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In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 9 ( 2020-09), p. 2354-2363

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0959-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Hematological Oncology, Wiley, Vol. 37, No. 4 ( 2019-10), p. 508-512

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v37.4

DOI: 10.1002/hon.2655

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 2001443-0

In: American Journal of Hematology, Wiley, Vol. 97, No. 5 ( 2022-05)

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v97.5

DOI: 10.1002/ajh.26502

Language: English

Publisher: Wiley

Publication Date: 2022

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3118-3118

Abstract: BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overall management of chronic lymphocytic leukemia (CLL). Although several data derived from clinical trials suggest that ibrutinib increases the risk of atrial fibrillation (AF), the incidence of AF in a real-life cohort of CLL patients is unknown. Furthermore, it would be clinically relevant to identify patients at high risk of AF during ibrutinib. The aim of this study is to report the prevalence and risk factors of AF in ibrutinib-naive CLL, in order to define a predictive model for the development of AF and to test it in a cohort of subjects receiving ibrutinib. METHODS. We retrospectively analyzed data from 860 ibrutinib-naive CLL patients, referred to the Padua University hospital. Comorbidities, clinical and biological prognostic markers were analyzed using the Mann-Whiney, Fisher exact or Chi-square tests, when appropriated. Time to AF (TTAF) and overall survival (OS) were evaluated with Kaplan-Meier method. Univariate and multivariate Cox models were run to identify independent factors associated with AF. Then, risk values were obtained based on the hazard ratios. The score for AF was calculated as the sum of each risk values. Subsequently, the model was evaluated in a cohort of 354 ibrutinib-treated patients referred from 8 Italian hematological centers. RESULTS. Among the 860 patients from Padua hospital, 60% were male, 49% were older than 65 years, 73% were Binet A stage at diagnosis and 41% underwent at least one line of treatment. A prior history of AF was present in 21 patients (2.4%) at CLL diagnosis, while, among the remaining 839 patients without a previous history of AF, 47 (5.6%) developed it after a median follow-up of 9.4 years, resulting in an estimated incidence of almost 0.8% cases/year. Moreover, the median OS for patients with AF was significantly shorter than that patients without AF (12 vs 22 years, p 〈 0.0001). Based on univariate and multivariate analysis, variables associated with the risk of AF were: age 〉 65 years (p=0.001, 1 point), male gender (p=0.003, 1 point), valvular hearth diseases (p=0.001, 2 points), cardiopathy (p 〈 0.001, 3 points), hyperthyroidism (p=0.001, 1 point), chronic lung diseases (p=0.001, 1 point), diabetes mellitus (p=0.023, 1 point), severe infections (p=0.019, 1 point). As expected, no clinical and biological prognostic markers (i.e. Binet stage, IGHV mutation, TP53 abnormalities) for CLL were associated with an increased risk of AF. A predictive model was designed based on these factors and it stratified patients into 4 different groups. The estimated TTAF after 15 years of follow-up were 0%, 10%, 19% and 61% for patients with score 0, 1-2, 3-4, and ≥5 respectively (p 〈 0.001, Fig. 1A). Furthermore, it underwent internal validation using the bootstrap method. Subsequently, we applied our AF model to a cohort of 354 ibrutinib-treated patients, 64% were male, the median age was 69 years, 88 were treatment-naive, 70% U-IGHV and 39% harbored TP53 abnormalities. Forty-four subjects developed AF after a median observation of 25 months, with an estimated 2-year TTAF of 12%. Only 9 out of the 44 patients (20%) discontinued ibrutinib. Sixteen patients (4%) were classified as AF score 0, 218 (62%) score 1-2, 73 (21%) score 3-4 and 46 (13%) at least score 5. Our model was also able to identify patients at a higher risk AF during ibrutinib, in fact the 2-year risk of AF was 0%, 5%, 17% and 40% for patients with score 0, 1-2, 3-4, and ≥5 respectively (p 〈 0.001, Fig. 1B). Patients with a score of 5 or higher have a risk 20 times higher to developed AF than the other subjects (HR 19.6, 95% interval 7-52, p 〈 0.0001). So far, the OS of ibrutinib-treated patients with AF was not inferior to that of patients who did not developed AF (2-years OS 89% and 82%, respectively p=0.1252), but the median follow-up is only 2 years. CONCLUSIONS. In this study, variables associated with an increased risk of developing AF were identified and recapitulated into a scoring system. Our model proved to be a valid tool to identify patients at a higher risk of developing AF, including ibrutinib-treated patients. Taking these data into account, patients with a score ≥5 should be carefully monitored during ibrutinib treatment given the very high-risk of developing AF or should be considered for alternative therapies. Disclosures Visentin: janssen: Consultancy, Honoraria. Mauro:abbvie: Other: board member; janssen: Other: board member. Reda:Janssen and Cilag: Consultancy; ABBVIE: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Molica:Jansen: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board; AbbVie: Other: Advisory board. Rigolin:Gilead: Research Funding. Tedeschi:Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cortelezzi:novartis: Consultancy; abbvie: Consultancy; roche: Consultancy; janssen: Consultancy. Coscia:Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Karyopharm: Research Funding. Cuneo:Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Trentin:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding; Janssen: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114899

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1782-1782

Abstract: Abstract 1782 The aims of LE.P.RE. study include the identification of clinical and biological factors associated with clinical response and toxicity of lenalidomide monotherapy in relapsed/refractory CLL patients enrolled from 9 Italian centers. Lenalidomide treatment schedule starts with 5 mg daily and increases of 5 mg daily every two weeks, up to 25 mg daily or maximum tolerated dose. Therapy is scheduled to be administered for 12 courses (1 course = 4 weeks) unless disease progression or excessive toxicity are observed. Here we show preliminary results about the first 20 enrolled patients up to the 4th treatment course. Patients received a mean daily lenalidomide dose of 8 mg in the 1st course, 10 mg in the 2nd, 14 mg in the 3rd and 4th. Four patients left the study at the 1st course (1 acute renal failure ARF, 1 infection, 1 second neoplasia likely related to CLL, 1 consent withdrawal) and 3 patients at the 3rd (1 Tumor Flare Reaction TFR, 1 infection, 1 thrombocytopenia). The observed toxicities are listed in Table 1. After the 4th course, 13 patients were evaluable for response: 9 partial response (PR), 3 progressive disease (PD) and 1 stable disease (SD) [ORR 69%]. Table 1 Hematological and extra hematological toxicities (n° tot cases=20) grade n° cases grade n° cases Thrombocytopenia 03/04/11 7 TLS 2 1 Neutropenia 03/04/11 14 TFR 1-2 4 Anemia 03/04/11 2 Second Neoplasia 1 Death 1 ARF 02/03/11 3 Infection 03/04/11 3 We compared the levels of several cytokines measured by ELISA in plasma of the 20 patients at baseline and day+8 of therapy. We observed a significant increase of IL2 Receptor (mean 55,31 vs 112,14 ng/ml; p 〈 0,001), IL2 (14,15 vs 17,27 pg/ml; p=0,019), CCL3 (5,21 vs 21,23 pg/ml; p 〈 0,001), CCL4 (24,76 vs 72,99 pg/ml; p=0,003), IL10 (2,65 vs 6,33 pg/ml; p=0,001), IL1b (0,94 vs 2,77 pg/ml; p=0,048), TNFa (35,00 vs 140,59 pg/ml; p 〈 0,001) and IL8 (0,31 vs 3,50 pg/ml; p=0,037) and a decrease of Thrombospondin 1 (693 vs 488 ng/ml; p=0,037). Interestingly, we found that IL1b level decreased from baseline to day+8 in the 4 non responder (PD+SD) patients while increasing in the 9 responder (PR) patients. Moreover, we found that the 5 patients that experienced TFR or tumor lysis syndrome TLS had significantly higher CCL3 level at baseline than the other 15 patients (p=0,025). We also studied peripheral blood cell subsets (T, B, NK, monocyte, dendritic and endothelial cells) in the 20 patients by flow cytometry. From baseline to day+8 we observed a significant increase of the Thelper1/Thelper2 ratio (p 〈 0,001), T cytotoxic1/Tcytotoxic2 ratio (p=0,001) and memory T cells % (p 〈 0,001) as well as a decrease of naïve T cells % (p 〈 0,001) and mean CD69 expression on T cells (p=0,016). Moreover, the expression of CD40 (p=0,001), CD80 (p=0,018), CD86 (p=0,003) and CD95 (p=0,008) were found to be increased on B-CLL cells. Finally, we observed a decrease of endothelial progenitors cells (EPC) (p=0,032) and live circulating endothelial cells (CEC) (p 〈 0,001) and an increase of dead CEC (p 〈 0,001). Interestingly, there was a significant difference in activated CEC (mean 53,57 vs 81,63 CEC %; p=0,031) and resting CEC (46,54 vs 18,37; p=0,031) at baseline between responders and non responders, respectively. Moreover, the patients exhibiting TFR or TLS showed a higher % of CD4+CD3+ cells (p=0,009) and CD4+CD8+ cells (p=0,036) at day+8 than the others. In conclusion: (i) the increase of inflammatory cytokines IL2R, IL2, CCL3, CCL4, IL10, IL1b and TNFa observed from baseline to day+8 suggests that lenalidomide can induce immune activation; (ii) the augmentation of IL2, IL2R and memory T cells and the decrease of naïve T cells noticed from baseline to day+8 indicate that lenalidomide can promote T cell activation; (iii) the shift toward Thelper1 and Tcytotoxic1 phenotypes and the increased expression of co-stimulatory molecules on B-CLL cells observed from baseline to day+8 suggest that lenalidomide can promote an active T cell response against leukemic cells; (iv) the alterations in EPC and CEC noticed from baseline to day+8 suggest that lenalidomide may also have an anti angiogenic action. Moreover, our preliminary data seem to show interesting biological differences among CLL patients that respond or do not respond to lenalidomide treatment, which if replicated in additional patients and with increasing time on therapy could give important information for predicting which patients may best respond to therapy or may experience TFR or TLS. Disclosures: Maffei: CELGENE CORPORATION: Research Funding. Off Label Use: Lenalidomide, a thalidomide analogue, is an immunomodulatory drug (IMiD) with antitumoural activity reported in various malignant disorders including multiple myeloma and myelodysplastic syndrome. At preclinical level, lenalidomide has shown to decrease the production of several prosurvival cytokines. This drug is also reported to modulate an effector cell immune response through the activation of T and natural killer cells, inducing apoptosis directly on tumour cells. Currently available data indicate that lenalidomide is active also in heavily pre-treated CLL patients. However, in order to reduce toxicity and to optimize the therapeutic index of lenalidomide treatment in CLL patients, it is necessary to identify features of tumour cells that differ between responder and non responder patients. Hence, we propose a multicenter, phase II study designed in order to identify potential predictive factors correlating with response and toxicity to Lenalidomide treatment in relapsed/refractory CLL patients. Martinelli:CELGENE CORPORATION: Research Funding. Debbia:CELGENE CORPORATION: Research Funding. Rigolin:CELGENE CORPORATION: Research Funding. Rizzotto:CELGENE CORPORATION: Research Funding. Castelli:CELGENE CORPORATION: Research Funding. Bonacorsi:CELGENE CORPORATION: Research Funding. Bulgarelli:CELGENE CORPORATION: Research Funding. Fiorcari:CELGENE CORPORATION: Research Funding. Zucchini:CELGENE CORPORATION: Research Funding. Santachiara:CELGENE CORPORATION: Research Funding. Forconi:CELGENE CORPORATION: Research Funding. Rossi:CELGENE CORPORATION: Research Funding. Laurenti:CELGENE CORPORATION: Research Funding. Palumbo:CELGENE CORPORATION: Research Funding. Vallisa:CELGENE CORPORATION: Research Funding. Cuneo:CELGENE CORPORATION: Research Funding. Gaidano:CELGENE CORPORATION: Research Funding. Luppi:CELGENE CORPORATION: Research Funding. Marasca:CELGENE CORPORATION: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1782.1782

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3300-3300

Abstract: Background. Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant advancement in the treatment of patients with chronic lymphocytic leukemia (CLL) and has the potential of inducing durable remissions of the disease. In the new scenario of targeted agents for CLL, there is an increasing interest in identifying patients who may gain the maximum benefit in terms of disease control by a single shot of FCR chemo-immunotherapy. Purpose. Here we aimed at identifying predictors of durable remission after first line FCR treatment. Methods. The study was based on 405 progressive and previously untreated CLL patients who consecutively received standard FCR (up to 6 cycles) as first line therapy in 19 hematologic centers between 2001 and 2010. According to an intention to treat approach, all patients who received at least one FCR cycle were registered in the study. This series was representative of a FCR treated CLL cohort with respect to baseline characteristics, including age (median: 61 years; 〉 65 years in 33% of patients), gender (male in 68% of patients), stage (progressive Binet A in 11% of patients; Binet B in 59%; Binet C in 30%) and number of FCR courses (median: 6; 〈 6 in 42% of patients). Most patients were evaluable for IGHV mutation status (unmutated in 192/296, 65%) and genomic aberrations at treatment requirement (17p deletion in 30/306, 9.8%; 11q deletion in 56/300, 19%; +12 in 70/298, 23%; 13q deletion in 108/301, 36%). Results. After a median follow-up of five years, 159 patients have progressed and 72 have died, accounting for a 5-year progression free survival (PFS) according to the IWCLL criteria of 47% (median: 58 months) and for a 5-year overall survival (OS) of 81% (median: not reached). When the demographic effects of age, gender and year of treatment were compensated, the 5-year and 10-year survival of the whole CLL cohort were 85% and 68%, respectively, of those expected in the matched normal general population (p 〈 0.001). By multivariate analysis, unmutated IGHV genes, 11q deletion and 17p deletion maintained independent association with both PFS and OS, thus providing the rationale to utilize them in the development of a model to predict remission duration after FCR. By recursive partitioning analysis, 17p deletion was the most important variable in predicting PFS after FCR, followed by 11q deletion and IGHV mutation status (Fig. 1A). Based on the application of an amalgamation algorithm, cases harboring unmutated IGHV genes and 11q deletion were grouped into a single category because they showed an identical drop of the PFS curve (Fig. 1A). By this approach, three CLL subgroups were hierarchically classified. Clinical features and treatment indication were superimposable across the three risk groups. The low risk category comprised patients harboring mutated IGHV genes but neither 11q or 17p deletion, and accounted for 26% of all cases. Most of the low risk patients (67%) remained free of progression after FCR (Fig. 1B), and their hazard of relapse dropped to zero after 5 years of follow-up. Consistently, the PFS curve of low risk patients plateaued after 5-years from FCR (Fig 1B). The life expectancy of low risk patients (91% at 5 year) was superimposable to that observed in the matched normal general population (Fig. 1D), indicating that neither the disease, nor complications of its treatment affected survival in this favorable group of CLL. Conversely, patients belonging to the intermediate risk (IGHV unmutated and/or 11q deleted) and high risk (17p deleted) categories showed a constant increase of the hazard of progression over time and almost all were projected to relapse after FCR, although at a different rate: 10% per year of follow-up in the intermediate risk group and 17% per year of follow-up in the high risk group (Fig. 1B-C). The 5-year life expectancy of intermediate and high-risk patients was significantly impaired compared to that observed in the matched general population (85% and 60%, respectively) (Fig. 1D), indicating an excess of deaths related to the disease or treatment complications in these unfavorable groups of CLL. Conclusions. The combination of three biomarkers that are routinely tested at treatment allows to segregate a subgroup of CLL (IGHV mutated without 17p or 11q deletion) that may achieve a durable remission after first line FCR treatment and experience an expected survival similar to that of the general population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3300.3300

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Hematology & Oncology, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2022-08-26)

Abstract: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Type of Medium: Online Resource

ISSN: 1756-8722

URL: Article

DOI: 10.1186/s13045-022-01333-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2429631-4

In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-11-21)

Abstract: One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the G-CHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL ( p = 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS, p = 0.0061) and time to next treatment (TTNT, p = 0.0043), but not overall survival (OS, p = 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients ( p = 0.0190 and 0.0137), they were superimposable for IGHV mutated patients ( p = 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79% vs . 68% vs . 38% for CR, PR and SD/PD; p & lt; 0.0001) and measurable residual disease (MRD) influenced PFS (78% vs . 53% for undetectable MRD vs . detectable MRD, p = 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumab-based treatment.

Type of Medium: Online Resource

ISSN: 2234-943X

URL: Article

URL: Article

DOI: 10.3389/fonc.2022.1033413

DOI: 10.3389/fonc.2022.1033413.s001

Language: Unknown

Publisher: Frontiers Media SA

Publication Date: 2022

detail.hit.zdb_id: 2649216-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 17, No. 10 ( 2017-10), p. S11-S12

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2017.09.039

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 59, No. 2 ( 2018-02), p. 423-433

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428194.2017.1339872

Language: English

Publisher: Informa UK Limited

Publication Date: 2018

detail.hit.zdb_id: 2030637-4