-67. | Aricle | PubMed Abstract | PubMed Full Text Relling MV, Boyet JM, Blanco JG, Raimondi S, Behm FG, Sandlund JT, Rivera GK, Kun LE, Evans WE and Pui CH. Granulocyte colonysimulaing factor and the risk of secondary myeloid malignancy ater etoposide treatment. Blood. 2003; 101:3862-7. | Aricle | PubMed Lyman GH, Dale DC, Wolf DA, Culakova E, Poniewierski MS, Kuderer NM and Crawford J. Acute myeloid leukemia or myelodysplasic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-simulaing factor: a systemaic review. J Clin Oncol. 2010; 28:2914-24. | Aricle | PubMed Abstract | PubMed Full Text van Dalen EC, van den Berg H, Raphael MF, Caron HN and Kremer LC. Should anthracyclines and dexrazoxane be used for children with cancer? Lancet Oncol. 2011; 12:12-3. | Aricle | PubMed Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Consine LS, Mendenhall NP, Sposto R, Chauvenet A and Schwartz CL. Dexrazoxane-associated risk for acute myeloid leukemia/ myelodysplasic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol. 2007; 25:493-500. | Aricle | PubMed Barry EV, Vrooman LM, Dahlberg SE, Neuberg DS, Asselin BL, Athale UH, Clavell LA, Larsen EC, Moghrabi A, Samson Y, Schorin MA, Cohen HJ, Lipshultz SE, Sallan SE and Silverman LB. Absence of secondary malignant neoplasms in children with high-risk acute lymphoblasic leukemia treated with dexrazoxane. J Clin Oncol. 2008; 26:1106-11. | Aricle | PubMed Micallef IN, Lillington DM, Apostolidis J, Amess JA, Neat M, Mathews J, Clark T, Foran JM, Salam A, Lister TA and Rohainer AZ. Therapy-related myelodysplasia and secondary acute myelogenous leukemia ater high-dose therapy with autologous hematopoieic progenitor-cell support for lymphoid malignancies. J Clin Oncol. 2000; 18:947-55. | Aricle | PubMed Lenz G, Dreyling M, Schiegnitz E, Haferlach T, Hasford J, Unterhalt M and Hiddemann W. Moderate increase of secondary hematologic 10 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. malignancies ater myeloablaive radiochemotherapy and autologous stem-cell transplantaion in paients with indolent lymphoma: results of a prospecive randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol. 2004; 22:4926-33. | Aricle | PubMed Krishnan A, Bhaia S, Slovak ML, Arber DA, Niland JC, Nademanee A, Fung H, Bhaia R, Kashyap A, Molina A, O’Donnell MR, Parker PA, Sniecinski I, Snyder DS, Spielberger R, Stein A and Forman SJ. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantaion for lymphoma: an assessment of risk factors. Blood. 2000; 95:1588-93. | Aricle | PubMed Hake CR, Graubert TA and Fenske TS. Does autologous transplantaion directly increase the risk of secondary leukemia in lymphoma paients? Bone Marrow Transplant. 2007; 39:59-70. | Aricle | PubMed Felix CA. Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol. 2001; 36:525-35. | Aricle | PubMed Relling MV, Yanishevski Y, Nemec J, Evans WE, Boyet JM, Behm FG and Pui CH. Etoposide and animetabolite pharmacology in paients who develop secondary acute myeloid leukemia. Leukemia. 1998; 12:34652. | Aricle | PubMed Leone G, Pagano L, Ben-Yehuda D and Voso MT. Therapy-related leukemia and myelodysplasia: suscepibility and incidence. Haematologica. 2007; 92:1389-98. | Aricle | PubMed Seedhouse C, Faulkner R, Ashraf N, Das-Gupta E and Russell N. Polymorphisms in genes involved in homologous recombinaion repair interact to increase the risk of developing acute myeloid leukemia. Clin Cancer Res. 2004; 10:2675-80. | Aricle | PubMed Allan JM, Wild CP, Rollinson S, Willet EV, Moorman AV, Dovey GJ, Roddam PL, Roman E, Cartwright RA and Morgan GJ. Polymorphism in glutathione S-transferase P1 is associated with suscepibility to chemotherapy-induced leukemia. Proc Natl Acad Sci U S A. 2001; 98:11592-7. | Aricle | PubMed Abstract | PubMed Full Text Sheikhha MH, Tobal K and Liu Yin JA. High level of microsatellite instability but not hypermethylaion of mismatch repair genes in therapy-related and secondary acute myeloid leukaemia and myelodysplasic syndrome. Br J Haematol. 2002; 117:359-65. | Aricle | PubMed Seedhouse C and Russell N. Advances in the understanding of suscepibility to treatment-related acute myeloid leukaemia. Br J Haematol. 2007; 137:513-29. | Aricle | PubMed Naoe T, Takeyama K, Yokozawa T, Kiyoi H, Seto M, Uike N, Ino T, Utsunomiya A, Maruta A, Jin-nai I, Kamada N, Kubota Y, Nakamura H, Shimazaki C, Horiike S, Kodera Y, Saito H, Ueda R, Wiemels J and Ohno R. Analysis of geneic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese paients with therapy-related leukemia/ myelodysplasic syndrome and de novo acute myeloid leukemia. Clin Cancer Res. 2000; 6:4091-5. | Aricle | PubMed Worrillow LJ, Travis LB, Smith AG, Rollinson S, Smith AJ, Wild CP, Holowaty EJ, Kohler BA, Wiklund T, Pukkala E, Roman E, Morgan GJ and Allan JM. An intron splice acceptor polymorphism in hMSH2 and risk of leukemia ater treatment with chemotherapeuic alkylaing agents. Clin Cancer Res. 2003; 9:3012-20. | Aricle | PubMed Fern L, Pallis M, Ian Carter G, Seedhouse C, Russell N and Byrne J. Clonal haemopoiesis may occur ater convenional 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. Br J Haematol. 2004; 126:63-71. | Aricle | PubMed Bolufer P, Collado M, Barragan E, Calasanz MJ, Colomer D, Tormo M, Gonzalez M, Brunet S, Batlle M, Cervera J and Sanz MA. Proile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol. 2007; 136:590-6. | Aricle | PubMed Guillem VM, Collado M, Terol MJ, Calasanz MJ, Esteve J, Gonzalez M, Sanzo C, Nomdedeu J, Bolufer P, Lluch A and Tormo M. Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia ater treatment of breast cancer and hematological malignancies. Leukemia. 2007; 21:1413-22. | Aricle | PubMed Zebisch A, Czernilofsky AP, Keri G, Smigelskaite J, Sill H and Troppmair J. Signaling through RAS-RAF-MEK-ERK: from basics to bedside. Curr doi: 10.7243/2052-434X-2-3 Med Chem. 2007; 14:601-23. | Aricle | PubMed 89. Hasle H. Patern of malignant disorders in individuals with Down’s syndrome. Lancet Oncol. 2001; 2:429-36. | Aricle | PubMed 90. Mathew CG. Fanconi anaemia genes and suscepibility to cancer. Oncogene. 2006; 25:5875-84. | Aricle | PubMed 91. Pagana L, Pulsoni A, Tosi ME, Avvisai G, Mele L, Mele M, Marino B, Visani G, Cerri R, Di Bona E, Invernizzi R, Nosari A, Clavio M, Allione B, Coser P, Candoni A, Levis A, Camera A, Melillo L, Leone G and Mandelli F. Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia. Br J Haematol. 2001; 112:109-17. | Aricle | PubMed 92. Denayer E, de Ravel T and Legius E. Clinical and molecular aspects of RAS related disorders. J Med Genet. 2008; 45:695-703. | Aricle | PubMed 93. Li FP, Fraumeni JF, Jr., Mulvihill JJ, Blatner WA, Dreyfus MG, Tucker MA and Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988; 48:5358-62. | Aricle | PubMed 94. Lauchle JO, Braun BS, Loh ML and Shannon K. Inherited predisposiions and hyperacive Ras in myeloid leukemogenesis. Pediatr Blood Cancer. 2006; 46:579-85. | Aricle | PubMed 95. Beaumont M, Sanz M, Carli PM, Maloisel F, Thomas X, Detourmignies L, Guerci A, Gratecos N, Rayon C, San Miguel J, Odriozola J, Cahn JY, Huguet F, Vekhof A, Stamatoulas A, Dombret H, Capote F, Esteve J, Stoppa AM and Fenaux P. Therapy-related acute promyelocyic leukemia. J Clin Oncol. 2003; 21:2123-37. | Aricle | PubMed 96. Gombos DS, Hungerford J, Abramson DH, Kingston J, Chantada G, Dunkel IJ, Antoneli CB, Greenwald M, Haik BG, Leal CA, Medina-Sanson A, Scheler AC, Veerakul G, Wieland R, Bornfeld N, Wilson MW and Yu CB. Secondary acute myelogenous leukemia in paients with reinoblastoma: is chemotherapy a factor? Ophthalmology. 2007; 114:1378-83. | Aricle | PubMed 97. Hoyle CF, de Bastos M, Wheatley K, Sherrington PD, Fischer PJ, Rees JK, Gray R and Hayhoe FG. AML associated with previous cytotoxic therapy, MDS or myeloproliferaive disorders: results from the MRC’s 9th AML trial. Br J Haematol. 1989; 72:45-53. | Aricle | PubMed 98. Larson RA, Wernli M, Le Beau MM, Daly KM, Pape LH, Rowley JD and Vardiman JW. Short remission duraions in therapy-related leukemia despite cytogeneic complete responses to high-dose cytarabine. Blood. 1988; 72:1333-9. | Aricle | PubMed 99. Kantarjian HM, Estey EH and Keaing MJ. Treatment of therapy-related leukemia and myelodysplasic syndrome. Hematol Oncol Clin North Am. 1993; 7:81-107. | Aricle | PubMed 100. Takeyama K, Seto M, Uike N, Hamajima N, Ino T, Mikuni C, Kobayashi T, Maruta A, Muto Y, Maseki N, Sakamaki H, Saitoh H, Shimoyama M and Ueda R. Therapy-related leukemia and myelodysplasic syndrome: a large-scale Japanese study of clinical and cytogeneic features as well as prognosic factors. Int J Hematol. 2000; 71:144-52. | Aricle | PubMed 101. Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W and Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoieic stem cell transplant. Leuk Lymphoma. 2010; 51:995-1006. | Aricle | PubMed 102. Hale GA, Heslop HE, Bowman LC, Rochester RA, Pui CH, Brenner MK and Krance RA. Bone marrow transplantaion for therapyinduced acute myeloid leukemia in children with previous lymphoid malignancies. Bone Marrow Transplant. 1999; 24:735-9. | Aricle | PubMed 103. Leahey AM, Friedman DL and Bunin NJ. Bone marrow transplantaion in pediatric paients with therapy-related myelodysplasia and leukemia. Bone Marrow Transplant. 1999; 23:21-5. | Aricle | PubMed 104. Sandler ES, Friedman DJ, Mustafa MM, Winick NJ, Bowman WP and Buchanan GR. Treatment of children with epipodophyllotoxin-induced secondary acute myeloid leukemia. Cancer. 1997; 79:1049-54. | Aricle | PubMed 105. Tabori U, Revach G, Nathan PC, Strahm B, Rachlis A, Shago M, Grant R, Doyle J and Malkin D. Toxicity and outcome of children with treatment related acute myeloid leukemia. Pediatr Blood Cancer. 2008; 50:17-23. 11 Henk Van Den Berg, Hematology and Leukemia 2014, http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf | Aricle | PubMed 106. Michels SD, McKenna RW, Arthur DC and Brunning RD. Therapy-related acute myeloid leukemia and myelodysplasic syndrome: a clinical and morphologic study of 65 cases. Blood. 1985; 65:1364-72. | Aricle | PubMed 107. Lowenberg B, Downing JR and Burnet A. Acute myeloid leukemia. N Engl J Med. 1999; 341:1051-62. | Aricle | PubMed 108. Anderson JE, Kopecky KJ, Willman CL, Head D, O’Donnell MR, Luthardt FW, Norwood TH, Chen IM, Balcerzak SP, Johnson DB and Appelbaum FR. Outcome ater inducion chemotherapy for older paients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002; 100:3869-76. | Aricle | PubMed 109. Ballen KK and Anin JH. Treatment of therapy-related acute myelogenous leukemia and myelodysplasic syndromes. Hematol Oncol Clin North Am. 1993; 7:477-93. | PubMed 110. Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paieta E, Bennet JM and Rowe JM. Mitoxantrone, etoposide, and cytarabine with or without valspodar in paients with relapsed or refractory acute myeloid leukemia and highrisk myelodysplasic syndrome: a phase III trial (E2995). J Clin Oncol. 2004; 22:1078-86. | Aricle | PubMed 111. Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes HE, Balcerzak SP and Appelbaum FR. A double-blind placebo-controlled trial of granulocyte colony-simulaing factor in elderly paients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood. 1998; 91:3607-15. | Aricle | PubMed 112. Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaum FR and Willman CL. Acute myeloid leukemia in the elderly: assessment of mulidrug resistance (MDR1) and cytogeneics disinguishes biologic subgroups with remarkably disinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood. 1997; 89:3323-9. | Aricle | PubMed 113. Steinbach D, Furchtbar S, Sell W, Lengemann J, Hermann J, Zintl F and Sauerbrey A. Contrary to adult paients, expression of the mulidrug resistance gene (MDR1) fails to deine a poor prognosic group in childhood AML. Leukemia. 2003; 17:470-1. | Aricle | PubMed 114. Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone RM, Ritz J, Alyea EP, Anin JH and Soifer RJ. Impact of cytogeneics on outcome of de novo and therapy-related AML and MDS ater allogeneic transplantaion. Biol Blood Marrow Transplant. 2007; 13:655-64. | Aricle | PubMed Abstract | PubMed Full Text 115. Litzow MR, Tarima S, Perez WS, Bolwell BJ, Cairo MS, Camita BM, Cutler CS, de Lima M, Dipersio JF, Gale RP, Keaing A, Lazarus HM, Luger S, Marks DI, Maziarz RT, McCarthy PL, Pasquini MC, Phillips GL, Rizzo JD, Sierra J, Tallman MS and Weisdorf DJ. Allogeneic transplantaion for therapy-related myelodysplasic syndrome and acute myeloid leukemia. Blood. 2010; 115:1850-7. | Aricle | PubMed Abstract | PubMed Full Text 116. Stolzel F, Pirrmann M, Aulitzky WE, Kaufmann M, Bodenstein H, Bornhauser M, Rollig C, Kramer M, Mohr B, Oelschlagel U, Schmitz N, Soucek S, Thiede C, Ehninger G and Schaich M. Risk straiicaion using a new prognosic score for paients with secondary acute myeloid leukemia: results of the prospecive AML96 trial. Leukemia. 2011; 25:420-8. | Aricle | PubMed 117. Quesnel B, Kantarjian H, Bjergaard JP, Brault P, Estey E, Lai JL, Tilly H, Stoppa AM, Archimbaud E, Harousseau JL and et al. Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature. J Clin Oncol. 1993; 11:2370-9. | Aricle | PubMed 118. Larson RA. Is secondary leukemia an independent poor prognosic factor in acute myeloid leukemia? Best Pract Res Clin Haematol. 2007; 20:29-37. | Aricle | PubMed 119. Kern W, Haferlach T, Schnitger S, Hiddemann W and Schoch C. Prognosis in therapy-related acute myeloid leukemia and impact of karyotype. J Clin Oncol. 2004; 22:2510-1. | Aricle | PubMed 120. Park SH, Chi HS, Cho YU, Jang S and Park CJ. Evaluaion of prognosic factors in paients with therapy-related acute myeloid leukemia. Blood Res. 2013; 48:185-92. | Aricle | PubMed Abstract | PubMed Full doi: 10.7243/2052-434X-2-3 Text 121. Pulsoni A, Pagano L, Lo Coco F, Avvisai G, Mele L, Di Bona E, Invernizzi R, Leoni F, Marmont F, Mele A, Melillo L, Nosari AM, Pogliani EM, Vignei M, Visani G, Zagonel V, Leone G and Mandelli F. Clinicobiological features and outcome of acute promyelocyic leukemia occurring as a second tumor: the GIMEMA experience. Blood. 2002; 100:1972-6. | Aricle | PubMed 122. Kayser S, Dohner K, Krauter J, Kohne CH, Horst HA, Held G, von Lilienfeld-Toal M, Wilhelm S, Kundgen A, Gotze K, Rummel M, Nachbaur D, Schlegelberger B, Gohring G, Spath D, Morlok C, Zucknick M, Ganser A, Dohner H and Schlenk RF. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult paients with newly diagnosed AML. Blood. 2011; 117:2137-45. | Aricle | PubMed 123. Yakoub-Agha I, de La Salmoniere P, Ribaud P, Suton L, Watel E, Kuentz M, Jouet JP, Marit G, Milpied N, Deconinck E, Gratecos N, Leporrier M, Chabbert I, Caillot D, Damaj G, Dauriac C, Dreyfus F, Francois S, Molina L, Tanguy ML, Chevret S and Gluckman E. Allogeneic bone marrow transplantaion for therapy-related myelodysplasic syndrome and acute myeloid leukemia: a long-term study of 70 paients-report of the French society of bone marrow transplantaion. J Clin Oncol. 2000; 18:963-71. | Aricle | PubMed 124. Anderson JE, Gooley TA, Schoch G, Anasei C, Bensinger WI, Clit RA, Hansen JA, Sanders JE, Storb R and Appelbaum FR. Stem cell transplantaion for secondary acute myeloid leukemia: evaluaion of transplantaion as iniial therapy or following inducion chemotherapy. Blood. 1997; 89:2578-85. | Aricle | PubMed 125. Feldman EJ. Does therapy-related AML have a poor prognosis, independent of the cytogeneic/molecular determinants? Best Pract Res Clin Haematol. 2011; 24:523-6. | Aricle | PubMed 126. Chang C, Storer BE, Scot BL, Bryant EM, Shulman HM, Flowers ME, Sandmaier BM, Witherspoon RP, Nash RA, Sanders JE, Bedalov A, Hansen JA, Clurman BE, Storb R, Appelbaum FR and Deeg HJ. Hematopoieic cell transplantaion in paients with myelodysplasic syndrome or acute myeloid leukemia arising from myelodysplasic syndrome: similar outcomes in paients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood. 2007; 110:1379-87. | Aricle | PubMed Abstract | PubMed Full Text 127. Ostgard LS, Kjeldsen E, Holm MS, Brown Pde N, Pedersen BB, Bendix K, Johansen P, Kristensen JS and Norgaard JM. Reasons for treaing secondary AML as de novo AML. Eur J Haematol. 2010; 85:217-26. | Aricle | PubMed 128. Woodard P, Barield R, Hale G, Horwitz E, Leung W, Ribeiro R, Rubnitz J, Srivistava DK, Tong X, Yusuf U, Raimondi S, Pui CH, Handgreinger R and Cunningham JM. Outcome of hematopoieic stem cell transplantaion for pediatric paients with therapy-related acute myeloid leukemia or myelodysplasic syndrome. Pediatr Blood Cancer. 2006; 47:931-5. | Aricle | PubMed 129. Aguilera DG, Vaklavas C, Tsimberidou AM, Wen S, Medeiros LJ and Corey SJ. Pediatric therapy-related myelodysplasic syndrome/acute myeloid leukemia: the MD Anderson Cancer Center experience. J Pediatr Hematol Oncol. 2009; 31:803-11. | Aricle | PubMed 130. Seymour JF, Juneja SK, Campbell LJ, Ellims PH, Estey EH and Prince HM. Secondary acute myeloid leukemia with inv(16): report of two cases following paclitaxel-containing chemotherapy and review of the role of intensiied ara-C therapy. Leukemia. 1999; 13:1735-40. | Aricle | PubMed Citation: van den Berg H. Treatment related myeloid malignancies in childhood. Hematol Leuk. 2014; 2:3. http://dx.doi.org/10.7243/2052-434X-2-3 12