Diagnosis Of t-AML Research Articles

Successful treatment of both double minute of C-MYC and BCL-2 rearrangement containing large B-cell lymphoma with subsequent unfortunate development of therapy-related acute myeloid leukemia with t(3;3)(q26.2;q21)

Double minute chromosomes (DMs), although relatively frequently encountered in solid tumors, are rare in hematologic neoplasms such as acute myeloid leukemia (AML), and even rarer in lymphoid neoplasms. t(3;3)(q26.2;q21) is a very rare genetic alteration observed in myeloid neoplasm. Herein we report an interesting and unique case of concomitant C-MYC DMs and t(14;18)-containing large B-cell lymphoma, which was successfully treated with R-hyper-CVAD; unfortunately, the patient has developed a therapy-related AML (t-AML) 2 years since the start of his lymphoma treatment. His t-AML contains both t(3;3)(q26.2;q21) and monosomy 7, and the patient died of AML 10 months after the initial diagnosis of t-AML despite clinical remission. To the best of our knowledge, this is the first reported case of C-MYC DM-containing de novo large B-cell lymphoma, which was successfully treated with complete remission, but unfortunately died of t-AML harboring t(3;3)(q21;q26).

Predictive factors for latency period and a prognostic model for survival in patients with therapy‐related acute myeloid leukemia

Therapy-related acute myeloid leukemia (t-AML) is an increasingly recognized sequela in patients receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. This study assessed factors related to the latency period (LP) between the antecedent disorder (AD) and t-AML diagnosis and developed a comprehensive prognostic model to predict overall survival (OS). We evaluated a cohort of newly diagnosed t-AML patients treated with cytarabine-based induction therapy from 2001 to 2011. Multivariable linear and proportional hazards models were used to assess the impact of different classes of chemotherapy on the LP and to identify independent prognostic factors for OS. Of 730 treated AML patients, 58 (7.9%) had t-AML. Median LP to t-AML was 5.6 years (range, 0.5-38.4). 64% of patients achieved CR and median OS was 10.7 months. Independent prognostic factors of short LP were age at AD (P < 0.0001) and prior treatment with mitotic inhibitors (P = 0.05). Unfavorable cytogenetics (P = 0.004), antecedent hematologic or autoimmune disease (P = 0.01), age >60 (P = 0.03), and platelet count <30,000 μL (P = 0.04) at the time of t-AML diagnosis were prognostic for inferior OS. A prognostic model using these factors was developed that risk stratified t-AML patients into two groups: favorable and unfavorable. Patients in the favorable group had a median OS of 37.6 months compared with 6.4 months in patients comprising the unfavorable group (P < 0.0001). Multicomponent prognostic models integrating disease or treatment-related covariates can help better understand how t-AML evolves; and can be clinically useful in risk stratifying t-AML patients undergoing induction therapy.

Predicting Therapy-Related Acute Myeloid Leukemia By Routine Laboratory Values: An Analysis Of 126 Patients With Breast Cancer Referred For Bone Marrow Biopsy At Memorial Sloan-Kettering Cancer Center

The incidence of therapy related AML (t-AML) after adjuvant treatment of breast cancer has been estimated at 0.5%-1% of all patients in retrospective studies. While the absolute incidence of t-AML is low, the high prevalence of breast cancer in the United States – 2.8 million Americans are currently living with a diagnosis of breast cancer (http://seer.cancer.gov/statfacts/html/breast.html) - makes the burden of t-AML significant.Oncologists and hematologists are often confronted with a breast cancer patient who develops unexplained cytopenias. The differential diagnosis includes therapy-related myelodysplastic syndrome (t-MDS) or t-AML, chemotherapy effect, or breast cancer metastatic to the bone marrow. We evaluated factors that might inform whether a patient had t-MDS or t-AML to determine whether a bone marrow biopsy was indicated to aid diagnosis or whether a patient could be reassured and monitored with close outpatient follow up.128 patients seen at Memorial Sloan-Kettering Cancer Center (MSKCC) who had a diagnosis of breast cancer, referred for a bone marrow biopsy between 2002 and 2012 were identified using the MSKCC institutional database and 126 patients were included in the analysis (2 excluded because of missing BM biopsy dates). Baseline characteristics of the patients are detailed in table 1. Patients were grouped based on bone marrow biopsy result: those who were found to have t-MDS or t-AML, those with breast cancer metastatic to the bone marrow, and those with a hypocellular marrow with no evidence of MDS, leukemia, or metastatic breast carcinoma. Logistic regression analysis was performed.Table 1Distribution of Characteristics by Bone Marrow Biopsy ResultCharacteristicAllAML/MDSMetastatic BC in Bone MarrowNeitherN=126N=40N=45N=41ANC≥1.5k93 (74%)17 (43%)42 (93%)34 (83%)<1.5k32 (25%)22 (55%)3 (7%)7 (17%)missing1 (1%)100Median (Range)2.5 (0 - 11.4)1.3 (0 - 11.4)3 (1.2 - 7.9)2.5 (0.3 - 7.8)Hemoglobin≥1083 (66%)25 (63%)19 (42%)39 (95%)<1043 (34%)15 (38%)26 (58%)2 (5%)Median (Range)10.7 (6.1 - 16)10.8 (6.1 - 16)9.6 (6.4 - 15.5)12 (8.5 - 14.2)Platelets≥100k64 (51%)12 (30%)17 (38%)35 (85%)<100k61 (48%)27 (68%)28 (62%)6 (15%)missing1 (1%)100Median (Range)113 (10 - 904)69 (25 - 464)82 (10 - 904)181 (49 - 574)Prior Anthracycline or Alkylating AgentsNeither37 (29%)9 (23%)14 (31%)14 (34%)At least 1 agent89 (71%)31 (78%)31 (69%)27 (66%)In univariate analysis, low absolute neutrophil count (ANC) < 1.5K was significantly associated with increased likelihood of t-MDS/t-AML versus metastatic breast cancer or no disease compared to those who had an ANC ≥1.5k (OR=9.8, 95%CI(3.9, 24.5), p<0.0001). Thrombocytopenia (<100k) was significantly associated with an increased likelihood of t-MDS/t-AML or metastatic breast cancer to bone marrow compared with no malignant disease.By multivariable analysis, both ANC and thrombocytopenia remained significantly associated with an increased likelihood of t-MDS/t-AML after controlling for hemoglobin and the receipt of any anthracycline or alkylating agent prior to BM biopsy (OR=9.8, 95%CI(3.7, 25.5), p<0.0001 for ANC; OR=3.1, 95%CI(1.2, 8.2), p=0.02 for platelets).In breast cancer patients with unexplained and persistent cytopenias, neutropenia <1.5K and thrombocytopenia <100K show a statistically significant correlation with subsequent diagnosis of t-AML or t-MDS on bone marrow biopsy. This finding is unique in that it gives the clinician the ability to correlate severity of cytopenias with the likely underlying etiology for these cytopenias. This can be used as a tool to determine the need for and timing of a bone marrow biopsy, help reassure patients and guide the practicing hematologist and breast oncologist. Disclosures:No relevant conflicts of interest to declare.

Predictive Factors for Latency Period and a Prognostic Model for Survival in Patients with Therapy-Related AML.

AbstractAbstract 2589▪▪This icon denotes a clinically relevant abstractTherapy-related acute myeloid leukemia (t-AML) is an increasingly recognized sequela in patients (pts) receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. Factors that adversely affect treatment response and survival in t-AML pts include poor cytogenetics, type of antecedent disorder (AD) and type of preceding therapy. The goal of this study was to design a comprehensive prognostic model integrating pt disease- and treatment-related characteristics to predict clinical outcome and to assess factors related to the latency period (LP) between the AD and t-AML diagnosis (dx).We evaluated a retrospective cohort of newly diagnosed t-AML pts treated at Cleveland Clinic from 2001 to 2011. Data on age at initial dx of AD, type of AD, preceding treatment, type of chemotherapy, age at t-AML dx, gender, peripheral blood counts at t-AML dx, peripheral and marrow blasts, pathologic classification, metaphase cytogenetics (per CALGB/Alliance 8461 criteria), LP, complete remission (CR) and overall survival (OS) measured from t-AML dx were collated from our IRB approved AML database. Multivariable log-linear, logistic, and proportional hazards models with step-wise variable selection were used to identify independent predictors of each outcome.Of 730 patients treated with cytarabine-based induction chemotherapy over the 10-year period, 77 had t-AML. Most (68%) were female; median age at dx of antecedent disorder was 56 years (range, 16–75); median age at t-AML dx was 61 yrs (range, 19–79); and median latency period to t-AML dx was 4.6 yrs (range, 0.5–38.4). Most (71%) had an antecedent solid tumor [breast cancer (44%), prostate (10%); colon (6%), other organ sites (8%); 23% had a prior hematologic malignancy [non-Hodgkin lymphoma (16%), Hodgkin lymphoma (4%), and leukemia (4%)]; and 5% had autoimmune diseases. Previous treatments for AD included radiation (26%), chemotherapy (30%), and chemotherapy and radiation (44%). Of 57 pts previously treated with chemotherapy, 68% received alkylating agents, 65% anthracyclines, 51% mitotic inhibitors (MI) and 30% all three drug classes. Cytogenetic risk distribution at t-AML dx was: favorable (19%), intermediate-risk (52%), and unfavorable (29%). Overall, 48 pts (62%) achieved a CR with induction chemotherapy and median OS was 9.6 months, with 30% surviving >2 years.Independent prognostic factors of shorter LP were age at AD >55 (p=.001) and prior treatment with MI (p=.001). Median LP for pts aged <55 at AD with no prior treatment with MI was 7.6 yrs, compared to 4.6 yrs for pts <55 exposed to MI, 4.6 years for pts age >55 but no prior MI, and 2.0 years for pts >55 and prior treatment with MI. Age at t-AML (p=.001) was the only independent predictor of CR. Independent predictors for inferior OS were unfavorable cytogenetics (p=.002), antecedent hematologic or autoimmune disease (p=0.007) and platelet counts <25000/μL at the time of t-AML dx (p=0.02). A prognostic model based on these factors categorized t-AML pts into two risk groups based on previous diagnosis type, cytogenetics, and platelet count at t-AML dx (Table 1). This score-based risk stratification used a cutoff of 2 points to categorize pts as favorable or unfavorable. Pts with a favorable profile had an estimated median OS of 28.4 months compared to 5.0 months for pts with an unfavorable profile (p=.0003).In conclusion, multicomponent prognostic models that integrate well-established disease or treatment-related covariates can be clinically helpful in risk stratifying t-AML pts undergoing induction therapy, identifying those who might benefit from more intensive interventions.Table 1Predictive model for OS using cytogenetics, antecedent disease and platelet count at t-AML diagnosisRisk GroupScorePatientsNMedian Survival (Months)Hazard Ratio (95% CI)pSolid tumor (0 points) and favorable cytogenetics (0) ORSolid tumor (0), intermediate cytogenetics (2), and platelets > 25000 (0) ORFavorable0 or 23828.4Hematologic/autoimmune (2), favorable cytogenetics (0), and platelets >25000 (0)Unfavorable cytogenetics (3) ORSolid tumor (0), intermediate cytogenetics (2) and platelets < 25000 (2) ORUnfavorable>2375.02.70 (1.57-4.64).0003Hem/autoimmune (2), favorable cytogenetics (0) and platelets <25000 (2) ORHematologic/autoimmune (2) and intermediate cytogenetics (2) Disclosures:No relevant conflicts of interest to declare.

Therapy‐related acute myeloid leukemia (t‐AML) with poor‐risk cytogenetics in two patients with persistent molecular complete remission of acute promyelocytic leukemia

Therapy-related acute myeloid leukemia (t-AML) is a clinical syndrome occurring as a complication after cytotoxic and/or radiation therapy. The incidence of t-AML after acute promyelocytic leukemia (APL), all-transretinoic acid (ATRA), and anthracycline-based therapy is rather low. However, because of the high remission rates and long-term overall survival achieved with current APL treatments, late complications related to antileukemic therapy should be taken into account, giving priority to efficacy agents with the lowest potential of leukemogenesis, despite individual genetic susceptibilities that are not well known. Here, we report two cases of t-AML observed in two young women who achieved a rapid, complete molecular remission (CMR) of APL and who were still in CMR when t-AML was diagnosed. These t-AMLs shared some clinical and biological features such as poor-risk cytogenetics and a rapidly progressing, unfavorable outcome. Retrospective RT-PCR WT1 expression from the onset of APL to t-AML diagnosis did not prove to be a good marker for t-AML development.

Influence of type of antecedent disorder on outcome of therapy-related AML.

6628 Background: Therapy-related AML (tAML) is an increasingly recognized consequence of chemoradiotherapy among cancer survivors but the latency period from antecedent diagnosis to its development is variable and not well-defined. Metaphase cytogenetics (MC) at tAML diagnosis effect prognosis, but the influence of the type of antecedent disorder for which treatment was previously given is less clear. Methods: We assessed retrospectively whether the type of antecedent diagnosis requiring therapy that led to tAML was predictive of response and overall survival (OS) following development of tAML. Results: Of 64 tAML patients (pts) treated with 7+3 chemotherapy over a seven year period, 67% had prior chemo/radiotherapy for a solid tumor (ST), 27% for a hematologic malignancy (HM), and 6% for an autoimmune disorder (AI). At tAML diagnosis, 18 pts (28%) had unfavorable MC, 33 (52%) intermediate, and 12 (19%) favorable, by CALGB risk criteria. The median latency from chemo/radiotherapy exposure to tAML was 4.7 years (range .5 – 41.5) and was inversely correlated to pt age (younger pts had longer latency, even if <65 years, Spearman r=-.42, p=.002). In multivariable analysis age at primary diagnosis (p<.001) and prior mitotic inhibitor exposure (p=.03) were predictors of shorter latency. Median age was 60 years, and 41 pts (64%) achieved CR. Age >60 was the only significant factor predictive of poor response. 2-year OS was 28%, with an estimated median OS of 11.7 months. Unfavorable MC (p=.01, hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.14-2.73) and an antecedent HM or AI (p=.04, HR 1.92, 95% CI 1.02-3.58) were independent predictors of inferior OS. There was a trend for worse OS among pts developing tAML 3-10 years following exposure, compared to tAML <3 or >10 years. Pts with unfavorable MC or with intermediate MC and tAML arising from HM or AI had significantly worse median OS than pts with favorable MC or with intermediate MC and tAML arising from ST (8.1 vs 20.8 months, p=.01, HR 2.24, 95%CI 1.21-4.15). Conclusions: The type of antecedent disorder for which pts receive therapy prior to development of tAML is relevant prognostically. Compared to pts treated for prior ST, pts treated for prior HM or AI exhibit worse OS to induction chemotherapy for tAML.

Azacytidine (AZA) as First Line Therapy in AML: Results of the French ATU Program.

Abstract 843 Background:AZA prolongs survival in higher-risk MDS including patients (pts) with 20-29 % marrow blasts, now considered WHO-AML ( Lancet Onc, 2009). However, no large AML cohorts (especially with '30% marrow blasts) treated upfront with AZA have been reported. Methods:An AZA compassionate program (ATU) was initiated in France in Dec 2004 for higher risk MDS, and AML considered not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed WHO AML pts having received at least 1 cycle of AZA in the 42 centers with complete pt reporting, excluding those previously treated by IC, allo SCT, low dose AraC or a hypomethylating agent. Results:138 pts were included between Dec 2004 and Dec 2008; M/F: 86/52; median age 73 years (y) (range 31-87), 117 pts (85%) were > 65 y and 54 (40%) >75y. 65 pts (47%) had prior WHO MDS and 30 pts (22%) therapy related (tAML). 44 pts (32%) had 20-29% marrow blasts. Median WBC was 3.0 G/L [0.8-111.5]. Karyotype (MRC classification), was intermediate (int) in 60 pts,( including 38 normal (NK), and 7 isolated +8 ) adverse in 67 pts (including 42 -7/ del7q, 41 del5q/-5, 45 complex karyotype, two 3q26) and failed in 11 pts.With a median follow-up of 11.3 months, pts received a median of 4.5 AZA cycles (range 1-26). Treatment was according to FDA-EMEA approved schedule for MDS in 95 pts (69%) and a less intensive schedule (5d/4w, or <75 mg/m2/d) in 31% pts, 29 pts (21%) received concomitant valproic acid (VPA).First evaluation was made after 3 to 4 cycles. An overall AML response (ie according to AML-IWG criteria) was observed in 29 pts (21%) including 19 CR (14%), 3 CRp (2%) and 7 PR (5%) after a median of 3 cycles (1 – 11). An additional 25 pts (who had no CR, CRi or PR) achieved hematologic improvement (HI, according to MDS-IWG 2006 criteria). Neither any pretreatment characteristic including age, preceding MDS, tAML, karyotype, WBC, marrow blast %, combination with VPA were correlated with AML response. Median time to progression after AML response was 7.6 monthsIn the 138 pts, 1 y-OS was 40%, 2 y OS 18% and median OS 10.2 months. In univariate analysis, pre-treatment characteristics negatively influencing OS were higher WBC, adverse cytogenetics, higher absolute PB blasts and diagnosis of tAML. In multivariate analysis: higher WBC (p=0.018), and adverse cytogenetics (p=0.0006) retained prognostic significance for OS. In particular, pts with WBC >10 G/L (32 pts in our cohort) carried poorer prognosis ( 1 y OS of 27% vs 44% ,p=0.01); NK had better OS (1-y OS: 66%) than adverse cytogenetics (1-y OS: 30%, p=0.01) but also other “intermediate-risk” abnormalities (1-y OS: 30%, p=0.03).Marrow blast % did not influence OS and survival, whatever the cut off chosen. In particular, pts with 20-29 % marrow blasts had 22% AML response and 1 y OS of 50%, compared to 21% and 1 y OS of 35%, respectively, in pts with >30% marrow blasts (p=NS and NS, respectively). Prior MDS also had no influence on survival.Overall, 33 pts required hospitalization during treatment, mainly for neutropenic fever.A landmark analysis at the time of evaluation showed that achievement of CR, CRi or PR was associated with improved OS (1y-OS 55% vs 31%,p=0.007). In pts with no AML-IWG response, however, achievement of HI also predicted better survival: 1 y-OS 55% vs 19 %, p=0.02.In the 54 pts older than 75 y (ie pts generally considered unfit for IC), 12 (22%) had AML response including CR in 9 (17%) and 3 PR (5%). 1y-OS was 41 % vs 38% for younger pts (p=NS). Hospitalisation was needed in 31% of them vs 32% in younger pts (p=NS). Conclusion:In this untreated cohort of generally older AML pts considered non candidates for intensive chemotherapy, response rate was 21% and 1 y OS 40%. Higher WBC counts and adverse karyotype were associated with poorer OS, but marrow blast %, whatever the threshold chosen, had no influence on outcome. Age above 75 y was associated with similar response and 1y OS. Finally, pts without AML IWG responses but with improved cytopenias also appeared to have improved survival. Disclosures:Off Label Use: Azacytidine is approved by FDA and EMEA in the treatment of high risk MDS and AML up to 30% of bone marrow blast.. Fenaux:CELGENE: Research Funding; AMGEN: Research Funding.

Therapy-Related Myelodysplastic Syndrome

In practice, cases of therapy-related myelodysplastic syndrome (t-MDS) are often classified according to morphologic schemes used for de novo MDS. However, there are few data addressing the appropriateness of such classification. We studied 155 patients with therapy-related acute myeloid leukemia (t-AML)/t-MDS to determine whether subclassification by the World Health Organization (WHO) criteria for de novo MDS provides prognostic information in t-MDS. In addition, we assessed whether cytogenetic stratification by the International Prognostic Scoring System (IPSS) guidelines or karyotypic complexity was prognostically important. We found no differences in median survival times among patients classified into the different WHO subgroup of MDS or according to their bone marrow blast percentage; our results indicate a uniformly poor outcome in t-MDS regardless of morphologic classification. However, significant survival differences correlated with cytogenetic stratification according to IPSS guidelines and/or karyotypic complexity. We found only a borderline difference in median survival of patients with an initial t-MDS diagnosis compared with patients with an initial t-AML diagnosis.

Etiology and Management of Therapy-Related Myeloid Leukemia

The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.

Therapy-related myeloid leukaemia: A model for leukemogenesis in humans

Therapy-related myeloid leukemia (t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We studied 306 consecutive patients referred to the University of Chicago with cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range: 3–83 years) at primary diagnosis and 58 years (range: 6–86 years) at secondary diagnosis were analyzed. Patients had received various cytotoxic agents including alkylating agents (240 patients, 78%) and topoisomerase II inhibitors (115 patients, 39%). One hundered and twenty-one (40%) had received CT alone, 43 (14%) had received RT alone, and 139 (45%) had received both modalities. At diagnosis of t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 ( n = 63), chromosome 7 ( n = 85), both chromosomes 5 and 7 ( n = 66), recurring balanced rearrangements ( n = 31), or other clonal abnormalities ( n = 39); 24 had a normal karyotype. Abnormalities of chromosomes 5 and/or 7 accounted for 76% of all cases with an abnormal karyotype. Seventeen patients had developed t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Patients presenting with acute leukemia were more likely to have a balanced rearrangement than those presenting with myelodysplasia (28% versus 4%, p < 0.0001). Shorter latency was observed for patients with balanced rearrangements (median: 28 months versus 67 months; p < 0.0001). Median survival after diagnosis of t-AML was 8 months; survival at 5 years was less than 10%. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34 + hematopoietic progenitor cells from t-AML patients. We found distinct subtypes of t-AML that have characteristic gene expression patterns. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a −5/del(5q) have a higher expression of genes involved in cell cycle control ( CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding interferon consensus sequence-binding protein ( ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis ( TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells ( FLT3) and cell survival ( BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of targeted therapies.

Coexistence of treatment-related MLL cleavage and rearrangement in a child with haemophagocytic lymphohistiocytosis

Treatment-related acute myeloid leukaemia (t-AML) is a serious complication of topoisomerase 2 inhibitor therapy and is characterised by the presence of mixed lineage leukaemia (MLL) rearrangement. By molecular tracking, we were able to show that MLL cleavage preceded gene rearrangement by 3 months and before the clinical diagnosis of t-AML in a patient with haemophagocytic lymphohistiocytosis. This is the first report on the sequential detection of the two biomarkers in treatment-related leukaemogenesis.

Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia

Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We established the emergence of the malignant clone in a child who developed t-AML with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leukemia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and their chimeric transcripts were characterized from samples collected at the time of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples. The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL-ENL fusion was not detectable in blood at the time of ALL diagnosis or after 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 16 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant clone was not present before therapy, arose early during chemotherapy, and was able to proliferate even during exposure to antileukemic therapy.

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.

To analyze therapy-related acute myeloid leukemias (tAMLs) with t(8;21), inv(16), or t(8;16). Twenty-five patients with tAML and t(8;21)(q22;q22), inv(16)(p13;q22), or t(8;16)(p11;p13) from seven centers, along with 23 previously published cases, were studied. Twenty-six, 16, and six patients, respectively, had t(8;21), inv(16), and t(8;16). Prior cancer was a solid tumor in 27 cases, and a hematologic malignancy in all other patients. Five patients had received prior radiotherapy (RT) alone, and 43 had received prior chemotherapy with or without RT. Prior chemotherapy included a drug that directly reacts with DNA (alkylating agent or cisplatin) and/or an agent that targets topoisomerase II (ATTop, an anthracycline or derivative or, less often, epipodophyllotoxin) in most patients. The interval between prior tumor and diagnosis of tAML was less than 3 years in most cases, and only seven patients had a preleukemic phase of disease. Morphology was M2 AML for t(8;21), M4eo for inv(16), and M4 or M5 for t(8;16). Sixteen of 21 (76%), 12 of 14 (86%), and zero of four patients with t(8;21), inv(16), and t(8;16), respectively, achieved complete remission (CR) with intensive chemotherapy. The actuarial disease-free survival rate at 24 months was 47% and 54% in patients with t(8;21) and inv(16), respectively. Like other tAMLs with a karyotype specific of de novo AML [balanced 11q23 rearrangement or t(15;17)], tAMLs with t(8;21), inv(16), or t(8;16) are usually characterized by a short latent period, previous treatment often combining a drug that directly reacts with DNA and an ATTop, and absence of preleukemic phase. Hematologic characteristics and response to treatment are also identical to those of de novo AML with the same karyotypes.