Bayard L Powell

Publications (65)719.79 Total impact

• Article: Clinical Role of microRNAs in Cytogenetically Normal Acute Myeloid Leukemia: miR-155 Upregulation Independently Identifies High-Risk Patients.

  Guido Marcucci, Kati S Maharry, Klaus H Metzeler, Stefano Volinia, Yue-Zhong Wu, Krzysztof Mrózek, Deedra Nicolet, Jessica Kohlschmidt, Susan P Whitman, Jason H Mendler, Sebastian Schwind, Heiko Becker, Ann-Kathrin Eisfeld, Andrew J Carroll, Bayard L Powell, Jonathan E Kolitz, Ramiro Garzon, Michael A Caligiuri, Richard M Stone, Clara D Bloomfield
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  ABSTRACT: PURPOSETo evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA. PATIENTS AND METHODS We evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155-associated gene and microRNA expression profiles were derived using microarrays.ResultsConsidering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-κB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis. CONCLUSIONmiR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.
  Journal of Clinical Oncology 05/2013; · 18.37 Impact Factor
• Article: Bortezomib Added to Daunorubicin and Cytarabine During Induction Therapy and to Intermediate-Dose Cytarabine for Consolidation in Patients With Previously Untreated Acute Myeloid Leukemia Age 60 to 75 Years: CALGB (Alliance) Study 10502.

  Eyal C Attar, Jeffrey L Johnson, Philip C Amrein, Gerard Lozanski, Martha Wadleigh, Daniel J Deangelo, Jonathan E Kolitz, Bayard L Powell, Peter Voorhees, Eunice S Wang, William Blum, Richard M Stone, Guido Marcucci, Clara D Bloomfield, Barry Moser, Richard A Larson
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  ABSTRACT: PURPOSEThe purpose of this study was to determine remission induction frequency when bortezomib was combined with daunorubicin and cytarabine in previously untreated older adults with acute myeloid leukemia (AML) and safety of bortezomib in combination with consolidation chemotherapy consisting of intermediate-dose cytarabine (Int-DAC). PATIENTS AND METHODS Ninety-five adults (age 60 to 75 years; median, 67 years) with previously untreated AML (including therapy-related and previous myelodysplastic syndrome) received bortezomib 1.3 mg/m(2) intravenously (IV) on days 1, 4, 8, and 11 with daunorubicin 60 mg/m(2) on days 1 through 3 and cytarabine 100 mg/m(2) by continuous IV infusion on days 1 through 7. Patients who achieved complete remission (CR) received up to two courses of consolidation chemotherapy with cytarabine 2 gm/m(2) on days 1 through 5 with bortezomib. Three cohorts with escalating dose levels of bortezomib were tested (0.7, 1.0, and 1.3 mg/m(2)). Dose-limiting toxicities were assessed during the first cycle of consolidation. The relationship between cell surface expression of CD74 and clinical outcome was assessed.ResultsFrequency of CR was 65% (62 of 95), and 4% of patients (four of 95) achieved CR with incomplete platelet recovery (CRp). Eleven patients developed grade 3 sensory neuropathy. Bortezomib plus Int-DAC proved tolerable at the highest dose tested. Lower CD74 expression was associated with CR/CRp (P = .04) but not with disease-free or overall survival. CONCLUSION The addition of bortezomib to standard 3 + 7 daunorubicin and cytarabine induction chemotherapy for AML resulted in an encouraging remission rate. The maximum tested dose of bortezomib administered in combination with Int-DAC for remission consolidation was 1.3 mg/m(2) and proved tolerable. Further testing of this regimen is planned.
  Journal of Clinical Oncology 11/2012; · 18.37 Impact Factor
• Article: RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures.

  Jason H Mendler, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Heiko Becker, Klaus H Metzeler, Sebastian Schwind, Susan P Whitman, Jihane Khalife, Jessica Kohlschmidt, [......], Thomas H Carter, Meir Wetzler, Joseph O Moore, Jonathan E Kolitz, Maria R Baer, Andrew J Carroll, Richard A Larson, Michael A Caligiuri, Guido Marcucci, Clara D Bloomfield
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  ABSTRACT: To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) and with gene/microRNA expression signatures. Younger (< 60 years; n = 175) and older (≥ 60 years; n = 225) patients with CN-AML treated with intensive cytarabine/anthracycline-based first-line therapy on Cancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene/microRNA expression profiles were derived using microarrays. RUNX1 mutations were found in 8% and 16% of younger and older patients, respectively (P = .02). They were associated with ASXL1 mutations (P < .001) and inversely associated with NPM1 (P < .001) and CEBPA (P = .06) mutations. RUNX1-mutated patients had lower complete remission rates (P = .005 in younger; P = .006 in older) and shorter disease-free survival (P = .058 in younger; P < .001 in older), overall survival (P = .003 in younger; P < .001 in older), and event-free survival (P < .001 for younger and older) than RUNX1 wild-type patients. Because RUNX1 mutations were more common in older patients and almost never coexisted with NPM1 mutations, RUNX1 mutation-associated expression signatures were derived in older, NPM1 wild-type patients and featured upregulation of genes normally expressed in primitive hematopoietic cells and B-cell progenitors, including DNTT, BAALC, BLNK, CD109, RBPMS, and FLT3, and downregulation of promoters of myelopoiesis, including CEBPA and miR-223. RUNX1 mutations are twice as common in older than younger patients with CN-AML and negatively impact outcome in both age groups. RUNX1-mutated blasts have molecular features of primitive hematopoietic and lymphoid progenitors, potentially leading to novel therapeutic approaches.
  Journal of Clinical Oncology 07/2012; 30(25):3109-18. · 18.37 Impact Factor
• Article: Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia: Results of Cancer and Leukemia Group B Study 19802.

  Wendy Stock, Jeffrey L Johnson, Richard M Stone, Jonathan E Kolitz, Bayard L Powell, Meir Wetzler, Peter Westervelt, Guido Marcucci, Daniel J Deangelo, James W Vardiman, Diane McDonnell, Krzysztof Mrózek, Clara D Bloomfield, Richard A Larson
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  ABSTRACT: BACKGROUND: Cancer and Leukemia Group B (CALGB) Study 19802, a phase 2 study, evaluated whether dose intensification of daunorubicin and cytarabine could improve disease-free survival (DFS) in adults with acute lymphoblastic leukemia (ALL) and whether high-dose systemic and intrathecal methotrexate could replace cranial radiotherapy for central nervous system (CNS) prophylaxis. METHODS: One hundred sixty-one eligible, previously untreated patients ages 16 to 82 years (median age, 40 years) were enrolled, and 33 (20%) were aged ≥60 years. RESULTS: One hundred twenty-eight patients (80%) achieved complete remission (CR). Dose intensification of daunorubicin and cytarabine was feasible. At a median follow-up of 10.4 years for surviving patients, the 5-year DFS rate was 25% (95% confidence interval, 18%-33%), and the overall survival (OS) rate was 30% (95% confidence interval, 23%-37%). Patients aged <60 years who received the 80 mg/m(2) dose of daunorubicin had a DFS of 33% (95% confidence interval, 22%-44%) and an OS of 39% (95% confidence interval, 29%-49%) at 5 years. Eighty-four patients (52%) relapsed, including 9 patients (6%) who had isolated CNS relapses. The omission of cranial irradiation did not result in higher than historic CNS relapse rates. CONCLUSIONS: Intensive systemic, oral, and intrathecal methotrexate dosing permitted the omission of CNS irradiation in adult patients with ALL. This intensive approach using higher doses of daunorubicin and cytarabine failed to result in an overall improvement in DFS or OS compared with historic CALGB studies. Future therapeutic strategies for adults with ALL should be tailored to specific age and molecular genetic subsets. Cancer 2012. © 2012 American Cancer Society.
  Cancer 06/2012; · 4.77 Impact Factor
• Article: Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia.

  Robert E Gallagher, Barry K Moser, Janis Racevskis, Xavier Poiré, Clara D Bloomfield, Andrew J Carroll, Rhett P Ketterling, Diane Roulston, Esther Schachter-Tokarz, Da-Cheng Zhou, [......], Greg Koval, Dorie A Sher, James H Feusner, Martin S Tallman, Richard A Larson, Bayard L Powell, Frederick R Appelbaum, Elisabeth Paietta, Cheryl L Willman, Wendy Stock
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  ABSTRACT: Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD(+)) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD(+) (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD(+). Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD(+)), which were differentially associated with PRα/LBD(+) depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD(+) were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD(+), high, S-isoform. These exploratory results suggest that differing PRα/LBD(+) activities may interact with FLT3-ITD(+) or ACA, that FLT3-ITD(+) and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD(+) were also associated with reduced postrelapse survival.
  Blood 06/2012; 120(10):2098-108. · 9.90 Impact Factor
• Article: miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia.

  Ann-Kathrin Eisfeld, Guido Marcucci, Kati Maharry, Sebastian Schwind, Michael D Radmacher, Deedra Nicolet, Heiko Becker, Krzysztof Mrózek, Susan P Whitman, Klaus H Metzeler, [......], Bayard L Powell, Thomas H Carter, Joseph O Moore, Jonathan E Kolitz, Meir Wetzler, Michael A Caligiuri, Richard A Larson, Stephan M Tanner, Albert de la Chapelle, Clara D Bloomfield
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  ABSTRACT: High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.
  Blood 04/2012; 120(2):249-58. · 9.90 Impact Factor
• Article: Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia.

  Guido Marcucci, Klaus H Metzeler, Sebastian Schwind, Heiko Becker, Kati Maharry, Krzysztof Mrózek, Michael D Radmacher, Jessica Kohlschmidt, Deedra Nicolet, Susan P Whitman, [......], Bayard L Powell, Thomas H Carter, Jonathan E Kolitz, Meir Wetzler, Andrew J Carroll, Maria R Baer, Joseph O Moore, Michael A Caligiuri, Richard A Larson, Clara D Bloomfield
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  ABSTRACT: To determine the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in primary cytogenetically normal acute myeloid leukemia (CN-AML). Four hundred fifteen previously untreated adults were analyzed for DNMT3A mutations and established prognostic gene mutations and expression markers. Gene- and microRNA-expression profiles were derived using microarrays. Younger (< 60 years; n = 181) and older (≥ 60 years; n = 234) patients had similar frequencies of DNMT3A mutations (35.3% v 33.3%). Missense mutations affecting arginine codon 882 (R882-DNMT3A) were more common (n = 92; 62%) than those affecting other codons (non-R882-DNMT3A). DNMT3A-mutated patients did not differ regarding complete remission rate, but had shorter disease-free survival (DFS; P = .03) and, by trend, overall survival (OS; P = .07) than DNMT3A-wild-type patients. In multivariable analyses, DNMT3A mutations remained associated with shorter DFS (P = .01), but not with shorter OS. When analyzed separately, the two DNMT3A mutation types had different significance by age group. Younger patients with non-R882-DNMT3A mutations had shorter DFS (P = .002) and OS (P = .02), whereas older patients with R882-DNMT3A mutations had shorter DFS (P = .005) and OS (P = .002) after adjustment for other clinical and molecular prognosticators. Gene- and microRNA-expression signatures did not accurately predict DNMT3A mutational status. DNMT3A mutations are frequent in CN-AML, and their clinical significance seems to be age dependent. DNMT3A-R882 mutations are associated with adverse prognosis in older patients, and non-R882-DNMT3A mutations are associated with adverse prognosis in younger patients. Low accuracy of gene- and microRNA-expression signatures in predicting DNMT3A mutation status suggested that the role of these mutations in AML remains to be elucidated.
  Journal of Clinical Oncology 03/2012; 30(7):742-50. · 18.37 Impact Factor
• Article: FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group.

  Matthew A Kutny, Barry K Moser, Kristina Laumann, James H Feusner, Alan Gamis, John Gregory, Richard A Larson, Bayard L Powell, Wendy Stock, Cheryl L Willman, William G Woods, Soheil Meshinchi
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  ABSTRACT: FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n = 50). Forty-two of the 104 patients (40%) had either FLT3/ITD (n = 28, 27%) or FLT3/ALM (n = 15, 14%). Median diagnostic WBC count was 23,400 cells/µl vs. 3,600 cells/µl for those with and without FLT3/Mut (P < 0.001), and similar results for the cohort of 50 patients treated on C9710 (P < 0.001). In patients treated on C9710, presence of a FLT3 mutation was highly correlated with diagnostic WBC count >10,000 (P = 0.004), microgranular variant histology (P = 0.035), and a lower remission rate (P = 0.009). In patients who received ATRA (C9710 or CCG-2911, n = 8), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P = 0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P = 0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease.
  Pediatric Blood & Cancer 02/2012; 59(4):662-7. · 1.89 Impact Factor
• Article: ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category.

  Klaus H Metzeler, Heiko Becker, Kati Maharry, Michael D Radmacher, Jessica Kohlschmidt, Krzysztof Mrózek, Deedra Nicolet, Susan P Whitman, Yue-Zhong Wu, Sebastian Schwind, [......], Thomas H Carter, Meir Wetzler, Joseph O Moore, Jonathan E Kolitz, Maria R Baer, Andrew J Carroll, Richard A Larson, Michael A Caligiuri, Guido Marcucci, Clara D Bloomfield
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  ABSTRACT: The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (≥ 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall survival (OS; P = .006), and event-free survival (EFS; P = .002). Within the European LeukemiaNet (ELN) genetic categories of older CN-AML, ASXL1 mutations associated with inferior CR rate (P = .02), OS (P < .001), and EFS (P < .001) among ELN Favorable, but not among ELN Intermediate-I patients. Multivariable analyses confirmed associations of ASXL1 mutations with unfavorable CR rate (P = .03), DFS (P < .001), OS (P < .001), and EFS (P < .001) among ELN Favorable patients. We identified an ASXL1 mutation-associated gene-expression signature, but no microRNA-expression signature. This first study of ASXL1 mutations in primary CN-AML demonstrates that ASXL1-mutated older patients, particularly within the ELN Favorable group, have unfavorable outcomes and may be candidates for experimental treatment approaches.
  Blood 12/2011; 118(26):6920-9. · 9.90 Impact Factor
• Article: Phase II trial of vorinostat and gemtuzumab ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia.

  Roland B Walter, Bruno C Medeiros, Bayard L Powell, Charles A Schiffer, Frederick R Appelbaum, Elihu H Estey
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  ABSTRACT: Histone deacetylase inhibitors such as vorinostat enhance gemtuzumab ozogamicin efficacy in vitro. We, therefore, investigated vorinostat+gemtuzumab ozogamicin for adults aged 60 years and over with untreated acute myeloid leukemia. We stratified patients into 2 groups (group 1: patients aged ≥ 70 years and performance status 2-3; group 2: aged 60-69 years with performance status 0-3 or aged ≥ 70 years and performance status 0-1). Responses were monitored separately in group 2 patients with normal or favorable cytogenetics (group 2A) and other cytogenetics (group 2B). Among 31 patients, 6 (19.4%) achieved complete remission, and one (3.2%) achieved complete remission with incomplete platelet recovery; these patients had a higher median overall survival than non-responders (553 vs. 131 days, P = 0.0026). Response rates were: group 1, one of 10 (10.0%); group 2A, 6 of 13 (46.2%); and group 2B, none of 8 (0%). These data indicate that vorinostat+gemtuzumab ozogamicin has activity that is mostly confined to patients with normal karyotype disease. ClinicalTrial.gov: NCT00673153.
  Haematologica 12/2011; 97(5):739-42. · 6.42 Impact Factor
• Article: Arsenic trioxide in acute promyelocytic leukemia: potion not poison.

  Bayard L Powell
  Expert Review of Anti-infective Therapy 09/2011; 11(9):1317-9. · 2.65 Impact Factor
• Article: Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia.

  Sebastian Schwind, Guido Marcucci, Jessica Kohlschmidt, Michael D Radmacher, Krzysztof Mrózek, Kati Maharry, Heiko Becker, Klaus H Metzeler, Susan P Whitman, Yue-Zhong Wu, Bayard L Powell, Maria R Baer, Jonathan E Kolitz, Andrew J Carroll, Richard A Larson, Michael A Caligiuri, Clara D Bloomfield
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  ABSTRACT: Low MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene-embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.
  Blood 08/2011; 118(15):4188-98. · 9.90 Impact Factor
• Article: Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

  Heiko Becker, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Klaus H Metzeler, Susan P Whitman, Sebastian Schwind, Jessica Kohlschmidt, Yue-Zhong Wu, Bayard L Powell, Thomas H Carter, Jonathan E Kolitz, Meir Wetzler, Andrew J Carroll, Maria R Baer, Joseph O Moore, Michael A Caligiuri, Richard A Larson, Guido Marcucci, Clara D Bloomfield
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  ABSTRACT: The alleles of the Wilms tumor 1 (WT1) polymorphism rs16754 harbor adenine (A) or guanine (G). Recently, rs16754 has been reported to affect the outcome of patients with cytogenetically normal acute myeloid leukemia. To validate this finding, we investigated pretreatment features and outcome associated with rs16754 in a large cohort of patients with cytogenetically normal acute myeloid leukemia. Four-hundred and thirty-three intensively treated and molecularly characterized cytogenetically normal patients with de novo acute myeloid leukemia (18-83 years old) were analyzed for rs16754. To gain biological insights, we studied the gene- and microRNA-expression profiles for associations with rs16754. Three-hundred and nine (71%) patients were homozygous for A (WT1(AA)), 112 (26%) were heterozygous (WT1(AG)) and 12 (3%) were homozygous for G (WT1(GG)). For comparison with previous studies, we grouped WT1(AG) and WT1(GG) patients and compared them with WT1(AA) patients divided into younger (<60 years) and older (≥60 years) adults. We found no independent prognostic impact of WT1(AA). However, WT1(GG) patients, who were less often Caucasian than WT1(AG) (P=0.001) or WT1(AA) (P=0.008) patients, and had TET2 mutations more often than WT1(AG) (P=0.02) patients, had, among patients with FLT3-internal tandem duplication and/or NPM1 wild-type, better disease-free (P=0.02) and overall survival (P=0.04) than WT1(AA) and WT1(AG) patients combined. Unsupervised and supervised analyses of the gene- and microRNA-expression profiles suggested that there were no distinct expression patterns associated with any rs16754 genotype. We did not observe the previously reported adverse impact of WT1(AA) but found favorable outcomes associated with the homozygous WT1(GG). Considering its low frequency, confirmatory studies are necessary. The biological significance of rs16754 remains questionable as no distinct expression profiles were associated with the genotypes.
  Haematologica 06/2011; 96(10):1488-95. · 6.42 Impact Factor
• Article: TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study.

  Klaus H Metzeler, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Dean Margeson, Heiko Becker, John Curfman, Kelsi B Holland, Sebastian Schwind, Susan P Whitman, [......], Thomas H Carter, Meir Wetzler, Joseph O Moore, Jonathan E Kolitz, Maria R Baer, Andrew J Carroll, Richard A Larson, Michael A Caligiuri, Guido Marcucci, Clara D Bloomfield
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  ABSTRACT: To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I-risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I-risk patients and found distinct mutation-associated microRNA signatures in both ELN groups. TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
  Journal of Clinical Oncology 02/2011; 29(10):1373-81. · 18.37 Impact Factor
• Article: BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

  Sebastian Schwind, Guido Marcucci, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Kelsi B Holland, Dean Margeson, Heiko Becker, Susan P Whitman, Yue-Zhong Wu, Klaus H Metzeler, Bayard L Powell, Jonathan E Kolitz, Thomas H Carter, Joseph O Moore, Maria R Baer, Andrew J Carroll, Michael A Caligiuri, Richard A Larson, Clara D Bloomfield
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  ABSTRACT: BAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene-embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients.
  Blood 12/2010; 116(25):5660-9. · 9.90 Impact Factor
• Article: Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710.

  Bayard L Powell, Barry Moser, Wendy Stock, Robert E Gallagher, Cheryl L Willman, Richard M Stone, Jacob M Rowe, Steven Coutre, James H Feusner, John Gregory, Stephen Couban, Frederick R Appelbaum, Martin S Tallman, Richard A Larson
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  ABSTRACT: Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).
  Blood 11/2010; 116(19):3751-7. · 9.90 Impact Factor
• Article: FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

  Susan P Whitman, Kati Maharry, Michael D Radmacher, Heiko Becker, Krzysztof Mrózek, Dean Margeson, Kelsi B Holland, Yue-Zhong Wu, Sebastian Schwind, Klaus H Metzeler, [......], Thomas H Carter, Jonathan E Kolitz, Meir Wetzler, Joseph O Moore, Richard M Stone, Andrew J Carroll, Richard A Larson, Michael A Caligiuri, Guido Marcucci, Clara D Bloomfield
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  ABSTRACT: The clinical impact of FLT3-internal tandem duplications (ITDs), an adverse prognostic marker in adults aged < 60 years with primary cytogenetically normal acute myeloid leukemia (CN-AML), requires further investigation in older patients. In CN-AML patients aged ≥ 60 years treated on Cancer and Leukemia Group B frontline trials, we found that FLT3-ITD remained associated with shorter disease-free survival (P < .001; hazard ratio = 2.10) and overall survival (P < .001; hazard ratio = 1.97) in multivariable analyses. This impact on shorter disease-free survival and overall survival was in patients aged 60-69 (P < .001, each) rather than in those aged ≥ 70 years. An FLT3-ITD-associated gene-expression signature revealed overexpression of FLT3, homeobox genes (MEIS1, PBX3, HOXB3), and immunotherapeutic tar-gets (WT1, CD33) and underexpression of leukemia-associated (MLLT3, TAL1) and erythropoiesis-associated (GATA3, EPOR, ANK1, HEMGN) genes. An FLT3-ITD-associated microRNA-expression signature included overexpressed miR-155 and underexpressed miR-144 and miR-451. FLT3-ITD identifies older CN-AML patients with molecular high risk and is associated with gene- and microRNA-expression signatures that provide biologic insights for novel therapeutic approaches.
  Blood 11/2010; 116(18):3622-6. · 9.90 Impact Factor
• Article: Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

  Sebastian Schwind, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Kelsi B Holland, Dean Margeson, Susan P Whitman, Christopher Hickey, Heiko Becker, Klaus H Metzeler, [......], Claudia D Baldus, Shujun Liu, Ramiro Garzon, Bayard L Powell, Jonathan E Kolitz, Andrew J Carroll, Michael A Caligiuri, Richard A Larson, Guido Marcucci, Clara D Bloomfield
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  ABSTRACT: To evaluate the prognostic significance of expression levels of a single microRNA, miR-181a, in the context of established molecular markers in cytogenetically normal acute myeloid leukemia (CN-AML), and to gain insight into the leukemogenic role of miR-181a. miR-181a expression was measured in pretreatment marrow using Ohio State University Comprehensive Cancer Center version 3.0 arrays in 187 younger (<60 years) adults with CN-AML. Presence of other molecular prognosticators was assessed centrally. A gene-expression profile associated with miR-181a expression was derived using microarrays and evaluated by Gene-Ontology analysis. Higher miR-181a expression associated with a higher complete remission (CR) rate (P=.04), longer overall survival (OS; P=.01) and a trend for longer disease-free survival (DFS; P=.09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P=.009), and longer DFS (P<.001) and OS (P<.001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥60 years) patients with CN-AML. A miR-181a-associated gene-expression profile was characterized by enrichment of genes usually involved in innate immunity. To our knowledge, we provide the first evidence that the expression of a single microRNA, miR-181a, is associated with clinical outcome of patients with CN-AML and may refine their molecular risk classification. Targeted treatments that increase endogenous levels of miR-181a might represent novel therapeutic strategies.
  Journal of Clinical Oncology 11/2010; 28(36):5257-64. · 18.37 Impact Factor
• Article: P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808.

  Jonathan E Kolitz, Stephen L George, Guido Marcucci, Ravi Vij, Bayard L Powell, Steven L Allen, Daniel J DeAngelo, Thomas C Shea, Wendy Stock, Maria R Baer, Vera Hars, Kati Maharry, Eva Hoke, James W Vardiman, Clara D Bloomfield, Richard A Larson
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  ABSTRACT: Cancer and Leukemia Group B 19808 (CALGB 19808) is the only randomized trial of a second-generation P-glycoprotein (Pgp) modulator in untreated patients with acute myeloid leukemia (AML) younger than age 60 years. We randomly assigned 302 patients to receive induction chemotherapy regimens consisting of cytosine arabinoside (Ara-C; A), daunorubicin (D), and etoposide (E), without (ADE) or with (ADEP) PSC-833 (P). The incidence of complete remission was 75% with both regimens. Reversible grade 3 and 4 liver and mucosal toxicities were significantly more common with ADEP. Therapy-related mortality was 7% and did not differ by induction arm. Excess cardiotoxicity was not seen with high doses of D in ADE. The median disease-free survival was 1.34 years in the ADE arm and 1.09 years in the ADEP arm (P = .74, log-rank test); the median overall survival was 1.86 years in the ADE arm and 1.69 years in the ADEP arm (P = .82). There was no evidence of a treatment difference within any identifiable patient subgroup. Inhibition of Pgp-mediated drug efflux by PSC-833 did not improve clinical outcomes in younger patients with untreated AML. This trial was registered at www.clinicaltrials.gov as #NCT00006363.
  Blood 09/2010; 116(9):1413-21. · 9.90 Impact Factor
• Article: Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

  Heiko Becker, Guido Marcucci, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Dean Margeson, Susan P Whitman, Peter Paschka, Kelsi B Holland, Sebastian Schwind, [......], Bayard L Powell, Thomas H Carter, Jonathan E Kolitz, Meir Wetzler, Andrew J Carroll, Maria R Baer, Joseph O Moore, Michael A Caligiuri, Richard A Larson, Clara D Bloomfield
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  ABSTRACT: We previously reported the adverse prognostic impact of Wilms tumor 1 gene (WT1) mutations in younger adult cytogenetically normal acute myeloid leukemia (CN-AML). Here, we investigated 243 older (> or = 60 years) primary CN-AML patients. WT1 mutated (WT1mut) patients (7%) had FLT3-ITD more frequently (P < .001), lower hemoglobin (P = .01), higher white blood cell count (P = .03) and percentage blood blasts (P = .03), and a shorter overall survival (P = .08) than WT1 wild-type (WT1wt) patients. Comparing older and younger WT1mut patients, they had similar pretreatment characteristics and outcome. By contrast, among WT1wt CN-AML, younger patients had a significantly better outcome. A WT1 mutation-associated gene-expression signature, reported here for the first time, included CD96, a leukemia stem cell-specific marker, and genes involved in gene regulation (eg, MLL, PML, and SNRPN) and in proliferative and metabolic processes (eg, INSR, IRS2, and PRKAA1), supporting the role of mutated WT1 in deregulating multiple homeostatic processes. Our results indicate that WT1mut CN-AML represents a distinct entity with poor treatment response across age groups. This study has been registered at www.clinicaltrials.gov as #NCT00900224.
  Blood 05/2010; 116(5):788-92. · 9.90 Impact Factor