1. Evaluation Of The Hematological, Cytogenetic, Molecular Responses And Imatinib Resistance [1. Evaluación De La Respuesta Hematológica, Citogenética, Molecular Y A La Resistencia Al Imatinib]

[No abstract available]194 SUPPL.S36S37B J. Druker, F. Guilhot, S. O'Brien, R. A. Larson. Long-term benefits of imagine (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study. N. on behalf of the IRIS (International Randomized IF. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 24, No. 18S (June 20 Supplement), 2006: 6506 (oral presentation in ASCO meeting)Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilhot F, HorowitzM, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R, Hehlmann R. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European Leukemianet. Blood. 2006 May 18: [Epub ahead of print]Hughes TP, Deininger MW, Hochhaus A, Branford S, Radich JP, Kaeda J, Baccarani M, Cortes J, Cross NC, Druker BJ, Gabert J, Grimwade D, Hehlmann R,Kamel-Reid S, Lipton JH, Longtine J, Martinelli G, Saglio G, Soverini S, Stock W, Goldman JM. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors - Review and recommendations for 'harmonizing' current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006 Mar 7[Epub ahead of print]Simonsson, B., on behalf of IRIS study group. Beneficial effects of cytogenetic and molecular response on long term outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IB): Up-date from the IRIS study (2005) Blood, 106, pp. 52a. , abstract 166HOCHHAUS, A., Cytogenetic and molecular mechanisms of resistance to Imatinib (2003) Seminars in Hematology, 40, pp. 69-7

Management of chronic myeloid leukemia during pregnancy: a retrospective analysis at a single center

We analyzed the management and outcomes of pregnancies of patients with chronic myeloid leukemia at a single center over fifteen years. Among the 203 CML female patients, there were ten pregnancies in seven women, all of them not planned. In three cases, the chronic myeloid leukemia diagnosis was made during pregnancy. Five patients received tyrosine kinase inhibitors in the first weeks of pregnancy and the drug was interrupted until delivery. One patient lost complete cytogenetic response, and two patients lost the hematological response. A patient with a stable major molecular response had two successful pregnancies without loss of response. There were four premature births. There were no maternal adverse events, fetal malformation or death. All patients received Interferon-alpha during gestation, and two received hydroxyurea for a short period. Leukapheresis was performed in two patients for hyperleukocytosis control. One patient with sickle cell disease died from disease progression six months after delivery. Conclusions: The tyrosine kinase inhibitors ministration should be interrupted during pregnancy. Patients should be advised to achieve a stable and deep molecular response if they plan to conceive, to avoid the risk of disease progression412125128sem informaçãosem informaçã

Philadelphia-negative Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities.342140149Tefferi, A., Vainchenker, W., Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies (2011) J Clin Oncol., 29 (5), pp. 573-582. , Comment in: J Clin Oncol. 2011;29(18):e564-5Laszlo, J., Myeloproliferative disorders (MPD): Myelofibrosis, myeloscrerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia (1975) Semin Hematol., 12 (4), pp. 409-432Vardiman, J.W., Harris, N.L., Brunning, R., The World Health Organization (WHO) classification of the myeloid neoplasms (2002) Blood., 100 (7), pp. 2292-2302. , Comment in: Blood. 2003;101(7):2895-6Tefferi, A., Vardiman, J.W., Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms (2008) Leukemia., 22 (1), pp. 14-22. , Comment in: Leukemia. 2008;22(11):2118-9Vardiman, J.W., Thiele, J., Arber, D.A., Brunning, R.D., Borowitz, M.J., Porwit, A., The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes (2009) Blood, 114 (5), pp. 937-951. , Comment in: Blood. 2010;115(3):748-9author reply 749-50Thiele, J., Kvasnicka, H.M., Facchetti, F., Franco, V., van der Walt, J., Orazi, A., European consensus on grading bone marrow fibrosis and assessment of cellularity (2005) Haematologica., 90 (8), pp. 1128-1132Thiele, J., Kvasnicka, H.M., Diehl, V., Standardization of bone marrow features-does it work in hematopathology for histological discrimination of different disease patterns? (2005) Histol Histopathol., 20 (2), pp. 633-644Thiele, J., Kvasnicka, H.M., The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis (2009) Curr Hematol Malig Rep., 4 (1), pp. 33-40Ahmed, A., Chang, C.C., Chronic idiopathic myelofibrosis: Clinicopathologic features, pathogenesis and prognosis (2006) Arch Pathol Lab Med., 130 (8), pp. 1133-1143Chauffaille, M.L., Neoplasias mieloproliferativas: Revisão dos critérios diagnósticos e dos aspectos clínicos (2010) Rev Bras Hematol Hemoter., 32 (4), pp. 308-316Maciel, J.F., de Lourdes Chauffaille, M., Inaoka, R.J., Colleoni, G.W., Yamamoto, M., Essential Thrombocythemia after treatment of non-Hodgkin's Lymphoma (2007) Leuk Res., 31 (11), pp. 1593-1595Gangat, N., Tefferi, A., Thanarajasingam, G., Patnaik, M., Schwager, S., Ketterling, R., Cytogenetic abnormalities in essential thrombocythemia: Prevalence and prognostic significance (2009) Eur J Haematol., 83 (1), pp. 17-21Baxter, E.J., Scott, L.M., Campbell, P.J., East, C., Fourouclas, N., Swanton, S., Vassiliou, G.S., Green, A.R., Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders (2005) Lancet., 365 (9464), pp. 1054-1061. , Cancer Genome Project. Erratum in: Lancet. 2005;366(9480):122Levine, R.L., Pardanani, A., Tefferi, A., Gilliland, D.G., Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders (2007) Nat Rev Cancer., 7 (9), pp. 673-683Barosi, G., Bergamaschi, G., Marchetti, M., Vannucchi, A.M., Guglielmelli, P., Antonioli, E., Massa, M., Barbui, T., JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis (2007) Blood., 110 (12), pp. 4030-4036. , Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Italian Registry of MyelofibrosisKantarjian, H., Schiffer, C., Jones, D., Cortes, J., Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: Practical advice on use and interpretation of monitoring methods (2008) Blood, 111 (4), pp. 1774-1780Guglielmelli, P., Barosi, G., Specchia, G., Rambaldi, A., Lo Coco, F., Antonioli, E., Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele (2009) Blood, 114 (8), pp. 1477-1483Tefferi, A., Lasho, T.L., Huang, J., Finke, C., Hanson, C.A., Mesa, R.A., Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival (2008) Leukemia., 22 (4), pp. 756-761Tefferi, A., Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1 (2010) Leukemia., 24 (6), pp. 1128-1138Tefferi, A., Thiele, J., Orazi, A., Kvasnicka, H.M., Barbui, T., Hanson, C.A., Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel (2007) Blood., 110 (4), pp. 1092-1097. , Comment in: Blood. 2008;111(3): 1741author reply 1742Johansson, P., Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia (2006) Semin Thromb Hematost, 32 (3), pp. 171-173Giuglielmelli, P., Tefferi, A., Advances in understanding and management of myeloproliferative neoplasms (2009) CA Cancer J Clin., 59 (3), pp. 171-191Girodon, F., Bonicelli, G., Schaffer, C., Mounier, M., Carillo, S., Lafon, I., Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: A population-based study (2009) Haematologica., 94 (6), pp. 865-869Harrison, C.N., Bareford, D., Butt, N., Campbel, P., Conneally, E., Drummond, M., Erber, W., Everington, T., Guideline for investigation and management of adults and children presenting with a thrombocytosis (2010) Br J Haematol., pp. 352-375Lussana, F., Caberlon, S., Pagani, C., Kamphuisen, P.W., Buller, H.R., Cattaneo, M., Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: A systematic review (2009) Thromb Res., 124 (4), pp. 409-417Biergegard, G., Long-term management of thombocytosis in essential thrombocythaemia (2009) Ann Hematol., 88 (1), pp. 1-10Landolfi, R., Gennaro, L., Prevention of thrombosis in polycythemia vera and essential thrombocythemia (2008) Haematologica., 93 (3), pp. 331-335. , Comment on: Haematologica. 2008;93(3):372-80Finazzi, G., Ruggeri, M., Rodeghiero, F., Barbui, T., Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis (2003) Blood., 101 (9), p. 3749. , Comment on: Blood. 2001;97(4):863-6Beer, P., Erber, W., Campbell, P., Green, A., How I treat essential thrombocythemia (2011) Blood., 117 (5), pp. 1472-1482. , Comment in: Blood. 2011;118(4):1179-80author reply 1180-1Kerbauy, D.M., Gooley, T.A., Sale, G.E., Flowers, M.E., Doney, K.C., Georges, G.E., Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. (2007) Biol Blood Marrow Transplant., 13 (3), pp. 355-365Spivak, J., Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation (2010) Ann Intern Med., 152 (5), pp. 300-306Swerdlow, S.H., (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, , International Agency for Research on Cancer., World Health Organization., Louis A. Duhring Fund. 4th ed. Lyon, France: International Agency for Research on CancerTefferi, A., Vaidya, R., Caramazza, D., Finke, C., Lasho, T., Pardanani, A., Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: A comprehensive cytokine profiling study (2011) J Clin Oncol., 29 (10), pp. 1356-1363Barosi, G., Mesa, R.A., Thiele, J., Cervantes, F., Campbell, P.J., Verstovsek, S., Dupriez, B., Tefferi, A., Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A consensus statement from the International Working Group for Myelofibrosis Research and Treatment (2008) Leukemia., 22 (2), pp. 437-438. , International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)Cervantes, F., Dupriez, B., Pereira, A., Passamonti, F., Reilly, J.T., Morra, E., Vannucchi, A.M., New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment (2009) Blood, 113 (13), pp. 2895-2901. , Comment in: Blood. 2010;115(3):745author reply 745-6Passamonti, F., Cervantes, F., Vannucchi, A.M., Morra, E., Rumi, E., Cazzola, M., Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis (2010) Blood., 116 (15), pp. 2857-2858Tefferi, A., Siragusa, S., Hussein, K., Schwager, S.M., Hanson, C.A., Pardanani, A., Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis--prognostic relevance is independent of IPSS or karyotype (2010) Am J Hematol., 85 (1), pp. 14-17. , Comment in: Am J Hematol. 2010;85(1):4-5Caramazza, D., Begna, K.H., Gangat, N., Vaidya, R., Siragusa, S., van Dyke, D.L., Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: A single center study of 433 patients (2011) Leukemia., 25 (1), pp. 82-88Mesa, R.A., Nagorney, D.S., Schwager, S., Allred, J., Tefferi, A., Palliative goals, patient selection, and perioperative platelet management: Outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic (2006) Cancer., 107 (2), pp. 361-370Elliott, M.A., Tefferi, A., Splenic irradiation in myelofibrosis with myeloid metaplasia: A review (1999) Blood Rev., 13 (3), pp. 163-170Ballen, K.K., Shrestha, S., Sobocinski, K.A., Zhang, M.J., Bashey, A., Bolwell, B.J., Outcome of transplantation for myelofibrosis (2010) Biol Blood Marrow Transplant., 16 (3), pp. 358-367Verstovsek, S., Kantarjian, H., Mesa, R.A., Pardanani, A.D., Cortes-Franco, J., Thomas, D.A., Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis (2010) N Engl J Med., 363 (12), pp. 1117-1127. , Comment in: N Engl J Med. 2010363(12): 1180-2N Engl J Med. 2010;363(25):2464author reply 2464-5discussion 2465Pardanani, A., Gotlib, J.R., Jamieson, C., Cortes, J.E., Talpaz, M., Stone, R.M., Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis (2011) J Clin Oncol., 29 (7), pp. 789-796. , J Clin Oncol. 2011;29(7):781-3Vaquez, H., Sur une forme spéciale de cyanose s'accompgnant d'hyperglobulie excessive et persistant (1892) Comptes rendus de La Société de Biologie, 44, pp. 384-388. , ParisOsler, W., Chronic cyanosis with polycythemia and enlarged spleen: A new clinical entity (2008) Am J Med Sci., 335 (6), pp. 411-417. , Comment in: Am J Med Sci 2008;335(6):418-9Berlin, N.I., Diagnosis and classification of the polycythemias (1975) Semin Hematol., 12 (4), pp. 339-351Kralovics, R., Passamonti, F., Buser, A.S., Teo, S.S., Tiedt, R., Passweg, J.R., A gain-of-function mutation of JAK2 in myeloproliferative disorders (2005) N Engl J Med., 352 (17), pp. 1779-1790. , Comment in: N Engl J Med. 2005;353(13):1416-7author reply 1416-7N Engl J Med. 2005;352(17):1744-6Passamonti, F., Rumi, E., Pietra, D., della Porta, M.G., Boveri, E., Pascutto, C., Relation between JAK2(V617F) mutation status, granulocyte activation and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders (2006) Blood., 107 (9), pp. 3676-3682Scott, L.M., Tong, W., Levine, R.L., Scott, M.A., Beer, P.A., Stratton, M.R., JAK2 exon 12 mutations in polycythemia vera and idiopathic eritrocytosis (2007) N Engl J Med., 356 (5), pp. 459-468. , Comment in: N Engl J Med. 2007;356(5):444-5McMullin, M., Reilly, J.T., Campbell, P., Bareford, D., Green, A., Harrison, C., Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis (2007) Br J Haematol, 138, pp. 812-823Crisà, E., Venturino, E., Passera, R., Prina, M., Schinco, P., Borchiellini, A., A retrospective study on 226 polycythemia vera patients: Impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and nonalkylating drugs (2010) Ann Hematol., 89 (7), pp. 691-699Barbui, T., Carobbio, A., Rambaldi, A., Finazzi, G., Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: Is leukocytosis a causative factor? (2009) Blood., 114 (4), pp. 759-763Barosi, G., Birgegard, G., Finazzi, G., Griesshammer, M., Harrison, C., Hasselbalch, H.C., Response criteria for essential thrombocythemia and polycythemia vera: Result of a European LeukemiaNet consensus conference (2009) Blood., 113 (20), pp. 4829-4833Barbui, T., Barosi, G., Birgegard, G., Cervantes, F., Finazzi, G., Griesshammer, M., Harrison, C., Tefferi, A., Philadelphia-Negative Classical Myeloproliferative Neoplass: Critical Concepts and Management Recommendations from European Leukemianet (2011) J Clin Oncol., 29 (6), pp. 761-770. , European LeukemiaNet. Comment in: J Clin Oncol. 2011;29(18):e564-5Rambaldi, A., Dellacasa, C.M., Salmoiraghi, S., A phase 2 A study of the histone-deacetylase inhibitor in patients with JAK2V617F positive myeloproliferative neoplasms. {abstract} (2008) Blood, 112, p. 100. , (não localizada)Chauffaille, M.L.L.F., Neoplasias mieloproliferativas: Revisão dos critérios diagnósticos e dos aspectos clínicos (2010) Rev Bras Hematol. Hemoter, 32 (4), pp. 308-316Tefferi, A., Patnaik, M.M., Pardanani, A., Eosinophilia: Secondary, clonal and idiopatic (2006) Br J Haematol., 133 (5), pp. 468-492Fletcher, S., Bain, B., Diagnosis and treatment of hypereosinophilic syndromes (2007) Curr Opin Hematol., 14 (1), pp. 37-42Metcalfe, D.D., Mast cells and mastocytosis (2008) Blood., 112 (4), pp. 946-95

Conventional Chemotherapy For Acute Myeloid Leukemia: A Brazilian Experience.

CONTEXT: Young patients affected by acute myeloid leukemia (AML) achieve complete remission (CR) using conventional chemotherapy in about 55-85%. However, 30% of patients fail to achieve CR and the remission duration is often only about 12 months. More intensive treatment after CR seems to be necessary in order to maintain CR and obtain a definitive cure. In Brazil, few reports have been published on this important subject. OBJECTIVE: The aim of this study was to describe a Brazilian experience in the treatment of "de novo" acute myeloid leukemia (AML) in younger adult patients (age < 60 years). DESIGN: Retrospective analysis. SETTING: University Hospital, Hematology and Hemotherapy Center, State University of Campinas, Brazil. PARTICIPANTS: Newly diagnosed cases of "de novo" AML in the period from January 1994 to December 1998 were evaluated retrospectively, in relation to response to treatment, overall survival (OS) and disease free survival (DFS). Cases with acute promyelocytic leukemia (APL) were also included in this analysis. RESULTS: On the basis of an intention to treat, 78 cases of AML, including 17 cases of APL, were evaluated. The overall median follow-up was 272 days. The complete remission (CR) rate was 63.6% in the AML group (excluding APL) and 78% in the APL group. The 5-year estimated disease-free survival (DFS) was 80% for the APL group and 34% for the AML group (P = 0.02). The 5-year estimated overall survival (OS) was 52% for the APL group and 20.5% for the AML group, respectively (P = NS). Relapse was observed in 12/39 (30.7%) patients with AML and 1/11 (9%) with APL. CONCLUSIONS: These results are similar to those reported in the literature. However, relapse and mortality rates remain high, and a search for more aggressive strategies in order to prevent relapse is recommended.118617317

High-dose Sequential Chemotherapy Versus A Less Intensive Regimen Followed By Peripheral Blood Autologous Hematopoietic Stem Cell Transplantation As Salvage Treatment In Relapsed And Refractory Hodgkin's Disease

Background and Objective. High-dose sequential chemotherapy (HDS) has been given to patients with Hodgkin's disease (HD) before autologous hematopoietic stem cell transplantation (HSCT), but its effectiveness has not been evaluated in comparison with less-aggressive regimens. In this study we compared HDS with a less-aggressive regimen as preparation to autologous HSCT in patients with HD. Design and Methods. Retrospective non-randomized comparison between patients receiving HDS (group 1, n=52) or a less-aggressive regimen (group 2, n=60). HDS consisted of the sequential administration of cyclophosphamide (7 g/m 2) and G-CSF (300 μg/day) with stem cell collection, methotrexate (8 g/m2) plus vincristine (1.4 mg/m2), and etoposide (2 g/m2). Group 2 patients received of 2 cycles of DHAP, followed by cyclophosphamide (1.5 g/m2) plus G-CSF and stem cell collection. Results. Group 1 patients were more likely to have stage IV (40% vs. 13%, p=0.001) and bulky disease (62% vs. 39%, p=0.02) at diagnosis. Disease status after chemotherapy improved in 59% in group 1 and 8% in group 2 (p&lt;0.001), mostly in patients with disease progression (DP): 50% in group 1 (4 CR and 12 PR) and none in group 2 (p&lt;0.001). Treatment-related toxicity occurred in 5/32 patients with DP in group 1, and 0/28 patients in group 2 (p=0.01). Overall survival was 49% in group 1 and 59% in group 2 (p=0.098). Interpretation and Conclusions. HDS seems to be useful in patients with DP, whereas patients with CR do well with less-intensive chemotherapy.278185Canellos, G.P., Anderson, J.R., Propert, K.J., Nissen, N., Cooper, M.R., Henderson, E.S., Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD (1992) N Engl J Med, 327, pp. 1478-1484Connors, J.M., State-of-the-art therapeutics: Hodgkin's lymphoma (2005) J Clin Oncol, 23, pp. 6400-6408Lister, T.A., Crowther, D., Sutcliffe, S.B., Glatstein, E., Canellos, G.P., Young, R.C., Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting (1989) J Clin Oncol, 7, pp. 1630-1636Hasenclever, D., Diehl, V., A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease (1998) N Engl J Med, 339, pp. 1506-1514Loureiro, M., Morais, J.C., Milito, C.B., Portugal, R.D., Pulcheri, W., Spector, N., Expression of Epstein-Barr virus in patients with Hodgkin's disease: Report of 64 cases from Rio de Janeiro, Brazil (2004) J Bras Patol Med Lab, 40, pp. 37-40de Souza, C.A., Vassallo, J., Lorand-Metze, I., Hodgkin's disease in Brazil: A clinicopathologic study (1997) Haematologica, 82, pp. 127-128Spector, N., Nucci, M., Oliveira De Morais, J.C., Maiolino, A., Portugal, R.D., Costa, M.A., Clinical factors predictive of bone marrow involvement in Hodgkin's disease (1997) Leuk Lymphoma, 26, pp. 171-176Canellos, G.P., Niedzwiecki, D., Long-term follow-up of Hodgkin's disease trial (2002) N Engl J Med, 346, pp. 1417-1418Spector, N., Costa, M.A., Morais, J.C., Biasoli, I., Solza, C., De Fatima, G.M., Intensified ABVP chemotherapy for the primary treatment of Hodgkin's disease (2002) Oncol Rep, 9, pp. 439-442Linch, D.C., Winfield, D., Goldstone, A.H., Moir, D., Hancock, B., McMillan, A., Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: Results of a BNLI randomised trial (1993) Lancet, 341, pp. 1051-1054Schmitz, N., Pfistner, B., Sextro, M., Sieber, M., Carella, A.M., Haenel, M., Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: A randomised trial (2002) Lancet, 359, pp. 2065-2071Reece, D.E., Hematopoietic stem cell transplantation in Hodgkin disease (2002) Curr Opin Oncol, 14, pp. 165-170Baldissera, R.C., Aranha, J.F., Oliveira, G.B., Vigorito, A.C., Eid, K.A., Miranda, E.C., High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma (2002) Braz J Med Biol Res, 35, pp. 49-57Ferme, C., Mounier, N., Divine, M., Brice, P., Stamatoullas, A., Reman, O., Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: Results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial (2002) J Clin Oncol, 20, pp. 467-475Tarella, C., Cuttica, A., Vitolo, U., Liberati, M., Di, N.M., Cortelazzo, S., High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: A multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence (2003) Cancer, 97, pp. 2748-2759Josting, A., Rudolph, C., Mapara, M., Glossmann, J.P., Sienawski, M., Sieber, M., Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: Results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG) (2005) Ann Oncol, 16, pp. 116-123Josting, A., Autologous transplantation in relapsed and refractory Hodgkin's disease (2005) Eur J Haematol Suppl, 66, pp. 141-14

Establishment and validation of analytical reference panels for the standardization of quantitative BCR-ABL1 measurements on the international scale

Background: Current guidelines for managing Philadelphia-positive chronic myeloid leukemia include monitoring the expression of the BCR-ABL1 (breakpoint cluster region/c-abl oncogene 1, non-receptor tyrosine kinase) fusion gene by quantitative reverse-transcription PCR (RT-qPCR). Our goal was to establish and validate reference panels to mitigate the interlaboratory imprecision of quantitative BCR-ABL1 measurements and to facilitate global standardization on the international scale (IS). Methods: Four-level secondary reference panels were manufactured under controlled and validated processes with synthetic Armored RNA Quant molecules (Asuragen) calibrated to reference standards from the WHO and the NIST. Performance was evaluated in IS reference laboratories and with non–IS-standardized RT-qPCR methods. Results: For most methods, percent ratios for BCR-ABL1 e13a2 and e14a2 relative to ABL1 or BCR were robust at 4 different levels and linear over 3 logarithms, from 10% to 0.01% on the IS. The intraassay and interassay imprecision was &lt;2-fold overall. Performance was stable across 3 consecutive lots, in multiple laboratories, and over a period of 18 months to date. International field trials demonstrated the commutability of the reagents and their accurate alignment to the IS within the intra- and interlaboratory imprecision values of IS-standardized methods. Conclusions: The synthetic calibrator panels are robust, reproducibly manufactured, analytically calibrated to the WHO primary standards, and compatible with most BCR-ABL1 RT-qPCR assay designs. The broad availability of secondary reference reagents will further facilitate interlaboratory comparative studies and independent quality-assessment programs, which are of paramount importance for worldwide standardization of BCR-ABL1 monitoring results and the optimization of current and new therapeutic approaches for chronic myeloid leukemia. <br/