298 results on '"Morra, Enrica"'
Search Results
2. Fludarabine, cytarabine, and granulocyte-colony stimulating factor for the treatment of high risk myelodysplastic syndromes
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Ferrara, Felicetto, Leoni, Franco, Pinto, Antonio, Mirto, Salvatore, Morra, Enrica, Zagonel, Vittorina, Mele, Giuseppina, Ciolli, Stefania, Magrin, Silvana, and Montillo, Marco
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Myelodysplastic syndromes ,Fludarabine -- Evaluation ,Cytarabine -- Evaluation ,Granulocyte colony-stimulating factor -- Health aspects ,Health - Published
- 1999
3. Serum CA 125 is of clinical value in the staging and follow-up of patients with non-Hodgkin's lymphoma: correlation with tumor parameters and disease activity
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Lazzarino, Mario, Orlandi, Ester, Klersy, Catherine, Astori, Cesare, Brusamolino, Ercole, Corso, Alessandro, Bellio, Laura, Gargantini, Livio, Morra, Enrica, and Bernasconi, Carlo
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Glycoproteins -- Measurement ,Tumor staging -- Physiological aspects ,Non-Hodgkin's lymphomas -- Physiological aspects ,Health - Published
- 1998
4. The role of systemic high-dose cytarabine in the treatment of central nervous system leukemia: clinical results in 46 patients
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Morra, Enrica, Lazzarino, Mario, Brusamolino, Ercole, Pagnucco, Guido, Castagnola, Carlo, Bernasconi, Paolo, Orlandi, Ester, Corso, Alessandro, Santagostino, Alberto, and Bernasconi, Carlo
- Subjects
Cytarabine -- Dosage and administration ,Acute leukemia ,Non-Hodgkin's lymphomas ,Nervous system tumors ,Health - Abstract
Background. Given the good penetration of systemic high-dose cytarabine (HDara-C) into the cerebrospinal fluid (CSF), this approach was used to treat patients with central nervous system (CNS) leukemia, either isolated or with concurrent extraneurologic disease (END). Methods. From 1983 to 1991, 46 adults with CNS involvement were treated with systemic HDara-C: 25 had acute lymphoblastic leukemia (ALL), 15 had high-grade non-Hodgkin lymphoma (NHL), 5 had acute myelogenous leukemia (AML), and 1 had lymphoid blast crisis of chronic myelogenous leukemia. Induction consisted of HDara-C 3 g/[m.sup.2] every 12 hours, by 3-hour infusion, for 8 doses (30 patients), or 6 doses (16 patients), followed by 4 doses at day 21. Results. Of 46 patients, 29 (63%) achieved complete remission (CR): 15/15 with isolated CNS leukemia, and 14/31 (45%) with CNS and concurrent marrow or lymph node disease. Of 17 patients not meeting CR criteria because of persistent END, 11 showed complete CNS response. The first 10 remitters were consolidated with monthly 4-dose courses of HDara-C. The remaining 19 received postinduction multidrug chemotherapy (including vincristine, doxorubicin, cyclophosphamide, Lasparaginase, etoposide plus intermediate-dose ara-C, mitoxantrone plus HDara-C) and intrathecal methotrexate (MTX) [+ or -] cranial radiation therapy. One patient underwent autologous and one allogeneic bone marrow transplant. Median CR duration was 7 months (range, 2-56+): 8 months for patients with isolated CNS leukemia, and 4 months for those with concurrent END. In only two patients was CNS the primary site of relapse. Three patients with isolated CNS leukemia are disease-free at 23, 40, and 56 months. The main toxicity was myelosuppression. No patient showed dose-limiting neurologic toxicity. Conclusions. Systemic HDara-C appears effective therapy for CNS leukemia, maximally in cases with isolated CNS involvement. HDara-C may be combined safely with cranial radiation therapy and intrathecal MTX. This approach for CNS leukemia, however, needs to be combined with additional treatments to eradicate residual disease in extraneurologic compartments.
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- 1993
5. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial
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Horwitz, Steven, O'Connor, Owen A, Pro, Barbara, Illidge, Tim, Fanale, Michelle, Advani, Ranjana, Bartlett, Nancy L, Christensen, Jacob Haaber, Morschhauser, Franck, Domingo-Domenech, Eva, Rossi, Giuseppe, Kim, Won Seog, Feldman, Tatyana, Lennard, Anne, Belada, David, Illés, Árpád, Tobinai, Kensei, Tsukasaki, Kunihiro, Yeh, Su-Peng, Shustov, Andrei, Hüttmann, Andreas, Savage, Kerry J, Yuen, Sam, Iyer, Swaminathan, Zinzani, Pier Luigi, Hua, Zhaowei, Little, Meredith, Rao, Shangbang, Woolery, Joseph, Manley, Thomas, Trümper, Lorenz, Aboulafia, David, Advani, Ranjana, Alpdogan, Onder, Ando, Kiyoshi, Arcaini, Luca, Baldini, Luca, Bellam, Naresh, Bartlett, Nancy, Belada, David, Yehuda, Dina Ben, Benedetti, Fabio, Borchman, Peter, Bordessoule, Dominique, Brice, Pauline, Briones, Javier, Caballero, Dolores, Carella, Angelo Michele, Chang, Hung, Cheong, June Weon, Cho, Seok-Goo, Choi, Ilseung, Choquet, Sylvain, Colita, Andrei, Congui, Angela Giovanna, D'amore, Francesco, Dang, Nam, Davison, Kelly, de Guibert, Sophie, Brown, Peter de Nully, Delwail, Vincent, Demeter, Judit, di Raimondo, Francesco, Do, Young Rok, Domingo, Eva, Douvas, Michael, Dreyling, Martin, Ernst, Thomas, Fanale, Michelle, Fay, Keith, Feldman, Tatyana, Ferrero, Silvia Fernandez, Flinn, Ian Winchester, Forero-Torres, Andres, Fox, Christopher, Friedberg, Jonathan, Fukuhara, Noriko, Garcia-Marco, Jose, Cruz, Jorge Gayoso, Codina, Jose Gomez, Gressin, Remy, Grigg, Andrew, Gurion, Ronit, Christensen, Jacob Haaber, Haioun, Corinne, Hajek, Roman, Hanel, Mathias, Hatake, Kiyohiko, Hensen, Robert, Horowitz, Netanel, Horwitz, Steven, Huttmann, Andreas, Illes, Arpad, Illidge, Tim, Ishizawa, Kenichi, Islas-Ohlmayer, Miguel, Jacobsen, Eric, Janakiram, Murali, Jurczak, Wojciech, Kaminski, Mark, Kato, Koji, Kim, Won Seog, Kirgner, Ilya, Iyer, Swaminathan, Kuo, Ching-Yuan, Lazaroiu, Mihaela Cornelia, Du, Katell Le, Lee, Jong-Seok, LeGouill, Steven, Lennard, Anne, LaRosee, Paul, Levi, Itai, Link, Brian, Maisonneuve, Herve, Maruyama, Dai, Mayer, Jiri, McCarty, John, McKay, Pam, Minami, Yosuke, Mocikova, Heidi, Morra, Enrica, Morschhauser, Franck, Munoz, Javier, Nagai, Hirokazu, O'Connor, Owen, Opat, Stephen, Pettengell, Ruth, Pezzutto, Antonio, Pfreundschuh, Michael, Pluta, Andrzej, Porcu, PierLuigi, Pro, Barbara, Quach, Hang, Rambaldi, Alessandro, Renwick, William, Reyes, Ruben, Izquierdo, Antonia Rodriguez, Rossi, Giuseppe, Ruan, Jia, Rusconi, Chiara, Salles, Gilles, Santoro, Armando, Sarriera, Jose, Savage, Kerry, Shibayama, Hirohiko, Shustov, Andrei, Suh, Cheolwon, Sureda, Anna, Tanimoto, Mitsune, Taniwaki, Masafumi, Tilly, Herve, Tobinai, Kensei, Trneny, Marek, Trumper, Lorenz, Tsukamoto, Norifumi, Tsukasaki, Kunihiro, Vitolo, Umberto, Walewski, Jan, Weidmann, Eckhart, Wilhelm, Martin, Witzens-Harig, Mathias, Yacoub, Abdulraheem, Yamamoto, Kazuhito, Yeh, Su-Peng, Yoon, Sung-Soo, Yuen, Sam, Yun, Hwan Jung, Zain, Jasmine, and Zinzani, Pier Luigi
- Abstract
Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.
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- 2019
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6. Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia
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Leblond, Véronique, Kastritis, Efstathios, Advani, Ranjana, Ansell, Stephen M., Buske, Christian, Castillo, Jorge J., García-Sanz, Ramón, Gertz, Morie, Kimby, Eva, Kyriakou, Charalampia, Merlini, Giampaolo, Minnema, Monique C., Morel, Pierre, Morra, Enrica, Rummel, Mathias, Wechalekar, Ashutosh, Patterson, Christopher J., Treon, Steven P., and Dimopoulos, Meletios A.
- 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.
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- 2016
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7. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis
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Kröger, Nicolaus, Giorgino, Toni, Scott, Bart L., Ditschkowski, Markus, Alchalby, Haefaa, Cervantes, Francisco, Vannucchi, Alessandro, Cazzola, Mario, Morra, Enrica, Zabelina, Tatjana, Maffioli, Margherita, Pereira, Arturo, Beelen, Dietrich, Deeg, H. Joachim, and Passamonti, Francesco
- 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.
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- 2015
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8. Overview on clinical trials in Waldenstrom's macroglobulinemia
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Tedeschi, Alessandra, Frustaci, Anna Maria, Picardi, Paola, and Morra, Enrica
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Waldenstrom's macroglobulinemia is characterized by lymphoplasmocytic cells accumulation predominantly in bone marrow, secreting immunoglobulin M monoclonal protein. There is not a standard of care as disease is rare and there are no large randomized trials to address treatment. Asymptomatic patients should be observed. In symptomatic patients treatment should be individualized considering patient fitness and disease characteristics. In elderly unfit patients single agent treatment may be still considered an option. In younger and fit patients immunochemotherapy should be considered the standard of care as recent data showed an improvement in quality of responses, progression-free and overall survival. In this overview are reported the most significant clinical trials that may help in treatment decision.
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- 2014
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9. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus
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Dimopoulos, Meletios A., Kastritis, Efstathios, Owen, Roger G., Kyle, Robert A., Landgren, Ola, Morra, Enrica, Leleu, Xavier, García-Sanz, Ramón, Munshi, Nikhil, Anderson, Kenneth C., Terpos, Evangelos, Ghobrial, Irene M., Morel, Pierre, Maloney, David, Rummel, Mathias, Leblond, Véronique, Advani, Ranjana H., Gertz, Morie A., Kyriakou, Charalampia, Thomas, Sheeba K., Barlogie, Bart, Gregory, Stephanie A., Kimby, Eva, Merlini, Giampaolo, and Treon, Steven P.
- 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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10. Histopathological and immunohistochemical evaluation of bone marrow biopsy in myelodysplastic syndromes
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Boveri, Emanuela, Croci, Giorgio, Gianelli, Umberto, Gambacorta, Marcello, Isimbaldi, Giuseppe, Moro, Alessia, Gianatti, Andrea, Ungari, Marco, and Morra, Enrica
- Abstract
SUMMARY In myelodysplastic syndromes (MDS), bone marrow biopsy (BMB) is now considered part of a multidisciplinary approach to bone marrow (BM) examination that must include cytological and cytogenetic assessment, while flow-cytometry and molecular studies can provide additional useful information. Undervalued in the past, BM histology has recently grown in importance in terms of diagnosis (i.e., MDS with BM fibrosis, hypoplastic MDS) and prognostic assessment (i.e., clusters of CD34+blasts). Thus, BM histology must be considered complementary and not overlapping with the results of the other methods of BM study. Moreover, in recent years, numerous clinico-pathological studies have evidentiated, codified and standardized a series of histopathological parameters that are now considered essential for an effective and clinically useful histomorphological evaluation of the BMB. The aim of this work is to describe the histopathological and immunohistochemical approach to BMB that the pathologists of the Lombard Hematological Network (Rete Ematologica Lombarda [REL]; Italy) are carrying out on a standardized and shared basis in MDS patients.
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- 2013
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11. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction
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Xu, Lian, Hunter, Zachary R., Yang, Guang, Zhou, Yangsheng, Cao, Yang, Liu, Xia, Morra, Enrica, Trojani, Alessandra, Greco, Antonino, Arcaini, Luca, Varettoni, Marzia, Brown, Jennifer R., Tai, Yu-Tzu, Anderson, Kenneth C., Munshi, Nikhil C., Patterson, Christopher J., Manning, Robert J., Tripsas, Christina K., Lindeman, Neal I., and Treon, Steven P.
- 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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12. 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, Srdan, Kantarjian, Hagop M., Estrov, Zeev, Cortes, Jorge E., Thomas, Deborah A., Kadia, Tapan, Pierce, Sherry, Jabbour, Elias, Borthakur, Gautham, Rumi, Elisa, Pungolino, Ester, Morra, Enrica, Caramazza, Domenica, Cazzola, Mario, and Passamonti, Francesco
- 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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13. 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, Marco, Tedeschi, Alessandra, Petrizzi, Valeria Belsito, Ricci, Francesca, Crugnola, Monica, Spriano, Mauro, Spedini, Pierangelo, Ilariucci, Fiorella, Uziel, Lilj, Attolico, Immacolata, Vismara, Eleonora, De Blasio, Angelo, Zaccaria, Alfonso, and Morra, Enrica
- 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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14. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment)
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Passamonti, Francesco, Cervantes, Francisco, Vannucchi, Alessandro Maria, Morra, Enrica, Rumi, Elisa, Pereira, Arturo, Guglielmelli, Paola, Pungolino, Ester, Caramella, Marianna, Maffioli, Margherita, Pascutto, Cristiana, Lazzarino, Mario, Cazzola, Mario, and Tefferi, Ayalew
- Abstract
Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 × 109/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.
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- 2010
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15. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment
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Cervantes, Francisco, Dupriez, Brigitte, Pereira, Arturo, Passamonti, Francesco, Reilly, John T., Morra, Enrica, Vannucchi, Alessandro M., Mesa, Ruben A., Demory, Jean-Loup, Barosi, Giovanni, Rumi, Elisa, and Tefferi, Ayalew
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Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 × 109/L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P < .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival.
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- 2009
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16. Fludarabine-Based Combination Therapies for Waldenström's Macroglobulinemia
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Tedeschi, Alessandra, Alamos, Sara Miqueleiz, Ricci, Francesca, Greco, Antonino, and Morra, Enrica
- Abstract
In Waldenström's macroglobulinemia, treatment is currently reserved for symptomatic patients. For many years, conventional treatment consisted of alkylating agents with or without steroids. In the past decade, fludarabine has proved to be effective in untreated and previously treated patients, even in those who experience primary treatment failure with alkylating agents. Based on in vitro evidence of synergistic effects and on the promising results obtained in other lymphoproliferative disorders, attempts have been made to combine alkylating agents with purine analogues. Encouraging results with high responses have been observed with the association of fludarabine and cyclophosphamide. The addition of an effective and nonmyelosuppressive therapeutic agent such as rituximab to fludarabine-based therapy ameliorates the quality and the response rates. Despite the lack of randomized trials, the recent consensus report indicates that combination therapy either with nucleoside analogues and alkylating agents or with nucleoside analogues and rituximab are reasonable choices for primary therapy.
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- 2009
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17. A dynamic prognostic model to predict survival in post–polycythemia vera myelofibrosis
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Passamonti, Francesco, Rumi, Elisa, Caramella, Marianna, Elena, Chiara, Arcaini, Luca, Boveri, Emanuela, Del Curto, Cecilia, Pietra, Daniela, Vanelli, Laura, Bernasconi, Paolo, Pascutto, Cristiana, Cazzola, Mario, Morra, Enrica, and Lazzarino, Mario
- Abstract
Post–polycythemia vera myelofibrosis (post-PV MF) is a late evolution of PV. In 647 patients with PV, we found that leukocytosis leukocyte count > (15 × 109/L) at diagnosis is a risk factor for the evolution of post-PV MF. In a series of 68 patients who developed post-PV MF, median survival was 5.7 years. Hemoglobin level less than 100 g/L (10 g/dL) at diagnosis of post-PV MF was an independent risk factor for survival. The course of post-PV MF, however, is a dynamic process that implies a progressive worsening of clinical parameters. Using a multivariate Cox proportional hazard regression with time-dependent covariates, we found that a dynamic score based on hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100 × 109/L, and leukocyte count more than 30 × 109/L is useful to predict survival at any time from diagnosis of post-PV MF. The resulting hazard ratio of the score was 4.2 (95% CI: 2.4-7.7; P < .001), meaning a 4.2-fold worsening of survival for each risk factor acquired during follow up. In conclusion, leukocytosis at diagnosis of PV is a risk factor for evolution in post-PV MF. A dynamic score based on hemoglobin level, and platelet and leukocyte count predicts survival at any time from diagnosis of post-PV MF.
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- 2008
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18. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation
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Passamonti, Francesco, Randi, Maria Luigia, Rumi, Elisa, Pungolino, Ester, Elena, Chiara, Pietra, Daniela, Scapin, Margherita, Arcaini, Luca, Tezza, Fabiana, Moratti, Remigio, Pascutto, Cristiana, Fabris, Fabrizio, Morra, Enrica, Cazzola, Mario, and Lazzarino, Mario
- Abstract
Essential thrombocythemia (ET) may occur in women of childbearing age. To investigate the risk of pregnancy complications, we studied 103 pregnancies that occurred in 62 women with ET. The 2-tailed Fisher exact test showed that pregnancy outcome was independent from that of a previous pregnancy. The rate of live birth was 64%, and 51% of pregnancies were uneventful. Maternal complications occurred in 9%, while fetal complications occurred in 40% of pregnancies. The Mantel-Haenszel method showed that fetal loss in women with ET was 3.4-fold higher (95% confidence interval [CI]: 3-3.9; P < .001) than in the general population. Half of the women studied carried the JAK2 (617V>F) mutation, and a multivariate logistic regression model identified this mutation as an independent predictor of pregnancy complications (P = .01). Neither the platelet count nor the leukocyte count was a risk factor. JAK2 (617V>F)–positive patients had an odds ratio of 2.02 (95% CI: 1.1 - 3.8) of developing complications in comparison with JAK2 (617V>F)–negative patients. Aspirin did not prevent complication in JAK2 (617V>F)–positive patients and appeared to worsen outcome in JAK2 (617V>F)–negative patients. A relationship was found between JAK2 (617V>F) and fetal loss (P = .05). This study indicates that patients carrying the JAK2 (617V>F) mutation have higher risk of developing pregnancy complications.
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- 2007
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19. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2(617V>F) mutation
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Passamonti, Francesco, Randi, Maria Luigia, Rumi, Elisa, Pungolino, Ester, Elena, Chiara, Pietra, Daniela, Scapin, Margherita, Arcaini, Luca, Tezza, Fabiana, Moratti, Remigio, Pascutto, Cristiana, Fabris, Fabrizio, Morra, Enrica, Cazzola, Mario, and Lazzarino, Mario
- Abstract
Essential thrombocythemia (ET) may occur in women of childbearing age. To investigate the risk of pregnancy complications, we studied 103 pregnancies that occurred in 62 women with ET. The 2-tailed Fisher exact test showed that pregnancy outcome was independent from that of a previous pregnancy. The rate of live birth was 64%, and 51% of pregnancies were uneventful. Maternal complications occurred in 9%, while fetal complications occurred in 40% of pregnancies. The Mantel-Haenszel method showed that fetal loss in women with ET was 3.4-fold higher (95% confidence interval [CI]: 3-3.9; P< .001) than in the general population. Half of the women studied carried the JAK2(617V>F) mutation, and a multivariate logistic regression model identified this mutation as an independent predictor of pregnancy complications (P= .01). Neither the platelet count nor the leukocyte count was a risk factor. JAK2(617V>F)–positive patients had an odds ratio of 2.02 (95% CI: 1.1 - 3.8) of developing complications in comparison with JAK2(617V>F)–negative patients. Aspirin did not prevent complication in JAK2(617V>F)–positive patients and appeared to worsen outcome in JAK2(617V>F)–negative patients. A relationship was found between JAK2(617V>F) and fetal loss (P= .05). This study indicates that patients carrying the JAK2(617V>F) mutation have higher risk of developing pregnancy complications.
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- 2007
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20. Splenic marginal zone lymphoma: a prognostic model for clinical use
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Arcaini, Luca, Lazzarino, Mario, Colombo, Nora, Burcheri, Sara, Boveri, Emanuela, Paulli, Marco, Morra, Enrica, Gambacorta, Marcello, Cortelazzo, Sergio, Tucci, Alessandra, Ungari, Marco, Ambrosetti, Achille, Menestrina, Fabio, Orsucci, Lorella, Novero, Domenico, Pulsoni, Alessandro, Frezzato, Maurizio, Gaidano, Gianluca, Vallisa, Daniele, Minardi, Viviana, Tripodo, Claudio, Callea, Vincenzo, Baldini, Luca, Merli, Francesco, Federico, Massimo, Franco, Vito, and Iannitto, Emilio
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The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P< .001), albumin levels below 3.5 g/dL (P= .001), International Prognostic Index (IPI) scores of 2 to 3 (P< .001), lactate dehydrogenase (LDH) levels above normal (P< .001), age older than 60 years (P= .01), platelet counts below 100 000/μL (P= .04), HbsAg-positivity (P= .01), and no splenectomy at diagnosis (P= .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (× 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient.
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- 2006
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21. Update on treatment recommendations from the Third International Workshop on Waldenström's Macroglobulinemia
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Treon, Steven P., Gertz, Morie A., Dimopoulos, Meletios, Anagnostopoulos, Athanasios, Blade, Joan, Branagan, Andrew R., Garcia-Sanz, Ramon, Johnson, Stephen, Kimby, Eva, LeBlond, Veronique, Fermand, Jean-Paul, Maloney, David G., Merlini, Giampaolo, Morel, Pierre, Morra, Enrica, Nichols, Gwen, Ocio, Enrique M., Owen, Roger, and Stone, Marvin J.
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Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed.
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- 2006
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22. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study
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Cairoli, Roberto, Beghini, Alessandro, Grillo, Giovanni, Nadali, Gianpaolo, Elice, Francesca, Ripamonti, Carla Barbara, Colapietro, Patrizia, Nichelatti, Michele, Pezzetti, Laura, Lunghi, Monia, Cuneo, Antonio, Viola, Assunta, Ferrara, Felicetto, Lazzarino, Mario, Rodeghiero, Francesco, Pizzolo, Giovanni, Larizza, Lidia, and Morra, Enrica
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Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD816) was associated with a high white blood cell count at diagnosis (median, 29.60 × 109/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD816 mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT–) patients (90% vs 35.3%, P = .002; 25% vs 76.5%, P = .006, respectively). No difference in relapse incidence (P = .126) and OS (P = .474) was observed between the c-KIT mutated other than TKD816 (n = 7) and the c-KIT– patients. These findings indicate that c-KIT TKD816 mutation has a negative impact on the outcome of AML with t(8;21).
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- 2006
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23. Prognostic impact of c-KITmutations in core binding factor leukemias: an Italian retrospective study
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Cairoli, Roberto, Beghini, Alessandro, Grillo, Giovanni, Nadali, Gianpaolo, Elice, Francesca, Ripamonti, Carla Barbara, Colapietro, Patrizia, Nichelatti, Michele, Pezzetti, Laura, Lunghi, Monia, Cuneo, Antonio, Viola, Assunta, Ferrara, Felicetto, Lazzarino, Mario, Rodeghiero, Francesco, Pizzolo, Giovanni, Larizza, Lidia, and Morra, Enrica
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Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KITmutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KITTKD mutation at codon 816 (TKD816) was associated with a high white blood cell count at diagnosis (median, 29.60 × 109/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD816mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KITunmutated (c-KIT–) patients (90% vs 35.3%, P= .002; 25% vs 76.5%, P= .006, respectively). No difference in relapse incidence (P= .126) and OS (P= .474) was observed between the c-KITmutated other than TKD816(n = 7) and the c-KIT–patients. These findings indicate that c-KITTKD816mutation has a negative impact on the outcome of AML with t(8;21).
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- 2006
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24. Update on Recommendations for Assessing Response from the Third International Workshop on Waldenström's Macroglobulinemia
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Kimby, Eva, Treon, Steven P., Anagnostopoulos, Athanasios, Dimopoulos, Meletios, Garcia-Sanz, Ramon, Gertz, Morie A., Johnson, Stephen, LeBlond, Veronique, Fermand, Jean-Paul, Maloney, David G., Merlini, Giampaolo, Morel, Pierre, Morra, Enrica, Nichols, Gwen, Ocio, Enrique M., Owen, Roger, Stone, Marvin, and Bladé, Joan
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This report by an international consensus panel updates current recommendations for defining clinical response in Waldenström's macroglobulinemia (WM). The previously published response criteria incorporated parameters for monoclonal protein reduction and/or improvement of marrow and nodal involvement, and included definitions of complete and partial remissions. The criteria have been updated to include minor response and stable disease categories. In addition, the criteria now recognize that delayed responses after treatment with nucleoside analogues and biologic agents and the time point for assessing response in patients with WM should be considered so as to not miss or miscategorize a response. The new criteria should therefore help in better delineating responses to therapy in patients with WM, particularly with the wide use of nucleoside analogues and biologically based agents for this disease.
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- 2006
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25. Pharmacokinetic Behavior of Rituximab
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Regazzi, Mario B, Iacona, Isabella, Avanzini, Maria Antonietta, Arcaini, Luca, Merlini, Gianpaolo, Perfetti, Vittorio, Zaja, Francesco, Montagna, Michela, Morra, Enrica, and Lazzarino, Mario
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This study was designed to report the pharmacokinetic behavior of Rituximab in patients affected with different diseases and treated with different schedules of administration. A low tumor burden was a common feature of all patients (N = 48) included in our study, whereas the timing of Rituximab administration varied from weekly (groups 1, 2, 3) to monthly (group 4). Group 1 included patients with follicular lymphoma treated with 4 weekly doses of Rituximab after first-line chemotherapy with CHOP. At the start of Rituximab, patients were in partial or complete clinical response but showed persistence of disease at molecular level (bcl-2-positive) in bone marrow and/or peripheral blood. Patients in group 2 had autoimmune disorders and Rituximab was given to act on B-cells, interfering with their production of autoantibodies. In patients with amyloidosis (group 3), Rituximab was given to kill progenitor B-cells of the small clone terminating in amyloid-producing plasma cells. In groups 2 and 3, the target of monoclonal antibody was a population of small B cells, which make an intrinsic feature of the diseases. Group 4 included patients with relapsed or refractory follicular and mantle cell lymphoma who underwent a salvage program of immunochemotherapy, purging in vivo and autotransplant: the first of the six planned doses of Rituximab was administered after a debulking phase with a third-generation regimen, such as VACOP-B. An enzyme-linked immunoassay (ELISA) developed and validated in our laboratory was used for the pharmacokinetic study. Rituximab disposition was characterized by a 2-exponential decay, with a long elimination half-life of approximately 3 weeks (range, 248-859 hours). The total systemic clearance ranged between 3.1 and 11.9 mL/hr/m2. After 4 weekly infusions, Rituximab concentration was ∼2.5 μg/mL, which is approximately 85% of the steady-state level. Steady-state plasma concentrations of Rituximab were reached after 6 to 8 weekly infusions. The adopted pharmacokinetic model (2-compartment open model) seems to provide the best fit of Rituximab disposition both during and after treatment, even when different schedules of drug administration are used. Because several studies reported an association between response and serum Rituximab concentrations, a treatment based on a pharmacokinetic model may be useful for predicting the desired drug concentration.
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- 2005
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26. Quantitative PCR of bone marrow BCL2/IgH+cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma
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Rambaldi, Alessandro, Carlotti, Emanuela, Oldani, Elena, Starza, Irene Della, Baccarani, Michele, Cortelazzo, Sergio, Lauria, Francesco, Arcaini, Luca, Morra, Enrica, Pulsoni, Alessandro, Rigacci, Luigi, Rupolo, Maurizio, Zaja, Francesco, Zinzani, Pier Luigi, Barbui, Tiziano, and Foa, Robert
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By real-time quantitative polymerase chain reaction (RQ-PCR), we evaluated BCL2/IgH+cells in the bone marrow (BM) and peripheral blood (PB) from 86 patients with follicular lymphoma treated with the sequential administration of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. At diagnosis, the amount of BCL2/IgH+cells in the BM was low (1 BCL2/IgH+cell in 1000-100 000 normal cells) in 43% of patients, intermediate (1 in 100-1000) in 34%, and high (> 1 in 100) in 23%. A 2 log decrease of BCL2/IgH+cells was achieved after CHOP and an additional 2 log reduction following rituximab. By multivariate analysis, a low level of BCL2/IgH+cells in the BM at diagnosis was the best predictor for the achievement of a complete clinical and molecular response. At 5 years, the event-free survival rates of patients with a low/intermediate or high tumor infiltration in the BM were 59% and 32%, respectively. The freedom from recurrence of patients who achieved a molecular response in the BM, no matter whether after CHOP alone or CHOP and rituximab, was 64% as compared to 32% for patients who did not (P< .006). RQ-PCR performed at presentation on BM samples predicts treatment response and long-term clinical outcome in patients with follicular lymphoma.
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- 2005
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27. Quantitative PCR of bone marrow BCL2/IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma
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Rambaldi, Alessandro, Carlotti, Emanuela, Oldani, Elena, Starza, Irene Della, Baccarani, Michele, Cortelazzo, Sergio, Lauria, Francesco, Arcaini, Luca, Morra, Enrica, Pulsoni, Alessandro, Rigacci, Luigi, Rupolo, Maurizio, Zaja, Francesco, Zinzani, Pier Luigi, Barbui, Tiziano, and Foa, Robert
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By real-time quantitative polymerase chain reaction (RQ-PCR), we evaluated BCL2/IgH+ cells in the bone marrow (BM) and peripheral blood (PB) from 86 patients with follicular lymphoma treated with the sequential administration of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. At diagnosis, the amount of BCL2/IgH+ cells in the BM was low (1 BCL2/IgH+ cell in 1000-100 000 normal cells) in 43% of patients, intermediate (1 in 100-1000) in 34%, and high (> 1 in 100) in 23%. A 2 log decrease of BCL2/IgH+ cells was achieved after CHOP and an additional 2 log reduction following rituximab. By multivariate analysis, a low level of BCL2/IgH+ cells in the BM at diagnosis was the best predictor for the achievement of a complete clinical and molecular response. At 5 years, the event-free survival rates of patients with a low/intermediate or high tumor infiltration in the BM were 59% and 32%, respectively. The freedom from recurrence of patients who achieved a molecular response in the BM, no matter whether after CHOP alone or CHOP and rituximab, was 64% as compared to 32% for patients who did not (P < .006). RQ-PCR performed at presentation on BM samples predicts treatment response and long-term clinical outcome in patients with follicular lymphoma.
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- 2005
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28. Clinical Characteristics and Outcome of Immunoglobulin M–Related Disorders.
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Cesana, Clara, Barbarano, Luciana, Miqueleiz, Sara, Lucchesini, Camilla, Ricci, Francesca, Varettoni, Marzia, Filippini, Davide, Lazzarino, Mario, and Morra, Enrica
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- 2005
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29. Prognostic Factors for Transformation in Asymptomatic Immunoglobulin M Monoclonal Gammopathies.
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Morra, Enrica, Cesana, Clara, Klersy, Catherine, Barbarano, Luciana, Miqueleiz, Sara, Varettoni, Marzia, Lucchesini, Camilla, Ricci, Francesca, and Lazzarino, Mario
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- 2005
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30. The Role of Quantitative Polymerase Chain Reaction in the Management of Follicular Lymphoma Patients
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Perego, Roberto A, Cairoli, Roberto, Cornacchini, Giorgia, Bianchi, Cristina, Corizzato, Matteo, Tresoldi, Elisabetta, and Morra, Enrica
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Aims and background In order to increase the prognostic significance of polymerase chain reaction (PCR) data it has been suggested that quantitative PCR can be used to measure tumor burden. However, this option has not yet been definitely supported or refuted in patients with follicular lymphoma (FL). We decided to evaluate whether knowledge of the quantitative level of minimal residual disease and its variations can be of use in the management of FL patients.Methods We used qualitative and competitive PCR to study 11 patients with refractory or relapsed FL harboring the t(14;18) translocation who underwent autologous (nine patients) or allogeneic (two patients) stem cell transplantation (SCT). Competitive PCR was performed with a multiple competitor carrying specific sequences including Bcl2/lgH MBR and mcr, and the β-globin gene.Results After a median post-SCT follow-up of 44 months (range, 12-62), overall survival was 91% and disease-free survival 82%. The quantitative PCR data showed that: 1) effective chemotherapy before SCT substantially (1-2 log) reduced the tumor burden in the bone marrow (BM); 2) the increase in rearranged DNA detected in BM was associated with disease progression and relapse; 3) a PCR-negative autograft seemed to lead to lasting molecular remission even when it was performed in patients with a low level of BM infiltration before transplant; and 4) allo-SCT made and maintained the BM PCR negative even in the presence of a greater tumor burden before SCT. Six of the nine patients having CR after SCT (four auto and two allo) are in continuous molecular remission.Conclusions In FL patients qualitative and quantitative PCR may provide data that can be helpful for the prognostic evaluation of tumor progression and the early detection of impending relapse by highlighting biological features such as the quality of the infused material, the tumor burden at transplant, and the behavior of tumor cells after transplant.
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- 2005
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31. Cryoglobulinemia
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Morra, Enrica
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Mixed cryoglobulinemia (MC) type II is a disorder characterized by circulating cold-precipitable immune complexes composed of polyclonal immunoglobulin IgG and monoclonal IgM rheumatoid factor (RF). The systemic vasculitis which characterizes the disease is caused by the deposition of immune complexes on the walls of small vessels, and by the subsequent activation of the complement cascade. MC may be asymptomatic or lead to clinical manifestations characterized by a typical triad—purpura, arthralgia, and weakness—and in some cases by a more serious vasculitis with neurologic and renal involvement. In the vast majority (more than 90%) of patients, MC is associated with hepatitis C virus (HCV) infection, which is considered the triggering factor of the disease. The association between cryoglobulinemia and HCV infection, and the possible evolution to B-cell lymphomas usually after long-term follow-up, suggest the role of HCV infection both in the pathogenesis of MC and in lymphomagenesis. In fact, the virus chronically stimulates the polyclonal proliferation of B cells from which a monoclonal population may emerge. This paper also reviews the treatment strategies for MC syndrome, emphasizing the issue of the eradication of HCV, and the clinical and biological activity of ritux-imab for selective B-cell control.
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- 2005
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32. Clinical Characteristics and Outcome of Immunoglobulin M–Related Disorders
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Cesana, Clara, Barbarano, Luciana, Miqueleiz, Sara, Lucchesini, Camilla, Ricci, Francesca, Varettoni, Marzia, Filippini, Davide, Lazzarino, Mario, and Morra, Enrica
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We analyzed the clinical features and prognostic factors for transformation of immunoglobulin M–related disorders (IgM-RDs) to malignant lymphoproliferative disease (MLD) in 83 patients with IgM-RDs. We studied 19 patients with type I cryoglobulinemias, 56 patients with type II cryoglobulinemias, 5 patients with peripheral neuropathies (PNs), and 3 patients with idiopathic thrombocytopenic purpuras. Fourteen patients with cryoglobulinemias presented with mild to moderate hepatomegaly with or without splenomegaly. Fourteen patients with type II cryoglobulinemias had arthralgias and/or vascular purpura (12 receiving corticosteroids), and 7 presented with PN. These latter patients and those with PNs without cryoglobulinemia were treated with steroids, cyclophosphamide, or polychemotherapy with/without plasma-exchange. Cumulative probability of evolution to MLD at 5 years was 15% (95% CI; 5%-25%). At a median of 62 months (12-195 months), 8 cases of IgM-RDs (8.4%) evolved to overt Waldenström's macroglobulinemia (n = 6), 1 case to non-Hodgkin's lymphoma, and 1 case to B-cell chronic lymphocytic leukemia. At univariate analysis, male sex (P= 0.02), IgM level = 3 g/dL (P< 0.0001), detectable Bence Jones proteinuria (P= 0.0005), lymphocytosis (P= 0.049), and high erythrocyte sedimentation rate (P= 0.003) significantly correlated with the evolution risk. Age, blood cell counts, ß2-microglobulin level, degree of marrow lymphoplasmacytic infiltration, type of cryoglobulinemia, and hepatitis C virus positivity did not correlate with transformation. Although IgM-RDs represent a distinct clinical entity frequently requiring treatment in view of the IgM-related symptoms, their evolution probability and prognostic factors for malignant transformation seem to widely overlap those described for asymptomatic IgM monoclonal gammopathies.
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- 2004
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33. Prognostic Factors for Transformation in Asymptomatic Immunoglobulin M Monoclonal Gammopathies
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Morra, Enrica, Cesana, Clara, Klersy, Catherine, Barbarano, Luciana, Miqueleiz, Sara, Varettoni, Marzia, Lucchesini, Camilla, Ricci, Francesca, and Lazzarino, Mario
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We evaluated the risk of transformation of asymptomatic immunoglobulin (Ig) M monoclonal gammopathy (aIgM-MG) into symptomatic lymphoproliferative disease in 384 patients, in subgroups of patients with IgM MG of undetermined significance (MGUS) and smoldering Waldenström's macroglobulinemia (sWM). One hundred seventy-two patients with aIgM-MG with bone marrow (BM) histopathology and immunophenotyping were available for analysis. After a median of 45 months (range, 12-233 months), 45 cases of aIgM-MG (11.7%) evolved into lymphoproliferative disease, as follows: symptomatic WM (n = 41), non-Hodgkin's lymphoma (NHL; n = 2), IgM multiple myeloma (IgM-MM; n = 1), and primary amyloidosis (n = 1). Cumulative transformation probability at 5 and 10 years was 8% and 29%, respectively. The parameters significantly correlated with evolution were, at univariate analysis, BM lymphoplasmacytic infiltration, high erythrocyte sedimentation rate, hemoglobin (Hb) level, IgM size, and peripheral lymphocytosis; at multivariate analysis, the parameters were IgM size and peripheral lymphocytosis, with Hb level associated with a trend toward higher progression risk. Of the 138 cases of IgM-MGUS, 14 (10.1%) evolved (13 WM, 1 IgM-MM) after a median of 75 months (range, 12-117 months); of the 34 cases of sWM, 13 (38.2%) progressed to WM after 55 months (range, 13-154 months). In patients with IgM-MGUS, event-free survival at 5 and 10 years was 95% and 83%, respectively, and in patients with sWM, 77% and 42%, respectively (P= 0.0001). Among patients with aIgM-MG, those at high risk of evolution are patients with sWM, a distinct entity with clear BM evidence of NHL.
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- 2004
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34. Molecular histogenesis of posttransplantation lymphoproliferative disorders
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Capello, Daniela, Cerri, Michaela, Muti, Giuliana, Berra, Eva, Oreste, Pierluigi, Deambrogi, Clara, Rossi, Davide, Dotti, Giampietro, Conconi, Annarita, Viganò, Mario, Magrini, Umberto, Ippoliti, Giovanbattista, Morra, Enrica, Gloghini, Annunziata, Rambaldi, Alessandro, Paulli, Marco, Carbone, Antonino, and Gaidano, Gianluca
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Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease. (Blood. 2003;102: 3775-3785)
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- 2003
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35. Smouldering Waldenstrom's macroglobulinemia: Factors predicting evolution to symptomatic disease
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Cesana, Clara, Miqueleiz, Sara, Bernuzzi, Patrizia, Tresoldi, Elisabetta, Rossi, Valentina, D'Avanzo, Giovanna, Filippini, Davide, and Morra, Enrica
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Factors predicting evolution to symptomatic disease were investigated in 27 patients with smouldering Waldenstrom's macroglobulinemia (SWM) among 172 patients with Waldenstom's macroglobulinemia (WM), selected on the basis of the following criteria: (1) IgM paraprotein 3 g/dL, and/or (2) bone marrow (BM) lymphoplasmacytoid (LPC) infiltration = 30%, and/or (3) diffuse infiltration pattern on BM biopsy, and (4) no treatment requirement for at least 12 months. Cumulative probability of survival was calculated by means of Kaplan-Meier. The Mantel and Haenszel test and multivariate Cox model were used to identify possible predictors for evolution. At a median follow-up of 79 months (range, 14 to 204), 11 patients (40.7%) showed progression to symptomatic disease, with the median interval from diagnosis being 46 months (range, 12 to 154). Event-free survival (EFS) at 5 and 10 years was 65% (95% confidence interval [CI], 45% to 85%) and 53% (95% CI, 31% to 75%), respectively. At multivariate analysis, paraprotein 3 g/dL (hazard ratio [HR], 15.1; 95% CI, 3.01 to 75.64; P< .0009) and hemoglobin = 12.5 g/dL (HR, 3.75; 95% CI, 1.05 to 13.34; P< .042) independently predicted transformation into symptomatic disease (P< .0006). Neither BM findings nor other laboratory parameter was associated with overt WM development. In conclusion, in SWM monoclonal IgM levels 3 g/dL and hemoglobin levels = 12.5 gr/dL are likely to predict SWM transformation into active disease requiring treatment. Semin Oncol 30:231-235. © 2003 Elsevier Inc. All rights reserved.
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- 2003
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36. Predictive variables for malignant transformation in 452 patients with asymptomatic IgM monoclonal gammopathy
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Morra, Enrica, Cesana, Clara, Klersy, Catherine, Varettoni, Marzia, Cavanna, Luigi, Canesi, Bianca, Tresoldi, Elisabetta, Barbarano, Luciana, and Lazzarino, Mario
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The natural history of asymptomatic IgM monoclonal gammopathies (MG) and variables predicting evolution to symptomatic lymphoproliferative disorders were investigated in 452 patients diagnosed from 1975 to 2001. Univariate and multivariate Cox models were used to identify possible predictors of disease progression. At a median follow-up of 49 months (range, 12 to 233), 41 cases (9.1%) evolved to symptomatic Waldenstrom's macroglobulinemia (n = 36), non-Hodgkin's lymphoma (n = 2), B-cell chronic lymphocytic leukemia (n = 1), IgM multiple myeloma (n = 1), and primary amyloidosis (n = 1); the median interval from diagnosis was 53 months (range, 12 to 154). The cumulative probabilities of transformation into a symptomatic lymphoproliferative disease at 5 and 10 years were 8% (95% confidence interval [CI], 6% to 12%) and 21% (95% CI, 16% to 29%), respectively. At univariate analysis, monoclonal component size and hemoglobin level as continuous parameters, lymphocytosis (4 × 109/L), bone marrow lymphoplasmacytoid infiltration (10%), erythrocyte sedimentation rate (40 mm/h), and detectable Bence Jones proteinuria were significantly related with evolution probability. At multivariate analysis, paraprotein level (P< .0001), hemoglobin level (P< .05), and lymphocytosis (P< .0001) independently predicted malignant evolution (P< .0001). In conclusion, patients with asymptomatic IgM-MG showing hematological features predictive of progression should be carefully monitored in view of an early treatment of the disease. Semin Oncol 30:172-177. © 2003 Elsevier Inc. All rights reserved.
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- 2003
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37. Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia
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Owen, Roger G., Treon, Steven P., Al-Katib, Ayad, Fonseca, Rafael, Greipp, Philip R., McMaster, Mary L., Morra, Enrica, Pangalis, Gerassimos A., San Miguel, Jesus F., Branagan, Andrew R., and Dimopoulos, Meletios A.
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This presentation represents consensus recommendations for the clinicopathological definition of Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion. The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) and Revised European-American Lymphoma (REAL) classification criteria. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies. Simple criteria to distinguish patients with symptomatic WM who require therapy from those with asymptomatic WM and MGUS were also proposed. Patients with clinical features attributable to IgM monoclonal gammopathy but no overt evidence of lymphoma are considered to constitute a distinct clinical group and the term “IgM-related disorders” is proposed. Semin Oncol 30:110-115. © 2003 Elsevier Inc. All rights reserved.
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- 2003
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38. Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia
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Montillo, Marco, Tedeschi, Alessandra, O'Brien, Susan, Raimondo, Francesco Di, Lerner, Susan, Ferrajoli, Alessandra, Morra, Enrica, and Keating, Michael J.
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One of the mechanisms of action of cladribine is the inhibition of DNA repair of damage caused by radiation, alkylating agents, or other drugs. To determine its antitumor activity in combination with cyclophosphamide, we initiated a Phase II trial of the two agents in patients with advanced chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL). Twenty-nine patients with refractory or recurrent CLL or PLL received cladribine 4 mg/m2/day and cyclophosphamide 350 mg/m2/day (both administered intravenously) for 3 days every 4 weeks. Eleven patients (38%), nine with CLL and two with PLL, had a response. The median duration of response was 12 months. Severe extrahematologic toxicity (National Cancer Institute Grade 34) occurred in two patients, consisting of skin rash in one patient and progressive multifocal leukoencephalopathy in the other. The most common form of hematologic toxicity was severe neutropenia, which developed after 25% of the 84 courses was administered. Severe thrombocytopenia and anemia developed after 12% and 7% of the courses, respectively, and five episodes of anemia were immunomediated. In addition, three major infections resulted in the death of one patient. Although inferior to the combination fludarabine plus cyclophosphamide, this regimen showed interesting activity in patients with advanced CLL or PLL. Myelosuppression was the major dose-limiting toxic effect. Cancer 2003;97:11420. © 2003 American Cancer Society. DOI 10.1002/cncr.11000
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- 2003
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39. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study
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Sawyers, Charles L., Hochhaus, Andreas, Feldman, Eric, Goldman, John M., Miller, Carole B., Ottmann, Oliver G., Schiffer, Charles A., Talpaz, Moshe, Guilhot, Francois, Deininger, Michael W. N., Fischer, Thomas, O'Brien, Steve G., Stone, Richard M., Gambacorti-Passerini, Carlo B., Russell, Nigel H., Reiffers, Jose J., Shea, Thomas C., Chapuis, Bernard, Coutre, Steven, Tura, Sante, Morra, Enrica, Larson, Richard A., Saven, Alan, Peschel, Christian, Gratwohl, Alois, Mandelli, Franco, Ben-Am, Monique, Gathmann, Insa, Capdeville, Renaud, Paquette, Ronald L., and Druker, Brian J.
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Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.
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- 2002
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40. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma
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Rambaldi, Alessandro, Lazzari, Manuela, Manzoni, Cristina, Carlotti, Emanuela, Arcaini, Luca, Baccarani, Michele, Barbui, Tiziano, Bernasconi, Carlo, Dastoli, Giuseppe, Fuga, Giovanna, Gamba, Enrica, Gargantini, Livio, Gattei, Valter, Lauria, Francesco, Lazzarino, Mario, Mandelli, Franco, Morra, Enrica, Pulsoni, Alessandro, Ribersani, Michela, Rossi-Ferrini, Pier Luigi, Rupolo, Maurizio, Tura, Sante, Zagonel, Vittorina, Zaja, Francesco, Zinzani, PierLuigi, Reato, Gigliola, and Foa, Robin
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Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m2 intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity (P < .001).
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- 2002
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41. Anemia of Cancer: An Overview
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Cantoni, Silvia and Morra, Enrica
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- 2001
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42. Rituximab (IDEC-C2B8) Validation of a Sensitive Enzyme-Linked Immunoassay Applied to a Clinical Pharmacokinetic Study
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Iacona, Isabella, Lazzarino, Mario, Avanzini, Maria Antonietta, Rupolo, Maurizio, Arcaini, Luca, Astori, Cesare, Lunghi, Francesca, Orlandi, Ester, Morra, Enrica, Zagonel, Vittorina, and Regazzi, Mario B.
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Rituximab is a chimeric monoclonal antibody (MAb) directed against the B-cell CD20 antigen that has been approved for therapy of relapsed and resistant follicular non-Hodgkin's lymphoma (NHL). This study describes the development and validation of a highly sensitive, rapid, accurate, precise enzyme-linked immunosorbent assay (ELISA) to measure Rituximab serum concentrations. This study also describes the application of the ELISA method to a pharmacokinetic study in a homogeneous group of patients with follicular lymphoma who received 4 weekly doses of MAb at the standard dose of 375 mg/m2as consolidation of chemotherapy. In the patients in this study, the median Rituximab serum concentrations increased during therapy, and showed a slow decline during the posttreatment period. The Rituximab elimination half-life of approximately 20 days accounts for the demonstrated accumulation of MAb in serum samples. Because previous pharmacokinetic studies showed a correlation between Rituximab serum levels and tumor response, the ELISA method used in this study, which allows a precise control of serum concentrations, could be useful for predicting the final response to the MAb and for selecting patients able to benefit from higher dosage or repeated drug administration.
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- 2000
43. Trisomy 4 Leading to Duplication of a Mutated KITAllele in Acute Myeloid Leukemia with Mast Cell Involvement
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Beghini, Alessandro, Ripamonti, Carla B, Castorina, Pierangela, Pezzetti, Laura, Doneda, Luisa, Cairoli, Roberto, Morra, Enrica, and Larizza, Lidia
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A G→T transversion at nucleotide 2467 of the c-KIT gene leading to Asp816→Tyr (D816Y) substitution in the phosphotransferase domain has been previously identified in a patient with rapidly progressing AML-M2 and mast cell involvement; the patient's blasts had a 47,XY,+4,t(8;21)(q22;q22) karyotype. Herein we confirm the simultaneous presence of both major chromosomal changes by multicolor fluorescence in situ hybridization (FISH) on interphase CD34+ mononuclear cells. By setting up culture leukemic blasts, spontaneous differentiation of adherent cells with mast-cell like features was proved by histochemical and immunoenzymatic analyses. Fluorescence in situ hybridization evidence of trisomy 4 confirmed the origin of differentiated cells from the leukemic blasts. Semiquantitative polymerase chain reaction (PCR) and phosphoimage densitometry of wild-type and mutated KIT alleles on bone marrow blasts made it possible to demonstrate that chromosome 4 trisomy led to a double dosage of the mutated KIT allele. This finding, and that of trisomy 7 and MET mutation in hereditary renal carcinoma represent the only cases of human tumors in which an increased number of chromosomes carrying an oncogene activated by point mutation have been detected.
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- 2000
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44. A prospective study of residual-disease monitoring of theALL1/AF4 transcript in patients with t(4;11) acute lymphoblastic leukemia
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Cimino, Giuseppe, Elia, Loredana, Rapanotti, Maria Cristina, Sprovieri, Teresa, Mancini, Marco, Cuneo, Antonio, Mecucci, Cristina, Fioritoni, Giuseppe, Carotenuto, Mario, Morra, Enrica, Liso, Vincenzo, Annino, Luciana, Saglio, Giuseppe, De Rossi, Giulio, Foa`, Robin, and Mandelli, Franco
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Twenty-five patients (22 adults and 3 infants) withALL1/AF4-positive acute lymphoblastic leukemia (ALL) were prospectively monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) between January 1992 and July 1999. After high-dose induction and consolidation chemotherapy without bone marrow transplantation, all patients had a complete hematologic remission. Using nested RT-PCR (sensitivity 10-4), we observed conversion to PCR negativity in 11 (44%) of the patients. Thirteen of the 14 patients who did not have a molecular remission had a relapse at a median time of 4 months (range, 1 - 20 months). Of the 11 patients who had a conversion to PCR negativity, 5 reconverted to PCR positivity within 1 to 14 months. These 5 patients all progressed to hematologic relapse after 2, 3, 4, 4, and 7 months, respectively. Of the remaining 6 patients, 4 are in persistent hematologic and molecular remission at 12, 14, 88, and 96 months, whereas 2 are early in their follow-up. Actuarial probabilies of relapse and overall survival were 100% and 0% at 14 and 24 months and 67% and 43% at 96 and 100 months, respectively, in patients who had persistent RT-PCR positivity and in those who had a molecular remission. For both relapse and survival, the differences observed between the two groups were significant (P = .003 andP < .005, respectively). This study, which represents the first prospective analysis of residual-disease monitoring carried out in a substantial series of patients with t(4;11)-positive ALL, emphasizes the clinical relevance of RT-PCR-based methods to monitor minimal residual disease in this leukemia subset. (Blood. 2000;95:96-101)
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- 2000
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45. Low-Grade Malignancy Non-Hodgkin's Lymphomas: Prognostic Relevance of their Clinicopathologic Heterogeneity
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Brusamolino, Ercole, Magrini, Umberto, Canevari, Angelo, Castelli, Guglielmo, Morra, Enrica, Pagnucco, Guido, Isernia, Paola, and Bernasconi, Carlo
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We reviewed 182 consecutive adult patients with low-grade malignancy, non-Hodgkin's lymphomas classified according to the Kiel classification, followed at the Division of Hematology, Policlinico S. Matteo, Pavia, from January 1975 to December 1981, to recognize, in each histopathologic type, important subgroups from the prognostic standpoint. Median follow-up was 36 months. No significant differences were observed in the response rate to conventional therapy (radiotherapy for localized disease, CVP for advanced stages) between the 4 cytologic types. The centrocytic-centroblastic lymphoma with diffuse nodal architecture showed an intermediate-grade malignancy (median survival, 50 months) and underwent cytologic progression to the high-grade malignancy centroblastic type in 10% of the cases. Large-cell centrocytic and polymorphic lymphoplasmacytoid lymphomas had a poor prognosis (median survival less than 30 months) when treated with conventional therapy for favorable histologies, and 6% of the cases transformed into the high-malignancy immunoblastic type. Patients with lymphocytic lymphoma with bulky mediastinum had a median survival of 20 months. The identification of these subgroups with a worse prognosis may have therapeutic implications.
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- 1983
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46. Serum CA 125 is of clinical value in the staging and follow-up of patients with non-hodgkin's lymphoma<FNR HREF="fn1"></FNR><FN ID="fn1"> Presented in part at the 38th Annual Meeting of the American Society of Hematology, Orlando, Florida, December 6-10, 1996. </FN>
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Lazzarino, Mario, Orlandi, Ester, Klersy, Catherine, Astori, Cesare, Brusamolino, Ercole, Corso, Alessandro, Bellio, Laura, Gargantini, Livio, Morra, Enrica, and Bernasconi, Carlo
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CA 125 is a glycoprotein produced by epithelial ovarian tumors and by mesothelial cells; its levels also have been shown to be elevated in patients with non-Hodgkin's lymphoma (NHL). The authors evaluated serum CA 125 levels in patients with NHL to elucidate the frequency of this finding, its relationship with other presenting features, and its potential role as tumor marker. One hundred and fifty-seven patients underwent the first CA 125 assessment at onset, 54 at disease recurrence or progression, and 62 during complete remission (CR). Of the 157 patients evaluated at diagnosis (median CA 125: 26 U/mL; range, 2-1400 U/mL), 63 (40%) had increased CA 125 values. Higher CA 125 levels were associated with advanced disease, aggressive histology, mediastinal and/or abdominal involvement, bulky tumor, high tumor burden, effusions, contiguous extranodal extension, high serum lactate dehydrogenase (LDH) activity, and elevated β2-microglobulin (β2-M) levels. Parameters identified by multivariate analysis to be independently associated with high CA 125 were: aggressive histology, mediastinal and/or abdominal disease, bulky tumor, high serum LDH activity and β2-M serum levels, and the presence of effusion (P = 0.0000; explained variation = 0.64). Of the patients presenting with abnormal CA 125 levels, all those who achieved a CR (35) and 3 of the 6 who achieved a partial response had normalization of CA 125 values by the end of treatment. Conversely, CA 125 remained above normal values in 18 nonresponders. All 62 patients evaluated during CR showed normal CA 125 levels. Among patients first evaluated at disease recurrence or progression, 22 of 54 (41%) showed increased CA 125 levels, which were associated with the same parameters of disease found in patients examined at diagnosis. High serum CA 125 levels were found to correlate with mediastinal and/or abdominal involvement, high tumor mass, and effusions, reflecting the reaction of mesothelial cells to the tumor. Serum CA 125 is a reliable biologic marker for the staging and restaging of patients with lymphoma. Serial measurements are useful, in conjunction with other markers, for monitoring response to treatment. Cancer 1998;82:576-82. © 1998 American Cancer Society.
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- 1998
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47. In VivoDifferentiation of Mast Cells from Acute Myeloid Leukemia Blasts Carrying a Novel Activating Ligand-Independent C-kit Mutation
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Beghini, Alessandro, Cairoli, Roberto, Morra, Enrica, and Larizza, Lidia
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ABSTRACT: The primary role of protooncogene c-kit in mast cell differentiation is supported by the development of mast cells from CD34+/CD117+(c-kit) myeloid precursors. Growth factor independence, neoplastic transformation and differentiation of mast cells were found in association with c-kit activating mutations in both murine and human mastocytoma and mast cell diseases. We have identified a novel c-kit mutation (D816Y) in peripheral blood mononuclear cells from a patient with AML (M2), massive presence of mast cells in bone marrow and rapid progression of the disease. The mutation, a G→T transversion at nt 2467 of the c-kit gene resulting in Asp816→Tyr substitution, corresponds to the D814Y and D817Y mutations identified and characterized in the murine P815 mastocytoma and the rat RBL-2H3 mast cell leukemia cell lines. The absence of SCF transcripts that we found by RTPCR in the patient's blasts indicates that, also in humans, this activating mutation leads to SCF independent growth. The expression of the mutant allele on Kit signaling may be further enhanced by trisomy of chromosome 4 (carrying the c-kit gene) in the patient's blasts. From these findings it is concluded that mast cells could be generated from a leukemic CD34/CD117-positive clone, that combines the antigenic expression of mast cell precursor to the growth and differentiation factor-independence which was derived by the c-kit D816Y mutation.
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- 1998
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48. The Role of Interferon in the Treatment of Chronic Myelogenous Leukemia: Results and Prospects
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Morra, Enrica, Lazzarino, Mario, Alimena, Giuliana, Liberati, Anna, Grignani, Fausto, Mandelli, Franco, and Bernasconi, Carlo
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INTRODUCTION Philadelphia positive chronic myelogenous leukemia (Ph1+ CML) is a myeloproliferative disorder of clonal origin, due to neoplastic transformation of a pluripotent stem cell, and characterized by excessive proliferation of hemopoietic precursors and expansion of the myeloid cellular mass1. In 90-95% of cases, the disease is associated with a chromosomal abnormality, the Ph1 chromosome, derived from a reciprocal translocation t(9;22) (q34;q11) between chromosomes 9 and 222. The translocation of the proto-oncogene c-abl from its normal location on chromosome 9 to the break-point cluster region (bcr) of chromosome 22 involves the formation of a chimeric gene (abl-bcr), the product of which is a protein with increased tyrosine-kinase activity3,4. It seems likely that the bcr rearrangement plays an important role in the pathogenesis of CML. Characteristically, the disease presents two phases: a "benign" or chronic phase lasting about 3 years, well controlled by chemotherapy, and a terminal blastic phase, refractory to chronic-phase treatments, invariably fatal in 3-6 months and frequently associated with cytogenetic abnormalities additional to the Ph1.
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- 1992
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49. Interferon Alpha-2b as Therapy for Ph'-Positive Chronic Myelogenous Leukemia: A Study of 82 Patients Treated With Intermittent or Daily Administration
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Alimena, Giuliana, Morra, Enrica, Lazzarino, Mario, Liberati, Anna M., Montefusco, Enrico, Inverardi, Daniela, Bernasconi, Paolo, Mancini, Marco, Donti, Emilio, Grignani, Fausto, Bernasconi, Carlo, Dianzani, Ferdinando, and Mandelli, Franco
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The authors treated a total of 82 patients with Ph-positive chronic myelogenous leukemia (CML) with recombinant interferon alpha-2b (IFN α-2b). Sixty-five patients in chronic phase (CP), 28 of whom were untreated and 37 pretreated, and nine patients in accelerated phase (AP), were started on IFN three times a week. Patients in CP were randomized to receive 2 or 5 x 106IU/m , while patients in AP were all given the dose of 5 x 106IU/m2, in addition to concomitant chemotherapy. Patients in CP who were unresponsive to the lower dose were crossed to the higher dose. Of 63 evaluable patients in CP, 43 (68%) responded, 29 (46%) achieved complete hematologic response (CHR), and 14 (22%) achieved partial hematologic response (PHR). The response rate appeared to be significantly influenced by the IFN dose in pretreated patients. Of the nine patients in AP, two attained PHR and one CHR. More recently, eight previously untreated CP cases were submitted to daily IFN administration at doses from 2 to 5 x 106IU/m2. This daily schedule was also applied to patients who had obtained, with the intermittent treatment, a PHR persisting unmodified for six months (nine patients) or an unstable CHR (five patients). Seven of the eight previously untreated patients, and five of the nine PHR patients crossed to daily IFN reached CHR. In the total series of previously untreated patients, the response rate proved to be significantly influenced by the initial risk status. Cytogenetic improvement was seen in 37 of 53 responders (70%) treated for more than 3 months, the median of Ph‘-positive cells declining from 100% to 65% (range 0% to 95%). Complete suppression of Ph’ chromosome was observed in one case. The cytogenetic response was persistent for over 6 months in 21 patients, but the lowest value of Ph' positivity was usually unstable. At a median follow-up of 56 weeks, 23 of 36 (64%) CHR patients remain in continued disease control with IFN. A blastic transformation (BT) occurred in seven of 21 unresponsive patients and in one of the 36 CHR patients. The authors' data confirm that IFN a-2b, especially at daily doses, is effective in inducing clinical and cytogenetic response in a good proportion of patients with CML in the benign phase. Longer follow-ups will define the exact influence of this agent on the natural course of the disease. © 1988 by Grune & Stratton, Inc.
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- 1988
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50. 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, Francesco, Maffioli, Margherita, Cervantes, Francisco, Vannucchi, Alessandro Maria, Morra, Enrica, Barbui, Tiziano, Caramazza, Domenica, Pieri, Lisa, Rumi, Elisa, Gisslinger, Heinz, Knoops, Laurent, Kiladjian, Jean Jaques, Mora, Barbara, Hollaender, Norbert, Pascutto, Cristiana, Harrison, Claire, and Cazzola, Mario
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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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