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• Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts.

  Authors: Monika Horvathova, Katarina Kapralova, Zuzana Zidova, Dalibor Dolezal, Dagmar Pospisilova, Vladimir Divoky

  Haematologica.

  Background. Hypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be ameliorated with high-doseBackground. Hypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be ameliorated with high-dose erythropoietin supplementation. The aim of this study was to characterize and compare erythropoiesis in erythropoietin pre-treatment and post-treatment patient samples, as well as in a mouse model with a DMT1 mutation, the mk/mk mice. Design and Methods. Colony assays were used to compare the in vitro growth of pre-treatment and post-treatment erythroid progenitors in a DMT1-mutant patient. To compare with human data, high doses of erythropoietin were administered to mk/mk mice. The apoptotic status of erythroblasts, the expression of anti-apoptotic proteins, and the key components of the bone marrow-hepcidin axis were evaluated. Results. Erythropoietin therapy in vivo or the addition of a broad-spectrum caspase inhibitor in vitro significantly improved the growth of human DMT1-mutant erythroid progenitors. A decreased number of apoptotic erythroblasts was detected in the patient's bone marrow after erythropoietin treatment. In mk/mk mice, erythropoietin administration augmented activation of signal transducer and activator of transcription 5 (STAT5) and reduced apoptosis in bone marrow and spleen erythroblasts. mk/mk mice propagated on the 129S6/SvEvTac background resembled DMT1-mutant patients in increased plasma iron but differed in functional iron deficiency after erythropoietin administration. Co-regulation of hepcidin and growth differentiation factor 15 (GDF15) levels was observed in mk/mk mice but not in the patient. Conclusions. Erythropoietin inhibits apoptosis of DMT1-mutant erythroid progenitors and differentiating erythroblasts. Ineffective erythropoiesis associated with defective erythroid iron utilization due to DMT1 mutations has specific biological and clinical features.

• DangER: protein ovERload - targeting protein degradation to treat myeloma.

  Authors: Lauren I Aronson, Faith E Davies

  Haematologica.

  Myeloma is a malignancy of the antibody-producing plasma cells and as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers aMyeloma is a malignancy of the antibody-producing plasma cells and as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful, with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat-shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome. More recently, the role of autophagy has been realised in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical work on novel inhibitors targeting protein handling pathways.

• Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases.

  Authors: Carole Soussain, Sylvain Choquet, Emmanuelle Fourme, Daniel Delgadillo, Krimo Bouabdallah, Herve' Ghesquieres, Gandhi Damaj, Brigitte Dupriez, Jacques Vargaftig, Alberto Gonzalez, Caroline Houillier, Luc Taillandier, Khe Hoang-Xuan, Veronique Leblond

  Haematologica.

  Background. Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25 % to 40 %. EncouragingBackground. Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25 % to 40 %. Encouraging results have been shown with intensive chemotherapy followed by autologous hematopoietic stem-cell rescue. We report the results of a large multicenter retrospective analysis of intensive chemotherapy followed by hematopoietic stem-cell rescue in immunocompetent adult patients with primary central nervous system lymphoma or intraocular lymphoma after the failure of high-dose methotrexate-based treatment.Design and Methods. Patients were included if they received intensive chemotherapy with a combination of thiotepa, busulfan, and cyclophosphamide. Seventy-nine patients (median age, 52,4 years; range, 23 to 67 years) were identified. All of the patients except five received a salvage treatment after the failure of high-dose methotrexate. After salvage treatment and just before intensive chemotherapy followed by hematopoietic stem-cell rescue, 32 patients were in complete response, 26 patients were in partial response, 2 patients had stable disease and 19 patients had progressive disease.Results. With a median follow-up of 56 months, the 5-year overall survival probability was 51 % in the whole population and 62 % among patients who were chemosensitive to the salvage treatment. The 5-year event-free survival probability was 37.8 % in the whole population and 43.7 % in the chemosensitive subpopulation. Neurocognitive assessments in a subset of patients suggest no evidence of intensive chemotherapy-induced neurocognitive decline. Conclusions. Thiotepa, busulfan and cyclophosphamide-based intensive chemotherapy is an effective treatment for refractory and recurrent primary central nervous system lymphoma in chemosensitive patients up to 65 years. The role of intensive chemotherapy followed by hematopoietic stem-cell rescue in chemorefractory patients needs to be defined more accurately.

• Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification.

  Authors: Lingzhi Yan, Nana Ping, Mingqing Zhu, Aining Sun, Yongquan Xue, Changgeng Ruan, Hans G Drexler, Roderick A F Macleod, Depei Wu, Suning Chen

  Haematologica.

  Among 4780 consecutive adult acute lymphoblastic/myeloblastic leukemia (ALL/AML) patients, we identified 117 (2.4%) patients with mixed-phenotype acute leukemia fulfilling WHO 2008 criteria,Among 4780 consecutive adult acute lymphoblastic/myeloblastic leukemia (ALL/AML) patients, we identified 117 (2.4%) patients with mixed-phenotype acute leukemia fulfilling WHO 2008 criteria, classified: B-lymphoid+myeloid (n=64), T-lymphoid+myeloid (n=38), B+T-lymphoid (n=14), and trilineage (n=1). Of 92 patients karyotyped, 59 were abnormal, classified: complex (22/92), t(9;22)(q34;q11) (14/92), monosomy 7 (7/92), polysomy 21 (7/92), t(v;11q23) (4/92), t(10;11)(p15;q21) (3/92), while STIL-TAL1 fusion was detected in one (T+My) patient. After investigating common acute leukemia-related mutations in 17 genes, 12 out of 31 (39%) patients were found to have at least one mutation, classified with: IKZF1 deletion (4/31), and EZH2 (3/31), ASXL1 (3/31), ETV6 (2/31), NOTCH1 (1/31), and TET2 (1/31) mutations. Array-CGH revealed genomic deletions of CDKN2A (4/12), IKZF1 (3/12), MEF2C (2/12), BTG1 (2/12), together with BCOR, EBF1, K-RAS, LEF1, MBNL1, PBX3, and RUNX1 (1/12 each). Our results indicate that mixed-phenotype acute leukemia is a complex entity with heterogeneous clinical, immunophenotypic, cytogenetic, and molecular genetic features.

• A novel deletion of β-globin promoter causing high HbA2 in Indian population.

  Authors: Thiyagaraj Mayuranathan, Janakiram Rayabaram, Eunice Sindhuvi Edison, Alok Srivastava, Ramachandran V Shaji

  Haematologica.

  We identified a novel 4.056 kb deletion which spans ~2.7 kb downstream of HBD gene to middle of β IVS-2 in an Indian patient with β-thalassaemia major phenotype. The parents who were heterozygous forWe identified a novel 4.056 kb deletion which spans ~2.7 kb downstream of HBD gene to middle of β IVS-2 in an Indian patient with β-thalassaemia major phenotype. The parents who were heterozygous for this mutation showed high levels of HbA2 (>7%) as the promoter region of β-globin gene is deleted. We characterized the break points of this deletion to understand the molecular basis of this mutation and established the methods for rapid diagnosis of this mutation in the population. Interestingly, the patient showed β-thalassaemia major phenotype unlike other cases with homozygous state of deletions in the promoter region of β-globin gene.

• Late stage erythroid precursor production is impaired in mice with chronic inflammation.

  Authors: Olivier D Prince, Jacqueline M Langdon, Andrew J Layman, Ian C Prince, Miguel Sabogal, Howard H Mak, Alan E Berger, Chris Cheadle, Francis J Chrest, Qilu Yu, Nancy C Andrews, Qian-Li Xue, Curt I Civin, Jeremy D Walston, Cindy N Roy

  Haematologica.

  Background: We and others have shown previously that over expression of hepcidin antimicrobial peptide, independent of inflammation, induces several features of anemia of inflammation and chronicBackground: We and others have shown previously that over expression of hepcidin antimicrobial peptide, independent of inflammation, induces several features of anemia of inflammation and chronic disease, including hypoferremia, sequestration of iron stores and iron-restricted erythropoiesis. Because the iron-restricted erythropoiesis evident in hepcidin transgenic mice differs from the normocytic, normochromic anemia most often observed in anemia of inflammation, we tested the hypothesis that chronic inflammation may contribute additional features to anemia of inflammation that continue to impair erythropoiesis following the acute phase of inflammation in which hepcidin is active. Design and Methods: We contrasted erythropoiesis and iron handling in mice with turpentine-induced sterile abscesses with erythropoiesis and iron handling in hepcidin transgenic mice. We compared erythrocyte indices; expression of genes in the hepcidin regulatory pathway; tissue iron distribution; expression of heme and iron transport genes in splenic macrophages; the phenotype of erythroid maturation and chloromethyl dichlorodihydrofluorescein diacetate, acetyl ester fluorescence.Results: Mice with sterile abscesses exhibited an intense, acute inflammatory phase followed by a mild to moderate chronic inflammatory phase. We found that erythrocytes in mice with sterile abscesses were normocytic and normochromic in contrast to hepcidin transgenic mice. We also observed that although hypoferremia resolved in the late phases of inflammation, erythropoiesis remained suppressed, with evidence of inefficient maturation of erythroid precursors in the bone marrow of mice with sterile abscesses. Finally, we observed increased oxidative stress in erythroid progenitors and circulating erythrocytes of mice with sterile abscesses that was not evident in hepcidin transgenic mice.Conclusions: Our results suggest chronic inflammation inhibits late stages of erythroid production in the turpentine-induced sterile abscess model and induces features of impaired erythropoiesis which are distinct from hepcidin transgenic mice.

• Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

  Authors: Ygal Benhamou, Cyrielle Assie, Pierre-Yves Boelle, Marc Buffet, Rana Grillberger, Sandrine Malot, Alain Wynckel, Claire Presne, Gabriel Choukroun, Pascale Poullin [......] Jean-Bernard Palcoux, Christiane Mousson, Cecile Vigneau, Guy Bonmarchand, Bertrand Guidet, Lionel Galicier, Elie Azoulay, Hanspeter Rottensteiner, Agnes Veyradier, Paul Coppo

  Haematologica.

  Background. Acquired thrombotic thrombocytopenic purpura is still associated with a 10-20% death rate. So far, early prognostic factors of death could not be clearly identified. To identifyBackground. Acquired thrombotic thrombocytopenic purpura is still associated with a 10-20% death rate. So far, early prognostic factors of death could not be clearly identified. To identify prognostic factors associated with 1-month death in thrombotic thrombocytopenic purpura patients with acquired severe (< 10% of normal activity) ADAMTS13 deficiency.Design and Methods. Prospective cohort of patients included between October, 2000, and August, 2010. A validation cohort of patients was set up from September, 2010 to August, 2011. 281 (analysis cohort) and 66 (validation cohort) consecutive adult thrombotic thrombocytopenic purpura patients with acquired severe ADAMTS13 deficiency. 30-day mortality after treatment initiation according to characteristics at inclusion.Results. Non-survivors (11%) were older (P=10-6) and presented more frequently arterial hypertension (P=5.10-4) and ischemic heart disease (P=0.013). Prognosis was increasingly poor with age (p=0.004). On presentation, cerebral manifestations were more frequent in non-survivors(P=0.018) and serum creatinine level was higher (P=0.008). The most significant independent variables for determining death were age, severe cerebral involvement and LDH level >=10N. A 3-level risk score for early death was defined and confirmed in the validation cohort using these variables, with higher values corresponding to increased risk of early death.Conclusions. A risk score for early death was defined in patients with thrombotic thrombocytopenic purpura and validated on an independent cohort. This score should help to stratify early treatment and intensify patients with a worse prognosis.

• Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol.

  Authors: Virginie Gandemer, Sylvie Chevret, Arnaud Petit, Christiane Vermylen, Thierry Leblanc, Gerard Michel, Claudine Schmitt, Odile Lejars, Pascale Schneider, Francois Demeocq, Brigitte Bader-Meunier, Francoise Bernaudin, Yves Perel, Marie-Francoise Auclerc, Jean-Michel Cayuela, Guy Leverger, Andre Baruchel

  Haematologica.

  Purpose. The prognosis of relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long termPurpose. The prognosis of relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long term follow-up a retrospective study to address the outcome of ETV6/RUNX1-positive leukemia relapses.Design and Method. Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified as low or intermediate risk groups. Median follow-up after relapse was 54.2 months. All but three received a second-line salvage therapy and 16 underwent an allogeneic transplantation.Results. ETV6/RUNX1 greatly impacted on overall survival after relapse (3 year-survival= 64.7 % for positive versus 46.5 % for negative cases) (p= 0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (p=0.04). 81.4 % were late relapses, early combined or isolated extramedullar relapses. The 5-year survival rate of ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.6% when relapse occurred after 36 months (vs 34.9%). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.Conclusions. We found an excellent outcome for ETV6/RUNX1-positive leukemia relapses occurring over 36 months post-diagnosis. Duration of first complete remission may thus be a guide to define the treatment strategy of ETV6/RUNX1-positive leukemia relapse.

• Molecular characterization of identical, novel MLL-EPS15 translocation and individual genomic copy number alterations in monozygotic infant twins with acute lymphoblastic leukemia.

  Authors: Rishi Sury Kotecha, Jette Ford, Alex H Beesley, Denise Anderson, Catherine H Cole, Ursula R Kees

  Haematologica.

  Translocation of the EPS15 oncogene is rare in infant acute lymphoblastic leukemia, whereas the MLL gene is rearranged in 80% of cases. Molecular characterization of t(1;11)(p32;q23) in a monozygoticTranslocation of the EPS15 oncogene is rare in infant acute lymphoblastic leukemia, whereas the MLL gene is rearranged in 80% of cases. Molecular characterization of t(1;11)(p32;q23) in a monozygotic infant twin pair with acute lymphoblastic leukemia identified an identical, novel translocation between the MLL and EPS15 loci at both the genomic and transcript level, with the mechanism of DNA repair consistent with non-homologous end joining. Cytogenetic array analysis revealed three common aberrations in leukemia from both twins. Together with the identical breakpoint identified at the fine structural level, this provides further evidence for the in utero development of a pre-leukemic clone in one twin with transfer to the other by means of the shared placental circulation. A number of aberrations, however, were unique and individualized to each twin. Such differences at the molecular level may attribute to the clinical heterogeneity of infant acute lymphoblastic leukemia.

• Time point-dependent concordance of flow cytometry and RQ-PCR inminimal residual disease detection in childhood acute lymphoblasticleukemia.

  Authors: Giuseppe Gaipa, Giovanni Cazzaniga, Maria Grazia Valsecchi, Renate Panzer-Grümayer, Barbara Buldini, Daniela Silvestri, Leonid Karawajew, Oscar Maglia, Richard Ratei, Alessandra Benetello [......] Angela Schumich, Andre Schrauder, Tiziana Villa, Marinella Veltroni, Wolf-Dieter Ludwig, Valentino Conter, Martin Schrappe, Andrea Biondi, Michael Dworzak, Giuseppe Basso

  Haematologica.

  Background. Flow cytometric analysis of leukemia-associated immunophenotypes and polymerase chain reaction-based amplification of antigen-receptor genes rearrangements are reliable methods to monitorBackground. Flow cytometric analysis of leukemia-associated immunophenotypes and polymerase chain reaction-based amplification of antigen-receptor genes rearrangements are reliable methods to monitor minimal residual disease. Aim of this study was to compare the performances of these two methodologies in the detection of minimal residual disease in childhood acute lymphoblastic leukemia.Design and methods. Polymerase chain reaction and flow cytometry were simultaneously applied for prospective minimal residual disease measurements at days 15, 33 and 78 of induction therapy on 3565 samples from 1547 children with acute lymphoblastic leukemia enrolled into the AIEOP-BFM ALL 2000 trial. Results. The overall concordance was 80%, but different results were observed according to the time point. Most discordances were found at day 33 (concordance rate 70%) in samples that had significantly lower minimal residual disease. However, the discordance was not due to different starting materials (total versus mononucleated cells), but rather to cell input number. At day 33, cases with minimal residual disease below or above the 0.01% cut-off by both methods showed a very good (5-year-event free survival, 91.6%) or a poor (5-year-event free survival, 50.9%) outcome, respectively, whereas discordant cases showed similar event free survival (around 80%). Conclusions. Within the current BFM-based protocols, flow cytometry and polymerase chain reaction cannot simply substitute each other at single time points, and the concordance rates between them largely depend on the time point. Our findings suggest a potential complementary role of the two technologies in optimizing risk stratification in future clinical trials.

• ETS1 encoding a transcription factor involved in B-cell differentiation is recurrently deleted and downregulated in classical Hodgkin lymphoma.

  Authors: Birte Malaika Overbeck, Jose Inaki Martin-Subero, Ole Ammerpohl, Wolfram Klapper, Reiner Siebert, Maciej Giefing

  Haematologica.

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• Treg depletion through CD127 positive selection results in a population enriched in memory T cells: implications for anti-tumoral cell therapy.

  Authors: Soumia Touil, Michelle Rosenzwajg, Dan Avi Landau, Philippe Le Corvoisier, Frederic Charlotte, David Klatzmann, Sebastien Maury, Jose L Cohen

  Haematologica.

  Background. Donor lymphocyte infusions can induce remissions in patients with relapse after allogeneic hematopoietic stem cell transplantation. Nevertheless, some grafted patients never display anyBackground. Donor lymphocyte infusions can induce remissions in patients with relapse after allogeneic hematopoietic stem cell transplantation. Nevertheless, some grafted patients never display any signs of alloreactivity, neither following allogeneic hematopoietic stem cell transplantation nor after donor lymphocyte infusions. Consequently, they do not develop graft-versus-host disease and frequently do not respond to donor lymphocytes infusions. In a recently published clinical trial, we observed that CD4+CD25+Foxp3+ natural regulatory T cells elimination from the donor lymphocytes product could improve alloreactivity and the associated anti-tumor effect in a small proportion of patients with relapsed hematological malignancies. Here, we aimed to ameliorate the donor lymphocytes infusion effect by modifying the procedure of Treg depletion.Design and Methods. We directly compared regulatory T cells depletion from human peripheral blood mononuclear cells through CD127 positive selection versus CD25 negative selection. We tested the manipulated products (i) in vitro in mixed lymphocyte reactions and against a large variety of pathogens and (ii) in vivo in experimental graft-versus-host disease.Results. In vitro, we found that regulatory T cells depletion through CD127 positive selection improved both alloreactive and pathogen-specific immune responses. In vivo, we observed accelerated donor T cell division and enhanced graft-versus-host disease due to efficient regulatory T cells depletion accompanied by enrichment in memory T cells.Conclusions. Our results show that CD127 positive selection strategy is efficient to eliminate regulatory T cells from donor lymphocytes infusions and improves alloreactivity. This supports the evaluation of CD127 positive selection in place of CD25+ cell elimination for clinical applications.

• Towards a joint definition of European hematology.

  Authors: Gert Ossenkoppele, Gareth Evans-Jones, Ulrich Jaeger, Eva Hellström-Lindberg

  Haematologica. 97(5):636-637.

• Comment on "Second-generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia in whom imatinib therapy has failed" Haematologica 2011;96(12):1779-82.

  Authors: Michael Lauseker, Markus Pfirrmann, Verena S Hoffmann, Joerg Hasford

  Haematologica. 97(5):e14-5.

• Reply to Comment on "Stability of human rapamycin-expanded CD4+CD25+ T-regulatory cells" Haematologica 2011;96(9):1357-65.

  Authors: Eleonora Tresoldi, Ilaria Dell'albani, Angela Stabilini, Tatiana Jofra, Andrea Valle, Nicola Gagliani, Attilio Bondanza, Maria Grazia Roncarolo, Manuela Battaglia

  Haematologica. 97(5):e17.

• Improvements in the survival of children and adolescents with acute lymphoblastic leukemia.

  Authors: Jan Cools

  Haematologica. 97(5):635.

• Nuclear factor-κB dysregulation in splenic marginal zone lymphoma: new therapeutic opportunities.

  Authors: Luca Arcaini, Davide Rossi

  Haematologica. 97(5):638-40.

• Comment on "Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells" Haematologica 2011;96(9):1357-65.

  Authors: Haiqi He, Yi Lv

  Haematologica. 97(5):e16.

• Activating mutations of the FMS-like tyrosine kinase-3 internaltandem duplication (FLT3-ITD) at complete response and relapsein patients with acute myeloid leukemia.

  Authors: Aziz Nazha, Jorge Cortes, Stefan Faderl, Sherry Pierce, Naval Daver, Tapan Kadia, Gautam Borthakur, Raja Luthra, Hagop Kantarjian, Farhad Ravandi

  Haematologica.

  FMS like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are among the most frequent molecular aberrations in patients with acute myeloid leukemia. We retrospectively analyzed 324FMS like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are among the most frequent molecular aberrations in patients with acute myeloid leukemia. We retrospectively analyzed 324 patients with acute myeloid leukemia treated with frontline induction chemotherapy between October 2004 and March 2010. Fifty six patients had FLT3-ITD mutation at diagnosis. Fifty one (91%) patients with FLT3-ITD achieved complete remission. Thirteen patients had FLT3 analysis at complete remission. None had FLT3-ITD. Twenty five (49%) patients with FLT3-ITD relapsed. Of these, 13 (52%) had FLT3-ITD at relapse (3 negative and 9 not done). Among the 201 patients without FLT3-ITD at diagnosis, who achieved complete remission, 77 (38%) relapsed among whom 8 (10%) patients acquired FLT3-ITD clone. We conclude that FLT3-ITD mutations are unstable at follow-up and may occur for the first time at relapse. Therefore, FLT3-ITD cannot be used reliably for minimal residual disease monitoring in acute myeloid leukemia.

• Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy.

  Authors: Pratap Neelakantan, David Marin, Michael Laffan, John Goldman, Jane Apperley, Dragana Milojkovic

  Haematologica.

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• RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia.

  Authors: Sylvia Snauwaert, Stijn Vanhee, Glenn Goetgeluk, Greet Verstichel, Yasmine Van Caeneghem, Imke Velghe, Jan Philippe, Zwi N Berneman, Jean Plum, Tom Taghon, Georges Leclercq, Kris Thielemans, Tessa Kerre, Bart Vandekerckhove

  Haematologica.

  Background. Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of acute myeloid leukemia patients and low orBackground. Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of acute myeloid leukemia patients and low or non-existing expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia, which correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored.Design and Methods. Blood, leucapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA level on various sorted populations, either fresh or after manipulation.Results. High levels of RHAMM were expressed by CD34+CD38+ and CD34- acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34+CD38- leukemic stem cells, which was not different from that of CD34+CD38- hematopoietic stem cells of healthy controls. RHAMM was significantly upregulated in CD34+ cells of healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells.Conclusions. RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not significantly differ from the expression in hematopoietic stem cells of healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T cell-mediated immunotherapy.

• The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation.

  Authors: Teresa Caballero-Velazquez, Luis-Ignacio Sanchez-Abarca, Silvia Gutierrez-Cosio, Belen Blanco, Cristina Calderon, Carmen Herrero, Soraya Carrancio, Concepcion Rodriguez-Serrano, Maria Consuelo Del Cañizo, Jesus San Miguel, Jose-Antonio Perez-Simon

  Haematologica.

  Background. We have previously shown that Bortezomib induces a depletion of alloreactive T-cells and allows the expansion of T-cells with suppressive properties. In the current study we analyzed theBackground. We have previously shown that Bortezomib induces a depletion of alloreactive T-cells and allows the expansion of T-cells with suppressive properties. In the current study we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus host disease without hampering graft versus leukemia in the allogeneic transplant setting. Design and Methods. We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T-lymphocytes. Pathways involved in this synergy were also analyzed using western-blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease.Results. The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T-cell. Also the production of Th1 cytokines (IFNγ, IL-2 and TNF) was significantly inhibited. This effect was at least in part due to the inhibition of Erk and Akt phosphorilation. In vivo, the combination decreased the risk of graft versus host disease without hampering graft-versus-leukemia effect as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions. The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft versus host disease while maintaining the graft versus leukemia effect.

• Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis.

  Authors: Julien Broseus, Lourdes Florensa, Esther Zipperer, Susanne Schnittger, Luca Malcovati, Steven Richebourg, Eric Lippert, Jaroslav Cermak, Jyoti Evans, Morgane Mounier [......] Maria Luz Perez Sirvent, Bernardine Favre, Julien Guy, Esther Alonso, Nuhri Ahwij, Andres Jerez, Sylvie Hermouet, Marc Maynadie, Mario Cazzola, François Girodon

  Haematologica.

  Background. Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloidBackground. Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm, and to compare its clinical outcome with those of refractory anemia with ring sideroblasts and essential thrombocythemia.Design and Methods. We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, one patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare the outcome of the diseases.Results. In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (superior or inferior to 600 x 109/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (p<0.001), but better survival (p<0.001) and a higher risk of thrombosis (p=0.039) than patients with refractory anemia with ring sideroblasts.Conclusion. The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.

• Age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded.

  Authors: Renee A Douma, Melanie Tan, Roger Schutgens, Shannon M Bates, Arnaud Perrier, Cristina Legnani, Douwe H Biesma, Jeffrey S Ginsberg, Henri Bounameaux, Gualtiero Palareti, Marc Carrier, Gerben C Mol, Gregoire Le Gal, Pieter W Kamphuisen, Marc Righini

  Haematologica.

  Background. D-Dimer testing to rule out deep vein thrombosis is less useful in older patients due to lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of olderBackground. D-Dimer testing to rule out deep vein thrombosis is less useful in older patients due to lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis. Design and Methods. Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability for deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 μg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 μg/L in patients >50 years). Results. In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) with the age-adjusted versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non- high probability. Conclusions. The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.

• Thrombosis is associated with inferior survival in multiple myeloma.

  Authors: Sigurdur Y Kristinsson, Ruth M Pfeiffer, Magnus Bjorkholm, Sam Schulman, Ola Landgren

  Haematologica.

  Patients with multiple myeloma are at an increased risk of venous thromboembolism and arterial thrombosis. We assessed the impact of venous and arterial thrombosis on survival in a population-basedPatients with multiple myeloma are at an increased risk of venous thromboembolism and arterial thrombosis. We assessed the impact of venous and arterial thrombosis on survival in a population-based study on 9,399 multiple myeloma patients diagnosed in Sweden 1987-2005. We found multiple myeloma patients with (versus without) venous thromboembolism to have a higher mortality at 1-, 5-, and 10-years of follow-up, with hazards ratio=2.9 (95% confidence interval 2.4-3.5), 1.6 (1.5-1.8), and 1.6 (1.4-1.7), respectively. The risk of dying was increased among multiple myeloma patients with arterial thrombosis, hazard ratio=3.4 (3.0-3.8), 2.2 (2.0-2.3), and 2.1 (1.9-2.1), respectively. In landmark analyses at 6 months, early arterial and not venous thromboembolism was associated with a higher risk of dying. Thus, in contrast to prior smaller studies, we found the development of thrombosis to be associated with significantly poorer survival. The prevention of thrombosis in multiple myeloma is an important goal in the management of multiple myeloma patients.

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