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In: The Lancet Haematology, Elsevier BV, Vol. 7, No. 12 ( 2020-12), p. e861-e873

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(20)30323-9

Language: English

Publisher: Elsevier BV

Publication Date: 2020

In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 65, No. 11 ( 2017-11-13), p. 1884-1896

Abstract: Gram-negative bacteremia (GNB) is a major cause of illness and death after hematopoietic stem cell transplantation (HSCT), and updated epidemiological investigation is advisable. Methods We prospectively evaluated the epidemiology of pre-engraftment GNB in 1118 allogeneic HSCTs (allo-HSCTs) and 1625 autologous HSCTs (auto-HSCTs) among 54 transplant centers during 2014 (SIGNB-GITMO-AMCLI study). Using logistic regression methods. we identified risk factors for GNB and evaluated the impact of GNB on the 4-month overall-survival after transplant. Results The cumulative incidence of pre-engraftment GNB was 17.3% in allo-HSCT and 9% in auto-HSCT. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most common isolates. By multivariate analysis, variables associated with GNB were a diagnosis of acute leukemia, a transplant from a HLA-mismatched donor and from cord blood, older age, and duration of severe neutropenia in allo-HSCT, and a diagnosis of lymphoma, older age, and no antibacterial prophylaxis in auto-HSCT. A pretransplant infection by a resistant pathogen was significantly associated with an increased risk of posttransplant infection by the same microorganism in allo-HSCT. Colonization by resistant gram-negative bacteria was significantly associated with an increased rate of infection by the same pathogen in both transplant procedures. GNB was independently associated with increased mortality at 4 months both in allo-HSCT (hazard ratio, 2.13; 95% confidence interval, 1.45–3.13; P 〈 .001) and auto-HSCT (2.43; 1.22–4.84; P = .01). Conclusions Pre-engraftment GNB is an independent factor associated with increased mortality rate at 4 months after auto-HSCT and allo-HSCT. Previous infectious history and colonization monitoring represent major indicators of GNB. Clinical Trials registration NCT02088840.

Type of Medium: Online Resource

ISSN: 1058-4838 , 1537-6591

URL: Article

DOI: 10.1093/cid/cix690

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2017

detail.hit.zdb_id: 2002229-3

In: Diagnostic Molecular Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 11, No. 1 ( 2002-03), p. 2-8

Type of Medium: Online Resource

ISSN: 1052-9551

URL: Article

DOI: 10.1097/00019606-200203000-00002

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2002

detail.hit.zdb_id: 2045341-3

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1821-1821

Abstract: Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute's Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p 〈 0.001), and grade ≥3 was 15% vs 2.5% (p 〈 0.001), respectively. Most of NAEs occurred during the induction phase (52% in VTD and 70% in TD arms), while a minority were seen during consolidation therapy (6% in VTD and 8% in TD). Median time to onset of grade ≥2 PN was 83 days in the VTD arm compared with 37.5 days in TD arm (p=0.04). Overall, 89% of patients on VTD and 95% on TD had a complete resolution of PN within a median of 70 and 61 days (p=0.6), respectively. An improvement to at least grade 1 was recorded in 94% of patients in the VTD arm and in 95% on TD within a median of 78.5 and 61 days (p=0.4), respectively. Three patients (1%) on VTD and none on TD discontinued treatment due to neurological toxicity. Notably, development of grade ≥2 PN did not affect the rates of CR/nCR, and both time to progression (TTP) and PFS. By univariate analysis, characteristics of patients at baseline, including age, MM isotype, ISS stage and cytogenetic abnormalities such as del(13q), t(4;14) or del(17p), did not influence the development of grade ≥2 PN in both arms. GEP were analyzed in 127 patients assigned to the VTD arm (44 with and 83 without treatment-emergent grade ≥2 PN). Patients experiencing a grade ≥2 PN were characterized by the differential expression of 184 genes (p 〈 0.01). The genes showing the highest change in expression included NRN1 (involved in the axonal regeneration), GSTM1 (involved in the detoxification of electrophilic compounds by conjugation with glutathione), DCTN1 (whose mutations are associated in specific types of disease-associated axonal degeneration). GeneGO® pathway analysis of differentially expressed genes showed enrichment for genes mainly implicated in the regulation of cytoskeleton rearrangement and the axonal guidance: indeed, several genes, which are involved in the signal transfer from semaphorin and ephrin to the cytoskeletal and motor proteins resulted differentially expressed in patients who developed grade ≥2 PN (SEMA6A, SEMA4B, ACTA2, EPHA5, NEB). Conclusions: Although VTD incorporated into double ASCT was associated with a higher incidence of grade ≥2 PN compared with TD, the probability of complete resolution or improvement to at least grade 1 was comparable in both VTD- and TD-treated groups. Importantly, NAEs did not adversely affect the rate of CR/nCR, and TTP and PFS. No relationship between development of PN and both patient demographics and disease characteristics was observed. Conversely, GEP analysis of BMPCs from patients with VTD-induced PN showed the significant deregulated expression of genes involved in the nervous system function. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Tosi:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Mayers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1821.1821

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. 116, No. 21 ( 2010-11-19), p. 781-781

Abstract: Abstract 781 Aim of the present study was to evaluate the impact of bortezomib-based induction treatments on clinical outcomes of newly diagnosed multiple myeloma (MM) patients with unfavorable cytogenetic abnormalities. For this purpose, we analyzed 590 bortezomib-treated patients who were screened at diagnosis for the presence of del(13q), t(4;14) and del(17p) by fluorescence in situ hybridization (FISH) on highly purified bone marrow plasma cells. Patients were stratified into the following 3 groups based on 1) the absence of any cytogenetic abnormality (n=261, or 44%) or 2) the presence of del(13q) alone (n=175, or 30%) or 3) positivity for t(4;14) and/or del(17p) (n=154, or 26%). In the great majority of the patients, loss of 17p was detected in more than 70% of bone marrow plasma cells, a finding which precluded a comparison with patients carrying del(17p) in a lower percentage of plasma cells. After diagnosis, 218 patients received induction therapy with bortezomib-thalidomide-dexamethasone (VTD), while the remaining 372 patients were treated with bortezomib-melphalan-prednisone (VMP) (n=181) or VMP plus thalidomide (VMPT) (n=191). The median number of bortezomib infusions (1.3 mg/m2) actually received was 24. Baseline characteristics of the 3 groups of patients were comparable, with the exception of a higher frequency of ISS stage 3 among patients with t(4;14) and/or del(17p) as compared with the cytogenetic-negative group (29% vs 17%, respectively; p=0.003). The rates of absence or presence of del (13q), t(4;14) and/or del(17p) were comparable among patients receiving VTD or VMP or VMPT treatments. Best CR to overall treatment protocols was 39% for the cytogenetic-negative group and 44% for high-risk patients carrying t(4;14) and/or del(17p). With a median follow-up of 27.5 months, median PFS was 40.5 months for patients without cytogenetic abnormalities as compared with 34 months for the high-risk group (p=0.7), while it was not reached after 38 months in the group with del(13q) alone (p not statistically significant for comparison with the other two groups). Overall, the frequency of events was 31% for patients without cytogenetic abnormalities or with del(13q) alone in comparison with 38% for those with high-risk cytogenetic profiles (p=0.15). Median OS was not reached in any of the 3 groups. Forty-month projected OS rates were 89% for the cytogenetic-negative group, 81% for the group with del(13q) alone (p=0.6) and 77% for the high-risk group (p=0.003 for comparison between this latter and the cytogenetic-negative group). Patients with t(4;14) and/or del(17p) had a shorter OS after relapse in comparison with the cytogenetic-negative group (20-month projected rates: 60% vs 76%, respectively; p=0.01). To more carefully evaluate the prognostic relevance of high-risk cytogenetic abnormalities, we stratified patients in the high-risk group into the following 3 subgroups: 1) t(4;14)-positive but del(17p)-negative (84 patients); 2) del(17p)-positive in the absence of t(4;14) (54 patients); t(4;14)-positive and del(17p)-positive (16 patients). Median PFS was not reached after 40 months for patients with t(4;14) alone, while it was 33 months for patients with del(17p) alone (p=0.1) and was 18.5 months for those who carried both these abnormalities (p=0.0008 for comparison between these latter patients and t(4;14)-positive patients). Overall, the frequency of events was 30% and 41% for patients carrying either t(4;14) or del(17p), respectively (p=0.13), while it was as high as 69% for patients with both these abnormalities. The 40-month projected OS rates for these 3 subgroups were 79%, 82% and 64%, respectively (p not significant). In conclusion, the present analysis of a large series of newly diagnosed MM patients receiving bortezomib-based induction treatments showed that: 1) del(13q) alone had no adverse effect on both PFS and OS; 2) the presence of t(4;14) and/or del(17p) did not adversely influence PFS, but was associated with a shorter OS, due at least in part to a worse outcome after relapse; 3) in comparison with t(4;14), del(17p) alone did not predicted for shorter PFS and OS, possibly as a result of the relatively long-term exposure to bortezomib); 4) the presence of both del(17p) and t(4;14) was likely to confer a particularly dismal clinical outlook, a finding which needs to be confirmed in larger series of patients. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib-based treatment for newly diagnosed multiple myeloma. Petrucci:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:NOVARTIS: Honoraria; CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Palumbo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.781.781

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. 114, No. 22 ( 2009-11-20), p. 2828-2828

Abstract: Abstract 2828 Poster Board II-804 Studies including thalidomide showed a rate of severe infection that can be life-threatening complication or compromise compliance to therapy ranging from 6% to 22%. Therefore, antibacterial prophylaxis has become a routine clinical practice despite its role in the new-drugs era has to be defined. We performed a post-hoc analysis of patients treated with thalidomide based combinations within controlled trials in order to assess time, type and outcome of infections. We analysed the main demographic and disease related variables to search for factors affecting onset of infections during induction and build a risk model in order to perform targeted prophylaxis. Two hundred and twenty four patients were eligible for this study. Median age was 70 years (range 31-90 years) and 141 patients (63%) had more than 65 years. Fifty three percent of patients had de novo MM whereas the remaining had received thalidomide as second or subsequent lines of therapy. ISS stage 2-3 and renal impairment were present in 156 (69%) and 38 (17%) of patients, respectively. Induction therapy consisted in the following protocols: ThaDD (160 patients: 71.5%), ThaDD-V (42 patients: 19%), VMPT (9 patients: 4%), TD (8 patients: 3.5%) and VTD (5 patients: 2%). Prophylaxis for infections was administered to 168 patients (75%) and consisted of quinolones (72%) or thrimethoprim-sulphamethoxazole (28%). Eighty six patients (38.5%) developed an infection resulting of grade 3-4 in 39 of them (17.5%) (12% grade 3, 5.5% grade 4). Probability of infection at six months was 39% although that of severe infection was 20% (18% at 4 months and just 2% from 4 to 6 months). Among the 39 patients with severe infection, 23 (59%) developed pneumonia, 9 FUO (23%), 6 bacteremia (1 septic shock) and 1 an orbital abscess. Aetiology of severe infection was recognized in 7 patients (4 Gram-negative bacteria, 1 Gram-positive bacteria, 1 CMV and 1 probable fungal infection). Eighty percent of severe infections occurred during the first 3 courses of induction therapy and only 12% during neutropenia. Fifteen percent of patients undergoing antibiotic prophylaxis developed infection vs 25% of patients who did not (p= 0.084). There were no difference between quinolones and thrimethoprim-sulphamethoxazole prophylaxis regarding incidence of infections. The majority of infections were empirically treated and cured with wide spectrum antibiotic therapy except when a specific aetiology was recognized. Only one patient died because of septic shock during neutropenia and 2 patients withdrawn from protocol because of infection. In univariate analysis monoclonal component 〉 2 g (p=0.021), platelets 〈 130.000/ml (p= 0.005), newly diagnosed MM (p=0.083) and antibiotic prophylaxis (p=0.061) were factors predicting severe infection development whereas age, sex, ECOG performance status, MM type, D-S stage, plasmacell infiltration in bone marrow, haemoglobin concentration, serum b2-microglobulin, serum albumin, ISS, serum C-Reactive Protein, serum creatinine, previous stem cell transplantation were not. Cox regression analysis selected monoclonal component 〉 2 g (p=0.015 HR= 1.8) and platelets 〈 130.000/ml (p=0.003 HR= 2.3) as covariates associated to severe infection. The 25 patients without adverse factors, the 125 with 1 and the 74 with 2 adverse factors had a probability of severe infection equal to 4%, 17% and 32 % (p= 0.023), respectively. This model remains useful apart from prophylaxis since the probability of severe infection in patients with at least 1 risk factors receiving prophylaxis is 17% vs 4% in patients without risk factors. Of note, patients developing severe infection had a significantly higher incidence of deep venous thrombosis (DVT) compared with patients who did not (20.5% vs 9%: p= 0.041). DVT occurred after a median time of 0.9 months (range 0.1-5 months; 75% within 2 months) from infection onset. In conclusion, despite antibiotic prophylaxis, patients receiving thalidomide combination therapy can develop severe infections particularly pneumonia. Wide spectrum antibiotic therapy is effective in the majority of cases since viral or fungal infections are very rare. Patients with large size of disease, represented by high MC and low platelets count, are at higher risk of severe infection that in turn significantly increase the risk of DVT. Therefore, these patients at high-risk should receive more suitable antimicrobial prophylaxis. Disclosures: Off Label Use: Thalidomide, Bortezomib and Doxil.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2828.2828

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. 119, No. 10 ( 2012-03-08), p. 2310-2313

Abstract: It is unclear whether karyotype aberrations that occur in regions uncovered by the standard fluorescence in situ hybridization (FISH) panel have prognostic relevance in chronic lymphocytic leukemia (CLL). We evaluated the significance of karyotypic aberrations in a learning cohort (LC; n = 64) and a validation cohort (VC; n = 84) of patients with chronic lymphocytic leukemia with “normal” FISH. An abnormal karyotype was found in 21.5% and 35.7% of cases in the LC and VC, respectively, and was associated with a lower immunophenotypic score (P = .030 in the LC, P = .035 in the VC), advanced stage (P = .040 in the VC), and need for treatment (P = .002 in the LC, P = 〈 .0001 in the VC). The abnormal karyotype correlated with shorter time to first treatment and shorter survival in both the LC and the VC, representing the strongest prognostic parameter. In patients with chronic lymphocytic leukemia with normal FISH, karyotypic aberrations by conventional cytogenetics with novel mitogens identify a subset of cases with adverse prognostic features.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-11-395269

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 99-99

Abstract: Background. The incorporation of tyrosine kinase inhibitors (TKIs) in treatment schemes of Ph+ ALL has remarkably improved survival. In adult patients with Ph+ ALL, ponatinib in combination with chemotherapy showed a 3-year event-free survival rate of 69%, a 3-year overall survival (OS) of 83%, and a higher rate of response when compared with dasatinib plus chemotherapy. However, in unfit or elderly ALL patients, TKIs combined with chemotherapy are associations with higher toxicity. Therefore, we examined the efficacy and safety of steroids plus ponatinib alone for the treatment of elderly or unfit patients with Ph+ ALL in a multi-center Phase II prospective clinical Italian trial, GIMEMA LAL1811 (EudraCT number 2012-002761-35). Methods. From March 2014 to December 2016, we enrolled 44 patients with untreated Ph+ ALL, ≥ 60 years or unfit (i.e. for intensive chemotherapy and stem cell transplantation). Two out of 44 patients were not elegible for the study. Patients received oral administration of 45 mg/day of ponatinib for 8 consecutive courses of 6 weeks (w). Steroids were administered from day -14 to day 29 during course 1. Intrathecal therapy with methotrexate, cytarabine and dexametasone was performed every 28 days for central nervous system (CNS) disease prophylaxis. In patients with CNS disease at diagnosis, intrathecal therapy was administered twice a week until complete remission. Dose reduction of ponatinib was allowed for adverse events. Patient samples were obtained at diagnosis and at every course, BCR-ABL mutational analisys and BCR-ABL/ABL ratio by quantitative real time PCR was performed. Complete molecular response (CMR) was defined as BCR-ABL/ABL ratio below 0.01 or undetectable, and with a sensitivity of at least 30,000 molecules of ABL. Results. Forty-two patients were eligible for the study. Median age was 68 years (range 27-85). Nine out of 42 patients were & lt;60 years and were considered unfit. Twenty-six out of 42 patients had the p190 fusion transcript, 4/42 had p210, 12/42 had p190/p210. Steroid pretreatment was administered to 39; 14/39 patients had a reduction in circulating blasts of 75% or more before starting ponatinib. Primary endpoint (Complete hematological response (CHR) at 24w in 75% of patients) was prematurely reached. CHR was obtained in 40/42 patients (95,2%) after course 1 (6w). Thirty-eight out of 42 patients (90,5%) were in CHR after 8 courses (24w); 2 patients stopped treatment after 6w for disease relapse (1) and for excessive toxicity (1). Two patients dropped out after 12w for medical decision. A CMR was detected in 11/24 patients at 24w (45.8%; 14/38 patients not evaluable). Considering a CMR test sensitivity of at least 10,000 ABL molecules and testing peripheral blood whenever a bone marrow was not obtained, 20/33 patients (60.6% 5/38 patients not evaluable) were in CMR at 24w (figure 1). The median follow-up of the enrolled patients was 11.4 months (range 6-34.5). Overall survival (OS) at 6 months and 1 year was 97.6% (C.I 95%: 93.1%-100.0%) and 87.5% (C.I. 95%: 76.5%-99,9%) respectively (figure2). At week 24, 15/42 patients still received 45 mg of ponatinib daily, only 4/42 patients permanently withdrew study drug. During the study, 75 adverse events (AE) were reported; 36 of the 75 AEs were considered related to ponatinib. Twenty-six of the 75 AEs were considered serious (SAE); 13/26 SAEs were considered related to ponatinib. A death was suspected to be related to ponatinib. We performed BCR-ABL mutational analysis in 22 patients at diagnosis, and 15 patients at 24w. T315L (abundance 100%) was detected in a patient relapsed during ponatinib therapy. We could not identify the emergency of other mutations. Conclusions. Ponatinib and steroid show a high efficacy in newly diagnosed unfit/elderly Ph+ ALL patients. Toxicities were manageable and cardiovascular AEs were limited. In the small cohort of patients relapsed in the study, relapse mechanisms were unclear; only one patient had evidence of mutations that caused resistance to ponatinib. The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway could explain the therapeutic effectiveness. Acknowledgments. GIMEMA, ELN, AIL, AIRC, Regione-Università 2010-12, FP7 NGS-PTL, HARMONY, Fondazione del Monte BO e RA. Disclosures Soverini: Bristol-Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Bocchia: Novartis: Other: Travel grant; Celgene: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Cuneo: Abbvie: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Falini: Roche: Research Funding. Galieni: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board. Foà: Sandoz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Baccarani: Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.99.99

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4871-4871

Abstract: Recipients of allogeneic hematopoietic stem cell transplant (HSCT) have been excluded from clinical trials of SARS-CoV-2 messenger RNA (mRNA) vaccines; however, since these patients are at higher risk of severe complications following infection, they have been given high priority in vaccination campaigns worldwide. In this prospective observational study, we evaluated the immunogenicity of two BNT162b2 (Pfizer-BioNTech) vaccine doses in allogeneic HSCT recipients compared to healthy controls. IgG antibodies to the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 were analyzed by SARS-CoV-2 IgG II Quant (Abbott, Ireland). The cutoff value of the test used in this study is 7.1 BAU/mL (Binding Antibody Unit/mL) and the results greater than 7.1 indicate that seroconversion has occurred, as recommended by the manufacturer. Peripheral blood samples were collected for immunological analysis at three timepoints: pre-vaccine baseline (w0, before the first BNT162b2 dose), week 3 (w3, before the second vaccine dose) and week 5 (w5, 2 weeks following the second dose). Patients older than 18 years who received BNT162b2 vaccine following an HSCT at seven Italian centers were included in the study. Enrolled patients received two successive doses (at 3-week interval) at a median of 15 months (range 2-141) after HSCT. Twenty-nine age-matched health care workers who were vaccinated with BNT162b2 were recruited as the control group. Among the 34 patients evaluable for serological response, three patients were excluded from the analysis as the baseline serology demonstrated previous natural SARS-CoV-2 infection. On w3, after the first vaccine dose 7/31 (23%) patients developed anti-S IgG antibodies as compared to 28/29 (97%) controls (p & lt;0.01). HSCT recipients showed lower antibody titers (median 1.8 BAU, range 0-481) as compared to healthy controls (median 118 BAU, range 6-1172, p & lt;0.01). In univariate analysis, transplant-to-vaccination interval ( & gt;12 months, p & lt;0.01), baseline CD4+ T cell count ( & gt;200/mm3, p=0.01), and CD4+CD45RA+ T naive cell count ( & gt;100/ mm3, p & lt;0.01) were significantly associated with antibody response after the first vaccine dose. On w5, after the second vaccine dose, 24/31 (77%) of the patients showed antibody response, as compared to 99% of healthy controls (p & lt;0.01); in fact, 71% of non-responders to the first dose developed IgG antibodies after vaccine boost (Figure 1). Median antibody titer after second dose was 350 BAU/ml (0-21.731). In univariate analysis, no significant association was found between patient characteristics and immunogenicity after vaccine boost. Adverse events were rare and modest. Nine percent of the patients reported mild local reactions after vaccine administration, including pain at the injection site and less commonly local erythema, local lymphadenopathy, or swelling; 35% of patients reported systemic adverse events, and all were mild. The most frequently reported systemic reactions included weakness (15%), headache (9%), and diarrhea (3%). In conclusion, in recipients of HSCT, a single dose of the BNT162b2 SARS-CoV-2 vaccine yielded poor efficacy, while immunogenicity increased significantly after vaccine boost at day 21 after the first dose. Patients who received vaccines beyond one year after transplant were more likely to mount anti-S IgG antibodies, which could be due to a broader immune reconstitution, as we observed an enhanced response to single BNT162b2 vaccine dose in patients with higher CD4+ T cell and particularly CD4+CD45RA+ naïve T cell counts. Figure 1 Figure 1. Disclosures Kordasti: Alexion: Honoraria; Celgene: Research Funding; Beckman Coulter: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-152907

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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. 2281-2281

Abstract: Abstract 2281 Introduction. Imatinib is the standard of care for CML in early chronic phase. Until now, even in stable complete molecular response, discontinuation of imatinib is not recommended, and imatinib remains a life-saving drug to be taken chronically. Long term side effects, including the incidence of second malignancies, represent a potential relevant issue. Roy et al (Leukemia 2005) reported an unexpected incidence of second neoplasms in patients treated with imatinib after interferon (6/189 patients, 3.2%; urinary tract cancer: 4/6). In contrast, an analysis performed by Novartis Pharma (Pilot et al, Leukemia 2006) on 9518 patients treated with imatinib (including pre-treated patients) did not provided evidence for an increased overall incidence of second malignancies. According to epidemiologic data (Registro Tumori) in Italy, the annual incidence of neoplasms varies from 1%, in the range of age between 50 and 69 years, to 3% for patients over 70 years. AIM. To evaluate the incidence of second malignancies in CML patients treated with imatinib frontline. METHODS. Overall, 559 patients have been enrolled in 3 concurrent clinical studies of the GIMEMA CML Working Party: CML/021, Imatinib 800 mg in intermediate Sokal risk patients (Clin Trials Gov. NCT00514488); CML/022, Imatinib 400 mg vs 800 mg in high Sokal risk patients (Clin Trials Gov. NCT00510926); CML/023, observational, Imatinib 400 mg. We evaluated the incidence of II malignancy notified as severe adverse events reported by the GIMEMA clinical Centers. RESULTS. The median age at the diagnosis of CML was 52 (extr.18 – 84) years; 308 patients (55%) were ≥ 50 years. The median follow-up is currently 60 months. Eighteen patients (3.2%) developed a second malignancy at a median time of 20 months (extremes 2 – 52) from the start of imatinib therapy (Table 1); 4 of these malignancies (2 colon cancer and 2 NHL) were diagnosed within 6 months. All patients were older than 50 years (median 64, extremes 50 – 79) at the diagnosis of the second malignancy. Fifteen out of the 559 (2.7%) patients died due to second neoplasm progression. CONCLUSION. In this multicentre nation-wide experience of CML patients treated with imatinib frontline, the incidence of life-threatening or requiring hospitalization secondary neoplasms (severe adverse events), seems not to be superior to the observed incidence of neoplasm in the Italian national population. In particular, in contrast to what previously reported, no increased incidence of urinary tract cancer was observed. Disclosures: Gugliotta: Novartis: Honoraria. Castagnetti: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Martinelli: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Pane: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Saglio: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2281.2281

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7