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In: British Journal of Haematology, Wiley, Vol. 195, No. 3 ( 2021-11), p. 371-377

Abstract: COVID‐19 is associated with high mortality in patients with haematological malignancies (HM) and rate of seroconversion is unknown. The ITA‐HEMA‐COV project (NCT04352556) investigated patterns of seroconversion for SARS‐CoV‐2 IgG in patients with HMs. A total of 237 patients, SARS‐CoV‐2 PCR‐positive with at least one SARS‐CoV‐2 IgG test performed during their care, entered the analysis. Among these, 62 (26·2%) had myeloid, 121 (51·1%) lymphoid and 54 (22·8%) plasma cell neoplasms. Overall, 69% of patients (164 of 237) had detectable IgG SARS‐CoV‐2 serum antibodies. Serologically negative patients (31%, 73 of 237) were evenly distributed across patients with myeloid, lymphoid and plasma cell neoplasms. In the multivariable logistic regression, chemoimmunotherapy [odds ratio (OR), 3·42; 95% confidence interval (CI), 1·04–11·21; P  = 0·04] was associated with a lower rate of seroconversion. This effect did not decline after 180 days from treatment withdrawal (OR, 0·35; 95% CI: 0·11–1·13; P  = 0·08). This study demonstrates a low rate of seroconversion in HM patients and indicates that treatment‐mediated immune dysfunction is the main driver. As a consequence, we expect a low rate of seroconversion after vaccination and thus we suggest testing the efficacy of seroconversion in HM patients.

Type of Medium: Online Resource

ISSN: 0007-1048 , 1365-2141

URL: Issue

URL: Article

DOI: 10.1111/bjh.v195.3

DOI: 10.1111/bjh.17704

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 1475751-5

In: Blood, American Society of Hematology, Vol. 114, No. 21 ( 2009-11-19), p. 4696-4702

Abstract: Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P 〈 .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P 〈 .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2009-03-212449

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 922-922

Abstract: Introduction. The majority of SMZLs display an indolent course, however the disease is still incurable and a significant proportion of patients (~25-30%) experience poor outcomes surviving 〈 5 years. Molecular alterations of SMZL are promising biomarkers, which might improve risk stratification of patients. The main objective of the study is to test the impact of molecular aspects on disease-specific survival prognostication in newly diagnosed SMZL. Methods. IELSG46 is a multicenter, international, retrospective, observational study in which already existing and coded health-related personal and biological material is used. The study included adults, who received a diagnosis of SMZL on spleen histology with a follow up 〉 5 years, and for whom tumor material collected before initiation of medical therapy was available. Mutation analysis was performed by CAPP-seq targeted deep next generation sequencing of tumor genomic DNA. A stringent bioinformatic pipeline was applied to suppress the background noise allowing to call variants with a sensitivity of 5x10-2 in FFPE derived DNA. Copy number variations (CNVs) were identified by using the sequencing reads-based GATK4-CNV algorithm. IGHV rearrangements were obtained by using LymphoTrack® IGH FR1 Assay Panel kit. Molecular clusters were identified by an iterative algorithm that maximizes genetic distinctiveness of subgroups by reassigning patients between clusters that are created a priori based on the co-occurrence of genetic lesions. Relative survival, defined as the ratio between actuarial survival observed in the SMZL cohort and expected survival of the general population matched to patients by geographical origin, sex, age and calendar year of diagnosis, was calculated using the Ederer II method. Results. The analysis included 303 patients with a SMZL diagnosis confirmed on spleen histology. The sample size allowed to identify 30% differences in survival for molecular subgroups comprising at least 5% of cases with a statistical power between 80-100%. Median follow-up was 9.2 years. At 10 years, 85% of patients were alive, consistent with the known indolent behavior of this lymphoma. Genes recurrently affected by non-synonymous somatic mutations in 〉 10% of SMZL included KLF2 (24%), NOTCH2 (19%), KMT2D (15%), TNFAIP3 (13%), EP300 and TP53 (10%). Deletion 7q was documented in 25% of cases and IGHV1-2*04 usage in 32%. By cluster analysis, three major molecular subgroups were identified, each of them characterized by a NOTCH pathway mutated gene (Fig. 1A). The first cluster was defined by NOTCH2 and/or KLF2 mutations and was enriched in TNFAIP3 mutations and IGHV1-2*04 gene usage (Fig. 1A). The second cluster was defined by SPEN mutations, and was enriched in KMT2D and other epigenetic gene mutations (Fig. 1A). The third cluster was enriched in NOTCH1 mutations (Fig. 1A). By relative survival analysis, the NOTCH2/KLF2 cluster showed a lower survival compared to the matched general population, indicating a significant impact of the disease on patients' expected survival (Fig. 1B). Conclusions. The large sample size and inclusion of SMZL confirmed by spleen histopathology review allowed for precise estimation of the prevalence of KLF2 and NOTCH2 mutations in this lymphoma. Three molecular clusters were identified in SMZL, each of them containing a NOTCH pathway gene, supporting the relevance of NOTCH signaling in the pathogenesis of SMZL. Patients belonging to the NOTCH2/KLF2 cluster had a lower relative survival compared to the matched general population. Disclosures Traverse-Glehen: Astra Zeneca: Other: Travel; Takeda: Research Funding. Gomes da Silva:Roche: Other: Institution's payment for consultancy, Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Other: Travelling support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Ladetto:Celgene: Honoraria; Jannsen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria; Roche: Honoraria. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Omeros: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy; Roche: Consultancy; Celgene: Consultancy. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zinzani:MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles:Servier: Honoraria; Abbvie: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Morphosys: Honoraria; Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria. Zucca:Celltrion: Consultancy; AstraZeneca: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-115958

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. 112, No. 11 ( 2008-11-16), p. 3167-3167

Abstract: It is well known that cytogenetic abnormalities, the IgVH mutational status, ZAP-70 and CD38 have a significant prognostic role in chronic lymphocytic leukemia (CLL). We therefore designed a 1st line treatment approach for young CLL patients stratified according to the biological features of the disease. Between November 2005 and July 2008, previously untreated CLL patients ≤60 years, with advanced or progressive disease, from 21 Italian centers, were included in this study. High risk (HR) patients were defined by the presence of an adverse biologic profile: a 17p deletion in ≥20% of analyzed cells, or a 11q deletion associated with at least one additional poor prognostic factor (IgVH germline, ZAP-70+ ≥10% or CD38+ ≥7%), or a germline IgVH or mutated VH3-21 status and at least 2 additional unfavorable prognostic factors (ZAP+ ≥10%, CD38+ ≥7%, 6q deletion or trisomy 12). Low risk (LR) patients were defined by the absence of the above mentioned characteristics. For HR patients, treatment consisted of 4 monthly courses of Fludarabine and Campath-1H (FluCam; Flu 30 mg/m2 iv; Campath-1H 30 mg iv, days 1–3). Patients who achieved a response with evidence of residual disease - by CT scan, flow cytometry and/or PCR - received a post-induction therapy including a reduced intensity PBSCs allogeneic transplant or, in the absence of a sibling donor, an autologous PBSC transplant or, in the absence of a sufficient harvest, Campath-1H sc (30 mg weekly for a maximum of 12 weeks). For LR patients, treatment included 6 monthly courses of Fludarabine and Cyclophosphamide (FluCy; Flu 30 mg/m2 iv and Cy 250 mg/m2, days 1–3). Patients with no response after 4 courses, were treated with Campath-1H sc (30 mg weekly for a maximum of 12 weeks). All patients received Darbepoietin alpha in case of anemia, G-CSF and Ciprofloxacin in case of severe granulocytopenia and PC prophylaxis with Bactrim. In addition, patients treated with FluCam underwent weekly CMV antigenemia monitoring and valacyclovir prophylaxis (2g/8h). So far, 74 young patients with advanced or progressive disease fulfilling the above criteria have been included in the study, 41 (55%) with a HR profile and 33 (45%) with a LR profile. Forty-five patients have completed the induction therapy, 24 HR patients and 21 LR patients. A response was observed in 17 HR patients: OR 71%, CR 30%, with 17% of patients obtaining an MRD- status; and in 20 LR patients: OR 95%, CR 57%, with a 19% MRD negativity. The 7 FluCam refractory patients were characterized by the presence of a 17p deletion in 3 cases and by multiple enlarged nodes in 5 (bulky nodes: 3 cases). Grade III–IV granulocytopenia was the most common toxicity after FluCam and after FluCy. However, long-lasting cytopenia was observed only in cases treated with FluCy. Asymptomatic CMV reactivation was detected in 3 cases treated with FluCam. Four patients, all treated with FluCy, have died. The causes of deaths were: febrile granulocytopenia in 2 cases, cerebral hemorrhage in 1 and multiple cerebral abscesses of unknown origin in 1. At present, 9 HR patients who achieved a response to FluCam have undergone a PBSC transplantation (allogeneic 3, autologous 6). In conclusion, the first analysis of this study, focused on young CLL patients with progressive disease stratified according to the biologic profile of the disease, has shown a high CR rate after FluCy given to patients with a LR profile and a considerable response rate with a low number of CMV reactivations after FluCam administered to patients with a HR profile. Factors predicting FluCy-related myelotoxicity warrant further investigation.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.3167.3167

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1369-1369

Abstract: Abstract 1369 Introduction: Single-agent cladribine (2CdA) given intravenously or subcutaneously (sc) is highly effective in Hairy cell leukemia (HCL). However, HCL patients are projected to progress in their life-span or, in a minority, are refractory and may benefit from other treatment strategies. Parameters predicting efficacy of (sc)2CdA in HCL are scarcely known. Aims: In a national multicentre clinical trial (EudraCT code: ICGHCL2004) we prospectively sought parameters able to predict efficacy of sc2CdA in classic HCL requiring first treatment (1987 Consensus Criteria). Methods: Clinical data and samples were collected centrally for diagnostic revision according to the WHO criteria and for molecular analyses prior to treatment. Tumor IGH and TP53 analyses or Genome-wide DNA profiling was performed in the cases with 〉 10% or 〉 50% hairy cells (HC) in the test sample, respectively (Forconi, Blood 2009). Patients entering the study received 0.5–0.7 mg/kg sc2CdA as a single course. Efficacy endpoints were response to sc2CdA, treatment free interval (TFI), relapse free survival (RFS), and overall survival (OS). Responses were assessed on month 2 and 6 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as failures (mR/NR). TFI was measured in all patients from sc2CdA initiation to time of new treatment requirement. RFS was measured in patients with CR/PR from sc2CdA initiation to relapse. OS was measured from sc2CdA initiation to death. Results: Of 148 patients, 116 were males (78,4%). Median values were: age 52 years (range 30–83), splenomegaly below costal margin 2 cm (0-16), hemoglobin 11,8 (5-17 g/dL), PLT 77×10e9/L (14-255), WBC 2,7×10e9/L (0,7-48), HC 0,2×10e9/L (0-38). Serum B2microglobulin was twice above upper limit (B2M 〉 2X) in 9/122 patients (7,4%), IGH unmutated (UM) in 7/62 (11,3%) and TP53 mutated (mutTP53) in 2/62 (3,2%). Onehundred-forty patients (94,6%) had a CR/PR (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) a mR/NR (5 mR, 3,4%; 3 NR, 2%). Risk factors of sc2CdA failure were splenomegaly (p=.001, best-cutoff 〉 3 cm bcm by ROC and Youden's Test), WBC (p 〈 .001, best cut-off 〉 10×10e9/L), HC counts (p 〈 .001, best cut-off 〉 5×10e9/L), and B2M 〉 2X (p=.013). In 62 patients investigated for molecular features, UM-IGH and TP53 were confirmed as risk factors for mR/NR (p 〈 .001 and p=.011). Conversely, age, performance status, 2CdA schedule, lymphadenopathy, neutrophil, haemoglobin and platelet counts, prior transfusions, time from diagnosis to treatment, Jansen score, LDH, marrow infiltration and hairy cell index failed to predict response. After a median follow-up of 37,5 months (range 12–67), 5 year TFI, RFS and OS were 67%, 71% and 94%, respectively. Causes of death were one infection in progressive refractory disease, 2 cardiac events and 3 second tumors. By Kaplan-Maier estimates, risk factors of shorter TFI at diagnosis were splenomegaly (p=.007), WBC 〉 10×10e9/L (p 〈 .001) or HC 〉 5×10e9/L (p 〈 .001), UM-IGH (p 〈 .001), and TP53 disfunction (p=.002). By Cox multivariate analysis (covariates: HC 〉 5×10e9/L, spleen 〉 3cm, UM-IGH and mutTP53), UM-IGH (HR=8.1, 95%CI 1.7–38.1, p=.008, median TFI=8.5 months), high HC (HR=6.9, 95%CI 1.5–31.6, p=.012, TFI=27,4 months) and splenomegaly (HR=3.7, 95%CI 1.1–12.8, p=.039, TFI=49,3 months) scored as independent risk factors. Quality of response also predicted risk of short TFI (NR=mR 〉 PR 〉 CR, p 〈 .001). In the patients with beneficial response, univariate analysis of clinical parameters identified WBC 〉 5×10e9 (p=.016) and PR (p=.001)as risk factors of short RFS. Cox multivariate analysis revealed PR as the sole independent risk factor of relapse after a median of 46 months (HR=4.5, 95%CI 1,7-12,3, p=.003). 2CdA dose schedule was among other factors that did not associate with TFI or RFS. Conclusion: This data confirm that sc2CdA has potent activity in HCL. Tumor UM-IGH status, splenomegaly, high HC count (or leukocytosis) are confirmed as independent risk factors of treatment failure and rapid progression. RFS analysis identify PR as the sole independent factor of relapse risk in the patients initially responsive to sc2CdA. This analysis may have important implications for the selection of HCL patients that will require treatments alternative to single-agent 2CdA. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.1369.1369

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 139, No. 5 ( 2022-02-03), p. 732-747

Abstract: Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021012386

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia Research, Elsevier BV, Vol. 38, No. 2 ( 2014-02), p. 198-203

Type of Medium: Online Resource

ISSN: 0145-2126

URL: Article

DOI: 10.1016/j.leukres.2013.11.009

Language: English

Publisher: Elsevier BV

Publication Date: 2014

detail.hit.zdb_id: 2008028-1

In: Blood, American Society of Hematology, Vol. 121, No. 24 ( 2013-06-13), p. 4902-4905

Abstract: BCR subsets 2 and 8 show specific genetic profiles influencing CLL course.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2013-02-486209

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 701-701

Abstract: Abstract 701 Introduction: Hairy cell leukemia (HCL) is generally responsive to intravenous Cladribine (iv2CdA). Subcutaneous Cladribine (sc2CdA) is an alternative route with 100% bioavailability. In indolent non-Hodgkin lymphomas other than HCL, at the dose of 0.7 mg/kg/cycle, efficacy of sc2CdA is similar to iv2CdA and reduction to 0.5 mg/kg/cycle determines equivalent efficacy and lower toxicity. Aims: In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we prospectively evaluated toxicity and efficacy of sc2CdA given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 consecutive days (total dose 0.7 mg/kg, arm B) as a single course in classic HCL requiring first treatment. Method: Clinical data and diagnostic samples were collected from all patients for central revision of classical HCL diagnosis (WHO criteria) and for molecular analyses at the University of Siena, prior to study entry. Early grade 3–4 toxicity was assessed on days 7 to 30 after treatment, according to the 2003 NCI/CTCAE v3 criteria and occurrence of second tumors was assessed at every subsequent follow-up. Enpoints of sc2CdA efficacy were response to treatment, treatment free interval (TFI), relapse free survival (RFS), time to second tumor (TTST) and overall survival (OS). Responses to treatment were assessed on days 60 and 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as treatment failures (mR/NR). TFI was measured as the time elapsed from sc2CdA initiation to second treatment because of new progression or failure to sc2CdA. RFS was measured in patients with a CR/PR from treatment inititation to relapse. OS was measured from sc2CdA initiation to death for any cause. Result: of 156 patients screened centrally, 148 scored as classical HCL and entered the study. Gender (male total 116/148, 78,4%; arm A: 62/77, 80,5% vs arm B: 54/71, 76,1%), age (total: median age 52 years, range 30–83; arm A: median 56, range 30–83; arm B: median 51, range 33–82), clinical and laboratory parameters prior to treatment (including spleen, hemoglobin, platelet, leucocyte and hairy cell counts) were equally balanced in the two arms. Dose reduction was required in no patients from arm A and in 2 patients from arm B due to concurrent infection. Overall hematological toxicity was no different among the two treatment arms. Requirement of platelet transfusions (total 7/148, 4,7%; arm A: 2/77, 2,6% vs arm B: 5/71, 7%), red blood cell transfusion (total 32/148; 21,6%, arm A: 15/77, 19,5% vs arm B: 17/71, 23,9%), or G-CSF (total 102/148; 68,9%, arm A: 55/77, 71,4% vs arm B: 47/71, 66,2%) was no different among the two arms. However, a significantly higher non hematological toxicity (total 28/148; 18,9%, arm A: 9/77, 11,7% vs arm B: 19/71, 26,8%) was observed in arm B (p=.019). Non haematological toxicity was mainly represented by infections or FUO (total 25/148; 16,9%) that were significantly more frequent in arm B (arm A: 8/77, 10,4% vs arm B: 17/71, 23,9%, p=.028). Higher prevalence of toxicity resulted in a higher hospitalization rate in arm B than in arm A (total 29/148; 19,6%, arm A: 9/77, 11,7% vs arm B: 20/71, 28,2%, p=.012) and one early death was experienced because of lung aspergillosis in arm B. Onehundred-forty patients (94,6%) had a beneficial response (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) failed treatment (5 mR, 3,4%; 3 NR, 2%). Responses were equivalent in the two arms, with 72/77 (93,5%) beneficial responses (49/77 CR, 63,6%; 23/77 PR, 29,9%; 4/77 mR, 5,2% and 1/77 NR, 1,3%) in arm A versus 68/71 (95,8%) beneficial responses in arm B (52/71 CR, 73,2%; 16/71 PR, 22,5%; 1/71 mR, 1,4%; 2/71 NR, 2,8%). After a median follow-up of 36 months (range 12–66), 5 year TFI, RFS, TTST and OS were 67%, 71% 87% and 94%, respectively. Causes of late death were 2 cardiac events and 3 second tumors. No differences of TFI, RFS, TTST and OS were observed in the 2 arms of treatment. Conclusion: The present data indicate that overall activity of sc2CdA is similar to iv2CdA (Cheson, 1998). Furthermore, this study indicates that sc2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and significantly lower toxicity than sc2CdA at standard doses (0.7 mg/kg). The reduced infection rates and hospitalization rates of sc2CdA have important pharmaco-economic implications. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.701.701

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5531-5531

Abstract: Introduction. In chronic lymphocytic leukemia (CLL), CD49d, the alpha chain of the heterodimer CD49d/CD29 (VLA-4), is a strong negative prognosticator, and a key player of tumor cell-microenvironment interactions. The adhesive properties of VLA-4 can be rapidly inside-out activated by signals through the B-cell receptor (BCR), thus favoring the capability of the integrin to interact with its specific ligands. In this context, VLA-4 needs to be maintained in an activated state by a continuous stream of inside-out signals from the BCR, which can be triggered by canonical antigens as well as in an autonomous antigen-independent manner, a BCR-mediated signaling recently emphasized to specifically occur in CLL cells. Aim. To investigate the constitutive VLA-4 activation state in CLL cells and to connect this still not described feature with the presence of signals from the BCR continuously activating VLA-4. Methods. Expression of the integrin alpha (CD49c, CD49d, CD49e) and beta1 (CD29) chains was analyzed by flow cytometry. The VLA-4 activation state was investigated by flow cytometry using the conformational sensitive anti-CD29 monoclonal antibody HUTS21, employed in conjunction with sources of VLA-4 ligands: either autologous plasma-containing fibronectin (FN) and soluble (s) VCAM-1 or increasing concentrations of exogenously added LDV-containing peptides as a VLA-4 specific ligand. In detail: i) HUTS21 expression was analyzed using whole blood (WB) samples from 727 CLL patients. Negative controls were obtained after plasma depletion through washing of WB samples; ii) the VLA-4 activation state expressed as receptor occupancy (RO) (J Biol Chem, 284,14337, 2009) was analyzed in sequential (t=0, day14, day 30) frozen/thawed samples from CLL patients treated in vivo with ibrutinib (IB) in real-world (n=16) and from a clinical trial (NCT02827617, n=14). BCR engagement was performed using goat F(ab′)2 anti-human IgM. ELISA assays were used to quantify FN and sVCAM-1 in plasma samples. Results. According to the 30% cutoff, CD49d was expressed in 351/727 (48%), while CD29 was expressed in 676/727 (93%), and a strong correlation between CD49d and CD29 was observed (rho=0.7, p 〈 0.0001). Among CD49d positive CLL cases, 81/351 (23%) expressed a constitutively activated form of VLA-4 identified by 〉 20% (arbitrary cut-off) HUTS21 expression. Notably, HUTS21 positive expression was not circumscribed to VLA-4 expressing CLL, being also detected in 64/375 (17%) CD49d-, CD49c+ and/or CD49e+ CLL, thus envisioning a role of other integrins (CD49c and CD49e) in CLL cell interactions in tissues sites. HUTS21 expression did not correlate with a definite cytogenetic group, IGHV mutational status or with a specific IGHV family and stereotype. Depletion of the plasma component from the WB samples before HUTS21 staining significantly reduced the proportion of HUTS21 positive cells compared with those measured in WB samples (p=0.001, n=11), suggesting the need of plasma-borne ligands for HUTS21 epitope exposure. Consistently, both FN (mean 350 μg/ml) and sVCAM-1 (mean 4.8 μg/ml) were detected in the plasma of CLL cases, irrespective to HUTS21 positivity. According to these observations, variable constitutive VLA-4 activation states were observed in CLL cells collected at the pre-treatment stage from patients undergoing IB treatment (VLA-4 RO ranging from 0.22 to 0.40); these values significantly decreased in CLL cells collected at day 14 (p=0.03) and day 30 (p=0.02) on IB, suggesting an IB-dependent impairment of antigen-independent (autonomous) BCR signals. The variability of the constitutive VLA-4 activation levels observed at pre-treatment was paralleled by variable VLA-4 activation levels upon BCR triggering (VLA-4 RO ranging from 0.56 to 0.65). Of note, an inverse correlation between the VLA-4 constitutive level and the extent of anti-IgM induced-VLA-4 activation was found (n=19, rho=-0.5, p=0.0093), implying a competition between antigen-independent and antigen-driven BCR signalling. Conclusion. The presence of a constitutively activated form of VLA-4 is observed in a subset of CLL which might be connected to continuous VLA-4 inside-out stimulation derived from an autonomous BCR signaling, which is currently under evaluation. Disclosures Zaja: Takeda: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria; Abbvie: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111450

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7