Do MYC Alterations Matter in HIV-Associated Large B Cell Lymphomas? the "Euromyc" Study (a European retrospective study)

Abstract Introduction: In the general HIV negative population, patients (pts) with diffuse large B cell lymphoma (DLBCL) or high grade B cell lymphoma (HGBCL) carrying MYC rearrangements and BCL2 and/or BCL-6 translocations [double hit (DHL) or triple hit lymphomas (THL)] have shown a dismal prognosis when treated with standard R-CHOP and are frequently candidates to intensive therapeutic regimens, without having a standard of care. Moreover, several authors have demonstrated a negative prognostic impact of isolated MYC rearrangements [single hit lymphomas (SHL)] and the best therapeutic approach for SHL are even less clear. In HIV-associated "non Burkitt" large B cell lymphomas (Ly), scanty data are available on the prevalence and the clinical and prognostic impact of MYC rearrangements, with or without BCL2 and BCL6 concomitant translocations. Due to the peculiar biology and pathogenesis of HIV-associated Ly, data from HIV negative population cannot be simply translated to the HIV positive pts. Aim: To evaluate the impact of MYC rearrangements or translocations (isolated or with BCL2 and/or BCL6 translocations) on clinical features and outcome of HIV-associated large B cell Ly. Methods: Retrospective analysis of clinical characteristics, treatment received and outcome of all HIV-associated large B cell Ly [including DLBCL, B cell Ly unclassifiable, with features intermediate between DLBCL and Burkitt (BCLU), and HGBL] with MYC rearrangements or translocations, evaluated by FISH analysis, in 11 European centers, and comparison with pts who do not have the MYC alterations. Results: One hundred-sixty-one pts were enrolled, 49 (30%) had MYC translocation or other MYC rearrangements (MYC+ pts), and 112 (70%) were negative for MYC mutation (7 pts had MYC increased copy number) (MYC- pts). Table 1 shows the clinical characteristics of the two groups, and the treatment received. MYC+ pts had higher involvement of central nervous system at presentation (17% vs 3%, p 0,023), higher Ki67% (median 91% vs 85%, p 0,005), histology other than DLBCL (32% vs 9%, p 0,0001), concomitant translocation of BCL2 (14% vs 3%, p 0,022), germinal center B phenotype (according to Hans algorithm) (85% vs 49%, p 0,0001). No differences in CD4 count or HIV viral load at Ly diagnosis were found, while a previous diagnosis of AIDS was more frequent in the MYC- group (27% vs 10%, p 0,023). MYC+ pts received more frequently intensive treatment (iCT) (41% vs 12%, p 0,0001) and less frequently the standard CHOP regimen (41% vs 74%, p 0,001). Ten pts (9%) had a DHL/THL and had similar clinical characteristics compared to SHL. With a median follow-up of 62 months, there were no significant differences in overall survival (OS) and progression-free survival (PFS) between MYC+ and MYC- pts (5 years-OS and PFS were respectively 55% and 47% in MYC+ and 59% and 53% in MYC- pts). In univariate analysis for the whole population, IPI≥3, ECOG≥ 2 and increased LDH were related to a worse OS and PFS while BCL2 translocation correlated with shorter PFS alone. In multivariate analysis ECOG and IPI mainteined their negative prognostic impact on OS and PFS. In the MYC+ group, 41% pts received R-CHOP or CHOP-like treatment (group 1), 16% infusional therapy (group 2), 41% iCT (group 3), 2% palliative therapy (PT) (group 4); 5-years OS and PFS were 47% and 32% for group 1, 47% and 37% for group 2, 67% and 68% for group 3 and both 0% for group 4. Median OS and PFS were respectively 18 and 2 months for group 1, 29 and 7 months for group 2, both not reached for group 3, both 2 months for group 4. A significant difference between group 3 and group 1 both in therm of OS (p 0,054) and PFS (p 0,005) was observed (Figure 1). Pts with DHL/THL received R-CHOP (40%), infusional schedule (30%), iCT (20%) and PT (10%). No significant difference in term of PFS and OS were observed for each treatment group with DHL/THL respect to those with SHL. In DHL/THL, 5 years OS and PFS were 50% and 30%, respectively; in SHL 56% and 51%, respectively. Of note, no pts treated with iCT died from toxicity in the MYC+ group. Conclusion: In this retrospective analysis, MYC+ pts had not different clinical characteristics compared to MYC- pts other than higher proliferative index and and more CNS involvement at diagnosis. MYC+ pts were frequently treated with iCT, this aggressive approach seemed feasible and could allow to obtain better outcome compared to standard R-CHOP treatment but further prospective studies are needed. Figure 1 Figure 1. Disclosures Bastos-Oreiro: F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite: Speakers Bureau; Gilead: Honoraria; BMS-Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Arcaini: Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Gilead Sciences: Research Funding; Celgene: Speakers Bureau. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

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AML-CM Score Predicts Prognosis in Hemato-Geriatric Patients with New-Onset Acute Myeloid Leukemia (AML) Who Receive Hypomethylating Agents (HMA)

Blood ◽

10.1182/blood-2019-130630 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2617-2617

Author(s):

Giovanni Marconi ◽

Roberta di Nicola ◽

Chiara Sartor ◽

Mariachiara Abbenante ◽

Jacopo Nanni ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Advisory Committees ◽

Group 4 ◽

Group A ◽

Group 3 ◽

Group 2 ◽

Group B ◽

Idh2 Mutation ◽

Group 1

Background Although much efforts have been made to precisely define fitness of AML patients, in patients who are not candidate to chemotherapy, there is no prognostic model and the respective weight of AML biology and patient fitness are not well established. Here we test AML-CM score (Sorror, JAMA 2018), that is validated in fit population, in a set of old AML patients who received HMAs. Methods We retrospectively collected data of consecutive patients who received HMAs in our institution from 1st Jan 2008 with an age > 65 years at AML diagnosis. AML-CM score was applied to all the patients. Patients were divided in 4 groups (score 1-4: group 1, score 5-6: group 2; score 7-9: group 3, score > 9: group 4) and in 2 macro-groups (score 1-6: group A and score > 6 group B) for the analyses. Descriptive data are presented as median with interquartile ranges (IQR). Adverse events are graded according to CTCAE v4.03. Survival analysis was conducted with Kaplan-Meyer and are presented as 95% confidence intervals (C.I.) and differences in overall survival (OS) were tested with 2-side log rank test. Fisher exact test and Person's chi squared test were used whenever appropriate. Results At data cut-off, 1st Jan 2019, 60 consecutive patients received decitabine or azacytidine as 1st line therapy for AML. Median age of the population was 75.94 years (IQR 72.53-80.38). Most of the patients (37/62, 59.7%) had de novo AML, 19/62 (30.6%) had AML secondary to previous myeloid disorders and 6/62 (9.7%) had AML secondary to chemotherapy or radiotherapy. Most of the patients were smokers (19/33, 57.57%, 29 no data), and few were usual drinkers (4/16, 25.00%, 46 no data). In our set, out of 62 patients, 2 patients (3.2%) had inv(3), 1 (1.6%) a translocation involving 11q23, 1 (1.6%) del(5q), 4 (6.4%) mon(7) or del (7q), 1 (1.6%) del(17p), 15 (24.2%) complex karyotype, 27 (43.5%) normal karyotype, 4 (6.5%) other alterations and 5 were not evaluable; 3/17 (17.65%, 45 no data) harbored IDH2 mutation, 1/16 (6.25%) IDH2 mutation, 2/33 FLT3 mutation (6.06%, 29 no data), 1/24 (4.17%, 38 no data), 2/15 (13.33%, 47 no data) TP53 mutation. According to ELN 2017, 3/62 patients (4.83%) had low risk, 34/62 (54.84%) intermediate risk and 23/62 (37.10%) high risk AML. According to AML-CM score, 13/62 patients (20.97%) were in group A, 20/62 (32.36%) in group B, 21/62 (33.87%) in group C, 6/62 (9.68%) in group D, 2/62 (3.23%) were not allocated for incomplete AML-CM score. There was no difference in term of age, ELN risk, secondary AML prevalence, HMA administered, or response to HMA according to ELN criteria between group 1, 2, 3, 4 or between macro-group A and B. Cardiovascular comorbidity, diabetes mellitus, obesity, previous tumor, hypoalbuminemia, elevated LDH were prevalent in higher risk AML-CM groups (3-4) and in macro-group B. Median OS was 658 days (95% C.I. 316-1000) in group 1, 556 days (95% C.I. 463-649 in group 2, 243 days (95% C.I. 153-353) in group 3, 107 days (95% C.I. 47-167) in group 4 (p=.021, figure 1A). Furthermore, we observed a median OS of 589 days (95% C.I. 328-850) in macro-group A and 219 days (95% C.I. 96-342) in macro-group B (p=.003, figure 1B). Reduced survival was correlated with a non-statistical trend toward augmented incidence of infections and adverse events in higher risk AML-CM groups (3-4). Conclusions AML-CM is a useful indicator of prognosis in old patients that receive HMAs. Prognosis in our set is influenced by comorbidity (measured with AML-CM, a quantitative score) more than by disease biology. We identified a group of patients (macro-group A) that has median OS after HMAs outlying OS reported in literature. This brilliant result can be due to lower comorbidity. AML-CM could help in defining candidate patients for therapy intensification and care utilization or for team comorbidity management. GM and RDN equally contributed Figure 1 Disclosures Martinelli: Roche: Consultancy; Novartis: Consultancy; ARIAD: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Papayannidis:Pfizer: Honoraria; Teva: Honoraria; Shire: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Incyte: Honoraria. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: 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, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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EZH2 Upregulation Is Associated with Unfavorable Prognosis in Diffuse Large B-Cell Lymphoma through Potential RUNX3 Downregulation

Blood ◽

10.1182/blood.v128.22.5301.5301 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5301-5301

Author(s):

Denise Peker ◽

Samara Roman-Holba ◽

Yuri Kwon ◽

Jennifer Gordetsky ◽

Amitkumar Mehta ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Rna Expression ◽

Large B Cell Lymphoma ◽

Group 3 ◽

Group 2 ◽

Large B Cell ◽

Group 1

Abstract Introduction: The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in apoptosis, angiogenesis, cell migration and invasion. Putative tumor suppressor activity of RUNX3 has been presented extensively in the literature, particularly in solid epithelial tumors and recently in lymphoma with loss of expression favoring tumorigenesis and/or prognosis, but its role in diffuse large B-cell lymphoma (DLBCL) has not been studied. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. RUNX3 downregulation due to EZH2 upregulation has been shown in various solid tumors. In the present study, we investigated the EZH2 and RUNX3 RNA expression status in DLBCL and its impact on clinical outcome. Methods: A retrospective chart review was performed and 169 cases of DLBCL treated with chemoimmunotherapy between 2003 and 2013 were included. Immunodeficiency- or EBV-associated and MYC+ LBCL were excluded. Archived formalin-fixed-paraffin-embedded tissue samples were retrieved and RNA was extracted using commercially available kits. We correlated the RNA expression levels for EZH2 and RUNX3 in various sites using quantitative real-time PCR (Taqman assay) and custom designed primers for each gene. Control samples included three benign lymph nodes free of a neoplastic process. Results: We identified 66 cases of DLBCL, including25 nodal DLBCL and 41 extranodal DLBCL, with sufficient RNA extracted. Extranodal locations included testis (n=12), orbit (n=6), primary central nervous system (n=5), bone (n=3), breast (n=2) and viscera (n=13). The median age was 64 years (range 29- 81 years) with a female to male ratio of 0.4 (F=20 and M=46). Median overall survival (OS) was 28 months (1-156 months). Immunophenotypic subtype based on cell-of-origin using Hans algorithm was available in 63 cases; 34 cases were germinal center B-cell (GCB) type while 29 were non-GCB type. Treatment data was available in 63 cases and all patients received R-CHOP as initial therapy except three patients who died shortly after diagnosis. Forty-four cases showed higher expression of EZH2 and RUNX3 when compared to normal lymph nodes (p < 0.05). Nineteen out of 44 cases showed increased EZH2 and decreased RUNX3 expression (Group 1) while EZH2 expression was lower than RUNX3 in the remaining cases (Group 2). The remaining 22 DLBCL cases did not show significant correlation for expression (Group 3). Overall survival was significantly low in Group 1 compared to Group 2 and Group 3 (p =0.030 and p=0.026, respectively). There was no difference for OS between Groups 2 and 3 (p>0.05) (Figure 1). Conclusions: Our results showed that decreased RUNX3 RNA expression is associated with EZH2 overexpression and poses an adverse prognostic factor in DLBCL. Larger studies are needed to establish the prognostic and therapeutic utility of EZH2 and/or RUNX3. Disclosures Mehta: Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Roche Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Forero:University of Alabama at Birmingham: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

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First Results of a Prospective Study on Erythropoietin Biosimilar (Epoetin zeta) Use in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Blood ◽

10.1182/blood.v126.23.4477.4477 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4477-4477

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Jeremy Monfray ◽

Hélène Labussière-wallet ◽

Marie Balsat ◽

...

Keyword(s):

Board Of Directors ◽

Hematological Malignancies ◽

Control Group ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Epoetin Beta ◽

Epoetin Zeta ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Introduction: Anemia is the most common hematological abnormality in patients with cancer and hematological malignancies, and is associated with poor prognosis and outcomes that have a detrimental impact on the patient's condition and quality of life (QOL). Erythropoiesis-stimulating agents (ESA) represent a good treatment option in order to increase the hemoglobin level in patients with anemia. Anemia can also be treated by red blood cell transfusion, but this has a transient effect and is associated with risks such as exposure to infectious agents, iron overload, or transfusion-related acute lung injury. ESA also have safety concerns, including the established increased risk of venous thromboembolic events. However, they are currently the only therapeutic alternative to transfusions. We performed a prospective observational study in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies, with the primary objective of evaluating the effect of a new ESA biosimilar, epoetin zeta (Hospira) on patient QOL. Secondary objectives included hemoglobin (Hb) and platelet (Pt) recovery, safety, overall survival (OS) and relapse incidence. Results of this study were compared to two reference populations, one receiving epoetin beta (Roche) and one control group not treated with ESA. Here, we present preliminary results for the secondary objectives. Materials and methods: The study included adult patients with Hb level ≤11g/dl occurring after all types of allo-HSCT for any hematological disease (Table 1). Epoetin zeta (30,000 IU) was administered s.c. once per week for up to 6 months, and Hb levels were monitored weekly. Injections were stopped once the Hb level reached 12g/dl without transfusion. If after 4 injections, no improvement was observed, doses were doubled, and if after 8 injections, no improvement was observed, the patient was withdrawn from the study. The QOL was measured at baseline and at 1, 2, 3 and 6 months by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Epoetin zeta responders were defined as having Hb level ≥12g/dl (complete response, CR) or a ≥2g/dl increase (partial response, PR) compared with baseline value, in the absence of transfusion. Patients receiving epoetin zeta (group 1) were compared to a similar population receiving epoetin beta with the same procedures (group 2) and to a matched population not treated with ESA (group 3), taking into account the following variables: sex, age, diagnosis, disease status at allo-HSCT, conditioning regimen and HSC source. Results: Between December 2011 and September 2014, 58 patients (from 168 screened) were included in group 1, and compared to 59 patients in group 2 and 65 patients in group 3. The main exclusion criteria were ESA contra-indication and patient refusal. Patients in group 1 had lower Hb baseline levels compared to group 2; patient characteristics for each group are summarized in Table 1. The median number of injections/patient was 10 (range: 6-14) in group 1 and 8 (range: 2-28) in group 2. The cumulative incidence of CR was 80% in group 1 and 71% in group 2. The median time to achieve CR was 48 days (range: 35-70) in group 1, and 39 days (range: 14-180) in group 2. Eight patients withdrew due to ESA inefficacy in group 1 and 8 in group 2. Adverse events were all thromboembolic: 2 events in group 1 and 5 events in group 2, compared to 2 events in group 3 (p=0.34). The multivariate analysis studying different confounding factors on the cumulative incidence of CR showed a significant positive impact of younger age (p=0.001), and a negative impact of being female or having major ABO incompatibility. We did not find any significant difference in terms of OS and relapse rate between the 3 groups. Conclusion: We describe here, for the first time, preliminary data for ESA biosimilar epoetin zeta (Hospira) in allo-HSCT patients showing comparable efficacy and safety to an existing ESA, epoetin beta (Roche) with no impact on OS and relapse incidence, compared to a control group. The QOL and transfusion evaluations as well as a cost-effectiveness study are ongoing and results will be presented. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Acute Myeloid Leukemia with Myelodisplasia-Related Changes (AML-MRC) Defined Only By Morphological Findings May Not Represent a Poor Prognosis AML

Blood ◽

10.1182/blood-2019-129153 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2612-2612

Author(s):

Ana Pérez ◽

Olga Salamero ◽

Helena Pomares ◽

Maria Julia Montoro ◽

Montserrat Arnan Sangerman ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Poor Prognosis ◽

Advisory Committees ◽

Group 3 ◽

Group 2 ◽

Acute Myeloid ◽

Group 1

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response were defined according to the European Leukemia Net recommendations. Overall survival (OS) was considered as the time from the diagnosis to the last visit. Survival analysis were performed with Kaplan Meier method and comparisons with the log-rank test. Among 575 cases of AML identified, 186 (32.3%) met AML-MRC criteria and were included in the study. The main patient characteristics are shown in Table1. Median age was 72 (range, 22-88) years and 32% were female. Adverse karyotype was present in 29% of patients, being more prevalent in the AML-MRC group 2. Sixty one patients (33%) received an intensive chemotherapy approach and 36 (19%) an allogeneic stem cell transplantation. Patients in group 3 exhibit a higher probability of achieving a complete response than groups 1 and 2 (Table 2). After a median follow-up for survivors of 28.5 months (range, 5-130), 149 (80%) died in this period. Three years Overall Survival (OS) for patients in groups 1, 2 and 3 was 3 (0-117), 5 (0-93) and 10 (0-130) months, respectively (p=0.012) (Figure 1). Type of treatment (intensive, non intensive or best supportive care) and cytogenetic risk also showed impact on OS. Multivariant analysis adjusting these factors showed that patients in group 3 also presented better OS than patients in group 1 (HR=0,42 [IC95% 0,18-0,84], p=0,02), both with around a 30% of patients with adverse cytogenetics. To conclude the present study suggests that group 3 of AML-MRC, for which the diagnosis is based solely on morphologic findings, showed better prognosis than the other groups. A more detailed molecular characterization might contribute to improve prognostic stratification of this heterogeneous AML entity, particularly in patients with non-high risk cytogenetics. Disclosures Salamero: Pfizer: Honoraria; Daichii Sankyo: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Valcárcel:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: spouse is an employee in the company, Speakers Bureau; Pfizer: Honoraria. Bosch:AstraZeneca: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Discordance predictor between fractional flow reserve and resting full-cycle ratio in clinical characteristics

European Heart Journal ◽

10.1093/ehjci/ehaa946.2481 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Ohashi ◽

H Takashima ◽

H Ando ◽

A Suzuki ◽

S Sakurai ◽

...

Keyword(s):

Regression Analysis ◽

Fractional Flow Reserve ◽

Clinical Characteristics ◽

Fractional Flow ◽

Gold Standard Method ◽

Group 4 ◽

Flow Reserve ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Introduction Fractional flow reserve (FFR) is a gold standard method to evaluate functional lesion severity in daily clinical practice. Recently, the resting full-cycle ratio (RFR) which was newly developed resting indices was launched. Unlike other resting indices evaluated in diastolic phase, RFR is evaluated during entire cardiac phase. Previous studies showed discordance predictors between FFR and instantaneous wave-free ratio. However, it is previously unreported what predictor cause discordant outcome between FFR and RFR. Purpose The purpose of this study was to evaluate clinical predictors of discordance between FFR and RFR. Methods A total of 156 patients with 220 lesions were prospectively enrolled in this study. RFR was evaluated before inducing hyperemia. FFR was measured after intravenous adenosine triphosphate administration (180 mcg/kg/min). According to FFR and RFR values, the patients and lesions were classified into 4 groups: Concordant negative (Group-1 [n=114]: FFR >0.80, RFR >0.89); negative FFR and positive RFR (Group-2 [n=18]: FFR >0.80, RFR ≤0.89); positive FFR and negative RFR (Group-3 [n=25]: FFR ≤0.80, RFR >0.89); Concordant positive (Group-4 [n=63]: FFR ≤0.80, RFR ≤0.89). Among them, discordance predictors with clinical characteristics between RFR and FFR were compared using by two separate logistic regression analyses. (Group-1 vs. Group-2, Group-3 vs. Group-4, respectively). Age, sex and those predictors with a p value ≤0.10 were included in a multivariate regression analysis using by forward stepwise selection to identify independent predictors of discordance. Results On multiple regression analysis, hemodialysis (HD) (OR:6.072 [1.090–33.836]), peripheral artery disease (PAD) (OR:9.053 [1.776–46.162]) and left anterior descending artery (LAD) (OR:9.264 [2.092–41.031]) were significantly associated with positive RFR among negative FFR groups (Groupe 2 discordance). Conversely, diabetes mellitus (DM) (OR:0.212 [0.062–0.721]) and Hb (OR:1.480 [1.102–1.987]) were significantly associated with negative RFR among positive FFR groups (Groupe 3 discordance) Conclusions Since the clinical characteristics with HD, PAD, LAD, DM and Hb may influence concordant with FFR during RFR evaluation, it should be considered when interpreting RFR. Distribution and independent predictors Funding Acknowledgement Type of funding source: None

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A Comparison of Droplet Digital PCR and RT-qPCR for BCR-ABL1 Monitoring in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2019-125614 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2092-2092

Author(s):

Carmen Fava ◽

Paola Berchialla ◽

Jessica Petiti ◽

Maria Teresa Bochicchio ◽

Barbara Izzo ◽

...

Keyword(s):

Board Of Directors ◽

Digital Pcr ◽

Advisory Committees ◽

Coefficients Of Variation ◽

One Step ◽

Group 3 ◽

Group 5 ◽

Group 2 ◽

The One ◽

Group 1

Background: Monitoring of BCR-ABL1 molecular levels is essential for the management of Chronic Myeloid Leukemia (CML) patients treated with Tyrosine Kinases Inhibitors (TKIs). Real Time Quantitative PCR (RT-qPCR) is currently the standard method for assessing molecular remission (MR) in patients with CML. Recently, droplet digital PCR (ddPCR) has emerged to provide a more accurate detection of minimal residual disease (MRD). In order to hypothesize the use of this new technology in the clinical practice, in the era of TKI discontinuation, we designed a multi-centric study to evaluate the potential value of ddPCR in diagnostic routine. Aims of the study were:1) the evaluation of the agreement between the measures obtained by ddPCR and RT-qPCR and 2) the assessment of the repeatability of the two methods. Methods: Total RNA was extracted from 37 CML patients using Maxwell 16 LEV simplyRNA Blood kit (Promega), following the manufacturer's instructions. Samples were divided in 5 groups based on molecular response (MR) as follow: group 1, MR<3, n=5; group 2, MR 3, n=5; group 3, MR 4, n=9; group 4, MR 4.5, n=9 and group 5, MR 5, n=9. BCR-ABL1 p210 was quantified by RT-qPCR and ddPCR in 3 different Italian laboratories namely Lab A, Lab B and Lab C. Lab B and C performed 1 amplification session each, while Lab A performed 3 independent sessions. All ddPCR experiments were performed using Kit QXDxTM BCR-ABL%IS (Bio-Rad) on the QX200 system (Bio-Rad), according to the manufacturer's instructions. For RT-qPCR experiments, BCR-ABL1 p210 was quantified with three different methods: by using the One-Step BCR-ABL P210 ELITe MGB Kit (ELITech Group), according to manufacturer's protocol (Lab A); by using the One-Step Philadelphia SensiQuant Kit (Bioclarma), according to the manufacturer's instructions (Lab B) and as described in Gabert et al (Lab C). The results obtained were corrected for the laboratory-specific conversion factor, as recommended by Standard Operating Procedures of Labnet CML network (GIMEMA group). The target quantification for each sample was expressed as BCR-ABL1/ABL1 %IS for both RT-qPCR and ddPCR. Statistical analysis: Bland-Altman analysis was performed. For the measurement of the agreement we reported the bias, which is the mean of the difference between the methods, the 95% limits of agreement and the coefficient of variation. Residual variance and coefficients of repeatability (i.e. the upper limits of a prediction interval for the absolute difference between two measurements by the same method on the same item) were computed to achieve the second endpoint. An analysis of sensitivity on the labs was also carried out. All analyses were stratified by the level of disease. Results: A total of 370 measures were included in the analysis, 185 for ddPCR and 185 for RT-qPCR divided as follow: 50 for group 1 and for group 2, 90 for group 3, 4 and 5. In Table 1 we reported the median and interquartile range (IQR) for all levels of disease. Results of the Bland-Altman analysis are shown in Table 2. The coefficients of variation, which expresses the standard deviation as a percentage of the mean, were 2.35, 2.31, 1.10, 1.34, 39.12 in group 1, 2, 3, 4 and 5 respectively. The repeatability coefficients of ddPCR were smaller than qRT-PCR across all the levels of disease, showing a slightly better precision of ddPCR (Table 2). Conclusions: Higher coefficients of variation in group 1 and 2 were probably due to a greater heterogeneity of the patients. In fact, BCR-ABL1/ABL1 levels by RT-qPCR ranged between 1.43 and 6.94 and between 0.10 and 0.25 in group 1 and in group 2 respectively (Table 1). Sensitivity analysis showed that the high coefficient of variation in group 5 can be explained almost all by the variability observed in Lab B. Coefficient of repeatability of ddPCR was always smaller than RT-qPCR for all level of disease showing a slightly better precision. Our results showed that ddPCR has a good agreement with RT-qPCR and it is more precise to quantify BCR-ABL1 transcript levels, particularly for MR 4 and MR 4.5. Thus, ddPCR may be valuable in diagnostic routine. Disclosures Fava: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Martino:Bio-Rad: Employment. Saglio:Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy. Martinelli:Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy. Pane:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: research founding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Cilloni:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Preliminary Results Of A Mass Spectrometry Based Bottom Up Proteomic Approach On Bone Marrow Plasma Cells From Patients With Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v122.21.1887.1887 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1887-1887

Author(s):

Beycan Ayhan ◽

Duygu Ozer Demiralp ◽

Klara Dalva ◽

Meral Beksac

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Plasma Cell ◽

Plasma Cells ◽

B Cell Lymphoma ◽

Ionization Mass ◽

Advisory Committees ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Aim The molecular mechanisms responsible from evolution to malignant monoclonal plasmacytosis is still under investigation. The aim of this prospective study was to analyze the proteomics profile of plasma cells obtained from MGUS, SMM and symptomatic myeloma patients to be able to investigate the differences at protein level between patients with low vs high plasma cell content (PCC). Material and Methods Marrow samples were collected from 30 patients newly diagnosed with Multiple Myeloma (n: 28 symptomatic and n: 1 smoldering (SMM)) and n:1 MGUS) at Ankara University Department of Hematology. Plasma cells were isolated by CD138+ selection before protein extraction. The patients were classified mainly in to three groups according to marrow PCC by flow cytometry: group1: 0-9, group 2: 10-20 and group 3: >20 %. The protein profiles of these three groups were constructed and compared via 2D gel electrophoresis by using PDQuest 8.01 analysis. Up/down regulated protein spots were identified with Matrix-assisted laser desorption/ionization mass spectroscopy(MALDI) by Peptide Mass Fingerprinting (PMF) analysis Results All protein spots that were detected according to PCC with PDQuest analysis are as follows: 135 spots in group 1 142 spots in group 2 and 145 spots in group 3 Among these spots, 27 spots with significant expression density difference (at least 2-fold) were detected between group 1 and 2, 36 spots between group 1 and group 3 and 28 spots between group 2 and group 3. 36 of these protein spots were were used in peptide isolation by using trypsin. PMF analyses were carried out in MALDI-TOF mass spectrometer. From these spots, eight proteins were identified by using Mascot: Endoplasmin (ERp99), Calreticulin(ERp60), MZB1(Marginal zone B and B1 cell specific protein/pERp1), Actin cytoplasmic1(ACTB), Myeloblastin (Leukocyte proteinase 3), Thioredoxin domain-containing protein 5 (TXNDC5/ERp46), Apoptosis regulator B-cell lymphoma 2 (Bcl-2) and Peroxiredoxin-4 ( Table 1, Figure 1). The remaining 28 spots are under investigation. In group 3 the density of protein spots which contain Calreticulin, MZB1, Myeloblastin and TXCDN5 increased, and which contain Actin and Endoplasmin decreased significantly (Table 1). There was a negative corelation between the Peroxiredoxin expression level and the PCC which resulted in disappearance as the percentage of PCC increased. Moreover, not only Peroxiredoxin, but also BCL-2 protein was detected only in the group with PCC >20 %. To avoid the changes that can be attributable to PC counts equal amounts of protein were analyzed from each group. Conclusion Until now there is only one published study utilizing proteomics in MM and reports 268 proteins (Chun Hua Lu et al, J Proteomics Informatics 2010). Ours is the first proteomics study comparing plasma cell proteins with PCC. The functional properties of these proteins are summarized (Table 2). High protein production and folding plus Ca changes in MM support our findings on chaperons and Ca binding protein changes. Out of these eight proteins only bcl-2, MZB1 and calreticulin were previously reported to be involved in the biology of MM. Disclosures: Beksac: Janssen: 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; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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In-vivo evaluation of the effect of cyanoacrylate on prosthetic vascular graft infection – does cyanoacrylate increase the severity of infection?

VASA ◽

10.1024/0301-1526/a000867 ◽

2020 ◽

Vol 49 (4) ◽

pp. 281-284

Author(s):

Atıf Yolgosteren ◽

Gencehan Kumtepe ◽

Melda Payaslioglu ◽

Cuneyt Ozakin

Keyword(s):

Vascular Graft ◽

Graft Infection ◽

Vascular Graft Infection ◽

Group 4 ◽

Significant Difference ◽

Group 3 ◽

Group 2 ◽

Prosthetic Vascular Graft Infection ◽

Group 1

Summary. Background: Prosthetic vascular graft infection (PVGI) is a complication with high mortality. Cyanoacrylate (CA) is an adhesive which has been used in a number of surgical procedures. In this in-vivo study, we aimed to evaluate the relationship between PVGI and CA. Materials and methods: Thirty-two rats were equally divided into four groups. Pouch was formed on back of rats until deep fascia. In group 1, vascular graft with polyethyleneterephthalate (PET) was placed into pouch. In group 2, MRSA strain with a density of 1 ml 0.5 MacFarland was injected into pouch. In group 3, 1 cm 2 vascular graft with PET piece was placed into pouch and MRSA strain with a density of 1 ml 0.5 MacFarland was injected. In group 4, 1 cm 2 vascular graft with PET piece impregnated with N-butyl cyanoacrylate-based adhesive was placed and MRSA strain with a density of 1 ml 0.5 MacFarland was injected. All rats were scarified in 96th hour, culture samples were taken where intervention was performed and were evaluated microbiologically. Bacteria reproducing in each group were numerically evaluated based on colony-forming unit (CFU/ml) and compared by taking their average. Results: MRSA reproduction of 0 CFU/ml in group 1, of 1410 CFU/ml in group 2, of 180 200 CFU/ml in group 3 and of 625 300 CFU/ml in group 4 was present. A statistically significant difference was present between group 1 and group 4 (p < 0.01), between group 2 and group 4 (p < 0.01), between group 3 and group 4 (p < 0.05). In terms of reproduction, no statistically significant difference was found in group 1, group 2, group 3 in themselves. Conclusions: We observed that the rate of infection increased in the cyanoacyrylate group where cyanoacrylate was used. We think that surgeon should be more careful in using CA in vascular surgery.

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Does Perioperative Hemoglobin A1c Level Affect the Incidence, Pattern and Mortality of Lower Extremity Amputation?

Current Vascular Pharmacology ◽

10.2174/1570161116666180123112529 ◽

2019 ◽

Vol 17 (4) ◽

pp. 354-364

Author(s):

Hassan Al-Thani ◽

Moamena El-Matbouly ◽

Maryam Al-Sulaiti ◽

Noora Al-Thani ◽

Mohammad Asim ◽

...

Keyword(s):

Glycemic Control ◽

Lower Extremity ◽

Hazard Ratio ◽

Lower Extremity Amputation ◽

Group 4 ◽

Group 3 ◽

Group 5 ◽

Group 2 ◽

Extremity Amputation ◽

Group 1

Background: We hypothesized that perioperative HbA1c influenced the pattern and outcomes of Lower Extremity Amputation (LEA). Methods: A retrospective analysis was conducted for all patients who underwent LEA between 2000 and 2013. Patients were categorized into 5 groups according to their perioperative HbA1c values [Group 1 (<6.5%), Group 2 (6.5-7.4%), Group 3 (7.5-8.4%), Group 4 (8.5-9.4%) and Group 5 (≥9.5%)]. We identified 848 patients with LEA; perioperative HbA1c levels were available in 547 cases (Group 1: 18.8%, Group 2: 17.7%, Group 3: 15.0%, Group 4: 13.5% and Group 5: 34.9%). Major amputation was performed in 35%, 32%, 22%, 10.8% and 13.6%, respectively. Results: The overall mortality was 36.5%; of that one quarter occurred during the index hospitalization. Mortality was higher in Group 1 (57.4%) compared with Groups 2-5 (46.9%, 38.3%, 36.1% and 31.2%, respectively, p=0.001). Cox regression analysis showed that poor glycemic control (Group 4 and 5) had lower risk of mortality post-LEA [hazard ratio 0.57 (95% CI 0.35-0.93) and hazard ratio 0.46 (95% CI 0.31-0.69)]; this mortality risk persisted even after adjustment for age and sex but was statistically insignificant. The rate of LEA was greater among poor glycemic control patients; however, the mortality was higher among patients with tight control. Conclusion: The effects of HbA1c on the immediate and long-term LEA outcomes and its therapeutic implications need further investigation.

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Association between cervical disc disease and lesions of multiple sclerosis

The Neuroradiology Journal ◽

10.1177/1971400920983565 ◽

2021 ◽

pp. 197140092098356

Author(s):

Marwan Alkrenawi ◽

Michael Osherov ◽

Azaria Simonovich ◽

Jonathan Droujin ◽

Ron Milo ◽

...

Keyword(s):

Spinal Cord ◽

Cervical Disc ◽

Cervical Disc Disease ◽

Disc Disease ◽

Group 4 ◽

Demyelinating Lesions ◽

Grade Ii ◽

Group 3 ◽

Group 2 ◽

Group 1

Background Cervical discopathy and demyelinating lesions often co-exist in patients with multiple sclerosis (MS). Our study examines the possible association between these two pathologies. Methods Medical records and cervical magnetic resonance imaging scans of MS patients with cervical discopathy who were seen at our MS clinic during 2018 were retrospectively reviewed. The severity of the disc disease was classified as grade I (no compression), grade II (compression of the dural sac) and grade III (cord compression). The spinal cord in each scan was divided into six segments corresponding to the intervertebral space of the spine (C1–C6). Each segment was defined as containing demyelinating lesion and disc pathology (group 1), demyelinating lesion without disc pathology (group 2), disc pathology without demyelinating lesion (group 3) and no demyelinating lesion or disc pathology (group 4). Fisher’s exact test was used to test the association between demyelinating lesions and disc pathology. Results Thirty-four MS patients with cervical discopathy were included in the study (26 females; average age 42.9 ± 13.7 years; average disease duration 8.4 ± 5.4 years). A total of 204 spinal cord segments were evaluated. Twenty-four segments were classified as group 1, 27 segments as group 2, 52 segments as group 3 and 101 segments as group 4. There was no association between demyelinating lesions and the grade of disc disease ( p = 0.1 for grade I, p = 0.3 for grade II and p = 1 for grade III disc disease). Conclusion Our study did not find any association between cervical disc disease and demyelinating spinal cord lesion.

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