149 results on '"Morra, Enrica"'
Search Results
2. Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment.
- Author
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Trojani A, Pungolino E, Dal Molin A, Lodola M, Rossi G, D'Adda M, Perego A, Elena C, Turrini M, Borin L, Bucelli C, Malato S, Carraro MC, Spina F, Latargia ML, Artale S, Spedini P, Anghilieri M, Di Camillo B, Baruzzo G, De Canal G, Iurlo A, Morra E, and Cairoli R
- Subjects
- Female, Humans, Male, Middle Aged, Time Factors, ATP-Binding Cassette Transporters blood, Cell Cycle drug effects, Gene Expression Regulation, Leukemic drug effects, Janus Kinases blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Neoplasm Proteins blood, Pyrimidines administration & dosage, STAT Transcription Factors blood, Signal Transduction drug effects
- Abstract
Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis., Competing Interests: The authors have declared that non-financial competing interests exist. Novartis funded reagents and materials for the experiments in our laboratory, and provided nilotinib for this study. Novartis had no role in study design, data collection, analysis and interpretation, decision to publish or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There was no additional external funding received for this study.
- Published
- 2019
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3. Lymphomas associated with chronic hepatitis C virus infection: A prospective multicenter cohort study from the Rete Ematologica Lombarda (REL) clinical network.
- Author
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Rattotti S, Ferretti VV, Rusconi C, Rossi A, Fogazzi S, Baldini L, Pioltelli P, Balzarotti M, Farina L, Ferreri AJM, Laszlo D, Speziale V, Varettoni M, Sciarra R, Morello L, Tedeschi A, Frigeni M, Defrancesco I, Zerbi C, Flospergher E, Nizzoli ME, Morra E, and Arcaini L
- Subjects
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Follow-Up Studies, Humans, Italy epidemiology, Male, Middle Aged, Prospective Studies, Survival Rate, Hepacivirus, Hepatitis C, Chronic diagnosis, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic mortality, Interferons administration & dosage, Lymphoma, Non-Hodgkin diagnosis, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin mortality
- Abstract
Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease., (© 2019 John Wiley & Sons, Ltd.)
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- 2019
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4. Nilotinib induced bone marrow CD34+/lin-Ph+ cells early clearance in newly diagnosed CP-chronic myeloid leukemia.
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Pungolino E, Rossi G, De Canal G, Trojani A, D'adda M, Perego A, Orlandi EM, Lunghi F, Turrini M, Borin L, Iurlo A, Latargia ML, Carraro MC, Spina F, Lodola M, Artale S, Anghilieri M, Spedini P, Cantoni S, Di Camillo B, Morra E, and Cairoli R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antigens, CD34 analysis, Bone Marrow Cells pathology, Cell Count, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Male, Middle Aged, Neoplastic Stem Cells pathology, Prospective Studies, Protein Kinase Inhibitors therapeutic use, Young Adult, Bone Marrow Cells drug effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Pyrimidines pharmacology
- Published
- 2018
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5. Wide-transcriptome analysis and cellularity of bone marrow CD34+/lin- cells of patients with chronic-phase chronic myeloid leukemia at diagnosis vs. 12 months of first-line nilotinib treatment.
- Author
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Trojani A, Pungolino E, Rossi G, D'Adda M, Lodola M, Camillo BD, Perego A, Turrini M, Orlandi E, Borin L, Iurlo A, Malato S, Spina F, Latargia ML, Lanza F, Artale S, Anghilieri M, Carraro MC, Canal G, Morra E, and Cairoli R
- Subjects
- Antigens, CD34 blood, Bone Marrow Cells pathology, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia, Myeloid, Chronic-Phase blood, Leukocyte Count, Protein-Tyrosine Kinases therapeutic use, Time Factors, Treatment Outcome, Bone Marrow Cells metabolism, Gene Expression Profiling methods, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics, Pyrimidines therapeutic use
- Abstract
Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder with heterogeneous biological and clinical features. The biomolecular mechanisms of CML response to tyrosine-kinase inhibitors are not fully defined., Objective: We undertook a gene expression profiling (GEP) study of selected bone marrow (BM) CD34+/lin- cells of chronic-phase CML patients at diagnosis and after 12 months of TKI nilotinib to investigate molecular signatures characterizing both conditions.
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- 2017
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6. Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia.
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Castillo JJ, Garcia-Sanz R, Hatjiharissi E, Kyle RA, Leleu X, McMaster M, Merlini G, Minnema MC, Morra E, Owen RG, Poulain S, Stone MJ, Tam C, Varettoni M, Dimopoulos MA, Treon SP, and Kastritis E
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- Advisory Committees, Humans, London, Practice Guidelines as Topic, Waldenstrom Macroglobulinemia diagnosis
- Abstract
The diagnosis of Waldenström macroglobulinaemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM., Competing Interests: JJC received honoraria from Celgene and Pharmacyclics, and research funding from Abbvie, Gilead, Millennium and Pharmacyclics. RGS received honoraria from Bristol-Myers Squibb, Janssen and Takeda and. EH received honoraria from Amgen, Gilead and Janssen. GM received honoraria from GlaxoSmithKline, Janssen and Millennium-Takeda. RGO received honoraria from Celgene, Janssen, Pharmacyclics and Roche, and research funding from Celgene. CT received honoraria and research funding from Janssen and Roche. MAD received honoraria from Amgen, Celgene, Janssen and Novartis. SPT received research funding and/or honoraria from Gilead, Janssen, Onyx and Pharmacyclics. EK received honoraria from Amgen, Janssen and Takeda and. RAK, XL, MM, MCM, EM, SP, MJS, MV have no conflict of interest to disclose., (© 2016 John Wiley & Sons Ltd.)
- Published
- 2016
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7. Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia.
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Leblond V, Kastritis E, Advani R, Ansell SM, Buske C, Castillo JJ, García-Sanz R, Gertz M, Kimby E, Kyriakou C, Merlini G, Minnema MC, Morel P, Morra E, Rummel M, Wechalekar A, Patterson CJ, Treon SP, and Dimopoulos MA
- Subjects
- Humans, Practice Guidelines as Topic standards, Waldenstrom Macroglobulinemia therapy
- Abstract
Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM., (© 2016 by The American Society of Hematology.)
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- 2016
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8. Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia.
- Author
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Xu L, Hunter ZR, Tsakmaklis N, Cao Y, Yang G, Chen J, Liu X, Kanan S, Castillo JJ, Tai YT, Zehnder JL, Brown JR, Carrasco RD, Advani R, Sabile JM, Argyropoulos K, Lia Palomba M, Morra E, Trojani A, Greco A, Tedeschi A, Varettoni M, Arcaini L, Munshi NM, Anderson KC, and Treon SP
- Subjects
- Adult, Aged, Aged, 80 and over, Amino Acid Substitution, Female, Genomic Instability, Humans, Immunoglobulin M blood, Lymphoma, B-Cell, Marginal Zone genetics, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance genetics, Myeloid Differentiation Factor 88 genetics, Polymerase Chain Reaction methods, Sequence Analysis, DNA methods, Mutation, Receptors, CXCR4 genetics, Waldenstrom Macroglobulinemia genetics
- Abstract
CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2016
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9. The influence of disease and comorbidity risk assessments on the survival of MDS and oligoblastic AML patients treated with 5-azacitidine: A retrospective analysis in ten centers of the "Rete Ematologica Lombarda".
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Molteni A, Riva M, Borin L, Bernardi M, Pelizzari AM, Freyrie A, Della Porta M, Nichelatti M, Ravano E, Quaresmini G, Mariotti J, Caramazza D, Ubezio M, Guarco S, Gigli F, Greco R, Cairoli R, and Morra E
- Subjects
- Adult, Aged, Aged, 80 and over, Comorbidity, Female, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Myelodysplastic Syndromes epidemiology, Myelodysplastic Syndromes pathology, ROC Curve, Retrospective Studies, Risk Factors, Young Adult, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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10. Prognostic relevance of the flow cytometric count of medullar blasts in myelodysplastic syndromes.
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Molteni A, Riva M, Cesana C, Speziale V, Nichelatti M, Scarpati B, Greco R, Ravano E, Cairoli R, Rossini S, and Morra E
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Bone Marrow Cells metabolism, Bone Marrow Examination, Cell Count, Female, Humans, Immunophenotyping, Male, Middle Aged, Myelodysplastic Syndromes mortality, Prognosis, Bone Marrow pathology, Bone Marrow Cells pathology, Flow Cytometry, Myelodysplastic Syndromes diagnosis
- Abstract
Objective: The medullar blast count is a milestone in the prognostic assessment in myelodysplastic syndromes (MDS). The optical microscopy (OM) may sometimes be inaccurate in this disease. The aim of this work is to test the flow immunocytometric (FCM) determinations of medullar immature cells (CD45(±) ) and the expression, among them, of CD33, CD34, and CD117 markers, for their prognostic relevance., Methods: In a retrospective analysis of 98 patients affected by MDS, the IPSS was re-calculated by means of the FCM determination of blasts. Survival of patients at low or intermediate-1 IPSS risk was compared with the survival of patients at intermediate-2 or high IPSS risk. In the 64 cases with OM blast count lower than 5%, the survival of patients with the FCM count of medullar blasts ≤2% was compared with that of patients with FCM count >2%., Results: Each single marker had a prognostic weight comparable to the optical blast count. The FCM blast count was particularly efficient in distinguishing the risk of having up to 2% or more than 2% of blasts in patients without OM excess of blasts., Conclusion: This method is interesting as prognostic tool, especially in patients without excess of blast., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2015
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11. Post-remission intensive treatment after induction chemotherapy is feasible in selected elderly patients with acute myeloid leukemia and age ≥75 years: a retrospective analysis of the Rete Ematologica Lombarda.
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Bernardi M, Zappasodi P, Fracchiolla N, Marbello L, Todisco E, Pagani C, Carrabba M, Rossi M, Guidotti F, Mancini V, Santoro A, Borlenghi E, Ciceri F, Morra E, and Rossi G
- Subjects
- Aged, Aged, 80 and over, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Retrospective Studies, Survival Rate, Induction Chemotherapy, Leukemia, Myeloid, Acute diet therapy, Leukemia, Myeloid, Acute mortality
- Published
- 2015
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12. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.
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Kröger N, Giorgino T, Scott BL, Ditschkowski M, Alchalby H, Cervantes F, Vannucchi A, Cazzola M, Morra E, Zabelina T, Maffioli M, Pereira A, Beelen D, Deeg HJ, and Passamonti F
- Subjects
- Adult, Allografts, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Proportional Hazards Models, Young Adult, Hematopoietic Stem Cell Transplantation, Primary Myelofibrosis mortality, Primary Myelofibrosis surgery
- Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21-0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate-1 risk., (© 2015 by The American Society of Hematology.)
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- 2015
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13. Autologous stem cell transplantation with in vivo purged progenitor cells shows long-term efficacy in relapsed/refractory follicular lymphoma.
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Arcaini L, Morello L, Tucci A, Rusconi C, Ladetto M, Rattotti S, Bonfichi M, Bottelli C, Gabutti C, Bernasconi P, Varettoni M, Gotti M, Troletti D, Guerrera ML, Fiaccadori V, Sciarra R, Ferretti VV, Alessandrino EP, Rossi G, and Morra E
- Subjects
- Adult, Aged, Anthracyclines administration & dosage, Antibodies, Monoclonal, Murine-Derived administration & dosage, Cyclophosphamide administration & dosage, Female, Gene Expression, Humans, Lymphoma, Follicular mortality, Lymphoma, Follicular pathology, Male, Middle Aged, Neoplasm Grading, Prednisone administration & dosage, Prospective Studies, Proto-Oncogene Proteins c-bcl-2 deficiency, Proto-Oncogene Proteins c-bcl-2 genetics, Recurrence, Rituximab, Survival Analysis, Transplantation, Autologous, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols, Hematopoietic Stem Cell Mobilization methods, Hematopoietic Stem Cell Transplantation, Lymphoma, Follicular therapy
- Abstract
High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2015
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14. Feasibility of romiplostim discontinuation in adult thrombopoietin-receptor agonist responsive patients with primary immune thrombocytopenia: an observational retrospective report in real life clinical practice.
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Carpenedo M, Cantoni S, Coccini V, Fedele M, Morra E, and Pogliani EM
- Abstract
Thrombopoietin mimetics are new treatment options for patients with immune throm-bocytopenia (ITP). Because of their mechanism of action, long-term administration was envisioned in order to maintain effective thrombopoiesis. We report on 30 romiplostim treated patients: 13/27 responders (48%) achieved stable platelet counts on a mean romiplostim dose of 2.43 µg/kg and were able to stop romiplostim after a mean of 44.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 26 months (range 12-52). No bleeding events occurred during the observational period. No specific patient's features nor pattern of early response seemed to predict for sustained response. However, patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Our observations support feasibility of romiplostim safe suspension in a relevant proportion of ITP patients.
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- 2015
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15. Rapid clearance of HCV-related splenic marginal zone lymphoma under an interferon-free, NS3/NS4A inhibitor-based treatment. A case report.
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Rossotti R, Travi G, Pazzi A, Baiguera C, Morra E, and Puoti M
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- Adult, Biopsy, Hepatitis C, Chronic virology, Humans, Intracellular Signaling Peptides and Proteins, Lymphoma etiology, Lymphoma pathology, Male, Splenic Neoplasms etiology, Splenic Neoplasms pathology, Antiviral Agents therapeutic use, Carrier Proteins antagonists & inhibitors, DNA, Viral analysis, Hepacivirus genetics, Hepatitis C, Chronic complications, Lymphoma drug therapy, Splenic Neoplasms drug therapy, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
Chronic infection with hepatitis C virus (HCV) may lead to B cell activation and transformation into non-Hodgkin lymphoma (NHL). Molecular mechanisms of B cell transformation by HCV are poorly understood. One of the most common lymphoproliferative disorders in HCV-infected patients is splenic marginal zone lymphoma (SMZL). A case of a 42-years old man, affected by HCV-related SMZL, effectively treated with an IFN-free, NS3-NS4A inhibitor-based regimen, is hereby described. The patient was treated for 16 weeks with faldaprevir, deleobuvir, and ribavirin, achieving a very rapid viral eradication without relevant toxicities. A rapid haematologic response was noted as well, with a statistically significant correlation between viral decay and lymphocyte improvement (coefficient r = 0.55, p = 0.042). The viral clearance led to SMZL cure, even without the use of IFN. Thus, the causative role, played by HCV in SMZL development, is once again reinforced, whereby the antiviral, rather than the anti-proliferative activity of IFN is indirectly proven. A regimen including DAAs should be considered when treating a HCV-related extra-hepatic disease., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
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16. Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia.
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Tedeschi A, Picardi P, Ferrero S, Benevolo G, Margiotta Casaluci G, Varettoni M, Baratè C, Motta M, Gini G, Goldaniga MC, Visco C, Zaja F, Belsito Petrizi V, Ravelli E, Gentile M, Urbano MA, Franceschetti S, Ghione P, Orsucci L, Frustaci AM, Gaidano G, Vitolo U, and Morra E
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride administration & dosage, Female, Follow-Up Studies, Humans, Male, Middle Aged, Recurrence, Retreatment, Retrospective Studies, Rituximab administration & dosage, Salvage Therapy, Treatment Outcome, Waldenstrom Macroglobulinemia diagnosis, Waldenstrom Macroglobulinemia mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Waldenstrom Macroglobulinemia drug therapy
- Abstract
According to the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines on Waldenström macroglobulinemia, bendamustine (B) may be considered a suitable therapeutic option. To address the role of B in combination with rituximab (BR), we analyzed the outcome of 71 patients with relapsed/refractory disease, median age 72 years, treated with R 375 mg/m(2) day 1 and B days 1 and 2 (dosage ranging from 50 to 90 mg/m(2)). Patients had previously received a median number of 2 lines of treatment (range 1-5). Overall and major response rates were 80.2% and 74.6%. Major toxicity was grade 3/4 neutropenia occurring in 13% of courses. There was no significant association between baseline features or patients' characteristics and response achievement. Median progression-free survival was not reached after a median follow-up of 19 months (range 3-54). None of the patients developed aggressive lymphoma or secondary myelodysplastic syndrome/acute myeloid leukemia. BR was found to be an active and well-tolerated salvage regimen leading to rapid disease control.
- Published
- 2015
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17. Bendamustine and subcutaneous alemtuzumab combination is an effective treatment in relapsed/refractory chronic lymphocytic leukemia patients.
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Montillo M, Tedeschi A, Gaidano G, Coscia M, Petrizzi VB, Orlandi E, Cascavilla N, Ghia P, Motta M, Gallamini A, Frustaci AM, Rossi D, De Paoli L, Nichelatti M, Morra E, and Massaia M
- Subjects
- Adolescent, Adult, Aged, Alemtuzumab, Bendamustine Hydrochloride, Drug Administration Schedule, Drug Combinations, Female, Humans, Injections, Intravenous, Injections, Subcutaneous, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Recurrence, Survival Analysis, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Alkylating therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Nitrogen Mustard Compounds therapeutic use
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- 2014
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18. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.
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Dimopoulos MA, Kastritis E, Owen RG, Kyle RA, Landgren O, Morra E, Leleu X, García-Sanz R, Munshi N, Anderson KC, Terpos E, Ghobrial IM, Morel P, Maloney D, Rummel M, Leblond V, Advani RH, Gertz MA, Kyriakou C, Thomas SK, Barlogie B, Gregory SA, Kimby E, Merlini G, and Treon SP
- Subjects
- Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Bendamustine Hydrochloride, Boronic Acids therapeutic use, Bortezomib, Clinical Trials as Topic, Consensus Development Conferences as Topic, Disease Progression, Everolimus, Hematopoietic Stem Cell Transplantation, Humans, Immunologic Factors therapeutic use, Nitrogen Mustard Compounds therapeutic use, Pyrazines therapeutic use, Rituximab, Salvage Therapy, Sirolimus analogs & derivatives, Sirolimus therapeutic use, Treatment Outcome, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Waldenstrom Macroglobulinemia therapy
- Abstract
Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.
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- 2014
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19. Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience.
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Nosari AM, Pioltelli ML, Riva M, Marbello L, Nichelatti M, Greco A, Molteni A, Vismara E, Gabutti C, Volonterio A, Lombardi P, and Morra E
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- Aged, Antifungal Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Humans, Incidence, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders drug therapy, Male, Middle Aged, Mortality, Mycoses diagnosis, Mycoses drug therapy, Prognosis, Retrospective Studies, Treatment Outcome, Lymphoproliferative Disorders complications, Mycoses complications, Mycoses epidemiology
- Abstract
Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.
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- 2014
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20. Carfilzomib: a new opportunity for WM patients.
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Morra E
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- Female, Humans, Male, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Peripheral Nervous System Diseases prevention & control, Waldenstrom Macroglobulinemia drug therapy
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- 2014
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21. Current management of CML patients: Summary of the Italian Consensus Meeting held in Rome, April 11-12, 2013.
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Breccia M, Alimena G, Baccarani M, Bocchia M, Di Raimondo F, Gambacorti-Passerini C, Gozzini A, Morra E, Pane F, Pregno P, Rege-Cambrin G, Rosti G, Specchia G, Vigneri P, and Saglio G
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- Disease Management, Humans, Treatment Outcome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy
- Abstract
Treatment of Chronic Myeloid Leukaemia (CML) has evolved rapidly in the last 10 years. The objectives of this national consensus meeting were to describe the optimal procedures to perform at diagnosis, the most appropriate choice of tyrosine kinase inhibitor (TKI) in the first line setting, the correct monitoring procedures, the appropriate timing for resistance identification allowing a rapid TKI switch, and the future possibility of treatment discontinuation. A panel of experts in CML management were invited for a 2-day workshop. Prior to the conference, the organizing committee selected several topics and assigned them to different physicians divided in four groups. Issues discussed were (1) role of cytogenetic and molecular response monitoring in 2013; (2) frontline treatment of CML in 2013 and therapeutic objectives; (3) how to monitor response and when to change therapy after resistance or non-optimal responses; (4) possible therapy discontinuation after achievement of deep and stable molecular responses. Different national experts reviewed the literature, analyzed levels of evidence for each topic and, after extensive discussions within smaller working groups, presented their conclusions during the meeting. Each consensus aim was then evaluated by a general vote in the plenary sessions., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
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- 2014
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22. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts.
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Passamonti F, Maffioli M, Cervantes F, Vannucchi AM, Morra E, Barbui T, Caramazza D, Pieri L, Rumi E, Gisslinger H, Knoops L, Kiladjian JJ, Mora B, Hollaender N, Pascutto C, Harrison C, and Cazzola M
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Janus Kinases antagonists & inhibitors, Kaplan-Meier Estimate, Male, Middle Aged, Nitriles, Primary Myelofibrosis mortality, Prognosis, Protein Kinase Inhibitors therapeutic use, Pyrimidines, Primary Myelofibrosis drug therapy, Pyrazoles therapeutic use
- Abstract
The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.
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- 2014
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23. Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition.
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Morra E, Varettoni M, Tedeschi A, Arcaini L, Ricci F, Pascutto C, Rattotti S, Vismara E, Paris L, and Cazzola M
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- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Neoplasms, Second Primary epidemiology, Retrospective Studies, Risk, Waldenstrom Macroglobulinemia drug therapy, Watchful Waiting, Genetic Predisposition to Disease, Neoplasms, Second Primary etiology, Waldenstrom Macroglobulinemia complications, Waldenstrom Macroglobulinemia genetics
- Abstract
Background: Several population-based and cohort studies have reported an increased risk of second cancers in lymphoproliferative disorders (LPDs). The cause of second cancers in LPDs is probably multifactorial, and the relative contribution of treatments, genetic predisposition, and immune dysfunction typical of LPDs is still unclear., Patients and Methods: We retrospectively studied 230 patients with Waldenström macroglobulinemia (WM) to assess the frequency, characteristics, and predictive factors of second cancers and to evaluate whether patients with WM are at higher risk of second cancers compared with an age- and sex-matched control population., Results: In a competing-risk model, the cumulative incidence of solid cancers was 6% at 5 years, 11% at 10 years, and 17% at 15 years, whereas the incidence of hematologic malignancies was 4% at 5 years, 7% at 10 years, and 8% at 15 years. Compared with an age- and sex-matched population, the overall risk of second cancers was 1.7-fold higher than expected (95% confidence interval [CI], 1.22-2.38; P = .002). Patients with WM were at increased risk for diffuse large B-cell lymphoma (DLBCL) (standardized incidence ratio [SIR], 8.64; 95% CI, 3.88-19.22; P < .0001), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (SIR 9.5; 95% CI, 3.6-25.3; P < .0001), and brain cancer (SIR, 7.59; 95% CI, 1.9-30.4; P < .0001). The risk of a second hematologic malignancy was 5-fold higher in treated than in untreated patients (P = .08)., Conclusion: Patients with WM are at increased risk of DLBCL, MDS/AML, and brain cancers compared with the general population. Further studies are needed to clarify whether the increased incidence of second cancers is related to treatments, to the immunologic impairment associated with the disease, or to genetic predisposition., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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24. Hematological improvement during iron-chelation therapy in myelodysplastic syndromes: the experience of the "Rete Ematologica Lombarda".
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Molteni A, Riva M, Pellizzari A, Borin L, Freyrie A, Greco R, Ubezio M, Bernardi M, Fariciotti A, Nador G, Nichelatti M, Ravano E, and Morra E
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Ferritins blood, Humans, Iron blood, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Retrospective Studies, Transfusion Reaction, Young Adult, Blood Cell Count, Erythrocyte Indices, Iron Chelating Agents therapeutic use, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes therapy
- Abstract
To analyze the unpredicted event of hematological improvement (HI) during iron-chelation therapy (ICT), we reviewed a series of 53 myelodysplastic patients with transfusion dependency in a retrospective study involving 8 centers afferent to the "Rete Ematologica Lombarda". According to the IWG response criteria published in the year 2000, we observed erythroid responses in 19 patients (35.1%), 5 major (9.2%) and 14 minor (25.9%). In the assessable patients, platelet response was 8/13 (61%) and neutrophil response was 13/17 (76.4%). Only in patients with erythroid improvement, multilineage responses were observed. Apparently, patients with greater erythropoiesis dysfunction may take more advantage., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
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- 2013
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25. Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups.
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Onida F, Barosi G, Leone G, Malcovati L, Morra E, Santini V, Specchia G, and Tura S
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- Disease Management, Humans, Leukemia, Myelomonocytic, Chronic diagnosis, Consensus, Leukemia, Myelomonocytic, Chronic therapy, Practice Guidelines as Topic standards, Societies, Medical standards, World Health Organization
- Abstract
With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥ 10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients.
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- 2013
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26. Should a positive direct antiglobulin test be considered a prognostic predictor in chronic lymphocytic leukemia?
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Ricci F, Tedeschi A, Vismara E, Colombo C, Veronese S, Nichelatti M, Cairoli R, Morra E, and Montillo M
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- Adult, Aged, Aged, 80 and over, Coombs Test instrumentation, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Male, Middle Aged, Prognosis, Retrospective Studies, Coombs Test methods, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
- Abstract
Background: The clinical course of patients with B-cell CLL is often complicated by autoimmune phenomena. The DAT might be positive at some time during the course of the disease in up to 35% of cases. The aim of this retrospective study was to investigate the relationship between the occurrence of a positive DAT and biological features of CLL patients., Patients and Methods: In our institution, 146 untreated patients with CLL were studied using the DAT., Results: According to the statistical analysis, a high level of β2-microglobulin and unmutated IgHV emerged as factors significantly related to the presence of DAT positivity. Time to first TFS was significantly shorter in DAT-positive patients. The adverse effect of a DAT positive result was maintained in terms of TFS when patients with mutated IgHV status were excluded from statistical analysis., Conclusion: These results suggest that the DAT might provide additional prognostic information regarding patients with IgHV unmutated status., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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27. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
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Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, and Platzbecker U
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Arsenic Trioxide, Arsenicals adverse effects, Consolidation Chemotherapy, Disease-Free Survival, Female, Humans, Induction Chemotherapy, Leukemia, Promyelocytic, Acute genetics, Maintenance Chemotherapy, Male, Middle Aged, Neutropenia chemically induced, Oxides adverse effects, Thrombocytopenia chemically induced, Tretinoin adverse effects, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenicals therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Oxides therapeutic use, Tretinoin therapeutic use
- Abstract
Background: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity., Methods: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%., Results: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity., Conclusions: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).
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- 2013
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28. Old and new prognostic factors in acute myeloid leukemia with deranged core-binding factor beta.
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Cairoli R, Beghini A, Turrini M, Bertani G, Nadali G, Rodeghiero F, Castagnola C, Lazzaroni F, Nichelatti M, Ferrara F, Pizzolo G, Pogliani E, Rossi G, Martinelli G, and Morra E
- Subjects
- Adolescent, Adult, Age Factors, Core Binding Factor beta Subunit genetics, Female, Follow-Up Studies, Gene Expression, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Leukocyte Count, Leukocytes pathology, Male, Middle Aged, Mutation, Prognosis, Proto-Oncogene Proteins c-kit blood, Proto-Oncogene Proteins c-kit genetics, Sex Factors, Survival Analysis, Antineoplastic Agents therapeutic use, Core Binding Factor beta Subunit blood, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute diagnosis
- Abstract
Acute myeloid leukemia (AML) with deranged core-binding factor beta (CBFβ) is usually associated with a favorable prognosis with 50-70% of patients cured using contemporary treatments. We analyzed the prognostic significance of clinical features on 58 patients with CBFβ-AML aged ≤60 years. Increasing age was the only predictor for survival (P <0.001), with an optimal cut-point at 43 years. White blood cells (WBCs) at diagnosis emerged as an independent risk factor for relapse incidence (P = 0.017), with 1.1% increase of hazard for each 1.0 × 10(9) /L WBC increment. KIT mutations lacked prognostic value for survival and showed only a trend for relapse incidence (P = 0.069)., (Copyright © 2013 Wiley Periodicals, Inc.)
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- 2013
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29. Splenectomy as a curative treatment for immune thrombocytopenia: a retrospective analysis of 233 patients with a minimum follow up of 10 years.
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Vianelli N, Palandri F, Polverelli N, Stasi R, Joelsson J, Johansson E, Ruggeri M, Zaja F, Cantoni S, Catucci AE, Candoni A, Morra E, Björkholm M, Baccarani M, and Rodeghiero F
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Incidence, Infant, Male, Middle Aged, Postoperative Complications epidemiology, Prognosis, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic mortality, Retrospective Studies, Treatment Outcome, Young Adult, Purpura, Thrombocytopenic, Idiopathic surgery, Splenectomy
- Abstract
The treatment of choice in steroid-resistant immune thrombocytopenia is still controversial due to the recent advent of new drugs (anti-CD20 antibodies and thrombopoietin mimetics) that have encouraged a generalized tendency to delay splenectomy. Consequently, it is extremely importance to define the efficacy and safety of splenectomy in the long term. We retrospectively analyzed the data of 233 patients affected by immune thrombocytopenia who underwent splenectomy between 1959 and 2001 in 6 European hematologic institutions and who have now a minimum follow up of ten years from surgery. Of the 233 patients, 180 (77%) achieved a complete response and 26 (11%) a response. Sixty-eight of 206 (33%) responsive patients relapsed, mostly (75%) within four years from first response. In 92 patients (39.5%), further treatment was required after splenectomy that was effective in 76 cases (83%). In 138 patients (59%), response was maintained free of any treatment at last contact. No significant association between baseline characteristics and likelihood of stable response was found. Overall, 73 (31%) and 58 (25%) patients experienced at least one infectious or hemorrhagic complication, which was fatal in 2 and 3 patients, respectively. A stable response to splenectomy was associated with a lower rate of infections (P=0.004) and hemorrhages (P<0.0001). Thrombosis developed in 18 patients (8%) and was fatal in 4. Splenectomy achieved a long-term stable response in approximately 60% of cases. Complications mainly affected non-responding patients and were fatal in a minority.
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- 2013
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30. Verifying Hellström-Lindberg score as predictive tool for response to erythropoietin therapy according to the "International Working Group" criteria, in anemic patients affected by myelodysplastic syndrome: a monocentric experience.
- Author
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Molteni A, Riva M, Greco R, Nichelatti M, Ravano E, Marbello L, Nosari A, and Morra E
- Subjects
- Adult, Aged, Aged, 80 and over, Anemia diagnosis, Databases, Factual, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Prognosis, ROC Curve, Risk Factors, Treatment Outcome, Anemia drug therapy, Anemia etiology, Erythropoietin therapeutic use, Myelodysplastic Syndromes complications
- Abstract
The Hellström-Lindberg score (HLS) (1997) is designed to predict erythroid response to erythropoietin treatment in myelodysplastic patients. In order to test the validity of this scoring system, 58 patients affected by myelodysplastic syndrome, treated with a "standard dose" approach between 2001 and 2010, were analyzed. The response to erythropoietin treatment was evaluated in accordance with the "international working group" (IWG) criteria. Among the patients only two were scored "poor," 12 "intermediate," and 44 "good" (15 of whom were scored "3" and 29 "4"). Although the system was verified as a predictive tool for response to erythropoietin therapy, we noted that of patients scored as "good," those with a numerical score of "4" responded more frequently than did those scored "3", as evaluated under both the 2006- and 2000-IWG ("major response") criteria. The modest response rate in patients scoring "3" did not show a difference in response rate in comparison to the "intermediate" group. The present data suggest that only patients scoring "4" on the scale may show an adequate response to the standard dose erythropoietin therapy, while frontline high-dose therapy should be offered to other patients. A further analysis considering endogenous erythropoietin as a possible determinant of response revealed the optimal cut-off value of 80 mIU/mL, instead of the value of 100 mIU/mL utilized by the HLS.
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- 2013
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31. Microarray demonstrates different gene expression profiling signatures between Waldenström macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.
- Author
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Trojani A, Greco A, Tedeschi A, Lodola M, Di Camillo B, Ricci F, Turrini M, Varettoni M, Rattotti S, and Morra E
- Subjects
- Bone Marrow Cells metabolism, Carbohydrate Metabolism genetics, Cluster Analysis, Humans, Immunoglobulin M blood, Monoclonal Gammopathy of Undetermined Significance metabolism, Signal Transduction, Syndecan-1 genetics, Syndecan-1 metabolism, Waldenstrom Macroglobulinemia metabolism, Gene Expression Profiling, Monoclonal Gammopathy of Undetermined Significance genetics, Waldenstrom Macroglobulinemia genetics
- Abstract
Waldenström macroglobulinemia (WM) (symptomatic and indolent) and immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgMMGUS) can be identified based on the bone marrow (BM) infiltration and the existence of symptoms. The purpose of this study was to investigate the biological and genetic characteristics of both disorders comparing the molecular signature of WM versus IgMMGUS using microarray analysis. We investigated BM CD19(+) cells isolated from 21 WM patients and 10 IgMMGUS cases, and CD138(+) BM cells isolated from all of the WM patients and 4 of the IgMMGUS cases. Gene expression profiling of WM versus IgMMGUS CD19(+) cells highlighted 151 differently expressed genes and the comparison with CD138(+) cells demonstrated 43 differently expressed genes in WM versus IgMMGUS. Regulation of transcription, Janus kinase/signal transducer and activator of transcription, PI3K/Akt/mammalian target of rapamycin, mitogen-activated protein kinase signaling pathways are the relevant gene ontology biological processes occurring in CD19(+) cells, and immune response, cell activation, and signaling processes developing in CD138(+) cells mainly distinguish WM and IgMMGUS., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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32. Fludarabine, cyclophosphamide, and rituximab in salvage therapy of Waldenström's macroglobulinemia.
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Tedeschi A, Ricci F, Goldaniga MC, Benevolo G, Varettoni M, Motta M, Pioltelli P, Gini G, Barate' C, Luraschi A, Vismara E, Frustaci AM, Nichelatti M, Vitolo U, Baldini L, and Morra E
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Female, Humans, Male, Middle Aged, Retrospective Studies, Rituximab, Salvage Therapy, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Waldenstrom Macroglobulinemia mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Waldenstrom Macroglobulinemia drug therapy
- Abstract
The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenström's macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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33. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction.
- Author
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Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X, Morra E, Trojani A, Greco A, Arcaini L, Varettoni M, Brown JR, Tai YT, Anderson KC, Munshi NC, Patterson CJ, Manning RJ, Tripsas CK, Lindeman NI, and Treon SP
- Subjects
- Adult, Aged, Alleles, Amino Acid Substitution physiology, Base Sequence, Case-Control Studies, Cell Transformation, Neoplastic genetics, DNA Mutational Analysis, Humans, Leucine genetics, Lymphoproliferative Disorders immunology, Male, Middle Aged, Molecular Sequence Data, Monoclonal Gammopathy of Undetermined Significance immunology, Monoclonal Gammopathy of Undetermined Significance metabolism, Polymorphism, Single Nucleotide physiology, Proline genetics, B-Lymphocytes metabolism, B-Lymphocytes pathology, Immunoglobulin M genetics, Immunoglobulin M metabolism, Lymphoproliferative Disorders genetics, Monoclonal Gammopathy of Undetermined Significance genetics, Myeloid Differentiation Factor 88 genetics, Polymerase Chain Reaction methods, Waldenstrom Macroglobulinemia genetics
- Abstract
By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.
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- 2013
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34. Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop.
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Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, Garcia-Sanz R, Ocio EM, Morra E, Morel P, Anderson KC, Patterson CJ, Munshi NC, Tedeschi A, Joshua DE, Kastritis E, Terpos E, Ghobrial IM, Leleu X, Gertz MA, Ansell SM, Morice WG, Kimby E, and Treon SP
- Subjects
- Antibodies, Monoclonal blood, Antibodies, Monoclonal therapeutic use, Antimetabolites therapeutic use, Bone Marrow Examination methods, Bone Marrow Examination standards, Boronic Acids therapeutic use, Bortezomib, Densitometry, Disease Progression, Disease-Free Survival, Forecasting, Hematopoiesis, Humans, Immunoglobulin Light Chains blood, Immunoglobulin M blood, Immunosuppressive Agents therapeutic use, Neoplasm, Residual, Nephelometry and Turbidimetry, Positron-Emission Tomography, Pyrazines therapeutic use, Remission Induction, Survival Analysis, Tomography, X-Ray Computed, Treatment Outcome, Waldenstrom Macroglobulinemia blood, Waldenstrom Macroglobulinemia pathology, Waldenstrom Macroglobulinemia drug therapy
- Abstract
This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials., (© 2012 Blackwell Publishing Ltd.)
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- 2013
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35. Regeneration-associated WNT signaling is activated in long-term reconstituting AC133bright acute myeloid leukemia cells.
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Beghini A, Corlazzoli F, Del Giacco L, Re M, Lazzaroni F, Brioschi M, Valentini G, Ferrazzi F, Ghilardi A, Righi M, Turrini M, Mignardi M, Cesana C, Bronte V, Nilsson M, Morra E, and Cairoli R
- Subjects
- AC133 Antigen, Animals, Antigens, CD metabolism, Bone Marrow Cells metabolism, Cell Line, Tumor, Gene Expression Profiling, Glycoproteins metabolism, Humans, Leukocytes, Mononuclear metabolism, Peptides metabolism, Phosphorylation, Primary Cell Culture, Proto-Oncogene Proteins genetics, Wnt Proteins genetics, Zebrafish, Hematopoietic Stem Cells metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Proto-Oncogene Proteins metabolism, Regeneration genetics, Wnt Proteins metabolism, Wnt Signaling Pathway genetics, beta Catenin metabolism
- Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/β-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated β-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)γc(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration.
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- 2012
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36. Improving survival trends in primary myelofibrosis: an international study.
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Cervantes F, Dupriez B, Passamonti F, Vannucchi AM, Morra E, Reilly JT, Demory JL, Rumi E, Guglielmelli P, Roncoroni E, Tefferi A, and Pereira A
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- Adult, Age Factors, Aged, Aged, 80 and over, Europe, Female, Humans, Male, Middle Aged, Primary Myelofibrosis diagnosis, Primary Myelofibrosis therapy, Risk, Sex Factors, Survival Rate trends, Young Adult, Primary Myelofibrosis mortality
- Abstract
Purpose: Despite the lack of major improvements in the treatment of primary myelofibrosis (PMF), there are recent indications that the survival of patients might have increased over the years. This study was aimed at ascertaining whether survival prolongation has actually occurred in PMF., Patients and Methods: A total of 802 patients diagnosed with PMF in four European countries were compared for the presentation of features and survival according to the diagnostic periods 1980 to 1995 (n = 434) and 1996 to 2007 (n = 368); relative survival was estimated for the two groups., Results: Patients diagnosed between 1996 and 2007 more often had constitutional symptoms (31% v 23%) but a lower incidence of marked anemia (31% v 39%), leukocytosis greater than 25 × 10(9)/L (9% v 13%), and blood blasts (27% v 33%); risk distribution was comparable between the two groups. Median survival was 4.6 years (95% CI, 4.0 to 5.1) for patients from 1980 to 1995 and 6.5 years (95% CI, 5.5 to 7.4) for patients from 1996 to 2007 (P < .001). The latter group of patients showed improved relative survival, especially for women, patients younger than age 65 years, and patients with low or intermediate-1-risk disease. Rates of PMF-attributable mortality at 5 and 10 years were significantly lower in the second period; this reduction in disease-specific mortality occurred across all patient subgroups, except in intermediate-2-risk or high-risk patients., Conclusion: Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations.
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- 2012
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37. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls.
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Verstovsek S, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Kadia T, Pierce S, Jabbour E, Borthakur G, Rumi E, Pungolino E, Morra E, Caramazza D, Cazzola M, and Passamonti F
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Clinical Trials, Phase I as Topic statistics & numerical data, Clinical Trials, Phase II as Topic statistics & numerical data, Clinical Trials, Phase III as Topic statistics & numerical data, Cohort Studies, Female, Follow-Up Studies, Humans, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 2 antagonists & inhibitors, Male, Medication Adherence statistics & numerical data, Middle Aged, Nitriles, Primary Myelofibrosis diagnosis, Primary Myelofibrosis epidemiology, Protein Kinase Inhibitors therapeutic use, Pyrimidines, Randomized Controlled Trials as Topic statistics & numerical data, Survival Analysis, Survivors statistics & numerical data, Treatment Outcome, Primary Myelofibrosis drug therapy, Primary Myelofibrosis mortality, Pyrazoles therapeutic use
- Abstract
Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.
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- 2012
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38. Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups.
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Hengeveld M, Suciu S, Karrasch M, Specchia G, Marie JP, Muus P, Petti MC, Rotoli B, Amadori S, Fioritoni G, Leoni P, Morra E, Thaler J, Resegotti L, Fazi P, Vignetti M, Mandelli F, Zittoun R, and de Witte T
- Subjects
- Adolescent, Adult, Age Factors, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Consolidation Chemotherapy standards, Europe, Female, Hematology methods, Hematology organization & administration, Humans, Induction Chemotherapy methods, International Cooperation, Italy, Maintenance Chemotherapy standards, Male, Medical Oncology methods, Medical Oncology organization & administration, Middle Aged, Societies, Medical organization & administration, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Consolidation Chemotherapy methods, Leukemia, Myeloid, Acute drug therapy, Maintenance Chemotherapy methods
- Abstract
The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group.
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- 2012
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39. Quality of life in elderly patients with essential thrombocythaemia. An Italian multicentre study.
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Oliva EN, Piccin A, Mazzucconi MG, Morra E, Recine U, Pogliani EM, Pane F, Gobbi M, Gugliotta L, Krampera M, Cascavilla N, Cacciola R, Cacciola E, Fioritoni G, Fanin R, Liberati AM, Angelucci E, and Tura S
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- Aged, Cross-Sectional Studies, Female, Humans, Italy, Male, Middle Aged, Surveys and Questionnaires, Thrombocythemia, Essential pathology, Quality of Life, Thrombocythemia, Essential physiopathology
- Abstract
Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts and increased incidence of thrombosis and haemorrhage. Median age at diagnosis is 65-70 years. Life expectancy is similar to that of the healthy population. Symptoms and complications may affect quality of life (QoL); in particular, in elderly patients ET may represent an additional burden. We performed a survey in 494 elderly ET patients to evaluate patient-reported outcomes (PROs). Comorbidities were present in 305 (62%) patients. Factorial analysis based on survey items representing psychological aspects of daily life identified an "attitude domain" with four clusters of patients: (A) very pessimistic (n = 99), (B) pessimistic (n = 101), (C) optimistic (n = 90), and (D) very optimistic (n = 107). Patients in cluster A had more comorbidities (p = 0.003) while patients in cluster D required fewer medical visits and were less disturbed by medications (p < 0.0001). Independent factors predicting Short-Form Health Survey, version 2 physical QoL were grade of optimism (p < 0.0001), gender (p = 0.007), and Charlson comorbidity index (p < 0.0001)). Grade of optimism and disturbances related to medication predicted mental QOL (p < 0.0001). In conclusion, physicians should take into consideration PROs, as "attitude" is associated with physical and mental QoL. Treatment should be tailored to patients' needs according to comorbidities, lifestyle, and psychological conditions.
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- 2012
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40. Erythroleukemia presenting with myeloid sarcoma of the lung as detected by immunophenotypic analysis of bronchoalveolar lavage fluid.
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Cesana C, Marbello L, Scarpati B, Calzavara E, Vanzulli A, Soriani S, Nosari A, and Morra E
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Diagnosis, Differential, Humans, Immunophenotyping, Leukemia, Erythroblastic, Acute drug therapy, Leukemia, Erythroblastic, Acute metabolism, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Male, Middle Aged, Prognosis, Sarcoma, Myeloid drug therapy, Sarcoma, Myeloid metabolism, Tomography, X-Ray Computed, Bronchoalveolar Lavage Fluid chemistry, Leukemia, Erythroblastic, Acute diagnosis, Lung Neoplasms diagnosis, Sarcoma, Myeloid diagnosis
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- 2012
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41. Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease.
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Tedeschi A, Benevolo G, Varettoni M, Battista ML, Zinzani PL, Visco C, Meneghini V, Pioltelli P, Sacchi S, Ricci F, Nichelatti M, Zaja F, Lazzarino M, Vitolo U, and Morra E
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Drug Administration Schedule, Female, Humans, Immunosuppression Therapy, Male, Middle Aged, Rituximab, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Waldenstrom Macroglobulinemia drug therapy
- Abstract
Background: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM)., Methods: Forty-three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m(2) intravenously on day 1 and fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses., Results: The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow-up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2-microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long-lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow-up., Conclusions: The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good-quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration., (Copyright © 2011 American Cancer Society.)
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- 2012
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42. Cerebral hemorrhage treated with NovoSeven in acute promyelocytic leukemia.
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Nosari A, Caimi TM, Zilioli V, Molteni A, Mancini V, and Morra E
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- Adult, Cerebral Hemorrhage complications, Humans, Male, Recombinant Proteins therapeutic use, Treatment Outcome, Cerebral Hemorrhage drug therapy, Factor VIIa therapeutic use, Leukemia, Promyelocytic, Acute complications
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- 2012
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43. An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia.
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Montillo M, Tedeschi A, Petrizzi VB, Ricci F, Crugnola M, Spriano M, Spedini P, Ilariucci F, Uziel L, Attolico I, Vismara E, De Blasio A, Zaccaria A, and Morra E
- Subjects
- Administration, Oral, Adult, Aged, Alemtuzumab, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Disease-Free Survival, Female, Humans, Injections, Subcutaneous, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Pilot Projects, Recurrence, Survival Rate, Time Factors, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell prevention & control
- Abstract
Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m² per day, oral cyclophosphamide 250 mg/m² per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.
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- 2011
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44. Flow cytometry and cytomorphology evaluation of hematologic malignancy in cerebrospinal fluids: comparison with retrospective clinical outcome.
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Cesana C, Klersy C, Scarpati B, Brando B, Faleri M, Bertani G, Gatti A, Volpato E, Barba C, Ferri U, Scampini L, Grillo G, Lando G, Nosari A, Morra E, and Cairoli R
- Subjects
- Cytodiagnosis standards, Female, Flow Cytometry standards, Humans, Immunophenotyping, Male, Retrospective Studies, Sensitivity and Specificity, Treatment Outcome, Cerebrospinal Fluid cytology, Cytodiagnosis methods, Flow Cytometry methods, Hematologic Neoplasms cerebrospinal fluid, Hematologic Neoplasms diagnosis, Hematologic Neoplasms pathology
- Abstract
An independent clinical assessment was compared with flow cytometry (FCM) and cytomorphology results obtained on 227 cerebrospinal fluids investigated for hematologic malignancy, in a retrospective longitudinal study with a median observation time of 11 months. A combined method assessment (CMA), defining "positive" a sample if at least one method gave "positive" results, was also tested. Eleven out of 55 screening samples and 53 out of 166 follow-up samples resulted positive at clinical evaluation. FCM and CM were concordant with positive clinical assessment in 68.5% and 51.5% of cases, respectively. According to CMA, 10.5% of samples (resulting false negative by either FCM or cytomorphology) were rescued as true positive. FCM retained significantly higher accuracy than cytomorphology (p=0.0065) and 100% sensitivity when at least 220 leukocytes were acquired. CMA accuracy was higher than FCM accuracy and significantly higher than cytomorphology accuracy in the analysis of all samples (p<0.0001), samples from mature B/T cell neoplasms (p=0.0021), and samples drawn after intrathecal treatment (p=0.0001). When acquiring ≤220 leukocytes, FCM accuracy was poor, and combining cytomorphology added statistically significant diagnostic advantage (p=0.0043). Although FCM is the best diagnostic tool for evaluating CSF, morphology seems helpful especially when clinically positive follow-up samples are nearly acellular.
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- 2011
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45. Plerixafor and G-CSF for PBSC mobilization in patients with lymphoma who failed previous attempts with G-CSF and chemotherapy: a REL (Rete Ematologica Lombarda) experience.
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Arcaini L, Laszlo D, Rizzi S, Balzarotti M, Antoniazzi F, Zilioli VR, Guggiari E, Farina L, Todisco E, Bonfichi M, Alamos SM, Rossi G, Martinelli G, and Morra E
- Subjects
- Adult, Aged, Antigens, CD34 blood, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzylamines, Combined Modality Therapy, Compassionate Use Trials, Cyclams, Female, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Male, Middle Aged, Treatment Outcome, Young Adult, Granulocyte Colony-Stimulating Factor administration & dosage, Hematopoietic Stem Cell Mobilization methods, Heterocyclic Compounds administration & dosage, Lymphoma therapy, Peripheral Blood Stem Cell Transplantation methods
- Abstract
Plerixafor has been previously reported to improve PBSC collection in pts undergoing PBSC mobilization. Aim of the study was to assess the efficacy of plerixafor and G-CSF in pts with lymphoma who failed previous attempts of PBSC mobilization with conventional schemes of chemotherapy+G-CSF. 35 heavily pre-treated lymphoma pts (29 NHL, 6 HL) classified as "poor mobilizers" were enrolled in a program of compassionate use of plerixafor in 7 Italian centres of REL (Rete Ematologica Lombarda). Median number of previous lines of therapy was 3 and median number of previous attempts of mobilizations was 2. The median number of circulating CD34+ cells/μL following plerixafor was 11/μL. It was ≥10/μL in 17 pts and ≥20/μL in 10 pts; 13 were able to collect ≥2×10(6) CD34+ cells/kg with a median of 1 apheresis procedure; 4 pts collected ≥4×10(6) CD34+ cells/kg. A total of 6 pts had proceeded to transplant at the time of analysis. The median dose of PBSCs infused was 4×10(6)/kg and hematopoietic recovery was regular. In conclusion, plerixafor combined with G-CSF allows a collection of adequate number of PBSC in approximately 40% of cases of poor mobilizer, heavily pre-treated pts with lymphoma, who need consolidation with ASCT., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
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- 2011
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46. Relationship between pharmacokinetic profile of subcutaneously administered alemtuzumab and clinical response in patients with chronic lymphocytic leukemia.
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Montagna M, Montillo M, Avanzini MA, Tinelli C, Tedeschi A, Visai L, Ricci F, Vismara E, Morra E, and Regazzi M
- Subjects
- Alemtuzumab, Antibodies, Monoclonal blood, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm blood, Antineoplastic Agents blood, Humans, Injections, Subcutaneous, Kinetics, Leukemia, Lymphocytic, Chronic, B-Cell blood, Lymphocyte Count, Middle Aged, Neoplasm, Residual, Treatment Outcome, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Alemtuzumab serum levels and clinical response after subcutaneous administration (10 mg 3 times/week for six weeks) have been explored in 29 chronic lymphocytic leukemia patients receiving the monoclonal antibody as consolidation. Serum concentrations after each administration gradually increased during the first week and more markedly during weeks 2 and 3, approaching the steady-state at week 6. Absorption continued slowly through the tissues for about 2-3 weeks after the last administration, starting to decrease thereafter. Difference between Responders and Non-responders was statistically significant: maximal concentration (Cmax) was 1.69 μg/mL vs. 0.44 μg/mL; concentration before subcutaneous administration (Cpre-dose) on day 15 was 0.7 vs. 0.21 μg/mL, area under curve (AUC0-12h) was 11.09 vs. 2.26 μgxh/mL for Responders and Non-responders, respectively. Higher systemic exposure to alemtuzumab correlated with a better clinical response and minimal residual disease. Results suggest that an adjusted schedule according to serum level could improve clinical outcome of patients receiving subcutaneous alemtuzumab.
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- 2011
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47. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib.
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Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D'Emilio A, Stagno F, le Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Piazza, Valsecchi MG, and Kim DW
- Subjects
- Adult, Aged, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Benzamides, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Imatinib Mesylate, Kaplan-Meier Estimate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Odds Ratio, Piperazines administration & dosage, Piperazines adverse effects, Polymerase Chain Reaction, Protein Kinase Inhibitors therapeutic use, Pyrimidines administration & dosage, Pyrimidines adverse effects, Remission Induction, Time Factors, Treatment Outcome, Antineoplastic Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Piperazines therapeutic use, Pyrimidines therapeutic use
- Abstract
Background: Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking., Patients and Methods: Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan-Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch-Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ(2) distribution. All statistical tests were two-sided., Results: A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression., Conclusions: In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.
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- 2011
- Full Text
- View/download PDF
48. The incidence of pleural and pericardial effusion is not higher in patients receiving dasatinib at low doses. (Reply).
- Author
-
Visani G, Breccia M, Montefusco E, Morra E, Santini V, and Isidori A
- Subjects
- Dasatinib, Humans, Incidence, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Thiazoles adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive complications, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Pericardial Effusion epidemiology, Pericardial Effusion etiology, Pleural Effusion epidemiology, Pleural Effusion etiology, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Thiazoles therapeutic use
- Published
- 2011
- Full Text
- View/download PDF
49. Mutations of CD79A, CD79B and EZH2 genes in immunodeficiency-related non-Hodgkin lymphomas.
- Author
-
Capello D, Gloghini A, Martini M, Spina M, Tirelli U, Bertoni F, Rinaldi A, Morra E, Rambaldi A, Sinigaglia F, Larocca LM, and Carbone A
- Subjects
- Adult, Amino Acid Sequence, Enhancer of Zeste Homolog 2 Protein, Humans, Male, Middle Aged, Molecular Sequence Data, Polycomb Repressive Complex 2, CD79 Antigens genetics, DNA-Binding Proteins genetics, Immunologic Deficiency Syndromes genetics, Lymphoma, Non-Hodgkin genetics, Mutation, Transcription Factors genetics
- Published
- 2011
- Full Text
- View/download PDF
50. Report from the Sixth International Workshop on Waldenström's Macroglobulinemia.
- Author
-
Treon SP, Merlini G, Morra E, Patterson CJ, and Stone MJ
- Subjects
- Female, Humans, Male, Waldenstrom Macroglobulinemia
- Published
- 2011
- Full Text
- View/download PDF
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