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In: European Journal of Plastic Surgery, Springer Science and Business Media LLC, Vol. 45, No. 4 ( 2022-08), p. 683-685

Type of Medium: Online Resource

ISSN: 1435-0130

URL: Article

DOI: 10.1007/s00238-021-01921-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 1464220-7

In: Journal of Lightwave Technology, Institute of Electrical and Electronics Engineers (IEEE), Vol. 36, No. 19 ( 2018-10), p. 4430-4437

Type of Medium: Online Resource

ISSN: 0733-8724 , 1558-2213

URL: Article

DOI: 10.1109/JLT.2018.2816242

Language: Unknown

Publisher: Institute of Electrical and Electronics Engineers (IEEE)

Publication Date: 2018

detail.hit.zdb_id: 2033229-4

detail.hit.zdb_id: 246121-3

In: Transplantation, Ovid Technologies (Wolters Kluwer Health), Vol. 79, No. 7 ( 2005-04), p. 802-806

Type of Medium: Online Resource

ISSN: 0041-1337

URL: Article

DOI: 10.1097/01.TP.0000156931.45209.E8

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2005

detail.hit.zdb_id: 2035395-9

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 10 ( 2021-10), p. 2813-2826

Abstract: Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1 -mutated(mut), chromatin/spliceosome-mut and TP53 -mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1 -mut AML. One was enriched for mutations in cohesin/DNA damage-related genes ( NPM1 /cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1 /cohesin-mut and NPM1 -mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1 /cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-021-01318-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3373-3373

Abstract: BACKGROUND: Many efforts have been made in the attempt to address the conundrum question of fitness definition ad prognosis prediction in elderly acute myeloid leukemia (AML) patients. Parametric definitions are expected to give an advantage in patient stratification; however, clinical examination remain de facto pivotal to formulate therapy decisions and frequently the comorbidities are empirically evaluated. METHODS: We conducted a multicenter study collecting baseline comorbidity, laboratory data, CTCAE 4.0.3 adverse events (AE), and outcome of elderly patients ( & gt;65 years old) with new onset AML who received hypomethylating agents as 1st line therapy. We tested the impact on prognosis of baseline clinical and biological risk factors. Furthermore, we evaluated a score - acute myeloid leukemia-composite model, AML-CM (Mukherjee et al, 2017) - developed in chemotherapy-eligible patients, that accounts for baseline comorbidities, laboratory parameters, age and cytogenetic-molecular risk. The study was approved by local Ethical Authority (316/2019/Oss/AOUBo). RESULTS: We collected data from 131 consecutive elderly patients who received 1 st line HMAs between January 2008 and January 2021. Patients had a median age of 76 years (IQR 72 -79). Seventy-seven out of 131 patients (58.8%) had de novo AML, 32/131 (32.8%) had secondary AML, and 11/131 (8.4%) had therapy-related AML. Out of 123 evaluable patients, 43 (34.9%) had complex karyotype, 1 (0.8%) inv(16), 59 (48.4) normal karyotype, 18 (14.7%) other alterations; 8/108 patients harbored FLT3 ITD mutation (7.4%, 23 not tested), 12/101 NPM1 mutation (11.9%, 30 not tested). Based on these data, 111 patients were evaluable for ELN2010 risk stratification; 9 over 111 patients (8.1%) were stratified in the low risk, 42/111 (37.8%) in intermediate-1 risk, 17/111(15.3%) in intermediate-2 risk, and 43/111 (38.7%) in high-risk class. As expected, most of the patients had at least one comorbidity. Particularly, baseline arrhythmia was present in 29/130 (22.1%, 1 no data), cardiovascular comorbidity in 20/130 (15.4%, 1 no data), diabetes in 20/131 (15.3%), cerebrovascular comorbidity in 11/131 (8.4%), kidney disease in 15/130 (11.5%, 1 no data), lung chronic disease 19/130 (14.6% 1 no data), hypoalbuminemia in 25/111 patients (22.5%, 20 no data). With a median follow up of 28.2 months, median overall survival (OS) of the entire cohort was 15.8 months (95% C.I. 11.2-19.4). We confirmed that patient who obtained a response (complete remission, partial response, hematological improvement) after 2 months of therapy had the best OS (figure A, median OS of 21 months for responders vs 7.4 months for non-responders, p & lt;.001). Interestingly, lung chronic disease (median OS 6.6 months in affected vs 16.5 months in non-affected, p=.013) and hypoalbuminemia (median OS 7.4 months in affected vs 18 months in non-affected p & lt;.001) confer significantly diminished OS. ELN2010 score impacted prognosis (median OS of 8.4 months for favorable, 23.4 months for int-1, 11.1 for 1int-2 and 6.5 months for high-risk, p=.004). To test the impact of comorbidities combined with cytogenetic and molecular risk, AML-CM was used. Our results indicate that AML-CM score was able to stratify prognosis in elderly patients receiving frontline HMAs (figure B, median OS in score group 1: 29.7 months, score group 2: 16.5 months, score group 3: 11.2 months, score group 4: 6.6 months, p=.038). The worse prognosis of patients with higher AML-CM score, which includes patients with increased baseline comorbidities, may be explained with a higher incidence of AEs (84.55, 116.01, 131.45, 229.3 events for 100 patients per year for score group 1,2,3, and 4, respectively) and infections (53.80, 55.10, 85.95, 140.13 events for 100 patients per year for score group 1,2,3, and 4, respectively), in patients with higher baseline comorbidities. CONCLUSION: In this study we found that baseline comorbidities, captured by AML-CM score, may define prognosis of elderly patients receiving 1st line HMAs; parametric comorbidity scores may improve our ability to predict outcome and tailor interventions. The impact of comorbidity on OS may be increased with novel and more aggressive therapy. For this reason, specific studies on functional fitness tests and geriatric assessments are highly warranted in patients receiving HMAs plus venetoclax. This work was supported by Bologna AIL. CP and AC shared last authorship. Figure 1 Figure 1. Disclosures Martinelli: Daichii Sankyo: Consultancy; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Cavo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Papayannidis: Pfizer, Amgen, Novartis: Honoraria. Curti: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: 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-2021-149459

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. 136, No. Supplement 1 ( 2020-11-5), p. 14-15

Abstract: JN and CP equally contributed Introduction In the setting of clinical trials Venetoclax (VEN) combined with hypomethylating agents (HMAs) has shown fair activity in R/R AML and impressive results in treatment-naïve elderly AML patients. However, no clear guidelines are available on real-life management, especially in the outpatient setting. This study involving R/R AML patients treated with VEN combined with HMAs aims to amelioratate physicians' knowledge about the administration of these regimens. Methods This is a single-center retrospective study involving AML patients treated with Venetoclax combined with HMAs. Data were collected in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results Thirty-one R/R AML patients have been treated with VEN plus HMAs from March 2018 to March 2020 and completed at least 1 therapy course (range 1-9, median 2, IQR 1.0 - 5.0) (Table 1: patients' characteristics). Seventeen out of 31 (54,8 %) had received intensive chemotherapy as induction therapy. Twenty-two patients (71 %) had already received HMAs therapy, of which 14/31 (45,2 %) as first and only previous line of therapy. VEN was combined with azacitidine in 13/31 (41,9%) and with decitabine in 18/31 patients (58.1 %). The majority of patients (22/31, 70,9%) received the first cycle as out-patients, special focus of our analysis. For clinical reasons, only 9 out of 31 (29,1 %) patients were hospitalized and were used as control. In the outpatients setting, VEN dose escalation was managed with at least a weekly laboratory and clinical monitoring and the drug was often increased more slowly to carefully prevent tumor lysis syndrome or other complications. Specifically, there has been a trend toward a ramp-up schedule different from that indicated in clinical trials in the outpatient setting in comparison with hospitalized patients (77,2 % vs 33,3 %). In term of safety, no cases of tumor lysis syndrome (TLS) and only 2 AEs were documented during ramp-up phase, both experienced by hospitalized patients. Seventeen AEs were documented during cycle 1, affecting more frequently hospitalized patients (77,9% vs 31,8 %). In the outpatient setting, the early 30-days and 60-days mortalities were 4,5 % (1/22) and 13,6 % (3/22), respectively, comparable to percentages documented in hospitalized subgroup (0% and 11,1%). Overall, with a median follow-up of 138 days (IQR 69 - 285), we reported 48 AEs, of which 28 were grade III-IV and the most common were hematological (13/28, 48,1 %) or infective (14/28, 51,8 %). Twenty out of 31 (64,5 %) patients reduced VEN dosage during treatment, of which 12/20 (60 %) due to occurring AEs, and remaining patients for azole coadministration. Eleven out of 31 (35,5 %) patients required hospitalization, specifically 3 out of 9 hospitalized patients (33,3 %) during the subsequent outpatient phase of treatment, and 8/22 (36,3 %) patients who underwent VEN therapy outpatient, of which only 2 during the first 28 days of treatment. Twenty-four and 5 AEs were followed by a VEN temporary (median duration 14 days, range 5-120) and permanent withdrawn, respectively. As for the rate of response, the Overall Response Rate (ORR) by VEN plus HMAs therapy in our R/R study population, defined as CR + CRi + HI, was 41,9 % (13/31), with a CR/CRi rate of 22,6 % (7/31). The median time to first response was 67.0 days (IQR 37.0 - 133.5) and the median duration of response was 131.0 days (IQR 89.0 - 151.0). Four out of 31 (12,9 %) patients received subsequent HSCT. The median OS was 285 days (95% C.I. 178 - 392), with no difference in OS between patients who underwent VEN plus HMAs outpatient and patients who underwent the first cycle hospitalized (p = 0,38). Conclusions With the limitations of a single-center retrospective study, our real-life data indicate that VEN plus HMAs is feasible in an outpatient management, without TLS or other limiting toxicities and with comparable early-mortality and toxicity profiles, even in the ramp-up phase and first therapeutic cycle. There was no significant impact of the outpatient management on treatment effectiveness, with data in line with published R/R AML cohorts. Further studies evaluating the clinical, social and economic impact of outpatient VEN-based treatments are highly warranted. Disclosures Papayannidis: Abbvie, Janssen, Novartis, Amgen, Pfizer:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive:Consultancy, Honoraria. OffLabel Disclosure: In R/R AML, available data regarding the combination of VEN plus HMAs come only from retrospective studies where VEN is administered as an off-label prescription due to its widespread approval for chronic lymphocytic leukemia due to promising results obtained in treatment-naive elderly AML patients

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-138719

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: BMC Cancer, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2018-12)

Type of Medium: Online Resource

ISSN: 1471-2407

URL: Article

DOI: 10.1186/s12885-018-5026-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2018

detail.hit.zdb_id: 2041352-X

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5098-5098

Abstract: Background The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor venetoclax has shown strong activity in R/R AML in controlled clinical trials, and recently impressive results in treatment-naïve AML elderly patients with acute myeloid leukemia. However, limited data are available in the real-life setting. Methods This is a multi-center (n=4), retrospective study involving patients with treatment-naïve or Relapsed/Refractory (R/R) AML treated with Venetoclax in combination with HMAs. Data were collected after anonymous aggregation, in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results Forty-four patients have been prescribed Venetoclax from March 2018 to June 2019 and completed at least 1 course of venetoclax (range 1-8, median 2, IQR 2.0 - 4.0), being evaluable in this analysis. Patients's characteristics are summarized in Table 1. Five/44 (11.4%) patients had a low risk AML, 21/44 (47.7%) had an intermediate risk AML and 14/44 (31.8%) patients had a high risk AML, according to ELN 2017 risk stratification (4 patients had no available ELN risk at baseline). Six out of 44 (13.6%) patients received Venetoclax in combination with HMAs as first line of therapy, whereas 14/44 (31%) as first line rescue for resistant AML, 15/44 (34.1%) at first relapse, 9/44 (20.5%) for second or further R/R AML. Among R/R patients who received Venetoclax, 17/38 (44.7%) and 21/38 (55.2 %) had received chemotherapy or HMAs as induction therapy, respectively. Overall, Venetoclax was combined with azacitidine in 19/44 patients (43.2%), with decitabine in 19/44 patients (43.2%), with Low-dose of Cytarabine in 5/44 (11.4%), and was performed in monotherapy in 1/44 (2.3%) patient. Three out of 44 patients (6.8%) received a maximum dosage of 100 mg daily, 2/44 (4.5%) received 200 mg, 37/44 (84.1%) received 400mg and 2/44 (4.5%) received 600 mg. Fifteen out of 44 (34.1%) patients reduced the dosage of venetoclax for concomitant Azole administration. The median follow-up is 75.5 (IQR 45.2 - 178.5) days for patients who received upfront venetoclax therapy, while 143 (IQR 49.2 - 235.7) days for R/R patients. In the first-line setting, no patients reduced venetoclax dosage for concomitant adverse events; two neutropenia grade IV and two thrombocytopenia grade III have been documented. In the R/R setting, 14/38 (36.6%) patients reduced venetoclax dosage for concomitant adverse events. Specifically, we reported 22 adverse events, of which 10 were grade III-IV (5 neutropenia grade IV, 2 pancytopenia grade IV, 1 neutropenia grade III and 2 febrile neutropenia grade III). The overall CR rate is 16.7 % in newly-onset AML patients and 28.9 % in R/R patients, respectively. Two out of 6 treatment-naive patients had an evaluable response at 2 months after the beginning of Venetoclax treatment, and 2/6 had an evaluable 4-months response: 1 stable disease (SD) and 1 disease progression (PD) at 2 months,1 SD e 1 complete remission (CR )at 4 months. Thirty-one out of 38 R/R patients had an evaluable response at 2 months and 21/38 had an evaluable 4-month response: 10 CR, 1 complete response with incomplete hematologic recovery (CRi), 14 SD and 6 PD at 2 months; 6 CR, 10 SD and 3 PD at 4 months have been documented. After a short follow-up period (75.5 days), no patients who received Venetoclax as upfront therapy underwent an allogeneic hematopoietic stem cell transplantation (HSCT). On the other hand, after a longer follow-up period (143 days), 5 out of 38 patients (13.2%) received a HSCT after Venetoclax therapy among R/R patients. Median Overall Survival was not reached in the newly-onset cohort. In R/R setting, median OS was 253 days (95% C.I. 157-349). Interpretation These data extend to the real-life setting some previous evidence obtained from trials. In particular, our data confirm that venetoclax plus HMAs or LDAC has an acceptable toxicity profile and is safe and manageable. However, especially in the R/R setting, hematological toxicity represents the most frequent adverse event, arising some concerns about the optimal drugs management. Although our data suggest a similar clinical activity of venetoclax combinations to that reported in clinical trials, further studies from the real-life setting are highly warranted to confirm venetoclax efficacy under normal clinical practice. GG and JN equally contributed CP and AC equally contributed Disclosures Boccadoro: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; 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; 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Papayannidis:Shire: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Teva: Honoraria. OffLabel Disclosure: Venetoclax is not approved to treat Acute Myeloid Leukemia in Italy

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128583

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 4111-4112

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-159981

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6119-6121

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157937

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7