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1. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview

Author

Baccarani, M, Castagnetti, F, Gugliotta, G, Rosti, G, Soverini, S, Albeer, A, Pfirrmann, M, Bekadja, Ma, Entasoltan, B, Nachi, M, Elghandour, A, El Sorady, M, Abdelfattah, R, El Nahass, Y, Samra, M, Azzazi, M, Elsobki, E, Moussa, M, Fahmy, O, Mattar, M, Shehata, Azmy, Se, (Azmy, E, 9 ), Emad), Bolarinwa, (Bolarinwa, Ra, ( 10 ), Rahman A., Eid, (Eid, S, Samir)( 11, ), Khelif, (Khelif, A, Abderrhaim)( 11, ), Hached, (Hached, F, Farhat)( 11, ), Menif, (Menif, S, Samia)( 12, ), Rahman, (Rahman, H, Hafizur)( 13, ), Huang, (Huang, Xj, Xiaojun)(, 14, 15, ), Jiang, (Jiang, Q, Qian)(, 14, (Ye, Yx, Yuanxin)( 16, ), Zhu, (Zhu, Hl, Huanling)( 16, ), Chen, (Chen, Sn, Suning)( 17, ), Varma, (Varma, N, Neelam)( 18, ), Ganesan, (Ganesan, P, Prasanth)( 19, ), Gundeti, (Gundeti, S, Sadashivudu)( 20, ), Malhotra, (Malhotra, H, Hemant)( 21, ), Radhakrishnan, (Radhakrishnan, Vs, ( 22 ), Vivek S., Kumar, (Kumar, L, Lalit)( 23, ), Sharawat, (Sharawat, Sk, Surender Kumar)( 23, ), Seth, (Seth, T, Tulika)( 24, ), Ausekar, (Ausekar, Bv, ( 25 ), B. V., Balasubramanian, (Balasubramanian, P, Poonkuzhali)( 26, ), Poopak, (Poopak, B, Behzad)(, 27, 28, ), Inokuchi, (Inokuchi, K, Koiti)( 29, ), Kim, (Kim, Dw, Dong-Wook)( 30, ), Kindi, Al, S (Al Kindi, Salam)( 31, ), Mirasol, (Mirasol, A, Angelina)( 32, ), Qari, (Qari, M, Mohammed)( 33, ), Goh, (Goh, Yt, Yeow Tee)( 34, ), Shih, (Shih, Ly, Lee-Yung)(, 35, 36, ), Branford, (Branford, S, Susan)(, 37, 38, ), Lion, (Lion, T, Thomas)( 39, ), Valent, (Valent, P, Peter)( 40, ), Burgstaller, (Burgstaller, S, Sonja)( 41, ), Thaler, (Thaler, J, Joseph)( 41, ), Labar, (Labar, B, Boris)( 42, ), Zadro, (Zadro, R, Renata)( 42, ), Mayer, (Mayer, J, Jiri)(, 43, 44, ), Zackova, (Zackova, D, Daniela)(, 43, Faber, (Faber, E, Edgar)( 45, ), Pallisgaard, (Pallisgaard, N, Niels)( 46, ), Xavier-Mahon, (Xavier-Mahon, F, Francois)( 47, ), Lippert, (Lippert, E, Eric)( 48, ), Cayuela, (Cayuela, Jm, Jean Michel)( 49, ), Rea, (Rea, D, Delphine)( 49, ), Millot, (Millot, F, Frederic)( 50, ), Suttorp, (Suttorp, M, Meinolf)( 51, ), Hochhaus, (Hochhaus, A, Andreas)( 52, ), Niederwieser, (Niederwieser, D, Dietger)( 53, ), Saussele, (Saussele, S, Susanne)( 54, ), Haferlach, (Haferlach, T, Torsten)( 55, ), Jeromine, (Jeromine, S, Sabine)( 55, ), Panayiotidis, (Panayiotidis, P, Panayiotis)(, 56, 57, ), Conneally, (Conneally, E, Eibhlin)( 58, ), Langabeer, (Langabeer, S, Steve)( 58, ), Nagler, (Nagler, A, Arnon)(, 59, 60, ), Rupoli, (Rupoli, S, Serena)( 61, ), Santoro, (Santoro, N, Nicola)( 62, ), Albano, (Albano, F, Francesco)( 63, ), Castagnetti, (Castagnetti, F, Fausto), Ottaviani, (Ottaviani, E, Emanuela)(, 64, 65, ), Rambaldi, (Rambaldi, A, Alessandro)(, 66, 67, ), Stagno, (Stagno, F, Fabio)( 68, ), Molica, (Molica, S, Stefano)( 69, ), Biagiotti, (Biagiotti, C, Caterina)( 70, ), Scappini, (Scappini, B, Barbara)( 70, ), Lemoli, (Lemoli, R, Roberto)( 71, ), Iurlo, (Iurlo, A, Alessandra)(, 72, 73, ), Pungolino, (Pungolino, E, Ester)( 74, ), Menna, (Menna, G, Giuseppe), Pane, (Pane, F, Fabrizio)( 76, ), Gottardi, (Gottardi, E, Enrico)(, 77, 78, ), Rege-Cambrin, (Rege-Cambrin, G, Giovanna)(, 77, Binotto, (Binotto, G, Gianni)( 79, ), Putti, (Putti, Mc, Maria Caterina)( 80, ), Falzetti, (Falzetti, F, Franca)( 81, ), Visani, (Visani, G, Giuseppe)( 82, ), Galimberti, (Galimberti, S, Sara)( 83, ), Musto, (Musto, P, Pellegrino)( 84, ), Abruzzese, (Abruzzese, E, Elisabetta)( 85, ), Breccia, (Breccia, M, Massimo)( 86, ), Giona, (Giona, F, Fiorina)( 86, ), Chiusolo, (Chiusolo, P, Patrizia)( 87, ), Sica, (Sica, S, Simona)( 87, ), Fava, (Fava, C, Carmen)( 88, ), Ferrero, (Ferrero, D, Dario)( 88, ), Tiribelli, (Tiribelli, M, Mario)( 89, ), Bonifacio, (Bonifacio, M, Massimiliano)( 90, ), Griskevicius, (Griskevicius, L, Laimonas)( 91, ), Musteata, (Musteata, V, Vasile)( 92, ), Janssen, (Janssen, J, Jeroen)( 93, ), Prejzner, (Prejzner, W, Witold)( 94, ), Sacha, (Sacha, T, Tomasz)( 95, ), Waclaw, (Waclaw, J, Joanna)( 95, ), Almeida, (Almeida, Am, Antonio Medina)( 96, ), Kulikov, (Kulikov, S, Sergei)( 97, ), Turkina, (Turkina, A, Anna)( 97, ), Bogdanovic, (Bogdanovic, A, Andrija)( 98, ), Zupan, (Zupan, I, Irena)( 99, ), Marce, (Marce, S, Silvia)( 100, ), Cervantes, (Cervantes, F, Francisco)( 101, ), Steegmann, (Steegmann, Jl, Juan Luis)( 102, ), Kotlyarchuk, (Kotlyarchuk, K, Konstyantyn)( 103, ), Milner, (Milner, Bj, ( 104 ), Benedict J., Rose, (Rose, S, Susan)( 105, ), Clench, (Clench, T, Tim)( 106, ), Waits, (Waits, P, Paula)( 107, ), Austin, (Austin, S, Steve)( 108, ), Wickham, (Wickham, C, Caroline)( 109, ), Clark, (Clark, R, Richard)( 110, ), Apperley, (Apperley, J, Jane), Claudiani, (Claudiani, S, Simone)( 111, ), Foroni, (Foroni, L, Letizia)( 111, ), Szydlo, (Szydlo, R, Richard)( 111, ), Burt, (Burt, E, Emma)( 112, ), Bescoby, (Bescoby, R, Ruth)( 113, ), Cork, (Cork, L, Leanne)( 113, ), O'Brien, (O'Brien, S, Stephen)( 113, ), Green, (Green, B, Bethaney)( 114, ), Hawtree, (Hawtree, S, Sarah)( 114, ), Watson, (Watson, M, Mark)( 114, ), Bengio, (Bengio, Rm, Raquel Maria)( 115, ), Larripa, (Larripa, I, Irene)( 115, ), Pavlovsky, (Pavlovsky, C, Carolina)( 116, ), Moiraghi, (Moiraghi, B, Beatriz)( 117, ), Pinna, De, CAR (Requiao de Pinna, Cristiane Almeida)( 118, ), Magalhaes, GHR (Romani Magalhaes, Gustavo Henrique)( 119, ), Pagnano, (Pagnano, K, Katia)( 120, ), Funke, (Funke, V, Vaneuza)( 121, ), Tavares, (Tavares, Rs, Renato Sampaio)( 122, ), Prado, (Prado, A, Adriana)( 123, ), Azevedo, (Azevedo, Aa, Alita Andrade)( 124, ), Fogliatto, (Fogliatto, L, Laura)( 125, ), Bonecker, (Bonecker, S, Simone)( 126, ), Centrone, (Centrone, R, Renato)( 127, ), Moellman, (Moellman, A, Artur)( 128, ), Conchon, (Conchon, M, Monika)( 130, ), Centurion, (Centurion, Me, Maria Elida)( 131, ), (Prado, Ai, Ana-Ines)( 132, ), Lopez, (Lopez, Jl, ( 133 ), J. L., Petruzziello, (Petruzziello, F, Fara)( 75, ), Bendit, (Bendit, I, Israel), Baccarani M., Castagnetti F., Gugliotta G., Rosti G., Soverini S., Albeer A., and Pfirrmann M.

Subjects
Male, 0301 basic medicine, Cancer Research, bcr-abl, Fusion Proteins, bcr-abl, Global Health, 0302 clinical medicine, hemic and lymphatic diseases, 80 and over, Odds Ratio, Prevalence, Age Factor, Chronic, Young adult, Child, MOLECULAR RESPONSE, Leukemic, Aged, 80 and over, Leukemia, Hematology, Gene Expression Regulation, Leukemic, CHRONIC MYELOGENOUS LEUKEMIA, Age Factors, Myeloid leukemia, Middle Aged, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Human, Adult, Transcriptional Activation, medicine.medical_specialty, Adolescent, Immunology, IMATINIB MESYLATE, DENDRITIC CELLS, CML PATIENTS, Young Adult, 03 medical and health sciences, Myelogenous, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, BCR/ABL TRANSCRIPT, Preschool, CYTOGENETIC RESPONSE, Aged, Science & Technology, CHRONIC-PHASE, business.industry, Infant, Newborn, Fusion Proteins, ABL FUSION PROTEINS, P190 BCR-ABL, Infant, 1103 Clinical Sciences, Odds ratio, Newborn, medicine.disease, International BCR-ABL Study Group, Settore MED/15 - MALATTIE DEL SANGUE, 030104 developmental biology, Imatinib mesylate, Gene Expression Regulation, BCR-ABL Positive, business, Chronic myelogenous leukemia
Abstract

There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associatedwith gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.

Published
2019
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2. Clinical characteristics, prognosis and treatment of myelofibrosis patients with severe thrombocytopenia

Author

Hernandez-Boluda, JC, Correa, JG, Alvarez-Larran, A, Ferrer-Marin, F, Raya, JM, Martinez-Lopez, J, Velez, P, Perez-Encinas, M, Estrada, N, Garcia-Gutierrez, V, Fox, ML, Luno, E, Kerguelen, A, Cuevas, B, Duran, MA, Ramirez, MJ, Gomez-Casares, M, Mata-Vazquez, MI, Regadera, A, Pereira, A, Cervantes, F, and Grupo Espanol de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN)

Subjects
Male, medicine.medical_specialty, Disease free survival, myelofibrosis, thrombocytopenia, Gastroenterology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Registries, Myelofibrosis, Survival rate, Aged, treatment, business.industry, Hematology, Middle Aged, bleeding, medicine.disease, Thrombocytopenia, Severe thrombocytopenia, Survival Rate, Primary Myelofibrosis, Spain, 030220 oncology & carcinogenesis, Female, prognosis, business, 030215 immunology
Published
2018

3. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet

Author

Baccarani M, Cortes J, PANE, FABRIZIO, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R, European L.e.u.k.e.m.i.a.N.e.t., Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R, Baccarani, M, Cortes, J, Pane, Fabrizio, Niederwieser, D, Saglio, G, Apperley, J, Cervantes, F, Deininger, M, Gratwohl, A, Guilhot, F, Hochhaus, A, Horowitz, M, Hughes, T, Kantarjian, H, Larson, R, Radich, J, Simonsson, B, Silver, Rt, Goldman, J, Hehlmann, R, and European, L. e. u. k. e. m. i. a. N. e. t.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Time Factors, allogeneic hematopoietic stem cell transplantation, chronic myeloid leukemia, cytogenetics, human, outcome assessment, priority journal, review, surgical risk, treatment failure, treatment outcome, treatment response, Dasatinib, Antineoplastic Agents, Review Article, Drug Administration Schedule, Piperazines, European LeukemiaNet, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, Humans, Transplantation, Homologous, Treatment Failure, Protein Kinase Inhibitors, Gene Expression Regulation, Leukemic, business.industry, alpha interferon, alpha2b interferon, hydroxyurea, imatinib, nilotinib, peginterferon, protein tyrosine kinase inhibitor, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Imatinib, medicine.disease, Europe, Transplantation, Thiazoles, Pyrimidines, Treatment Outcome, Imatinib mesylate, Nilotinib, Benzamides, Immunology, Imatinib Mesylate, Drug Monitoring, business, medicine.drug, Chronic myelogenous leukemia
Abstract

Purpose To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including monitoring, response definition, and first- and second-line therapy. Methods These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008. Results Cytogenetic monitoring was required at 3, 6, 12, and 18 months. Molecular monitoring was required every 3 months. On the basis of the degree and the timing of hematologic, cytogenetic, and molecular results, the response to first-line imatinib was defined as optimal, suboptimal, or failure, and the response to second-generation TKIs was defined as suboptimal or failure. Conclusion Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.

Published
2009

4. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis

Author

Rumi, E, Pietra, D, Pascutto, C, Guglielmelli, P, Martínez Trillos, A, Casetti, I, Colomer, D, Pieri, L, Pratcorona, M, Rotunno, G, Sant'Antonio, E, Bellini, M, Cavalloni, C, Mannarelli, C, Milanesi, C, Boveri, E, Ferretti, V, Astori, C, Rosti, V, Cervantes, F, Barosi, G, Vannucchi, Am, Cazzola, M, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators Collaborators Vannucchi AM, Balliu, M, Bartalucci, N, Biamonte, F, Bisognin, A, Bogani, C, Bortoluzzi, S, Bosi, A, Coppe, A, Fanelli, T, Fjerza, R, Loiacono, I, Marchioli, R, Martinelli, S, Masciulli, A, Pancrazzi, A, Paoli, C, Saccoman, C, Spolverini, A, Susini, Mc, Tozzi, L, Azzan, C, Badalucco, S, Balduini, A, Bonetti, E, Campanelli, R, Catarsi, P, Isgrò, Am, Lupo, Ml, Magrini, U, Massa, M, Poletto, V, Villani, L, Ambaglio, I, Bernasconi, P, Casetti, Ic, Catricalà, S, Elena, C, Fugazza, E, Gall, A, Malcovati, L, Ripamonti, F, Rossi, M, Dejana, E, Breviario, F, Corada, M, Erba, Bg, Rambaldi, A, Amaru, A, Barbui, T, Belotti, C, Boroni, C, Ferrari, Ml, Finazzi, G, Finazzi, Mc, Golay, J, Gritti, G, Salmoiraghi, S, Cilloni, Daniela, Campia, V, Carturan, S, Guerrasio, Angelo, Manfredini, R, Bianchi, E, Salati, S, Tagliafico, E, Tenedini, E, and Zini, R.

Subjects
Oncology, Male, Clinical Trials and Observations, Leukocytosis, DNA Mutational Analysis, Kaplan-Meier Estimate, Biochemistry, Risk Factors, hemic and lymphatic diseases, Aged, 80 and over, Leukemia, biology, Incidence (epidemiology), food and beverages, Anemia, Hematology, Middle Aged, Prognosis, Cell Transformation, Neoplastic, Female, medicine.symptom, Receptors, Thrombopoietin, Adult, medicine.medical_specialty, Adolescent, Immunology, Lower risk, Risk Assessment, Young Adult, Internal medicine, medicine, Humans, Myelofibrosis, Aged, Proportional Hazards Models, business.industry, Proportional hazards model, Cell Biology, Janus Kinase 2, medicine.disease, Thrombocytopenia, Primary Myelofibrosis, Mutation, biology.protein, business, Calreticulin
Abstract

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Published
2014

5. Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms. An European Leukemia Net study

Author

Martinelli, I, De Stefano, Valerio, Carobbio, A, Randi, Ml, Santarossa, C, Rambaldi, A, Finazzi, Mc, Cervantes, F, Arellano Rodrigo, E, Rupoli, S, Canafoglia, L, Tieghi, A, Facchini, L, Betti, Silvia, Vannucchi, Am, Pieri, L, Cacciola, R, Cacciola, E, Cortelezzi, A, Iurlo, A, Pogliani, Em, Elli, Em, Spadea, A, and Barbui, T.

Subjects
Adult, Male, Adolescent, Hormone Replacement Therapy, Comorbidity, Sinus Thrombosis, Contraceptives, Oral, Hormonal, Neoplasms, Multiple Primary, Sinus Thrombosis, Intracranial, Young Adult, Postoperative Complications, Pregnancy, Recurrence, Risk Factors, Hematologic Agents, Humans, Thrombophilia, Philadelphia Chromosome, Aged, Retrospective Studies, Aged, 80 and over, Venous Thrombosis, Myeloproliferative Disorders, Pregnancy Complications, Hematologic, Middle Aged, Intracranial, Settore MED/15 - MALATTIE DEL SANGUE, Italy, Spain, Female, Pulmonary Embolism, Pregnancy Complications, Neoplastic
Abstract

To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN-CVT) to 87 with MPN and other venous thrombosis (group MPN-VT) and 178 with MPN and no thrombosis (group MPN-NoT) matched by sex, age at diagnosis of MPN (±5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN-CVT and MPN-VT than in MPN-NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN-VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow-up period (6.1 vs. 10.3 years, P = 0.019), a higher long-term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN-CVT than in MPN-VT group (8.8% and 4.2% patient-years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05-3.72 and 2.09, 1.09-4.00, respectively).

Published
2014

6. FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis

Author

Desterke, C., Bilhou-Nabera, C., Guerton, B., Martinaud, C., Tonetti, C., Clay, D., Guglielmelli, P., Vannucchi, A., Bordessoule, D., Hasselbalch, H., Dupriez, B., Benzoubir, N., Bourgeade, M.F., Pierre-Louis, O., Lazar, V., Vainchenker, W., Bennaceur-Griscelli, A., Gisslinger, H., Giraudier, S., Le Bousse-Kerdiles, M.C., Bourhis, J.H., de Botton, S., Briere, J., Demory, J.L., Fenaux, P., Kiladjian, J.J., Pasquet, J.M., Lippert, E., Praloran, V., Morel, P., Rey, J., Roy, L., Viallard, J.F., Barosi, G., Cervantes, F., Griesshammer, M., Kreipe, H., Kvasnicka, H.M., Kušec, Rajko, Marchetti, M., Merup, M., Pahl, H., Palmblad, J., Reilly, J.T., Skoda, R., and Thiele, J.

Subjects
MAPK/ERK pathway, Cancer Research, Stromal cell, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, myelofibrosis, FLT3, MAPK, megakaryocytes, Antigens, CD34, Biology, p38 Mitogen-Activated Protein Kinases, Downregulation and upregulation, hemic and lymphatic diseases, Humans, Phosphorylation, Protein kinase A, FLT3, p38-MAPK, primary myelofibrosis, cancer, Megakaryopoiesis, Membrane Proteins, Hematopoietic Stem Cells, Enzyme Activation, Haematopoiesis, fms-Like Tyrosine Kinase 3, Oncology, Primary Myelofibrosis, Trk receptor, Leukocytes, Mononuclear, Cancer research, Mitogen-Activated Protein Kinases, Stromal Cells, Megakaryocytes
Abstract

Primary myelofibrosis (PMF) is characterized by increased number of hematopoietic progenitors and a dysmegakaryopoiesis which supports the stromal reaction defining this disease. We showed that increased ligand (FL) levels in plasma, hematopoietic progenitors, and stromal cells from PMF patients were associated with upregulation of the cognate Flt3 receptor on megakaryocytic (MK) cells. This connection prompted us to study a functional role for the FL/Flt3 couple in PMF dysmegakaryopoiesis, as a route to reveal insights into pathobiology and therapy in this disease. Analysis of PMF CD34+ and MK cell transcriptomes revealed deregulation of the mitogen-activated protein kinase (MAPK) pathway along with Flt3 expression. In PMF patients, a higher proportion of circulating Flt3+CD34+CD41+ cells exhibited an increased MAPK effector phosphorylation independently of Jak2V617F mutation. Activation of FL/Flt3 axis in PMF MK cell cultures, in response to FL, induced activation of the p38–MAPK cascade, which is known to be involved in inflammation, also increasing expression of its target genes (NFATC4, p53, AP-1, IL-8). Inhibiting Flt3 or MAPK or especially p38 by chemical, antibody, or silencing strategies restored megakaryopoiesis and reduced phosphorylation of Flt3 and p38 pathway effectors, confirming the involvement of Flt3 in PMF dysmegakaryopoiesis via p38 activation. In addition, in contrast to healthy donors, MK cells derived from PMF CD34+ cells exhibited an FL-induced migration that could be reversed by p38 inhibition. Taken together, our results implicate the FL/Flt3 ligand–receptor complex in PMF dysmegakaryopoiesis through persistent p38–MAPK activation, with implications for therapeutic prospects to correct altered megakaryopoiesis in an inflammatory context. Cancer Res; 71(8); 2901–15. ©2011 AACR.

Published
2011
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7. Is polycythemia vera a serious disease in young adults?

Author

Perea G, Remacha A, Besses C, Jiménez M, Lourdes Florensa, and Cervantes F

Subjects
Adult, Male, Adolescent, Age Factors, Humans, Female, Thrombosis, Child, Polycythemia Vera, Severity of Illness Index
Published
2001

8. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study

Author

Guardiola, P, Anderson, J, Bandini, G, Cervantes, F, Runde, V, Arcese, W, Bacigalupo, A, Przepiorka, D, O'Donnell, M, Polchi, P, Buzyn, A, Sutton, L, Cazals Hatem, D, Sale, G, de Witte, T, Deeg, H, and Gluckman, E

Subjects
Homologous, Adult, Male, Transplantation, Time Factors, Histocompatibility Testing, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Survival Analysis, United States, Hematopoiesis, Europe, Primary Myelofibrosis, Multivariate Analysis, Splenectomy, Humans, Female, Erythrocyte Transfusion, Settore MED/15 - Malattie del Sangue, Probability, Transplantation, Homologous, Follow-Up Studies
Published
1999

9. Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis

Author

Esteve J, Cervantes F, Rives S, Maria Rozman, Ma, Zarco, and Montserrat E

Subjects
Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Female, Leukemia, Lymphocytic, Chronic, B-Cell, Polymerase Chain Reaction, Aged, Immunophenotyping, Retrospective Studies
Abstract

The coexistence of chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (CLL) in the same patient is rare. A 71-year-old woman developed a B-lineage lymphoid blast crisis at 18 months after diagnosis of Ph-positive CML. At this time, a lymphoid cell population with morphologic and immunophenotypic features of CLL was demonstrated. The retrospective review of the tests performed at diagnosis and thereafter disclosed the presence of lymphoid nodules in the initial bone marrow biopsy in the absence of lymphocytosis. Subsequently, there was an appearance of moderate lymphocytosis in the following months. Therefore, diagnosis of CML and coexistent CLL was established. Although a transient remission of blast crisis was achieved, blast cells reappeared two months later and the patient died shortly afterwards. Molecular studies of the immunoglobulin heavy chain gene (IH) rearrangement pattern point to the origin of the diseases in two different cell clones. In addition, previously published cases of simultaneous CLL and CML are reviewed.

Published
1997

10. [Occult involvement of bone marrow in Hodgkin's disease: detection with magnetic resonance]

Author

Sanz L, Cervantes F, Jm, Mercader, Maria Rozman, Rozman C, and Montserrat E

Subjects
Adult, Male, Humans, Bone Marrow Diseases, Hodgkin Disease, Magnetic Resonance Imaging
Abstract

Although bone marrow biopsy is considered the best procedure to detect bone marrow involvement by Hodgkin's disease (HD), in recent years several studies have emphasized the value of magnetic resonance imaging (MRI). We present the case of a patient with HD apparently localized in a laterocervical lymph node, who also referred disestasiae at a region corresponding to D10 metamera. Bone marrow biopsy, vertebral TC and 67-Ga scintigraphy were all normal. However, a node of 1 cm in diameter was detected by MRI in the tenth dorsal vertebra. Because of the topographic coincidence between the patient's symptomatology and the MRI findings, the HD was considered to be in advanced stage and CMOPP/ABV chemotherapy was administered, this resulting in a rapid improvement of symptoms and disappearance of the MRI abnormalities. Since in the present case, the MRI determined a change in disease stage and treatment, the role of MRI as a complementary exploration of bone marrow biopsy to detect marrow involvement by HD is reviewed.

Published
1996

11. [Granulocyte abnormal chromatin clumping syndrome: report of a new case and review of the literature]

Author

Esteve J, Cervantes F, Maria Rozman, Lluís Aguilar J, Colomer D, and Rozman C

Subjects
Male, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Syndrome, Chromatin, Aged, Granulocytes
Abstract

Abnormal chromatin clumping syndrome (ACCS) is a rare granulocyte disease halfway between Ph'-negative chronic myelogenous leukaemia (CML) and the myelodysplastic syndromes. A new case of such syndrome is presented, the patient being a 65 year-old man with anaemia, thrombocytopenia and myelaemic leucocytosis with abnormal condensation of the neutrophils' chromatin. Marked granulocytic hyperplasia was present in the bone marrow with strikingly dysplastic features, along with a decrease of the remaining blood cell lines. Irregular nuclear outlines and heterochromatin clumps separated by euchromatin bands were seen in the more mature granulocytes upon ultrastructural studies. No cytogenetic abnormalities were found in the bone marrow, and no ber-abl gene rearrangement was present in white cells from peripheral blood. The clinical course was marked by persistence of the anaemia and increasing leucocytosis which required 6-mercaptopurine treatment. Acute myeloblastic leukaemia occurred one year later and the patient died shortly after. It was concluded, from this case and others reported in the literature, that, with regard to its clinical course and proliferative character, ACCS is closer to Ph'-negative, bcr-abl negative CML rather than to the myelodysplastic syndromes.

Published
1995

12. [Bone marrow transplantation from unrelated donors in chronic myeloid leukemia: the results in 15 patients]

Author

Sierra J, Carreras E, Rovira M, Batlle M, Urbano-Ispizua A, Marín P, Besson I, Merino A, Manuel Algara, and Cervantes F

Subjects
Adult, Male, Adolescent, Graft vs Host Disease, Middle Aged, Combined Modality Therapy, Tissue Donors, Spain, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Transplantation, Homologous, Female, Bone Marrow Transplantation, Follow-Up Studies
Abstract

Bone marrow transplantation (BMT) from a histocompatible donor is the only curative treatment in chronic myeloid leukemia (CML). Only a minority of patients dispose of an adequate donor from among his/her relatives. The remaining transplant receptors must look to unrelated donors (URD). The experience of the Escuela de Hematología Farreras Valentí (Farreras Valentí School of Hematology, Barcelona, Spain) in BMT from URD in CML in the first chronic phase is herein reported.Fifteen patients (9 males and 6 females, median age 33 years; range 14-48 years) were transplanted from October 1988 to May 1994. Serologic identity was expressed in the A, B and D loci in 9 cases and minor incompatibility in 6. Conditioning included total body irradiation and cyclophosphamide in 14 patients and busulphan plus cyclophosphamide in 1. Partial and selective T lymphocyte depletion was performed by elutriation in 7 cases.Primary implant failure was detected in 2 out of 14 risk patients (14%) and secondary failure was observed in 3 out of 12 cases (25%). The actuarial probability of acute graft versus host disease (GVHD) was 55 +/- 15% at 7 weeks with a probability of appearance with an intensity of II-IV of 31 +/- 13%. Five out of 7 patients with a survival of greater than 100 days, developed chronic GVHD (71%). Ten presented fatal complications. In 5 cases, death was due to pulmonary problems. Recurrence of CML was not observed in any of the patients in the series. The probability of disease free survival at 2 years was 30 +/- 12%.Bone marrow transplantation from an unrelated donor is an effective treatment for a proportion of patients with chronic myeloid leukemia although severe complications are frequent and originate a high mortality.

Published
1995

13. Neutrophilic pustulosis associated with chronic myeloid leukemia: a special form of Sweet's syndrome. Report of two cases

Author

Feliu E, Cervantes F, Ferrando J, Susana Puig, Jm, Mascaro, and Rozman C

Subjects
Male, Neutrophils, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Prednisone, Female, Middle Aged, Cyclophosphamide, Sweet Syndrome
Abstract

Two subjects with Ph-positive chronic myeloid leukemia (CML) in whom pustular Sweet's syndrome was diagnosed are reported. The first patient was a 47-year-old woman who developed fever, painful ulcers of the oral mucosa and vagina and generalized pustulous skin lesions 2 years after the diagnosis of CML. Histologically, the skin lesions consisted of dense neutrophilic infiltrates with perifollicular disposition. The microbiologic studies were negative. The lesions showed a favorable response to corticosteroids, but fever recurred with every attempt of tapering prednisone; it finally disappeared with the addition of oral cyclophosphamide. The second patient was a 45-year-old man who developed fever and disseminated pustules with histologic features consistent with Sweet's syndrome and negative microbiologic studies at 2.5 years after diagnosis of CML. The picture showed a dramatic response to prednisone and did not recur after the drug was discontinued. In both patients, CML remained stable after resolution of Sweet's syndrome.

Published
1992

14. [Blast crisis of chronic myeloid leukemia with positive Philadelphia chromosome: course and clinico-hematologic profile in 80 patients]

Author

Cervantes F, Maria Rozman, Salgado C, Jl, Vives-Corrons, Montserrat E, and Rozman C

Subjects
Male, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Female, Middle Aged, Blast Crisis
Abstract

The major initial clinical, hematological and cytogenetical features of a series of 80 patients with blastic crisis (BC) in chronic myelocytic leukemia with positive Philadelphia chromosome (Ph) were evaluated, and also were their outcome and response to therapy. Mean age of patients was 45 years (SD: 14.3). Ten patients fulfilled the criteria for initial BC, and 14 had extramedullary blastic infiltration. In one third there was an acceleration phase before the development of BC. The mean leukocyte count was 69 (SD 75) X 10(9)/l. In 40% there was anemia with hemoglobin less than 90 g/l, and 37.5% had thrombopenia with less than 100 X 10(9) cells/l. In most patients, serum lactic dehydrogenase activity was increased, and in one fourth the index of granulocyte alkaline phosphatase was high. In 9 patients, blast cells had a lymphoid phenotype and in 47 (59%) cytogenetic abnormalities in addition to Ph chromosome were found, usually consisting of 8 trisomy, duplication of Ph chromosome, and the presence of a 17q isochromosome. The median survival of the series was 4.8 months. When analyzed as a time-dependent variable, the achievement of a favorable therapeutic response (found in 26% of patients) was associated with a longer survival.

Published
1990

15. Low-dose vincristine in the treatment of corticosteroid-refractory idiopathic thrombocytopenic purpura (ITP) in non-splenectomized patients

Author

E. Feliu, Cervantes F, C. Diumenjo, Emili Montserrat, A. Grañena, and Rozman C

Subjects
Adult, Male, medicine.medical_specialty, Vincristine, Adolescent, medicine.drug_class, idiopathic thrombocytopenic purpura (ITP), medicine.medical_treatment, Splenectomy, Remission, Spontaneous, Drug Resistance, Spontaneous remission, Drug Administration Schedule, Refractory, immune system diseases, Adrenal Cortex Hormones, hemic and lymphatic diseases, medicine, Humans, business.industry, Low dose, General Medicine, Middle Aged, medicine.disease, Thrombocytopenic purpura, Surgery, Purpura, Thrombocytopenic, Corticosteroid, Female, business, medicine.drug, Research Article
Abstract

Eight non-splenectomized patients with corticosteroid-refractory idiopathic thrombocytopenic purpura (ITP) were treated with low-dose vincristine (1 mg/week up to a total dose of 4 mg). Complete remission was achieved in 2 cases and partial remission in 3. Bleeding stopped in one patient who failed to remit. No statistical relationship was found between the response to vincristine and the duration of the disease or the corticosteroid-therapy. Side effects were only observed in one patient. By comparing these results with those reported in the literature, it can be inferred that low-dose vincristine may be useful in the management of corticosteroid-refractory ITP.

Published
1980

16. [Analysis of response to treatment. Considerations on changing prognostic variables (time-dependent)]

Author

Rozman C, Montserrat E, Maria Rozman, Bladé J, and Cervantes F

Subjects
Biometry, Time Factors, Humans, Therapeutics, Mortality, Prognosis
Abstract

In the prognostic evaluations the initial variables, obtained at the time of diagnosis, and the evolutive or time-dependent variables, that appear during the course of the disease, should be clearly differentiated. If this separation is not strictly maintained inaccurate results may be obtained. The errors resulting from the use of an inappropriate methodology are illustrated in the present article on the basis of two series of patients. On the other hand, the advantages and shortcomings of alternative methods, which are valid for prognostic studies with evolutive or time-dependent variables, are discussed. Finally, recommendations are given for the particular instance where the response to therapy in a therapeutic trial is being assessed.

Published
1989

18. [Treatment with CEP (CCNU, VP-16 and prednimustine) in Hodgkin's disease resistant to CVPP and ABVD. Results in 21 patients]

Author

Cervantes F, Joan Carles Reverter, Bladé J, Montserrat E, and Rozman C

Subjects
Adult, Male, Prednimustine, Adolescent, Middle Aged, Vinblastine, Hodgkin Disease, Dacarbazine, Bleomycin, Doxorubicin, Lomustine, Vincristine, Procarbazine, Antineoplastic Combined Chemotherapy Protocols, Drug Evaluation, Humans, Prednisone, Female, Child, Etoposide
Published
1988

20. [Erythroblastopenia associated with chronic myelomonocytic leukemia]

Author

López-Guillermo A, Cervantes F, Jm, Ribera, Feliu E, Lourdes Florensa, and Rozman C

Subjects
Male, Erythroblasts, Bone Marrow, Mercaptopurine, Humans, Prednisone, Anemia, Leukemia, Myelomonocytic, Chronic, Aged
Abstract

A patient is presented in whom the diagnoses of chronic myelomonocytic leukaemia (CMML) and erythroblastopenia were simultaneously established. Besides the conventional criteria for both haemopathies, the culture of bone-marrow precursor cells showed lack of growth of the erythroid stem cells. 6-Mercaptopurine given as therapy for CMML failed to induce any favourable changes in erythroblastopenia, which in turn improved with prednisone. Nevertheless, the patients died five months after diagnosis due to acute transformation of the CMML.

21. The changing profile of Ph-positive chronic myeloid leukemia at presentation: possible impact of earlier diagnosis on survival

Author

Cervantes F, Jc, Hernández-Boluda, Ferrer A, Joan Cid, and Montserrat E

Subjects
Adult, Male, Time Factors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Female, Middle Aged, Survival Analysis, Aged
Abstract

Although there are indications that the profile of chronic myeloid leukemia (CML) at presentation has changed in recent years, information is scarce. The objective of the present study was to ascertain whether the initial features of CML have changed over time, as well as the possible impact on survival.The initial features of 167 patients diagnosed with chronic phase Ph-positive CML from 1972 to 1985 were compared with those of 174 such patients diagnosed at the same institution from 1985 to 1998. The survival of the two groups was also compared.CML patients diagnosed since 1985 were significantly older at presentation (mean age 47+17 vs 43+17 years, p = 0.04), were more often asymptomatic (36% vs 19%, p = 0.0003), less often had constitutional symptoms (30% vs 45%, p = 0.004), less frequently had splenomegaly (59% vs 75%, p = 0.0008) and hepatomegaly (35% vs 49%, p = 0.01), had less marked leukocytosis (mean WBC count 139+/-124x10(9)/L vs 179+/-132x10(9)/L, p = 0.007), with 30% of them showing an initial WBC count below 50x10(9)/L (vs 19%, p = 0.02), and showed less marrow blast cell infiltration (p = 0.0003). No significant differences were observed in the distribution by Sokal's risk groups. Median survival of patients diagnosed since 1985 was 5. 33 years (95% CI: 4.3-6.36), vs 4.06 years (95% CI: 3.28-4.84) for patients diagnosed before (p = 0.07). Finally, patients asymptomatic at diagnosis had a longer survival (median survival 5.7 years, 95% CI: 4.5-6.9, vs 4.1 years, 95% CI: 3.4-4.7, p = 0.03).A substantial proportion of CML patients are currently diagnosed early in the course of the disease. The effect of earlier diagnosis on survival prolongation in such patients should be taken into account.

22. [Granulocyte alkaline phosphatase activity in the chronic phase and blastic crisis of chronic myeloid leukemia. Sequential study of 43 patients]

Author

Bosch F, Cervantes F, Maria Rozman, Mj, Terol, Montserrat E, and Rozman C

Subjects
Adult, Male, Adolescent, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Female, Middle Aged, Alkaline Phosphatase, Blast Crisis, Aged, Granulocytes
Abstract

To evaluate in a sequential fashion the activity of the leukocyte alkaline phosphatase (LAP) in the chronic phase and the blastic crisis of chronic myelogenous leukaemia (CML).This study is comprised of 43 patients diagnosed of CML according to standard criteria. The initial LAP scores were compared with those recorded in the blastic crisis, using cytochemical methods. The statistical analysis was performed with Student's test and chi-square.The LAP activity at diagnosis was low in 40 of the 43 cases (93%), the score being 0 in 20 instances. In the blastic crisis low scores were found in 27 patients (63%), while LAP activity appeared normal or increased in 16 others (37%). When the LAP scores of the two phases of the disease were compared the differences were found statistically significant (p less than 0.0001 and p less than 0.0007, respectively).These results confirm that the onset of the blastic crisis of CML is often accompanied by an increase of the LAP activity, although this last persists low in the majority of the patients.

24. Sequential study of myeloid differentiation antigens of neutrophil granulocytes in different phases of chronic myeloid leukaemia: natural history and prognostic significance

Author

Rozman, M., Cervantes, F., Urbano-Ispizua, A., Evarist Feliu Frasnedo, Vives-Corrons, J. -L, and Rozman, C.

Subjects
Adult, Male, Time Factors, Neutrophils, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Chronic-Phase, Antigens, Differentiation, Myelomonocytic, Humans, Female, Leukemia, Myeloid, Accelerated Phase, Prognosis, Survival Analysis
Abstract

In an attempt to contribute to the knowledge of the natural history of Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) and its prognosis, we analyzed sequentially the myeloid differentiation antigens of peripheral blood neutrophil granulocytes (NG) in different evolutive stages of the disease. Four monoclonal antibodies (CD15, CD24, 31D8, and 13F6) were used, and a total number of 116 sequential studies were performed in 43 patients. At diagnosis, there is a significant decrease of NG expressing myeloid differentiation antigens, which recover to nearly normal levels after initial control of the disease. The onset reduction is probably due to the circulation of incompletely mature NG. In accelerated/blastic phase NG expressing myeloid differentiation antigens decrease again, probably due to a true antigen loss. This reduction could herald by a few months the development of accelerated/blastic phase. In such a case, its predictive strength is higher than that of the well recognized initial prognostic parameters in CML. These results indicate that the sequential study of NG myeloid differentiation antigens may contribute to both a better understanding of the natural history of CML and the evolutive prognosis of this disease.

25. [Treatment with cyclosporin A of the anemia associated with chronic lymphatic leukemia]

Author

Maria Rozman, Montserrat E, Cervantes F, Bladé J, Marín P, and Rozman C

Subjects
Adult, Male, Anemia, Cyclosporins, Middle Aged, Red-Cell Aplasia, Pure, Leukemia, Lymphocytic, Chronic, B-Cell, T-Lymphocytes, Regulatory, Thrombocytopenia, Antineoplastic Combined Chemotherapy Protocols, Humans, Chlorambucil, Erythropoiesis, Female, Vidarabine, Aged
Abstract

The anaemia accompanying chronic lymphocytic leukaemia (CLL) may have different causes (bone marrow infiltration, hypersplenism, immune haemolysis, haemorrhages) and is one of the poor-prognosis features of the disease. Treatment of advanced CLL patients with tumoral-infiltrative anaemia is based on chemotherapy. Nevertheless, some proofs seem to stress the important role played by suppressor T cells on the mechanism of the anaemia in such patients. As a result of these observations, cyclosporin A, a drug with proven efficacy in autoimmune diseases and bone marrow insufficiency, is being used in these cases. Three patients with advanced B-CLL and anaemia, refractory to treatment, received cyclosporin A (8-10 mg/kg, p.o. daily for 2-4 months). One of them recovered from anaemia and thrombocytopenia and is still in this situation after 11 months of suppression of therapy. Two other such cases are revised from the literature, as well as the role played by cyclosporin A in the therapy of CLL.

26. [Chronic myelomonocytic leukemia and solid neoplasms: is it a causal or a fortuitous association?]

Author

Rovira M, Cervantes F, Miquel Lozano, Jm, Ribera, Jc, Reverter, and Rozman C

Subjects
Aged, 80 and over, Male, Neoplasms, Multiple Primary, Neoplasms, Humans, Leukemia, Myelomonocytic, Chronic, Aged
Abstract

Out of a series of 36 patients with chronic myelomonocytic leukaemia (CMML), five cases are reported with the association of this hemopathy to solid neoplasms. In two patients this last was a cutaneous tumour, while the remainders had, respectively, papilloma of the bladder, carcinoma of the sigma, and cutaneous T-cell lymphoma. These neoplasms were diagnosed in all cases prior to the discovery of CMML. When applying the "patient/year" method, significantly higher frequency of solid tumours was found for CMML patients, which would support the hypothesis that this myelodysplasia could be regarded as a paraneoplastic condition.

27. [Laparoscopic splenectomy as an alternative to open surgery in the treatment of autoimmune thrombocytopenia]

Author

Jj, Espert, Eduardo m Targarona, Cervantes F, Bombuy E, Rives S, Balagué C, Perales M, Nomdedeu B, Montserrat E, and Trias M

Subjects
Adult, Male, Purpura, Thrombocytopenic, Idiopathic, Treatment Outcome, Splenectomy, Humans, Female, Laparoscopy, Middle Aged
Abstract

Several studies have shown the potential advantages laparoscopic splenectomy (LS) over open surgery. The aim of this study has been to evaluate the advantages of LS over open surgery in the treatment of autoimmune thrombocytopenia.54 consecutive patients splenectomized for the treatment of idiopathic thrombocytopenic purpura (ITP) or HIV-related thrombocytopenia were analyzed. Operative features (operative time, conversion to open surgery, accessory spleens), immediate (stay, analgesia and blood transfusion requirements) and late postoperative features (platelet count), as well as splenectomy-related complications in both surgical procedures were compared.Between February 1990 and February 1997, 54 splenctomies were performed for the treatment of autoimmune thrombocytopenia (ITP, n = 47, and HIV-related thrombocytopenia, n = 7). Eighteen were performed through an open approach, and 36 by laparoscopy. Both groups were comparable with regard to age, sex, platelet count, disease duration and body mass index. LS was completed in 34 cases (conversion to open surgery: 5.5%). The incidence of accessory spleens was 11% in the LS group and 5.5% in the open surgery group. Postoperative morbidity (16% vs 28%) and blood requirements (25% vs 33%) were lower after LS, but the differences did not reach statistical significance. Analgesia requirements (7 [SD 3] vs 11 [6]; p0.01) and postoperative stay (3.8 [2.6] vs 7.4 [3] days; p0.01) were significantly shorter after LS. Following splenectomy, the platelet counts became normal in 72% of patients submitted to LS and 78% of patients in the open surgery group. After 20 and 63 months mean follow-up, one patient in each group developed late complications.As compared to open surgery, LS offers a better immediate clinical outcome, with similar long-term results.

28. [Hemopoietic progenitor cell transplantation: 20 years' experience at the Hematology School 'Farreras-Valenti'/Clinical Hospital of Barcelona]

Author

Rozman C, Carreras E, Sierra J, Rovira M, Urbano-Ispizua A, Marín P, Bladé J, Cervantes F, López-Guillermo A, Nomdedeu B, Maria Rozman, Jl, Aguilar, Jl, Vives-Corrons, Mazzara R, Ordinas A, Jm, Ribera, Feliu E, Castillo R, Grañena A, and Montserrat E

Subjects
Adult, Survival Rate, Time Factors, Adolescent, Actuarial Analysis, Spain, Child, Preschool, Hematopoietic Stem Cell Transplantation, Humans, Middle Aged, Child
Abstract

Hemopoietic progenitor cell transplantation (HPCT) is acquiring an increasing role in the therapy for a variety of disorders. In this study, main characteristics and results of HPCT along 20 years are analyzed from the experience of Postgraduate School of Hematology "Farreras-Valentí" at the Hospital Clínic in Barcelona.Six-hundred ninety-five patients transplanted between June 1976 and January 1996 were analyzed. Median age (range) were 33 (4-63) years. The following aspects were considered: donor type, source or progenitor cells, type of disease and disease-stage at transplantation, transplant related mortality and survival.A total of 714 HPCT were performed (448 allogeneic, 13 isogeneic, 253 autogeneic). Allogeneic HPCT were from an HLA-identical sibling in 408 cases, from other familial donors in 10, and from non-familial donors in 30. Most HPCT from non-familial donors (93%) were performed during the last five years of the study (1991-1995). The source of hemopoietic progenitor cells was bone marrow in 625 instances (88%), peripheral blood in 88 (12%), and fetal liver in one. During more than 15 years, the only source of progenitors was the bone marrow; in contrast, in the last 3 years (1993-1995) transplants using peripheral blood were predominant. Main indications for HPCT were the following: acute leukemias (n = 387) (54%), chronic leukemias (n = 134) (19%), severe aplastic anemia (n = 58) (8%), lymphomas (n = 80) (11%), multiple myeloma (n = 39) (5%) and myelodysplastic syndromes (n = 14) (2%). In patients with hematological malignancies (n = 656), HPCT was performed in first complete remission or in first chronic phase in 321 instances (49%), in subsequent remissions in 144 (22%), and in more advanced stages in the remaining 191 (29%). In the more recent years, a progressive decrease in the number of HPCT for acute leukemia or aplastic anemia was observed, contrasting with an increase in transplants for lymphoma, multiple myeloma and myelodysplastic syndromes. Of note, a significant decrease in transplant related mortality was evident along the years, both after autogeneic HPCT (21% during 1985-1992 and 6% thereafter) (p = 0.001) and after allogeneic transplantation (54%, 44%, and 20% during the periods 1976-1984, 1985-1992 and 1993-1995, respectively) (p = 0.004). The fact translated into an increase in the actuarial probability of survival after allogeneic HPCT (25%, 33% and 58% in the three mentioned periods, respectively) (p = 0.0003), and after autogeneic HPCT (33% in the interim 1985-1992, and 55% in the period 1993-1995) (p = 0.001).During the last 20 years, HPCT has significantly evolved in aspects such as type of donor, source of progenitor cells and indications. Remarkably, a progressive decrease in transplant related mortality has been observed translating into a improvement in survival after the procedure.

29. Treatment of advanced resistant Hodgkin's disease with lomustine, etoposide, and prednimustine

Author

Cervantes F, Joan Carles Reverter, Montserrat E, and Rozman C

Subjects
Adult, Prednimustine, Adolescent, Lomustine, Antineoplastic Combined Chemotherapy Protocols, Humans, Middle Aged, Child, Hodgkin Disease, Etoposide, Neoplasm Staging
Abstract

Fifteen patients with Hodgkin's disease resistant to the chemotherapy combinations of cyclophosphamide, vinblastine, procarbazine and prednisone and doxorubicin, bleomycin, vinblastine, and dacarbazine were treated with lomustine, etoposide, and prednimustine. Four of them achieved complete remission and two achieved partial remission (overall response rate, 40%). The median duration of response was 5.5 months, with two complete responders relapsing at 4 and 17 months and the other two remaining disease-free at 7 and 18 months, whereas disease progression was observed at 2.5 and 6 months in the partial responders. Extrahematological toxicity was scarce. Severe myelosuppression was observed in only three patients. These results indicate that lomustine, etoposide, and prednimustine can play a role in the treatment of advanced resistant Hodgkin's disease.

30. [Extramedullary blast crisis in chronic myeloid leukemia]

Author

Cervantes F, Maria Rozman, Jm, Nicolás, López Guillermo A, and Rozman C

Subjects
Adult, Male, Brain Neoplasms, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Periosteum, Meningeal Neoplasms, Humans, Female, Lymph Nodes, Middle Aged, Blast Crisis
Abstract

Out of 113 cases of blastic crisis (BC) of Ph'-positive chronic myeloid leukaemia (CML), 13 had extramedullary involvement, this being the first BC manifestation in 5 instances. The median interval between extramedullary BC and bone marrow BC in these last was 2 months. Lymph nodes were the commonest extramedullary site of BC (8 cases), followed by osteoperiosteal and central nervous system (CNS). Lymph node BC occurred as generalised lymphadenopathy in most cases. Osteoperiosteal BC was seen as severe bone pain on osteolytic areas, whereas CNS blast crisis occurred as meningeal leukaemia in one case and chloroma in another. Lymphoid phenotype of blast cells was found in only 2 instances. The median survival of the patients after the onset of extramedullary involvement was 3 months.

31. [Neoplasms associated with chronic lymphatic leukemia. Incidence and characteristics in a series of 232 patients]

Author

López-Guillermo A, Joan Carles Reverter, Cervantes F, Viñolas N, Rovira M, Urbano-Ispizua A, Montserrat E, and Rozman C

Subjects
Adult, Aged, 80 and over, Male, Time Factors, Middle Aged, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Sex Factors, Actuarial Analysis, Risk Factors, Neoplasms, Humans, Chlorambucil, Female, Cyclophosphamide, Aged
Abstract

The frequency and features of associated neoplastic diseases and their impact on survival were evaluated in a series of 232 patients with chronic lymphocytic leukemia (CLL) who had been diagnosed during an 18 year period. Thirty-two patients (13.8%) had overall 38 neoplasias, 27 of which were diagnosed after CLL. There were no significant differences in the initial clinical and hematological features of the patients depending on whether they had or not a second neoplastic disease or on the time of its development. When compared with the normal population of similar age and sex, the patients with CLL, particularly females, had and increased risk to develop other tumors. The actuarial analysis showed that the risk of developing associated tumors increased through time up to 36% nine years after the diagnosis (27% when skin neoplasias were excluded). Although differences in survival were not found between patients with CLL and associated tumor and the rest of the series, most patients with noncutaneous neoplasia died as a direct consequence of it 18 months after its diagnosis.

32. Ph-positive chronic myeloid leukemia mimicking essential thrombocythemia and terminating into megakaryoblastic blast crisis: report of two cases with molecular studies

Author

Cervantes F, Urbano-Ispizua A, Villamor N, Feliu E, Milla F, Lopez-Guillermo A, Jm, Ribera, Isabel Granada, Jl, Vives-Corrons, and Montserrat E

Subjects
Diagnosis, Differential, Male, Bone Marrow, Biopsy, Karyotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Female, Middle Aged, Blast Crisis, Megakaryocytes, Thrombocytopenia, Aged
Abstract

Two patients with chronic myeloid leukemia (CML) presenting with the hematologic features of essential thrombocythemia (ET) are reported. At diagnosis they showed extremely high platelet counts (4985 and 2800 x 10(9)/l, respectively) and moderate leukocytosis (21 and 17 x 10(9)/l, respectively). In both cases, in addition to the Philadelphia chromosome (Ph), a rearrangement within the major breakpoint cluster region on chromosome 22 was demonstrated, with the breakpoint in the 3' extreme. In patient 1 the disease initially responded to radioactive phosphorus and hydroxyurea, but during the evolutive course a progressive increase in the white blood cell counts was noted, reaching values typical of the chronic phase of CML, and the patient eventually died from blast crisis 45 months after diagnosis. In patient 2, although good control of the platelet counts was achieved with hydroxyurea, the disease also evolved into a blast crisis four months after diagnosis. In both cases monoclonal antibodies and electron microscopy studies demonstrated the megakaryocytic nature of the blast cells. The above features are not consistent with the present and similar cases being Ph-positive ET. Instead, they should be regarded as a special form of CML characterized by a marked protagonism of the megakaryocytic component.

33. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

Author

Simona Soverini, Jeffrey H. Lipton, Richard A. Larson, Dietger Niederwieser, Andrey Zaritskey, Fabrizio Pane, Francois-Xavier Mahon, Jeroen Janssen, Richard E. Clark, François Guilhot, Juan Luis Steegmann, Jerald P. Radich, Michael W. Deininger, Andreas Hochhaus, Richard T. Silver, Susanne Saußele, Johan Richter, Timothy P. Hughes, Jane F. Apperley, Jiří Mayer, Henrik Hjorth-Hansen, Hagop M. Kantarjian, Jorge E. Cortes, Anna G. Turkina, Michele Baccarani, Gianantonio Rosti, Franck E. Nicolini, Philippe Rousselot, Giuseppe Saglio, Delphine Rea, Dong-Wook Kim, Ruediger Hehlmann, Charles A. Schiffer, Francisco Cervantes, Hochhaus A., Baccarani M., Silver R.T., Schiffer C., Apperley J.F., Cervantes F., Clark R.E., Cortes J.E., Deininger M.W., Guilhot F., Hjorth-Hansen H., Hughes T.P., Janssen J.J.W.M., Kantarjian H.M., Kim D.W., Larson R.A., Lipton J.H., Mahon F.X., Mayer J., Nicolini F., Niederwieser D., Pane F., Radich J.P., Rea D., Richter J., Rosti G., Rousselot P., Saglio G., Saussele S., Soverini S., Steegmann J.L., Turkina A., Zaritskey A., Hehlmann R., Hochhaus, A., Baccarani, M., Silver, R. T., Schiffer, C., Apperley, J. F., Cervantes, F., Clark, R. E., Cortes, J. E., Deininger, M. W., Guilhot, F., Hjorth-Hansen, H., Hughes, T. P., Janssen, J. J. W. M., Kantarjian, H. M., Kim, D. W., Larson, R. A., Lipton, J. H., Mahon, F. X., Mayer, J., Nicolini, F., Niederwieser, D., Pane, F., Radich, J. P., Rea, D., Richter, J., Rosti, G., Rousselot, P., Saglio, G., Saussele, S., Soverini, S., Steegmann, J. L., Turkina, A., Zaritskey, A., Hehlmann, R., Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut Bergonié [Bordeaux], UNICANCER, Centre Léon Bérard [Lyon], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Novartis Berlin Mathematical School, BMS Daiichi-Sankyo Janssen Pharmaceuticals Angelini Pharma Pfizer, The ELN panel for recommendations in CML comprises 34 experts from Europe, America, and the Asian-Pacific areas. The panel met six times at international meetings of the American Society of Hematology (2015, 2016), the European School of Hematology (2017), the ELN (2019), the European Investigators on CML (2019), and the European School of Hematology/International CML Foundation (2019). Five sets of key questions were submitted to panel members to complement the meetings. Discordant opinions were harmonized by email discussions, and a consensus of 75–100% was reached in most, but not all instances. Unresolved controversies are described in the discussion section. The costs of the meetings and the preparation of the interim and final reports were born entirely by ELN, a research network of excellence initiated by the European Union, now funded by donations and projects of ELN participants. There was no financial support from industry for any activity. Treatment recommendations are limited to the TKIs that have been approved with at least one indication in CML, either by the US Federal Drug Administration (FDA) or/and by the European Medicine Agency (EMA). The drugs are listed in the order of FDA approval. The panel acknowledges that not all drugs may be available worldwide and that the high price of some makes access to these drugs problematic in some countries., Conflict of interest Members of the expert panel declare the following potential conflicts of interest: AH, Research support: Novartis, BMS, MSD, Pfizer, Incyte. Honoraria: Novartis, BMS, Pfizer, Incyte, Takeda, Fusion Pharma. MB, Honoraria: Novartis, BMS, Pfizer, Incyte, Ariad, Takeda, Fusion Pharma. Logistic support: Novartis, BMS, Pfizer, Incyte, Ariad. CS, Research support: Ariad. Honoraria: Novartis, Teva, Pfizer, Juno, Astellas, Ambit. JFA, Research support: Incyte, Novartis, Pfizer. Honoraria: Incyte, Novartis, Pfizer, BMS. FC, Honoraria: Novartis, BMS, Pfizer, Incyte, Celgene, Italfarmaco. Travel grants: BMS, Celgene. REC, Research support: Novartis, Pfizer, BMS. Honoraria: Novartis, Pfizer, BMS, Ariad/Incyte, Jazz, Abbvie. JEC, Research support: BMS, Novartis, Pfizer, Sun Pharma, Takeda. Honoraria: Novartis, Pfizer, Takeda. MWD, Research support: Takeda, Novartis, Pfizer, Incyte, SPARC, TetraLogic Pharmaceuticals, Blueprint. Honoraria: Blueprint, Fusion Pharma, Novartis, Sangamo, Ascentage Pharma, Adelphi, CTI, BMS, Pfizer, Takeda, Medscape, Incyte, Humana, TRM, Ariad, Galena Biopharma. FG, Research support: Novartis, Roche. Honoraria: Novartis, BMS, Celgene. HHH, Research support: Pfizer, BMS, Merck, Austrian Orphan Pharma, Nordic Cancer Union. Honoraria: Pfizer, Incyte, Austrian Orphan Pharma. TPH, Research support: Novartis, BMS, Celgene. Honoraria: Novartis, BMS, Fusion Pharma. Travel grants: Novartis. JJ, Research support: Novartis, BMS. President, Apps for Care and Science, nonprofit foundation supported by Daiichi-Sankyo, Janssen, Incyte, BMS, Servier, Jazz, Celgene. Honoraria: Abbvie, Novartis, Pfizer, Incyte. HMK, Research support: AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, Pfizer. Honoraria: AbbVie, Actinium, Agios, Amgen, Immunogen, Pfizer, Takeda. DWK, Research support: Novartis, Pfizer, BMS, Takeda, Il-Yang Co. Honoraria: Novartis, BMS, Otsuka, Il-Yang Co. RAL, Research support: Astellas, Celgene, Cellectis, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals. Honoraria: Amgen, Celgene, CVS Caremark, Epizyme, Novartis, Takeda. JHL, Research support and honoraria: Novartis, BMS, Pfizer, Takeda. FXM, Research support and honoraria: Novartis. Travel grants: Celgene, Pfizer, Astra Zeneca. JM, Research support: Angelini, Pfizer, Novartis, BMS. Travel grants: Novartis. FN, Research support: Novartis, Incyte. Honoraria: Incyte biosciences, Novartis, BMS, Sun Pharma. Travel grants: Incyte biosciences, Novartis, BMS. DN, Research support: Daiichi, Honoraria: Cellectis. Travel grants: EUSA, Novartis, and Amgen. FP, Research support: Novartis. Honoraria: Novartis, BMS, Pfizer, Incyte. JPR, Research support: Novartis. Honoraria: Novartis, BMS, Ariad, Amgen, Takeda, Cepheid, Bio-Rad, Adaptive, Seagen, Gilead. DR, Honoraria: BMS, Novartis, Pfizer, Incyte. JR, Honoraria: Novartis, Pfizer. GR, Research support, honoraria, and travel grants: Novartis, BMS, Incyte, Pfizer, Roche. PR, Research support: Incyte, Pfizer. Honoraria: BMS, Incyte, Pfizer, Novartis. GS, Honoraria: Novartis, BMS, Incyte, Pfizer. SiS, Honoraria: Incyte. SuS, Research support: BMS, Incyte, Novartis. Honoraria: BMS, Incyte, Novartis, Pfizer. Travel grants: BMS, Incyte, Novartis. JLS, Research support, honoraria, and travel grants: BMS, Incyte, Novartis, Pfizer. AT, Honoraria: BMS, Novartis, Pfizer, Fusion Pharma. Travel grants: BMS, Novartis, Pfizer. AZ, Research support: Novartis, Celgene, Janssen. Travel grants: Novartis. RTS, RH, none.

Subjects
Oncology, Cancer Research, Consensus Development Conferences as Topic, Dasatinib, Fusion Proteins, bcr-abl, Quinoline, Gene Expression, Review Article, Tyrosine-kinase inhibitor, Antineoplastic Agent, European LeukemiaNet, 0302 clinical medicine, hemic and lymphatic diseases, 0303 health sciences, Aniline Compounds, Myeloid leukemia, Disease Management, Hematology, Aniline Compound, 3. Good health, 030220 oncology & carcinogenesis, Quinolines, Imatinib Mesylate, Bosutinib, Nitrile, medicine.drug, Human, medicine.medical_specialty, medicine.drug_class, Clinical Decision-Making, Protein Kinase Inhibitor, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Targeted therapies, Life Expectancy, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Nitriles, medicine, Humans, Protein Kinase Inhibitors, Chronic myeloid leukaemia, 030304 developmental biology, Monitoring, Physiologic, business.industry, Imatinib, Survival Analysis, Discontinuation, Pyrimidines, Nilotinib, Pyrimidine, Quality of Life, business
Abstract

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.

Published
2020
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34. The European Hematology Association Roadmap for European Hematology Research: a consensus document

Author

Engert, Andreas, Balduini, Carlo, Brand, Anneke, Coiffier, Bertrand, Cordonnier, Catherine, Doehner, Hartmut, de Wit, Thom Duyvene, Eichinger, Sabine, Fibbe, Willem, Green, Tony, de Haas, Fleur, Iolascon, Achille, Jaffredo, Thierry, Rodeghiero, Francesco, Salles, Gilles, Schuringa, Jan Jacob, Andre, Marc, Andre-Schmutz, Isabelle, Bacigalupo, Andrea, Bochud, Pierre-Yves, den Boer, Monique, Bonini, Chiara, Camaschella, Clara, Cant, Andrew, Cappellini, Maria Domenica, Cazzola, Mario, Lo Celso, Cristina, Dimopoulos, Meletios, Douay, Luc, Dzierzak, Elaine, Einsele, Hermann, Ferreri, Andres, De Franceschi, Lucia, Gaulard, Philippe, Gottgens, Berthold, Greinacher, Andreas, Gresele, Paolo, Gribben, John, de Haan, Gerald, Hansen, John-Bjarne, Hochhaus, Andreas, Kadir, Rezan, Kaveri, Srini, Kouskoff, Valerie, Kuehne, Thomas, Kyrle, Paul, Ljungman, Per, Maschmeyer, Georg, Mendez-Ferrer, Simon, Milsom, Michael, Mummery, Christine, Ossenkoppele, Gert, Pecci, Alessandro, Peyvandi, Flora, Philipsen, Sjaak, Reitsma, Pieter, Maria Ribera, Jose, Risitano, Antonio, Rivella, Stefano, Ruf, Wolfram, Schroeder, Timm, Scully, Marie, Socie, Gerard, Staal, Frank, Stanworth, Simon, Stauder, Reinhard, Stilgenbauer, Stephan, Tamary, Hannah, Theilgaard-Monch, Kim, Thein, Swee Lay, Tilly, Herve, Trneny, Marek, Vainchenker, William, Vannucchi, Alessandro Maria, Viscoli, Claudio, Vrielink, Hans, Zaaijer, Hans, Zanella, Alberto, Zolla, Lello, Zwaginga, Jaap Jan, Martinez, Patricia Aguilar, van den Akker, Emile, Allard, Shubha, Anagnou, Nicholas, Andolfo, Immacolata, Andrau, Jean-Christophe, Angelucci, Emanuele, Anstee, David, Aurer, Igor, Avet-Loiseau, Herve, Aydinok, Yesim, Bakchoul, Tamam, Balduini, Alessandra, Barcellini, Wilma, Baruch, Dominique, Baruchel, Andre, Bayry, Jagadeesh, Bento, Celeste, van den Berg, Anke, Bernardi, Rosa, Bianchi, Paola, Bigas, Anna, Biondi, Andrea, Bohonek, Milos, Bonnet, Dominique, Borchmann, Peter, Borregaard, Niels, Braekkan, Sigrid, van den Brink, Marcel, Brodin, Ellen, Bullinger, Lars, Buske, Christian, Butzeck, Barbara, Cammenga, Jorg, Campo, Elias, Carbone, Antonino, Cervantes, Francisco, Cesaro, Simone, Charbord, Pierre, Claas, Frans, Cohen, Hannah, Conard, Jacqueline, Coppo, Paul, Vives Corrons, Joan-Lluis, da Costa, Lydie, Davi, Frederic, Delwel, Ruud, Dianzani, Irma, Domanovic, Dragoslav, Donnelly, Peter, Drnovsek, Tadeja Dovc, Dreyling, Martin, Du, Ming-Qing, Dufour, Carlo, Durand, Charles, Efremov, Dimitar, Eleftheriou, Androulla, Elion, Jacques, Emonts, Marieke, Engelhardt, Monika, Ezine, Sophie, Falkenburg, Fred, Favier, Remi, Federico, Massimo, Fenaux, Pierre, Fitzgibbon, Jude, Flygare, Johan, Foa, Robin, Forrester, Lesley, Galacteros, Frederic, Garagiola, Isabella, Gardiner, Chris, Garraud, Olivier, van Geet, Christel, Geiger, Hartmut, Geissler, Jan, Germing, Ulrich, Ghevaert, Cedric, Girelli, Domenico, Godeau, Bertrand, Goekbuget, Nicola, Goldschmidt, Hartmut, Goodeve, Anne, Graf, Thomas, Graziadei, Giovanna, Griesshammer, Martin, Gruel, Yves, Guilhot, Francois, von Gunten, Stephan, Gyssens, Inge, Halter, Jorg, Harrison, Claire, Harteveld, Cornelis, Hellstrom-Lindberg, Eva, Hermine, Olivier, Higgs, Douglas, Hillmen, Peter, Hirsch, Hans, Hoskin, Peter, Huls, Gerwin, Inati, Adlette, Johnson, Peter, Kattamis, Antonis, Kiefel, Volker, Kleanthous, Marina, Klump, Hannes, Krause, Daniela, Hovinga, Johanna Kremer, Lacaud, Georges, Lacroix-Desmazes, Sebastien, Landman-Parker, Judith, LeGouill, Steven, Lenz, Georg, von Lilienfeld-Toal, Marie, von Lindern, Marieke, Lopez-Guillermo, Armando, Lopriore, Enrico, Lozano, Miguel, MacIntyre, Elizabeth, Makris, Michael, Mannhalter, Christine, Martens, Joost, Mathas, Stephan, Matzdorff, Axel, Medvinsky, Alexander, Menendez, Pablo, Migliaccio, Anna Rita, Miharada, Kenichi, Mikulska, Malgorzata, Minard, Veronique, Montalban, Carlos, de Montalembert, Mariane, Montserrat, Emili, Morange, Pierre-Emmanuel, Mountford, Joanne, Muckenthaler, Martina, Mueller-Tidow, Carsten, Mumford, Andrew, Nadel, Bertrand, Navarro, Jose-Tomas, el Nemer, Wassim, Noizat-Pirenne, France, O'Mahony, Brian, Oldenburg, Johannes, Olsson, Martin, Oostendorp, Robert, Palumbo, Antonio, Passamonti, Francesco, Patient, Roger, de Latour, Regis Peffault, Pflumio, Francoise, Pierelli, Luca, Piga, Antonio, Pollard, Debra, Raaijmakers, Marc, Radford, John, Rambach, Ralf, Rao, A. Koneti, Raslova, Hana, Rebulla, Paolo, Rees, David, Ribrag, Vincent, Rijneveld, Anita, Rinalducci, Sara, Robak, Tadeusz, Roberts, Irene, Rodrigues, Charlene, Rosendaal, Frits, Rosenwald, Andreas, Rule, Simon, Russo, Roberta, Saglio, Guiseppe, Sanchez, Mayka, Scharf, Ruediger E., Schlenke, Peter, Semple, John, Sierra, Jorge, So-Osman, Cynthia, Manuel Soria, Jose, Stamatopoulos, Kostas, Stegmayr, Bernd, Stunnenberg, Henk, Swinkels, Dorine, Taborda Barata, Joao Pedro, Taghon, Tom, Taher, Ali, Terpos, Evangelos, Thachil, Jecko, Tissot, Jean Daniel, Touw, Ivo, Toye, Ash, Trappe, Ralf, Traverse-Glehen, Alexandra, Unal, Sule, Vaulont, Sophie, Viprakasit, Vip, Vitolo, Umberto, van Wijk, Richard, Wojtowicz, Agnieszka, Zeerleder, Sacha, Zieger, Barbara, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital of Cologne [Cologne], Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Department of Internal Medicine I, Medizinische Universität Wien = Medical University of Vienna, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ege Üniversitesi, Engert, Andrea, Balduini, Carlo, Brand, Anneke, Coiffier, Bertrand, Cordonnier, Catherine, Döhner, Hartmut, De Wit, Thom Duyvené, Eichinger, Sabine, Fibbe, Willem, Green, Tony, De Haas, Fleur, Iolascon, Achille, Jaffredo, Thierry, Rodeghiero, Francesco, Sall Es, Gille, Schuringa, Jan Jacob, André, Marc, Andre Schmutz, Isabelle, Bacigalupo, Andrea, Bochud, Pierre Yve, Den Boer, Monique, Bonini, Chiara, Camaschella, Clara, Cant, Andrew, Cappellini, Maria Domenica, Cazzola, Mario, Celso, Cristina Lo, Dimopoulos, Meletio, Douay, Luc, Dzierzak, Elaine, Einsele, Hermann, Ferreri, André, De Franceschi, Lucia, Gaulard, Philippe, Gottgens, Berthold, Greinacher, Andrea, Gresele, Paolo, Gribben, John, De Haan, Gerald, Hansen, John Bjarne, Hochhaus, Andrea, Kadir, Rezan, Kaveri, Srini, Kouskoff, Valerie, Kühne, Thoma, Kyrle, Paul, Ljungman, Per, Maschmeyer, Georg, Méndez Ferrer, Simón, Milsom, Michael, Mummery, Christine, Ossenkoppele, Gert, Pecci, Alessandro, Peyvandi, Flora, Philipsen, Sjaak, Reitsma, Pieter, Ribera, José Maria, Risitano, ANTONIO MARIA, Rivella, Stefano, Ruf, Wolfram, Schroeder, Timm, Scully, Marie, Socie, Gerard, Staal, Frank, Stanworth, Simon, Stauder, Reinhard, Stilgenbauer, Stephan, Tamary, Hannah, Theilgaard Mönch, Kim, Thein, Swee Lay, Tilly, Hervé, Trneny, Marek, Vainchenker, William, Vannucchi, Alessandro Maria, Viscoli, Claudio, Vrielink, Han, Zaaijer, Han, Zanella, Alberto, Zolla, Lello, Zwaginga, Jaap Jan, Martinez, Patricia Aguilar, Van Den Akker, Emile, Allard, Shubha, Anagnou, Nichola, Andolfo, Immacolata, Andrau, Jean Christophe, Angelucci, Emanuele, Anstee, David, Aurer, Igor, Avet Loiseau, Hervé, Aydinok, Yesim, Bakchoul, Tamam, Balduini, Alessandra, Barcellini, Wilma, Baruch, Dominique, Baruchel, André, Bayry, Jagadeesh, Bento, Celeste, Van Den Berg, Anke, Bernardi, Rosa, Bianchi, Paola, Bigas, Anna, Biondi, Andrea, Bohonek, Milo, Bonnet, Dominique, Borchmann, Peter, Borregaard, Niel, Brækkan, Sigrid, Van Den Brink, Marcel, Brodin, Ellen, Bullinger, Lar, Buske, Christian, Butzeck, Barbara, Cammenga, Jörg, Campo, Elia, Carbone, Antonino, Cervantes, Francisco, Cesaro, Simone, Charbord, Pierre, Claas, Fran, Cohen, Hannah, Conard, Jacqueline, Coppo, Paul, Vives Corron, Joan Llui, Da Costa, Lydie, Davi, Frederic, Delwel, Ruud, Dianzani, Irma, Domanović, Dragoslav, Donnelly, Peter, Drnovšek, Tadeja Dovč, Dreyling, Martin, Du, Ming Qing, Dufour, Carlo, Durand, Charle, Efremov, Dimitar, Eleftheriou, Androulla, Elion, Jacque, Emonts, Marieke, Engelhardt, Monika, Ezine, Sophie, Falkenburg, Fred, Favier, Remi, Federico, Massimo, Fenaux, Pierre, Fitzgibbon, Jude, Flygare, Johan, Foà, Robin, Forrester, Lesley, Galacteros, Frederic, Garagiola, Isabella, Gardiner, Chri, Garraud, Olivier, Van Geet, Christel, Geiger, Hartmut, Geissler, Jan, Germing, Ulrich, Ghevaert, Cedric, Girelli, Domenico, Godeau, Bertrand, Gökbuget, Nicola, Goldschmidt, Hartmut, Goodeve, Anne, Graf, Thoma, Graziadei, Giovanna, Griesshammer, Martin, Gruel, Yve, Guilhot, Francoi, Von Gunten, Stephan, Gyssens, Inge, Halter, Jörg, Harrison, Claire, Harteveld, Corneli, Hellström Lindberg, Eva, Hermine, Olivier, Higgs, Dougla, Hillmen, Peter, Hirsch, Han, Hoskin, Peter, Huls, Gerwin, Inati, Adlette, Johnson, Peter, Kattamis, Antoni, Kiefel, Volker, Kleanthous, Marina, Klump, Hanne, Krause, Daniela, Hovinga, Johanna Kremer, Lacaud, George, Lacroix Desmazes, Sébastien, Landman Parker, Judith, Legouill, Steven, Lenz, Georg, Von Lilienfeld Toal, Marie, Von Lindern, Marieke, Lopez Guillermo, Armando, Lopriore, Enrico, Lozano, Miguel, Macintyre, Elizabeth, Makris, Michael, Mannhalter, Christine, Martens, Joost, Mathas, Stephan, Matzdorff, Axel, Medvinsky, Alexander, Menendez, Pablo, Migliaccio, Anna Rita, Miharada, Kenichi, Mikulska, Malgorzata, Minard, Véronique, Montalbán, Carlo, De Montalembert, Mariane, Montserrat, Emili, Morange, Pierre Emmanuel, Mountford, Joanne, Muckenthaler, Martina, Müller Tidow, Carsten, Mumford, Andrew, Nadel, Bertrand, Navarro, Jose Toma, El Nemer, Wassim, Noizat Pirenne, France, O’Mahony, Brian, Oldenburg, Johanne, Olsson, Martin, Oostendorp, Robert, Palumbo, Antonio, Passamonti, Francesco, Patient, Roger, De Latour, Regis Peffault, Pflumio, Francoise, Pierelli, Luca, Piga, Antonio, Pollard, Debra, Raaijmakers, Marc, Radford, John, Rambach, Ralf, Koneti Rao, A., Raslova, Hana, Rebulla, Paolo, Rees, David, Ribrag, Vincent, Rijneveld, Anita, Rinalducci, Sara, Robak, Tadeusz, Roberts, Irene, Rodrigues, Charlene, Rosendaal, Frit, Rosenwald, Andrea, Rule, Simon, Russo, Roberta, Saglio, Guiseppe, Sanchez, Mayka, Scharf, Rüdiger E., Schlenke, Peter, Semple, John, Sierra, Jorge, So Osman, Cynthia, Soria, José Manuel, Stamatopoulos, Kosta, Stegmayr, Bernd, Stunnenberg, Henk, Swinkels, Dorine, Barata, João Pedro Taborda, Taghon, Tom, Taher, Ali, Terpos, Evangelo, Thachil, Jecko, Tissot, Jean Daniel, Touw, Ivo, Toye, Ash, Trappe, Ralf, Traverse Glehen, Alexandra, Unal, Sule, Vaulont, Sophie, Viprakasit, Vip, Vitolo, Umberto, Van Wijk, Richard, Wójtowicz, Agnieszka, Zeerleder, Sacha, Zieger, Barbara, Hematology, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of York [York, UK], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pediatrics, Cell biology, Erasmus MC other, Pulmonary Medicine, Medical Oncology, Other departments, AII - Amsterdam institute for Infection and Immunity, Medical Microbiology and Infection Prevention, ACS - Amsterdam Cardiovascular Sciences, Clinical Haematology, Engert, A, Balduini, C, Brand, A, Coiffier, B, Cordonnier, C, Döhner, H, De, Wit, Td, Eichinger, S, Fibbe, W, Green, T, de Haas, F, Iolascon, A, Jaffredo, T, Rodeghiero, F, Salles, G, Schuringa, Jj, and the other authors of the EHA Roadmap for European Hematology, Research, Cancer Research UK, Biotechnology and Biological Sciences Research Council (BBSRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), De Wit, T, De Haas, F, Sall Es, G, Schuringa, J, André, M, Andre Schmutz, I, Bacigalupo, A, Bochud, P, Den Boer, M, Bonini, C, Camaschella, C, Cant, A, Cappellini, M, Cazzola, M, Celso, C, Dimopoulos, M, Douay, L, Dzierzak, E, Einsele, H, Ferreri, A, De Franceschi, L, Gaulard, P, Gottgens, B, Greinacher, A, Gresele, P, Gribben, J, De Haan, G, Hansen, J, Hochhaus, A, Kadir, R, Kaveri, S, Kouskoff, V, Kühne, T, Kyrle, P, Ljungman, P, Maschmeyer, G, Méndez Ferrer, S, Milsom, M, Mummery, C, Ossenkoppele, G, Pecci, A, Peyvandi, F, Philipsen, S, Reitsma, P, Ribera, J, Risitano, A, Rivella, S, Ruf, W, Schroeder, T, Scully, M, Socie, G, Staal, F, Stanworth, S, Stauder, R, Stilgenbauer, S, Tamary, H, Theilgaard Mönch, K, Thein, S, Tilly, H, Trneny, M, Vainchenker, W, Vannucchi, A, Viscoli, C, Vrielink, H, Zaaijer, H, Zanella, A, Zolla, L, Zwaginga, J, Martinez, P, Van Den Akker, E, Allard, S, Anagnou, N, Andolfo, I, Andrau, J, Angelucci, E, Anstee, D, Aurer, I, Avet Loiseau, H, Aydinok, Y, Bakchoul, T, Balduini, A, Barcellini, W, Baruch, D, Baruchel, A, Bayry, J, Bento, C, Van Den Berg, A, Bernardi, R, Bianchi, P, Bigas, A, Biondi, A, Bohonek, M, Bonnet, D, Borchmann, P, Borregaard, N, Brækkan, S, Van Den Brink, M, Brodin, E, Bullinger, L, Buske, C, Butzeck, B, Cammenga, J, Campo, E, Carbone, A, Cervantes, F, Cesaro, S, Charbord, P, Claas, F, Cohen, H, Conard, J, Coppo, P, Vives Corron, J, Da Costa, L, Davi, F, Delwel, R, Dianzani, I, Domanović, D, Donnelly, P, Drnovšek, T, Dreyling, M, Du, M, Dufour, C, Durand, C, Efremov, D, Eleftheriou, A, Elion, J, Emonts, M, Engelhardt, M, Ezine, S, Falkenburg, F, Favier, R, Federico, M, Fenaux, P, Fitzgibbon, J, Flygare, J, Foà, R, Forrester, L, Galacteros, F, Garagiola, I, Gardiner, C, Garraud, O, Van Geet, C, Geiger, H, Geissler, J, Germing, U, Ghevaert, C, Girelli, D, Godeau, B, Gökbuget, N, Goldschmidt, H, Goodeve, A, Graf, T, Graziadei, G, Griesshammer, M, Gruel, Y, Guilhot, F, Von Gunten, S, Gyssens, I, Halter, J, Harrison, C, Harteveld, C, Hellström Lindberg, E, Hermine, O, Higgs, D, Hillmen, P, Hirsch, H, Hoskin, P, Huls, G, Inati, A, Johnson, P, Kattamis, A, Kiefel, V, Kleanthous, M, Klump, H, Krause, D, Hovinga, J, Lacaud, G, Lacroix Desmazes, S, Landman Parker, J, Legouill, S, Lenz, G, Von Lilienfeld Toal, M, Von Lindern, M, Lopez Guillermo, A, Lopriore, E, Lozano, M, Macintyre, E, Makris, M, Mannhalter, C, Martens, J, Mathas, S, Matzdorff, A, Medvinsky, A, Menendez, P, Migliaccio, A, Miharada, K, Mikulska, M, Minard, V, Montalbán, C, De Montalembert, M, Montserrat, E, Morange, P, Mountford, J, Muckenthaler, M, Müller Tidow, C, Mumford, A, Nadel, B, Navarro, J, El Nemer, W, Noizat Pirenne, F, O’Mahony, B, Oldenburg, J, Olsson, M, Oostendorp, R, Palumbo, A, Passamonti, F, Patient, R, De Latour, R, Pflumio, F, Pierelli, L, Piga, A, Pollard, D, Raaijmakers, M, Radford, J, Rambach, R, Koneti Rao, A, Raslova, H, Rebulla, P, Rees, D, Ribrag, V, Rijneveld, A, Rinalducci, S, Robak, T, Roberts, I, Rodrigues, C, Rosendaal, F, Rosenwald, A, Rule, S, Russo, R, Saglio, G, Sanchez, M, Scharf, R, Schlenke, P, Semple, J, Sierra, J, So Osman, C, Soria, J, Stamatopoulos, K, Stegmayr, B, Stunnenberg, H, Swinkels, D, Barata, J, Taghon, T, Taher, A, Terpos, E, Thachil, J, Tissot, J, Touw, I, Toye, A, Trappe, R, Traverse Glehen, A, Unal, S, Vaulont, S, Viprakasit, V, Vitolo, U, Van Wijk, R, Wójtowicz, A, Zeerleder, S, Zieger, B, Andreas Engert, Carlo Balduini, Anneke Brand, Bertrand Coiffier, Catherine Cordonnier, Hartmut Döhner, Thom Duyvené de Wit, Sabine Eichinger, Willem Fibbe, Tony Green, Fleur de Haas, Achille Iolascon, Thierry Jaffredo, Francesco Rodeghiero, Gilles Salles, Jan Jacob Schuringa, the other authors of the EHA Roadmap for European Hematology Research, Anna Rita Migliaccio, EHA Roadmap for European Hematology, Research, Engert, A., Balduini, C., Brand, A., Coiffier, B., Cordonnier, C., Döhner, H., de Wit TD., Eichinger, S., Fibbe, W., Green, T., de Haas, F., Iolascon, A., Jaffredo, T., Rodeghiero, F., Salles, G., Schuringa, JJ., André, M., Andre-Schmutz, I., Bacigalupo, A., Bochud, PY., Boer, Md., Bonini, C., Camaschella, C., Cant, A., Cappellini, MD., Cazzola, M., Celso, CL., Dimopoulos, M., Douay, L., Dzierzak, E., Einsele, H., Ferreri, A., De Franceschi, L., Gaulard, P., Gottgens, B., Greinacher, A., Gresele, P., Gribben, J., de Haan, G., Hansen, JB., Hochhaus, A., Kadir, R., Kaveri, S., Kouskoff, V., Kühne, T., Kyrle, P., Ljungman, P., Maschmeyer, G., Méndez-Ferrer£££Simón£££ S., Milsom, M., Mummery, C., Ossenkoppele, G., Pecci, A., Peyvandi, F., Philipsen, S., Reitsma, P., Ribera, JM., Risitano, A., Rivella, S., Ruf, W., Schroeder, T., Scully, M., Socie, G., Staal, F., Stanworth, S., Stauder, R., Stilgenbauer, S., Tamary, H., Theilgaard-Mönch, K., Thein, SL., Tilly, H., Trneny, M., Vainchenker, W., Vannucchi, AM., Viscoli, C., Vrielink, H., Zaaijer, H., Zanella, A., Zolla, L., Zwaginga, JJ., Martinez, PA., van den Akker, E., Allard, S., Anagnou, N., Andolfo, I., Andrau, JC., Angelucci, E., Anstee, D., Aurer, I., Avet-Loiseau, H., Aydinok, Y., Bakchoul, T., Balduini, A., Barcellini, W., Baruch, D., Baruchel, A., Bayry, J., Bento, C., van den Berg, A., Bernardi, R., Bianchi, P., Bigas, A., Biondi, A., Bohonek, M., Bonnet, D., Borchmann, P., Borregaard, N., Brækkan, S., van den Brink, M., Brodin, E., Bullinger, L., Buske, C., Butzeck, B., Cammenga, J., Campo, E., Carbone, A., Cervantes, F., Cesaro, S., Charbord, P., Claas, F., Cohen, H., Conard, J., Coppo, P., Corrons, JL., Costa, Ld., Davi, F., Delwel, R., Dianzani, I., Domanović, D., Donnelly, P., Drnov?ek£££Tadeja Dovč£££ TD., Dreyling, M., Du, MQ., Dufour, C., Durand, C., Efremov, D., Eleftheriou, A., Elion, J., Emonts, M., Engelhardt, M., Ezine, S., Falkenburg, F., Favier, R., Federico, M., Fenaux, P., Fitzgibbon, J., Flygare, J., Foà, R., Forrester, L., Galacteros, F., Garagiola, I., Gardiner, C., Garraud, O., van Geet, C., Geiger, H., Geissler, J., Germing, U., Ghevaert, C., Girelli, D., Godeau, B., Gökbuget, N., Goldschmidt, H., Goodeve, A., Graf, T., Graziadei, G., Griesshammer, M., Gruel, Y., Guilhot, F., von Gunten, S., Gyssens, I., Halter, J., Harrison, C., Harteveld, C., Hellström-Lindberg, E., Hermine, O., Higgs, D., Hillmen, P., Hirsch, H., Hoskin, P., Huls, G., Inati, A., Johnson, P., Kattamis, A., Kiefel, V., Kleanthous, M., Klump, H., Krause, D., Hovinga, JK., Lacaud, G., Lacroix-Desmazes, S., Landman-Parker, J., LeGouill, S., Lenz, G., von Lilienfeld-Toal, M., von Lindern, M., Lopez-Guillermo, A., Lopriore, E., Lozano, M., MacIntyre, E., Makris, M., Mannhalter, C., Martens, J., Mathas, S., Matzdorff, A., Medvinsky, A., Menendez, P., Migliaccio, AR., Miharada, K., Mikulska, M., Minard, V., Montalbán, C., de Montalembert, M., Montserrat, E., Morange, PE., Mountford, J., Muckenthaler, M., Müller-Tidow, C., Mumford, A., Nadel, B., Navarro, JT., Nemer, We., Noizat-Pirenne, F., O'Mahony, B., Oldenburg, J., Olsson, M., Oostendorp, R., Palumbo, A., Passamonti, F., Patient, R., Peffault, R., Pflumio, F., Pierelli, L., Piga, A., Pollard, D., Raaijmakers, M., Radford, J., Rambach, R., Rao, AK., Raslova, H., Rebulla, P., Rees, D., Ribrag, V., Rijneveld, A., Rinalducci, S., Robak, T., Roberts, I., Rodrigues, C., Rosendaal, F., Rosenwald, A., Rule, S., Russo, R., Saglio, G., Sanchez, M., Scharf, RE., Schlenke, P., Semple, J., Sierra, J., So-Osman, C., Soria, JM., Stamatopoulos, K., Stegmayr, B., Stunnenberg, H., Swinkels, D., Barata£££João Pedro Taborda£££ JP., Taghon, T., Taher, A., Terpos, E., Thachil, J., Tissot, JD., Touw, I., Toye, A., Trappe, R., Traverse-Glehen, A., Unal, S., Vaulont, S., Viprakasit, V., Vitolo, U., van Wijk, R., Wójtowicz, A., Zeerleder, S., Zieger, B., Stem Cell Aging Leukemia and Lymphoma (SALL), and Çocuk Sağlığı ve Hastalıkları

Subjects
0301 basic medicine, Cancer Research, diagnosis, Health Services for the Aged, ACUTE PROMYELOCYTIC LEUKEMIA, Medizin, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, EHA Roadmap for European Hematology Research, Antineoplastic Agent, 0302 clinical medicine, European Hematology Association Roadmap, Germany, PERIPHERAL T-CELL, Medicine and Health Sciences, Hematopoiesi, genetics, Molecular Targeted Therapy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, ComputingMilieux_MISCELLANEOUS, Hematology, Genome, Hematopoietic Stem Cell Transplantation, Anemia, Awareness, Supply & distribution, Combined Modality Therapy, 3. Good health, Europe, THROMBOPOIETIN-RECEPTOR AGONISTS, Blood Disorder, Italy, Austria, haematology, Medicine, France, Immunotherapy, Infection, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Human, medicine.medical_specialty, Thrombopoietin Receptor Agonists, Consensus, Patients, Immunology, Antineoplastic Agents, Blood Coagulation, Gene Expression Profiling, Genetic Therapy, Genome, Human, Hematologic Diseases, Hematopoiesis, Humans, Consensu, [SDV.CAN]Life Sciences [q-bio]/Cancer, ACUTE MYELOID-LEUKEMIA, 1102 Cardiovascular Medicine And Haematology, Genetic therapy, methods, 03 medical and health sciences, blood, Internal medicine, medicine, Hematologi, THROMBOTIC THROMBOCYTOPENIC PURPURA, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ACUTE LYMPHOBLASTIC-LEUKEMIA, therapy, business.industry, CHRONIC LYMPHOCYTIC-LEUKEMIA, supply & distribution, STEM-CELL TRANSPLANTATION, economics, Hematologic Disease, Opinion Article, Transplantation, 030104 developmental biology, Family medicine, therapeutic use, drug effects, RANDOMIZED-CONTROLLED-TRIAL, HEMOLYTIC-UREMIC SYNDROME, pathology, business, chemical synthesis, 030215 immunology, Stem Cell Transplantation, transplantation
Abstract

WOS: 000379156300012, PubMed ID: 26819058, The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients., Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [BB/L023776/1, BB/I00050X/1, BB/K021168/1]; Cancer Research UKCancer Research UK [11831]; Medical Research CouncilMedical Research Council UK (MRC) [G1000801a]; Novo Nordisk FondenNovo Nordisk [NNF12OC1015986]; British Heart FoundationBritish Heart Foundation [FS/09/039/27788]; Cancer Research UKCancer Research UK [12765]; Medical Research CouncilMedical Research Council UK (MRC) [MR/L022982/1, MC_UU_12009/8, MC_U137981013, MC_PC_12009]

Published
2016
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35. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Author

Timothy P. Hughes, Martin C. Müller, Michael W. Deininger, Philippe Rousselot, Richard A. Larson, Michele Baccarani, Richard E. Clark, Fabrizio Pane, Andreas Hochhaus, Richard T. Silver, Henrik Hjorth-Hansen, Giuseppe Saglio, Jiri Mayer, Giovanni Martinelli, Jeffrey H. Lipton, Charles A. Schiffer, Dietger Niederwieser, Jerald P. Radich, Jane F. Apperley, Susanne Saußele, Gianantonio Rosti, Bengt Simonsson, François Guilhot, Francisco Cervantes, Simona Soverini, John M. Goldman, François Xavier Mahon, Juan Luis Steegmann, Rüdiger Hehlmann, Dong-Wook Kim, Hagop M. Kantarjian, Jorge E. Cortes, Baccarani, M, Deininger, Mw, Rosti, G, Hochhaus, A, Soverini, S, Apperley, Jf, Cervantes, F, Clark, Re, Cortes, Je, Guilhot, F, Hjorth Hansen, H, Hughes, Tp, Kantarjian, Hm, Kim, Dw, Larson, Ra, Lipton, Jh, Mahon, Fx, Martinelli, G, Mayer, J, M?ller, Mc, Niederwieser, D, Pane, Fabrizio, Radich, Jp, Rousselot, P, Saglio, G, Sau?ele, S, Schiffer, C, Silver, R, Simonsson, B, Steegmann, Jl, Goldman, Jm, Hehlmann, R., Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Müller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saußele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R., University of Bologna, University of Utah, and Université de Poitiers

Subjects
polymerase chain reaction, Fusion Proteins, bcr-abl, Review Article, protein-tyrosine kinase inhibitor, Biochemistry, Piperazines, cytogenetics, chemistry.chemical_compound, European LeukemiaNet, 0302 clinical medicine, imatinib mesylate, hemic and lymphatic diseases, dasatinib, BCR-ABL, Randomized Controlled Trials as Topic, 0303 health sciences, withdrawing treatment, Ponatinib, leukemia, Myeloid leukemia, Hematology, Prognosis, 3. Good health, Europe, chronic, Dasatinib, Treatment Outcome, 030220 oncology & carcinogenesis, Benzamides, medicine.drug, medicine.medical_specialty, myelocytic, Immunology, Antineoplastic Agents, second line treatment, 03 medical and health sciences, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, TYROSINE KINASE INHIBITORS, Humans, nilotinib, 030304 developmental biology, allogeneic stem cell transplant, business.industry, Cell Biology, Discontinuation, Transplantation, Thiazoles, Pyrimidines, Imatinib mesylate, Nilotinib, chemistry, business, CHRONIC MYELOID LEUKEMIA (CML), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Stem Cell Transplantation, transplantation
Abstract

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

Published
2013
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36. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia

Author

Andrija Bogdanovic, Boris Labar, Martin Höglund, Edgar Faber, Hele Everaus, Richard E. Clark, Adriana Colita, Rüdiger Hehlmann, Sonja Heibl, Anna G. Turkina, Ulla Olsson-Strömberg, Francisco Cervantes, Michele Baccarani, Tomasz Sacha, Verena S. Hoffmann, Michael Lauseker, Daniela Zackova, Markus Pfirrmann, Andreas Hochhaus, Laimonas Griskevicius, Perttu Koskenvesa, Susanne Saussele, Irena Preložnik Zupan, Joerg Hasford, Andrey Zaritskey, Gert J. Ossenkoppele, Fausto Castagnetti, Witold Prejzner, François Guilhot, Joelle Guilhot, Hematology laboratory, CCA - Cancer Treatment and quality of life, HUS Comprehensive Cancer Center, Department of Oncology, Hematologian yksikkö, University of Helsinki, Helsinki University Hospital Area, Pfirrmann M., Clark R.E., Prejzner W., Lauseker M., Baccarani M., Saussele S., Guilhot F., Heibl S., Hehlmann R., Faber E., Turkina A., Ossenkoppele G., Hoglund M., Zaritskey A., Griskevicius L., Olsson-Stromberg U., Everaus H., Koskenvesa P., Labar B., Sacha T., Zackova D., Cervantes F., Colita A., Zupan I., Bogdanovic A., Castagnetti F., Guilhot J., Hasford J., Hochhaus A., and Hoffmann V.S.

Subjects
Registrie, Male, Cancer Research, Epidemiology, European LeukemiaNet, 0302 clinical medicine, Risk groups, BOSUTINIB, Registries, CML, Aged, 80 and over, 0303 health sciences, DASATINIB, Hazard ratio, FRONTLINE, Myeloid leukemia, Hematology, IMATINIB TREATMENT, Middle Aged, Prognosis, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Female, PROGNOSTIC DISCRIMINATION, Sokal Score, Human, Adult, medicine.medical_specialty, Adolescent, Prognosi, Concordance, MODELS, 3122 Cancers, Protein Kinase Inhibitor, VALIDATION, Article, 03 medical and health sciences, Young Adult, Survival prognosis, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Long term survival, medicine, Humans, Hematologi, Protein Kinase Inhibitors, 030304 developmental biology, Aged, Probability, business.industry, Risk factors, business
Abstract

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Published
2020
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37. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results

Author

Sandip Acharya, Timothy P. Hughes, Agnès Guerci-Bresler, Anthony P. Schwarer, Ricardo Pasquini, Tara Glynos, Nelson Spector, Jeffrey H. Lipton, Francisco Cervantes, Darshan Dalal, Pedro Enrique Dorlhiac-Llacer, Mahon Fx, Brian Leber, Delphine Rea, Nelma D Clementino, Susan Branford, Suzanne Kamel-Reid, Israel Bendit, Hughes, TP, Leber, B, Cervantes, F, Spector, N, Pasquini, R, Clementino, NCD, Schwarer, AP, Dorlhiac-Llacer, PE, Mahon, FX, Rea, D, Guerci-Bresler, A, Kamel-Reid, S, Bendit, I, Acharya, S, Glynos, T, Dalal, D, Lipton, JH, and Branford, S

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Fusion Proteins, bcr-abl, Antineoplastic Agents, Pharmacology, patients, law.invention, 03 medical and health sciences, Bcr abl1, 0302 clinical medicine, Randomized controlled trial, law, hemic and lymphatic diseases, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, molecular responses, Humans, In patient, Letter to the Editor, Protein Kinase Inhibitors, Cross-Over Studies, business.industry, Imatinib, Hematology, Crossover study, Clinical trial, Imatinib mesylate, Pyrimidines, Nilotinib, 030220 oncology & carcinogenesis, Imatinib Mesylate, business, 030215 immunology, medicine.drug
Abstract

Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results

Published
2017

38. Long-term outcomes of imatinib treatment for chronic myeloid leukemia

Author

Andreas, Hochhaus, Richard A, Larson, François, Guilhot, Jerald P, Radich, Susan, Branford, Timothy P, Hughes, Michele, Baccarani, Michael W, Deininger, Francisco, Cervantes, Satoko, Fujihara, Christine-Elke, Ortmann, Hans D, Menssen, Hagop, Kantarjian, Stephen G, O'Brien, Brian J, Druker, G, Verhoef, Hochhaus, Andreas, Larson, Richard A, Guilhot, François, Radich, Jerald P, Branford, Susan, Hughes, Timothy P, Baccarani, Michele, Deininger, Michael W, Cervantes, Francisco, Fujihara, Satoko, Ortmann, Christine Elke, Menssen, Hans D, Kantarjian, Hagop, O'Brien, Stephen G, Druker, Brian J, CCA - Cancer Treatment and quality of life, Hematology, Universitat de Barcelona, and Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ, (plus IRIS Investigators: 180 collaborators), Martinelli G, et al.

Subjects
0301 basic medicine, Male, Intention to Treat Analysi, Antineoplastic Agent, 0302 clinical medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Chronic, CML, Leukemia, Cross-Over Studies, Medicine (all), Cytarabine, drug treatment, Cytogenetic Analysi, Enzyme inhibitors, General Medicine, Hematology, Cross-Over Studie, Middle Aged, Intention to Treat Analysis, Myeloid leukemia, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Imatinib Mesylate, Female, Survival Analysi, Human, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Leucèmia mieloide, Protein Kinase Inhibitor, Alpha interferon, Antineoplastic Agents, Follow-Up Studie, 03 medical and health sciences, Young Adult, Internal medicine, Multicenter trial, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, Aged, Follow-Up Studies, Interferon-alpha, Protein Kinase Inhibitors, Survival Analysis, Hematologia, neoplasms, Interferon alfa, Antineoplastic Combined Chemotherapy Protocol, Intention-to-treat analysis, business.industry, Imatinib, Crossover study, Surgery, 030104 developmental biology, Imatinib mesylate, Inhibidors enzimàtics, BCR-ABL Positive, business, Myelogenous
Abstract

BACKGROUND Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. METHODS In this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. RESULTS The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment. CONCLUSIONS Almost 11 years of follow-up showed that the efficacy of imatinib persisted over time and that long-term administration of imatinib was not associated with unacceptable cumulative or late toxic effects. (Funded by Novartis Pharmaceuticals; IRIS ClinicalTrials.gov numbers, NCT00006343 and NCT00333840.)

Published
2017
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39. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance

Author

Sarit Assouline, Dong-Wook Kim, Vikram Mathews, Jie Jin, Zhi Xiang Shen, Edo Vellenga, H. Jean Khoury, Ricardo Pasquini, Andrey Zaritskey, Hagop M. Kantarjian, Simon Durrant, Tim H. Brümmendorf, Jorge E. Cortes, Anna G. Turkina, Francisco Cervantes, Carlo Gambacorti-Passerini, Kathleen Turnbull, Eric Leip, Tamas Masszi, Virginia Kelly, Nadine Besson, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), GAMBACORTI PASSERINI, C, Brümmendorf, T, Kim, D, Turkina, A, Masszi, T, Assouline, S, Durrant, S, Kantarjian, H, Khoury, H, Zaritskey, A, Shen, Z, Jin, J, Vellenga, E, Pasquini, R, Mathews, V, Cervantes, F, Besson, N, Turnbull, K, Leip, E, Kelly, V, and Cortes, J

Subjects
Male, DIAGNOSED CHRONIC-PHASE, NILOTINIB, DURABLE CYTOGENETIC RESPONSES, Gastroenterology, Piperazines, hemic and lymphatic diseases, Aged, 80 and over, DASATINIB, Hematology, Aniline Compounds, CHRONIC MYELOGENOUS LEUKEMIA, Myeloid leukemia, Middle Aged, Dasatinib, Treatment Outcome, Benzamides, Leukemia, Myeloid, Chronic-Phase, Imatinib Mesylate, Quinolines, Female, TRIAL, Bosutinib, Complete Hematologic Response, medicine.drug, Adult, medicine.medical_specialty, Adolescent, ABL, INHIBITION, Antineoplastic Agents, chronic myeloid leukemia CML, Disease-Free Survival, Young Adult, Internal medicine, Nitriles, medicine, Humans, Protein Kinase Inhibitors, Aged, Dose-Response Relationship, Drug, business.industry, Imatinib, Original Articles, medicine.disease, THERAPY FAILURE, Surgery, Pyrimidines, Nilotinib, Drug Resistance, Neoplasm, SKI-606, business, Chronic myelogenous leukemia, Follow-Up Studies
Abstract

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. http://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00261846","term_id":"NCT00261846"}}NCT00261846. Am. J. Hematol. 89:732–742, 2014. © 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

Published
2014

40. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia

Author

Gert J. Ossenkoppele, Rüdiger Hehlmann, Joelle Guilhot, Bengt Simonsson, Francisco Cervantes, Michele Baccarani, Susanne Saussele, Verena S. Hoffmann, Joerg Hasford, Fausto Castagnetti, Markus Pfirrmann, Pfirrmann, M, Baccarani, Michele, Saussele, S, Guilhot, J, Cervantes, F, Ossenkoppele, G, Hoffmann, V. S, Castagnetti, Fausto, Hasford, J, Hehlmann, R, Simonsson, B., Hematology, and CCA - Biomarkers

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Myelogenous, 0302 clinical medicine, chronic myeloid leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, hemic and lymphatic diseases, medicine, Humans, In patient, neoplasms, Aged, Probability, Aged, 80 and over, Hematology, business.industry, Myeloid leukemia, Imatinib, Middle Aged, Prognosis, medicine.disease, Surgery, Clinical trial, Leukemia, Imatinib mesylate, 030220 oncology & carcinogenesis, Imatinib Mesylate, Female, business, 030215 immunology, medicine.drug
Abstract

In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

Published
2016
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41. Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia

Author

Felipe Prosper, Juan A. Castillejo, Francisco Cervantes, Lucia Cordeu, Jose Roman-Gomez, German Navarro, Leire Garate, Anabel Heiniger, Xabier Agirre, Antonio Jiménez-Velasco, Edurne San José-Enériz, Antoni Torres, [Román-Gómez,J, Castillejo,JA, Torres,A] Hematology Department, Reina Sofia Hospital, Cordoba, Spain. [Jiménez-Velasco,A, Navarro,G, Heiniger,A] Hematology Department, Carlos Haya Hospital, Malaga, Spain. [Aguirre,X, San Jose-Eneriz,E, Garete,L, Cordeu,L, Prosper,F] Hematology Department, Cellular Therapy Area, Clinica Universitaria /School of Medicine, Foundation for Applied Medical Research. University of Navarra, Pamplona, Spain. [Cervantes,F] Hematology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Spain., Supported by grants from Fondo de Investigacion Sanitaria (FIS, Spain) 06/0003, 03/0141, 01/0013-01, 01/F018, 02/1299, Navarra Goverment (31/2002), RETIC C03/10, Junta de Andalucia 03/143, and 03/144 and funds from IMABIS (Malaga. Spain), 'UTEproject CIMA',Fundación de Investigación Médica Mutua Madrileña Automovilista, and Asociacion Medicina e Investigacion (AMI).

Subjects
Male, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Interferons [Medical Subject Headings], Hypomethylation, Piperazines, Regiones promotoras genéticas, Epigenesis, Genetic, DEAD-box RNA Helicases, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], HAGE, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Methylation [Medical Subject Headings], hemic and lymphatic diseases, Testis, Promoter Regions, Genetic, CML, Regulation of gene expression, Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Bone Marrow Diseases::Myeloproliferative Disorders::Leukemia, Myelogenous, Chronic, BCR-ABL Positive [Medical Subject Headings], Reverse Transcriptase Polymerase Chain Reaction, musculoskeletal, neural, and ocular physiology, Myeloid leukemia, Hematology, Methylation, Prognosis, Neoplasm Proteins, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Reverse Transcriptase Polymerase Chain Reaction [Medical Subject Headings], Gene Expression Regulation, Neoplastic, Leukemia, Benzamides, DNA methylation, Imatinib Mesylate, Cancer/testis antigens, psychological phenomena and processes, Metilación del ADN, Cancer testis antigens, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Antineoplastic Agents, Biology, Antigens, Neoplasm, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::CpG Islands [Medical Subject Headings], medicine, Humans, Retractions, cardiovascular diseases, Leucemia mielogenosa crónica BCR-ABL positiva, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::RNA Helicases::DEAD-box RNA Helicases [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings], Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines [Medical Subject Headings], DNA Methylation, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Neoplasm [Medical Subject Headings], medicine.disease, Pirimidinas, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic [Medical Subject Headings], Interferones, Pyrimidines, Imatinib mesylate, Immunology, Cancer research, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Gene Components::Regulatory Elements, Transcriptional::Promoter Regions, Genetic [Medical Subject Headings], CpG Islands, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Piperazines [Medical Subject Headings], Interferons, Anatomy::Urogenital System::Genitalia::Genitalia, Male::Testis [Medical Subject Headings], K562 cells
Abstract

Journal Article; BACKGROUND AND OBJECTIVES Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies. DESIGN AND METHODS In this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction. RESULTS The TCC-S cell line showed demethylation of HAGE that was associated with over-expression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p

Published
2007
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42. Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia

Author

François Guilhot, Laurie Letvak, Richard A. Larson, Bayard L. Powell, Hermine Agis, Norbert Gattermann, Francisco Cervantes, Andreas Hochhaus, Brian J. Druker, Richard T. Silver, Hagop M. Kantarjian, Charlene So, Bengt Simonsson, Thea Kolsen Fischer, Jerald P. Radich, John D. Shepherd, Johan Lanng Nielsen, Alois Gratwohl, Jan J. Cornelissen, Insa Gathmann, Stephen G. O'Brien, Janice Gabrilove, Josy Reiffers, Michael W. Deininger, Kerry Taylor, Richard Stone, Michele Baccarani, Philippe Rousselot, Gregor Verhoef, John M. Goldman, Giuseppe Saglio, Timothy P. Hughes, Medical Oncology, Hematology, Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, and Larson RA

Subjects
Male, Oncology, medicine.medical_specialty, Fusion Proteins, bcr-abl, Antineoplastic Agents, Kaplan-Meier Estimate, Chronic phase chronic myelogenous leukemia, Disease-Free Survival, Piperazines, chemistry.chemical_compound, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Omacetaxine mepesuccinate, medicine, Humans, neoplasms, business.industry, Ponatinib, Cytarabine, Interferon-alpha, Myeloid leukemia, Imatinib, General Medicine, Protein-Tyrosine Kinases, Survival Analysis, Survival Rate, Dasatinib, Pyrimidines, Treatment Outcome, Imatinib mesylate, chemistry, Nilotinib, Benzamides, Immunology, Imatinib Mesylate, Female, business, Follow-Up Studies, medicine.drug
Abstract

The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy.We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events.The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events.After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

Published
2006
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43. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts

Author

Pierre Laneuville, Vishnu Reddy, Nelson Spector, Nelson Hamerschlak, Eduardo Olavarria, Richard A. Van Etten, Richard E. Clark, Dina Ben Yehuda, Jorge Milone, Ziad Salem, Richard T. Silver, Beatriz Moiraghi, Israel Bendit, David Gómez-Almaguer, Kensuke Usuki, Carmino DeSouza, Raquel Bengió, Madan Jagasia, Anthony P. Schwarer, Ayalew Tefferi, Tetsuzo Tauchi, Güray Saydam, Massimo Breccia, Pankaj Malhotra, Andrew Grigg, Jerald P. Radich, Camille N. Abboud, Moshe Talpaz, Elisabetta Abruzzese, Jenny Byrne, Guillermo J. Ruiz-Argüelles, Daniel J. DeAngelo, Francois-Xavier Mahon, Michael W. Deininger, Philipp le Coutre, Carlos Best, Ryuzo Ohno, Giuseppe Saglio, Jane F. Apperley, José A. López, Eduardo Bullorsky, Christopher Arthur, Richard Stone, Carolina Pavlovsky, Ibrahim C. Haznedaroglu, Ellin Berman, Alfonso Quintás-Cardama, David Marin-Costa, Johan Richter, Jianxiang Wang, Eduardo Cervera, Neil P. Shah, Saengsuree Jootar, Meir Wetzler, Jianda Hu, Richard A. Larson, Alvaro Aguayo, Timothy P. Hughes, Philippe Rousselot, Dragana Milojkovic, Xiao-Jun Huang, Iryna Dyagil, Steven M. Devine, Peter Browett, Vernon J. Louw, Kimmo Porkka, Hossam Kamel, Jesper Stentoft, Qian Jiang, Manuel Ayala, Andrey Zaritskey, Naeem Chaudhri, Muheez A. Durosinmi, John M. Goldman, Anna G. Turkina, Susan O'Brien, Jiri Mayer, Alicia Magarinos, Fawzi Abdel-Rahman, Brian J. P. Huntly, Hugues de Lavallade, Constantine S. Tam, Francisco Cervantes, Tessa L. Holyoake, Amir T. Fathi, Carlo Gambacorti-Passerini, Ekaterina Chelysheva, Adam D. Cohen, Junia V. Melo, Ernesto Fanilla, Tariq I. Mughal, Elias Jabbour, Naoto Takahashi, Itaru Matsumura, Jean Khoury, Paul J. Shami, Charles A. Schiffer, Dong-Wook Kim, Luis Meillon, Bassam Francis Matti, Henrik Hjorth-Hansen, Mahmoud Aljurf, Ali Bazarbachi, Hemant Malhotra, Hagop M. Kantarjian, Giovanni Martinelli, Joseph O. Moore, Jorge E. Cortes, Arnon Nagler, Paolo Vigneri, Ricardo Pasquini, Javier Pinilla-Ibarz, Elza Lomaia, Brian J. Druker, Tapan Saikia, David S. Snyder, Kazunori Ohnishi, Jeffrey H. Lipton, Pia Raanani, Abboud, C, Berman, E, Cohen, A, Cortes, J, Deangelo, D, Deininger, M, Devine, S, Druker, B, Fathi, A, Jabbour, E, Jagasia, M, Kantarjian, H, Khoury, J, Laneuville, P, Larson, R, Lipton, J, Moore, J, Mughal, T, O'Brien, S, Pinilla-Ibarz, J, Quintas-Cardama, A, Radich, J, Reddy, V, Schiffer, C, Shah, N, Shami, P, Silver, R, Snyder, D, Stone, R, Talpaz, M, Tefferi, A, Van Etten, R, Wetzler, M, Abruzzese, E, Apperley, J, Breccia, M, Byrne, J, Cervantes, F, Chelysheva, E, Clark, R, De Lavallade, H, Dyagil, I, Gambacorti-Passerini, C, Goldman, J, Haznedaroglu, I, Hjorth-Hansen, H, Holyoake, T, Huntly, B, Le Coutre, P, Lomaia, E, Mahon, F, Marin-Costa, D, Martinelli, G, Mayer, J, Milojkovic, D, Olavarria, E, Porkka, K, Richter, J, Rousselot, P, Saglio, G, Saydam, G, Stentoft, J, Turkina, A, Vigneri, P, Zaritskey, A, Aguayo, A, Ayala, M, Bendit, I, Bengio, R, Best, C, Bullorsky, E, Cervera, E, Desouza, C, Fanilla, E, Gomez-Almaguer, D, Hamerschlak, N, Lopez, J, Magarinos, A, Meillon, L, Milone, J, Moiraghi, B, Pasquini, R, Pavlovsky, C, Ruiz-Arguelles, G, Spector, N, Arthur, C, Browett, P, Grigg, A, Jianda, H, Huang, X, Hughes, T, Jiang, Q, Jootar, S, Kim, D, Malhotra, H, Malhotra, P, Matsumura, I, Melo, J, Ohnishi, K, Ohno, R, Saikia, T, Schwarer, A, Takahashi, N, Tam, C, Tauchi, T, Usuki, K, Wang, J, Abdel-Rahman, F, Aljurf, M, Bazarba-Chi, A, Yehuda, D, Chaudhri, N, Durosinmi, M, Kamel, H, Louw, V, Matti, B, Nagler, A, Raanani, P, and Salem, Z

Subjects
medicine.medical_specialty, Drug Industry, Cost effectiveness, Cancer drugs, Immunology, Alternative medicine, Antineoplastic Agents, Pharmacology, Biochemistry, Drug Costs, Antineoplastic Agent, Patents as Topic, Myelogenous, hemic and lymphatic diseases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Health care, Medicine, Drugs, Generic, Humans, Intensive care medicine, health care economics and organizations, Drug Cost, business.industry, Myeloid leukemia, Hematology, Cell Biology, medicine.disease, Leukemia, business, Large group, Human
Abstract

As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.

Published
2013

44. 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

Author

Curtis A. Hanson, Animesh Pardanani, Kebede Hussein, Ayalew Tefferi, Sergio Siragusa, Francisco Cervantes, Francesco Passamonti, Susan M. Schwager, Tefferi, A, Siragusa, S, Hussein, K, Schwager, SM, Hanson, CA, Pardanani, A, Cervantes, F, and Passamonti, F

Subjects
Adult, Male, medicine.medical_specialty, transfusion, myelofibrosis, PROGNOSIS, medicine.medical_treatment, myelofibrosis, Hematopoietic stem cell transplantation, Severity of Illness Index, Settore MED/15 - Malattie Del Sangue, Risk Factors, Internal medicine, Severity of illness, medicine, Humans, Myelofibrosis, Survival analysis, Aged, Retrospective Studies, Aged, 80 and over, Chromosome Aberrations, Hematology, business.industry, Patient Selection, Myelodysplastic syndromes, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Middle Aged, medicine.disease, Survival Analysis, Surgery, Primary Myelofibrosis, International Prognostic Scoring System, RBC transfusiion, Female, Erythrocyte Transfusion, business, Follow-Up Studies
Abstract

The International Prognostic Scoring System (IPSS) and karyotype are useful tools for risk stratification in primary myelofibrosis (PMF). We examined the additional prognostic impact of red blood cell transfusion need among 254 consecutive patients (median age, 59 years). Sixty-two patients ( approximately 24%) required transfusions at diagnosis whereas 22 ( approximately 9%) became transfusion-dependent and 170 remained transfusion-independent during the first year postdiagnosis; after a median follow-up of 55 months, the respective median survivals were 35, 25, and 117 months (P < 0.01). Multivariable analysis confirmed the IPSS- and karyotype-independent prognostic weight of transfusion status. Among IPSS intermediate-1 risk patients, overall median survival of 82 months was modified to 60 or 118 months, based on presence or absence of transfusion need, respectively (P < 0.01). The corresponding figures for intermediate-2/high risk patients were 30 and 64 months (P < 0.01). Documented causes of death did not include iron overload. We conclude that transfusion status in PMF downgrades or upgrades prognosis within specific IPSS categories; transfusion need is a marker of aggressive disease biology in PMF, as it is in myelodysplastic syndromes. (c) 2009 Wiley-Liss, Inc

Published
2009
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45. Survival in young patients with intermediate-/high-risk myelofibrosis: Estimates derived from databases for non transplant patients

Author

Francesco Passamonti, Ayalew Tefferi, Sergio Siragusa, Francisco Cervantes, Siragusa, S, Passamonti, F, Cervantes, F, and Tefferi, A

Subjects
Adult, Male, medicine.medical_specialty, Transplantation Conditioning, Adolescent, medicine.medical_treatment, bone marrow transplantation, Context (language use), myelofibrosis, Hematopoietic stem cell transplantation, Kaplan-Meier Estimate, Settore MED/15 - Malattie Del Sangue, myelofibrosis, survival, Young Adult, Pharmacotherapy, Internal medicine, medicine, Humans, Transplantation, Homologous, Young adult, Myelofibrosis, Retrospective Studies, business.industry, Age Factors, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Hematology, Middle Aged, medicine.disease, Surgery, Transplantation, Primary Myelofibrosis, Female, business, Follow-Up Studies
Abstract

Recent studies have suggested that allogenic stem cell transplantation (allo-SCT) might be a better treatment option, compared to drug therapy, for young patients with high-/intermediate-risk primary myelofibrosis (PMF). However, there are no controlled studies that validate this contention and allo-SCT is associated with a substantial risk of procedure-related mortality and morbidity. In a retrospective analysis of nontransplant PMF patients, who were both young (age

Published
2009

46. Coding sequence and intron-exon junctions of the c-myb gene are intact in the chronic phase and blast crisis stages of chronic myeloid leukemia patients

Author

Bruno Calabretta, Ilaria Iacobucci, Rita Bussolari, Olivia Candini, Dolors Colomer, Francesca Corradini, Simona Soverini, Giovanni Martinelli, Clara Guerzoni, Chiara Silvestri, Francisco Cervantes, Sara Cattelani, Tommaso Fasano, Sa Mariani, Luisa Pecorari, Bussolari R, Candini O, Colomer D, Corradini F, Guerzoni C, Mariani SA, Cattelani S, Silvestri C, Pecorari L, Iacobucci I, Soverini S, Fasano T, Martinelli G, Cervantes F, and Calabretta B.

Subjects
Cancer Research, Biology, Polymerase Chain Reaction, C-MYB, Exon, Proto-Oncogene Proteins c-myb, Gene Frequency, chronic myeloid leukemia, hemic and lymphatic diseases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Coding region, Humans, Gene, Chromatography, High Pressure Liquid, Neoplasm Staging, CHRONIC MYELOID LEUKEMIA, ABL, Polymorphism, Genetic, Base Sequence, denaturing-high performance liquid chromatography, breakpoint cluster region, proto-oncogene, Myeloid leukemia, Hematology, Exons, Sequence Analysis, DNA, medicine.disease, Molecular biology, Introns, c-Myb, Leukemia, Oncology, Cancer research, Disease Progression, K562 cells
Abstract

The c-myb gene encodes a transcription factor required for proliferation, differentiation and survival of normal and leukemic hematopoietic cells. c-Myb has a longer half-life in BCR/ABL-expressing than in normal cells, a feature which depends, in part, on PI-3K/Akt-dependent regulation of proteins interacting with the leucine zipper/negative regulatory region of c-Myb. Thus, we asked whether the stability of c-Myb in leukemic cells might be enhanced by mutations interfering with its degradation. We analyzed the c-myb gene in 133 chronic myeloid leukemia (CML) patients in chronic phase and/or blast crisis by denaturing-high performance liquid chromatography (D-HPLC) and sequence analysis of PCR products corresponding to the entire coding sequence and each exon-intron boundary. No mutations were found. We found four single nucleotide polymorphisms (SNPs) and identified an alternatively spliced transcript lacking exon 5, but SNPs frequency and expression of the alternatively spliced transcript were identical in normal and CML cells. Thus, the enhanced stability of c-Myb in CML blast crisis cells and perhaps in other types of leukemia is not caused by a genetic mechanism.

Published
2006

47. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet

Author

Rüdiger Hehlmann, Michael W. Deininger, Alois Gratwohl, Frederick R. Appelbaum, Michele Baccarani, François Guilhot, Hagop M. Kantarjian, Jorge E. Cortes, Dietger Niederwieser, Andreas Hochhaus, Mary M. Horowitz, Richard T. Silver, Francisco Cervantes, Bengt Simonsson, John M. Goldman, Giuseppe Saglio, Richard A. Larson, Timothy P. Hughes, Jane F. Apperley, Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilhot F, Horowitz M, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R, and Hehlmann R

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Immunology, Antineoplastic Agents, Hematopoietic stem cell transplantation, Transplantation, Autologous, Biochemistry, Chronic phase chronic myelogenous leukemia, Piperazines, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Transplantation, Homologous, Philadelphia Chromosome, Treatment Failure, Intensive care medicine, Chromosome Aberrations, business.industry, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Cell Biology, Hematology, Prognosis, medicine.disease, Combined Modality Therapy, Recombinant Proteins, Hematologic Response, Transplantation, Leukemia, Pyrimidines, Imatinib mesylate, Drug Resistance, Neoplasm, Benzamides, Interferon Type I, Mutation, Imatinib Mesylate, business, Complete Hematologic Response
Abstract

The introduction of imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid leukemia (CML). Although experience is too limited to permit evidence-based evaluation of survival, the available data fully justify critical reassessment of CML management. The panel therefore reviewed treatment of CML since 1998. It confirmed the value of IM (400 mg/day) and of conventional allogeneic hematopoietic stem cell transplantation (alloHSCT). It recommended that the preferred initial treatment for most patients newly diagnosed in chronic phase should now be 400 mg IM daily. A dose increase of IM, alloHSCT, or investigational treatments were recommended in case of failure, and could be considered in case of suboptimal response. Failure was defined at 3 months (no hematologic response [HR]), 6 months (incomplete HR or no cytogenetic response [CgR]), 12 months (less than partial CgR [Philadelphia chromosome-positive (Ph(+)) > 35%]), 18 months (less than complete CgR), and in case of HR or CgR loss, or appearance of highly IM-resistant BCR-ABL mutations. Suboptimal response was defined at 3 months (incomplete HR), 6 months (less than partial CgR), 12 months (less than complete CgR), 18 months (less than major molecular response [MMolR]), and, in case of MMolR loss, other mutations or other chromosomal abnormalities. The importance of regular monitoring at experienced centers was highlighted.

Published
2006

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