Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 115, No. 26 ( 2010-07-01), p. 5412-5417

Abstract: The optimal primary endpoint for acute graft-versus-host disease (GVHD) therapeutic trials has not been established. In a retrospective analysis, we examined the response of 864 patients who received prednisone 60 mg/m2/d for 14 days, followed by an 8-week taper, as initial therapy for acute GVHD from 1990-2007 at the University of Minnesota. Patients received grafts of human leukocyte antigen–matched sibling bone marrow (BM) or peripheral blood (PB; n = 315), partially matched sibling BM or PB (n = 24), unrelated donor BM or PB (n = 313), single (n = 89) or double (n = 123) umbilical cord blood. Day 28 responses were similar to day 56 responses and better than day 14 responses in predicting transplantation-related mortality (TRM). In multiple regression analysis, patients with no response at day 28 were 2.78 times (95% CI, 2.17-3.56 times; P 〈 .001) more likely to experience TRM before 2 years than patients with a response. Other factors associated with significantly worse 2-year TRM include older age, high-risk disease, severe GVHD, and partially matched related BM/PB. No other differences in response by donor source were observed. These data suggest that day 28 is the best early endpoint for acute GVHD therapeutic trials in predicting 2-year TRM.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2009-12-258442

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2942-2942

Abstract: Following cancer treatment haematological patients exhibit significant physical deconditioning and psychological distress resulting from the treatment and the disease. Exercise has been shown as a safe and effective method of rehabilitation in cancer patients, with the potential to reverse the deleterious effects following diagnosis. Our aim was to investigate the efficacy of an immediate or delayed exercise program on various patient outcomes post treatment. Patients and Methods Between July 2010 and December 2011, haematological cancer patients from Western Australia, who had completed chemotherapy treatment, were randomly assigned to immediate exercise (IEG; n=18) or a 12-week delayed exercise program (DEG; n=19). The exercise intervention incorporated aerobic and resistance training performed three times per week for 12-weeks. Patient rated outcomes (PRO) included cancer related fatigue (CRF), quality of life (QoL), psychological distress, exercise habit and behaviour. Physiological outcomes included cardiovascular fitness, muscle strength, physical function and body composition. Results Patient adherence to the exercise program was 85%, with patients completing, on average, 74 min per week of aerobic exercise and strength training intensity that ranged from 51-87% of maximum weight. A significant time by group interaction (p 〈 0.05) was seen for PRO and physiological outcomes including CRF (p=0.01), QoL (p≤0.001), aerobic fitness (p≤0.001) and muscle strength (p≤0.001). Follow-up t-tests showed a significant difference in change between the IEG and DEG from weeks 0-12 (p≤0.001 to p=0.046), and significant differences between groups from weeks 12-24 (p≤0.001 to p=0.050), with no significant differences between groups at baseline or final assessment on any variables. Conclusion A 12-week exercise program, whether commenced immediately post treatment or delayed by 12-weeks, resulted in significant statistical (p≤0.05) and clinical improvements in PRO including QoL and CRF, and physiological outcomes, including aerobic fitness, in haematological cancer patients without any exacerbation of symptoms. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2942.2942

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1134-1134

Abstract: Abstract 1134 Poster Board I-156 The optimal primary endpoint for acute GVHD treatment trials has not been established. In a retrospective analysis, we examined the response of 864 patients who received prednisone 60 mg/m2 for 14 days, followed by an 8 week taper, as initial therapy for acute GVHD from 1990-2007 at a single institution. Complete response (CR), partial response (PR), very good partial response (VGPR), and no response (NR) were scored at day 14, day 28 and day 56 after initiation of steroids. To determine the best endpoint, an index of concordance, the c-statistic (C), was performed to estimate the probability that patients with the better GVHD response will have lower transplant related mortality (TRM) than patients with a worse response. Median patient age was 32 (range, 0.2-69) years; 35% were 〈 18 years old. Patients received grafts of HLA-matched sibling bone marrow (BM) or peripheral blood (PB, n=315), partially matched sibling BM or PB (n=24), unrelated donor (URD) BM or PB (n=313), single umbilical cord blood (sUCB, n=89) or double UCB (dUCB, n=123). Prior to initiation of steroid therapy, initial GVHD grades were grade I in 230 (27%), grade II in 504 (58%), grade III in 119 (14%), and grade IV in 11 (1%). Initial GVHD organ involvement was skin only (57%), gut only (17%), liver only (1%) or multiorgan (25%). Day 28 responses were similar to day 56 responses (p=0.14) and better than day 14 responses (p=0.03) in predicting TRM. In multiple regression analysis, patients with NR at day 28 were 2.77 times more likely to have TRM than patients with CR, VGPR or PR while any response favored lower TRM (table). Factors associated with significantly worse 2 year TRM in patients with acute GVHD include: NR to steroids, partially matched BM/PB, high risk disease, older age and skin only GVHD. Factors not associated with TRM include CMV serostatus, conditioning therapy, GVHD prophylaxis, days to steroid treatment, and initial grade of GVHD. Table: Factors associated with 2 year TRM: multiple regression analysis Factor Relative Risk P value Overall P Value Day 28 Response (% patients) . . 〈 0.001     CR (53%) 1.0 .     VGPR (7%) 0.63 0.13     PR (4%) 1.22 0.45     NR (31%) 2.77 〈 0.001 Donor Type . . 〈 0.01     MSD BM/PBSC 1.0 .     URD well matched BM/PBSC 1.35 0.17     URD partial matched BM/PBSC 1.54 0.03     URD or sibling MM BM/PBSC 1.77 〈 0.001     Single UCB 1.06 0.83     Double UCB 0.79 0.36 Disease Risk . . 0.02     Standard 1.0 .     High 1.35 0.02 Age 1.0 0.02 0.02      〈 18 years 1.40     318 years Affected Organs (skin only) . . 0.05     Yes 1.0 .     No 1.36 0.05 Grade at Start of Steroid Therapy . . 0.11     I 1.0 .     II 1.08 0.60     III-IV 1.51 0.10 These data suggest that responses at day 28 or 56 are equally effective endpoints for acute GVHD trials. Day 14 responses cannot as accurately predict TRM. As patients with NR require further therapy in a timely manner, early progression or response by day 28 is the best endpoint to assess efficacy of initial therapy for acute GVHD. Prospective trials are still required to determine the best therapy for different subgroups of patients with acute GVHD, especially those identified to have predictably poor responses and high TRM. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1134.1134

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 690-690

Abstract: Background: High dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard curative option for patients with relapsed or refractory, chemosensitive, aggressive non-Hodgkin lymphoma (NHL). The optimal timing for ASCT following salvage chemotherapy is not known. Cancer Care Ontario (CCO)-the cancer agency for Ontario, Canada's largest province-treatment guidelines recommend that no more than 91 days should elapse from the first day of salvage chemotherapy to stem cell transplant. We evaluated the impact of time to stem cell transplant in the context of the international CCTG LY.12 phase 3 clinical trial. Methods: Patients with relapsed or refractory (R/R) aggressive NHL were randomly assigned to gemcitabine, cisplatin and dexamethasone (GDP) or dexamethasone, cytarabine, cisplatin (DHAP), with or without rituximab, followed by ASCT [Crump JCO 2014]. Time interval definitions were based on CCO guidelines: Total Wait Time (TWT) as the number of days from the first day of salvage chemotherapy to day of ASCT; Apheresis Wait Time (AWT) as the number of days from the first day of salvage to the first day of stem cell collection; Stem cell transplant Wait Time (SWT) as the number of days from the last day of stem cell collection to the day of ASCT. Patients were considered to have experienced a delay in TWT, AWT or SWT if the time intervals exceeded 91, 70 and 21 days respectively. Overall survival (OS) and event-free survival (EFS) from transplant date were compared between patients who met and exceeded TWT targets using a Cox proportional hazards model. A linear regression model was applied to analyze TWT as a continuous variable. Univariate and multivariate analyses were performed to estimate the adjusted hazard ratio (HR) for TWT for the following co-variables: age ≤60, performance status 0/1, disease stage (I/II), presence of ≤1 extranodal sites, and response after cycle 2 (complete response, CR; complete response, unconfirmed, CRu; partial response, PR). Results: Of 619 patients enrolled on LY.12, 307 (47%) had sufficient response to salvage chemotherapy and adequate stem cell collection to complete ASCT on protocol. Among these, median age was 54.6 years, 64% were male and 94% had a performance status of 0 or 1. International Prognostic Index (IPI) score at relapse was 0-1 in 45%, 2 in 31% and ≥3 in 24%. The majority of patients had poor risk disease at study entry; 58% had a best response of stable disease (SD) or progressive disease (PD) to primary therapy, or initial duration of response 〈 1 year. Following up to 2 cycles of salvage chemotherapy, 75/307 (24%) achieved CR/CRu, 142/307 (46%) achieved PR, 89/307 (29%) had SD. One patient had missing data. The median TWT for the total transplanted population was 91 days (range 50-217). Median AWT and SWT were 63 (range 0-151) and 26 (range 6-146) days, respectively. Fifty percent of patients exceeded TWT target of 91 days; 32% and 57% of patients exceeded AWT and SWT targets. There was no difference in median OS (HR 0.96, 95% CI 0.66-1.39, p=0.81) or EFS (HR 1.13, 95% CI 0.82-1.55, p=0.46) between patients who exceeded and met TWT targets. The 4-year OS for patients who met and exceeded TWT was 62% and 64%, respectively. The 4-year EFS for patients who met and exceeded TWT was 43% and 50%, respectively. When analyzed as a continuous variable, TWT did not affect OS (HR 0.99) or EFS (HR 0.99). Comparison of the quartiles with shortest and longest TWT demonstrated HR 0.72 (95% CI 0.42-1.26, p=0.25) for overall survival and 0.69 (95% CI 0.44-1.09, p=0.11) for EFS. Comparison of the 10th and 90th percentiles for TWT demonstrated HR 0.67 (95% CI 0.28-1.59, p=0.36) for overall survival and 0.71 (95% CI 0.35-1.44, p=0.34) for EFS. Only the presence of ≤1 extranodal sites of disease was found to be predictive of OS in the transplanted population on univariate and multivariate analysis (adjusted HR 0.51, p=0.005). The median TWT was longer for the 31 patients transplanted at Italian centers, compared to 266 transplanted at Canadian centers (median TWT 90 vs. 118 days, t 〈 0.0001). Conclusion: In this exploratory analysis, limited to patients who completed transplant on the LY.12 clinical trial, we did not find evidence that those meeting current CCO ASCT wait time targets had superior outcomes compared with those who did not. Table. Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kuruvilla: BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.690.690

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3636-3636

Abstract: Survival, proliferation, and resistance to chemotherapy in CLL cells have been consistently shown to be associated with the activity of the B-cell receptor (BCR) and the associated downstream pathways activated by it. Key molecules in this pathway are Lyn and Syk (Spleen tyrosine kinase), as well as PI3K, Btk (Bruton’s tyrosine kinase), and ERK. Dasatinib, given at standard doses, allows for serum levels well above 11 nM, the IC50 for the direct suppression of Lyn kinase and Btk. We have previously shown that dasatinib used as a single agent in patients with relapsed CLL results in lymph node responses in 60% of patients and partial responses in 20% of patients as defined by NCI-WG criteria. In the current study, patients with relapsed CLL were treated with a regimen combining dasatinib at 140 mg/day, days 1-14, with fludarabine (F) 25 mg/m2/day, days 1-3, and rituximab (R) 375 mg/m2 per cycle, repeated every 28 days, for up to 6 cycles. Patients were followed closely for response with CT scans every 2 months initially. Among the first 10 patients treated, the schedule of treatment was altered to determine signal transduction effects and resultant apoptosis of the CLL cells due to the different components of the regimen. Hence, only dasatinib was given on Day 1, only fludarabine and rituximab on Day 3, and all 3 drugs on Day 4. Blood samples were obtained from the patients before dosing and at 6 hours after treatment to measure effects on the CLL cells, which were isolated by standard Ficoll separation and frozen until the assays could be performed. For these 10 patients the median time to progression (TTP) was 21 months, and the initial clinical response was as follows: Site CR CRi PR SD PD ORR 95% CI Blood 4 2 4 0 0 100% 74%, 100% Nodes 6 1 1 1 1 80% 49%, 96% CT 2 0 2 6 0 40% 15%, 70% IWCLL 2 0 2 5 1 40% 15%, 70% Key: CR=complete response in blood = 〈 4,000/ul lymphocytes, CR in nodes = no nodes palpable by PE, CRi = complete response with incomplete blood recovery, PR=partial response, SD=stable disease, PD=progressive disease, ORR=overall response rate, CI=confidence interval. IWCLL = International Workshop on CLL criteria. The patterns of signal transduction in response to the various drugs at 6 hours are shown in aggregate for the patients below. The numbers represent the ratio of phosphorylated protein to total protein at the times indicated with respect to their baseline levels set as 100%. The phosphorylation sites tested were p-Lyn (Y416), p-Syk (Y352), p-ERK1/2 (T202/Y204). Phosphorylation at 6 h after indicated treatment – % of baseline ± SE (N=7): Day 1 (D) Day 3 (F+R, no D) Day 4 (D+F+R) p-Lyn/Lyn: 42% ± 3% 207% ± 63% 58% ± 13% p-Syk/Syk: 34% ± 15% 122% ± 67% 36% ± 15% p-ERK/ERK : 64% ± 22% 168% ± 40% 56% ± 22% The patterns of signal transduction for the 3 patients with the most favorable outcome (TTP and OS) were compared to that for the 4 patients with the poorest clinical outcome. The baseline ratios of phospho-ERK1/2 to ERK1/2 (pre-treatment) correlated most strongly with outcome. Those with a good outcome exhibited low basal p-ERK/ERK (mean 1.0, range 0.1 to 1.8 percent), while patients with a poor outcome exhibited high basal p-ERK/ERK (mean 22.1, range 2.2 to 65.6 percent). Conclusions: For most patients, dasatinib inhibits (directly or indirectly) phosphorylation of Lyn kinase, Syk kinase, and ERK1/2 in the first 6 hours. The degree of apoptosis (to be presented, but not shown here) resulting from this is variable and is probably affected by activation of the PI3K/Akt pathway and other pathways. The long-term clinical outcome of our patients correlated strongly with the baseline phosphorylation of ERK1/2, suggesting that future treatments of patients with CLL might benefit from targeting ERK directly, or by targeting other molecules in the MAPK pathway. Disclosures Off Label Use: Dasatinib for treatment of CLL is off-label use. We present a rationale for its use in CLL patients.. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Attar:Agios: Employment. Fathi:Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda pharmaceuticals International Co.: Research Funding; Exelixis: Research Funding; Ariad: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3636.3636

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4095-4095

Abstract: Introduction: In oncology clinical trials, overall survival (OS) is considered the gold standard efficacy endpoint. However, in multiple myeloma, the prolonged survival times and availability of multiple salvage therapies render it difficult to rely on OS as a primary endpoint. Instead, progression-free survival (PFS) or clinical response can be a relevant biomarker. At the same time, some health technology assessment bodies will only consider evidence based on patient-relevant endpoints, such as morbidity, mortality, and health-related quality of life (HRQoL), within their benefit assessments. Patient-reported outcomes (PROs) provide insights into how a treatment affects HRQoL, including symptoms and functioning. In the phase 3 MAIA trial, daratumumab, lenalidomide, and dexamethasone (D-Rd) demonstrated a significantly prolonged PFS and rapid and sustained improvements in PROs compared with lenalidomide and dexamethasone (Rd) alone at a median follow-up of 28 months. Updated results with longer follow-up confirmed a continued PFS benefit, deepening best clinical responses, and a significant OS benefit with D-Rd. Here, we report the results of analyses exploring the relationship between clinical efficacy endpoints and PROs in the MAIA trial. Methods: In MAIA (NCT02252172), TIE patients with NDMM were randomized to D-Rd or Rd until disease progression (PD) or unacceptable side effects. Clinical response and PD were defined per the International Myeloma Working Group uniform response criteria. PROs were assessed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, every 6 months thereafter until PD, or at end of treatment and at 8 and 16 weeks post-progression using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). The current analyses were conducted on patients with a baseline PRO assessment and ≥1 post-baseline PRO assessment using a clinical cutoff date of February 19, 2021. Patients from both treatment groups were pooled and stratified by best clinical response. For PROs, the threshold for clinically meaningful change from baseline was defined a priori as ≥10 points based on published literature. Analyses were conducted for the global health status (GHS), fatigue, and pain scales of the EORTC QLQ-C30. The proportions of patients with clinically meaningful improvement in these PROs from baseline at any time while on treatment were calculated for and compared across best clinical response subgroups. For this analysis, patients were censored at the time of PD or discontinuation of therapy. Results were summarized with odds ratios and 95% confidence intervals. Additionally, the proportions of patients with clinically meaningful worsening in PROs from baseline at the time of and post-progression were also calculated for those who had PD. No adjustments were made for multiplicity. Nominal P-values are presented. Results: Best clinical response at a median follow-up of 56.2 months for the 710 patients included in this analysis is shown in the Table. For GHS, fatigue, and pain, the proportion of patients who reported clinically meaningful improvement from baseline increased with increasing depth of best clinical response. Odds ratios comparing best clinical response vs stable disease reflect this relationship and are shown in the Figure. Of the 264 patients who experienced PD and had PRO data at the time of or post-progression, 38.6%, 54.9%, and 39.4% reported meaningful worsening of GHS, pain, and fatigue, respectively, at the time of or post-progression. Conclusions: Patients with deeper best clinical response were more likely to report meaningful improvements in PROs. Patients who experienced PD reported worsening of GHS and symptoms at the time of or following progression. These analyses provide evidence of the association between key clinical efficacy endpoints and PROs and demonstrate the patient relevance of these clinical endpoints. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: Takeda: Research Funding; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Janssen: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: abbvie: Honoraria; Celgene/BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Quach: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: GSK: Honoraria; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Johns Hopkins University: Other: Grant; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding. O'Dwyer: Bristol Myers Squibb: Research Funding; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Venner: Amgen: Research Funding; Celgene: Research Funding; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Celgen/BMS: Honoraria; Sanofi: Honoraria. Leleu: Sanofi: Honoraria; Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Emalex Biosciences: Consultancy; Janssen: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; SkylineDX: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150369

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Hematology, American Society of Hematology, Vol. 2011, No. 1 ( 2011-12-10), p. 336-343

Abstract: Peripheral T-cell lymphomas (PTCLs) encompass a group of rare and usually clinically aggressive diseases. The classification and diagnosis of these diseases are compounded by their marked pathological heterogeneity and complex clinical features. With the exception of ALK-positive anaplastic large cell lymphoma (ALCL), which is defined on the basis of ALK rearrangements, genetic features play little role in the definition of other disease entities. In recent years, hitherto unrecognized chromosomal translocations have been reported in small subsets of PTCLs, and genome-wide array-based profiling investigations have provided novel insights into their molecular characteristics. This article summarizes the current knowledge on the best-characterized genetic and molecular alterations underlying the pathogenesis of PTCLs, with a focus on recent discoveries, their relevance to disease classification, and their management implications from a diagnostical and therapeutical perspective.

Type of Medium: Online Resource

ISSN: 1520-4391 , 1520-4383

URL: Article

DOI: 10.1182/asheducation-2011.1.336

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 2084287-9

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4311-4311

Abstract: Abstract 4311 Myocardial infarction typically occurs after atherosclerotic plaque rupture that exposes collagen under high shear stress, favoring platelet adhesion, activation with ADP release, aggregation and platelet thrombus formation. There is a well-established genetic contribution to myocardial infarction, and we have previously shown a shear-dependent assay of platelet function is heritable (JTH 2007;5:1617). Collagen-induced platelet aggregation is highly heritable in African Americans (AAs) but not in European Americans, which may be relevant since AAs have the highest overall coronary heart disease mortality rate of all ethnic groups in the US. The mechanisms for these ethnic differences in platelet function are not clear. The goal of the current study was to identify genetic variants in AAs affecting the Platelet Function Analyzer (PFA)-100 (ADP cartridge) that is both collagen- and shear-dependent. We recruited healthy AA subjects and measured closure times in the PFA-100. Subjects were excluded if there was evidence of exposure to anti-platelet therapy (absent response to arachidonic acid). Closure times showed a normal distribution (mean CT = 96 sec +/− 20 sec [SD]). Genome-wide genotyping with the Infinium II Assay using the Illumina BeadStation 500 system was performed. After controlling for population admixture and excluding markers with a less than 95% call rate, 131 subjects passed criteria for ethnicity and successful genotyping of 956,604 tagSNPs. Statistical analysis identified a locus on chromosome 10 that appeared to be associated with PFA-100 closure times. Of the 7 most significantly associated SNPs, 5 were in SVIL, the gene encoding supervillin. The closest flanking genes to the SNP with the best P value were 〉 77 kb upstream (2 pseudogenes) and 〉 214 kb downstream (LTZ1; lysozyme-like 1). After adjusting for VWF and fibrinogen levels, rs10826650 in SVIL was associated with PFA-100 closure times (P = 5.92E–07). We pursued SVIL (chr 10p11.23) because it is known to form a high-affinity link between the actin cytoskeleton and the plasma membrane during cell spreading and disassembly of focal adhesions. Supervillin slows the rate of cell spreading and increases myosin contractility by linking the myosin II heavy chain with myosin light chain kinase. Supervillin also decreases the stability of focal adhesions and co-localizes with signaling molecules in cholesterol-rich lipid rafts. Prior work has identified 2 transcript variants encoding different isoforms of supervillin. Isoform 1 (supervillin) is reported to be most abundantly expressed in muscle, bone marrow, thyroid gland and salivary gland; isoform 2 (archvillin) is reported as muscle specific. Because neither isoform has been characterized in platelets, we performed gene expression analysis with 23 leukocyte depleted platelet (LDP) RNA samples ( 〈 1 leukocyte per 5 million platelets) using the Sentrix BeadChip and BeadStation system from Illumina, Inc. A probe recognizing both isoforms was highly expressed in these samples, whereas a probe specific for the archvillin isoform was barely detectable. The level of SVIL mRNA expression was higher than PECAM1 but less than GPIbα. These microarray data were confirmed by RT-PCR using LDP RNA and PCR primers specific for supervillin. Notably, SVIL was not detected in megakaryocyte lines, HEL or Meg-01. Anti-supervillin antisera recognized the appropriate sized ∼205 kD polypeptide by immunoblotting. PFA-100 closure times were found to directly correlate with supervillin (r = 0.481, P = 0.02) but not with archvillin (r = 0.11, P=n.s.) mRNA levels. In summary, we have demonstrated for the first time that platelets contain supervillin but not the alternately spliced isoform archvillin, and that expression is associated with PFA-100 closure times in AAs. Because higher supervillin expression was associated with longer closure times, this finding is consistent with an inhibitory role for supervillin in regulating the rapid actin cytoskeletal rearrangement required to form platelet thrombi on collagen under shear stress. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.4311.4311

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. 119-119

Abstract: Abstract 119 The role of hypomethylating agents is well established in patients with higher risk MDS. The activity and safety of these agents in patients with lower risk (IPSS low or int-1) is not well understood. We hypothesized based on prior in vitro data and cumulative experience with different routes of administration that subcutaneous (SQ) administration of decitabine (5-aza-2'-deoxycitidine) administered either daily for 3 days or weekly times 3 both every 4 weeks will be safe and active in patients with lower risk MDS. To test this hypothesis, we designed a phase II “play the winner” randomized study to compare the daily versus the weekly schedule of decitabine at a daily dose of 20 mg/m2 SQ. Operating characteristics of the design include a 1:1 randomization procedure with the first 40 patients (pts) and after that an adaptive procedure were pts are allocated based on preceding response characteristics. A maximum of 80 pts are plan to be treated on the study. Eligibility criteria include age older than 18 years with low or int-1 MDS by IPSS, adequate performance status and renal and hepatic functions. Pts that have received prior decitabine or 5-azacitidine are excluded. Pts that have received growth factors, lenalidomide or other investigational agents are required a wash out period of 30 days. Baseline transfusion requirements are recorded as baseline and during therapy. At the present time based on the data cut-off by July 10, 2009, 43 pts have been enrolled and treated on study with 22 on the daily times 3 arm and 21 on the weekly x 3 arm. Pt characteristics are: median age 70 years (range 32-87), median time from diagnosis 2.2 months (range 0-64), 36 (84%) pts with de novo disease, 10 (23%) with IPSS low and 32 (74%) with int-1, median WBC 5.6(range 0.6-26), Hgb 9.6 (range 4.9-14.4, platelets 97 (6-442), diploid cytogenetics 30 (70%), 13 pts (30%) with others (-Y, del5, del20, +8, others). Pt characteristics are well balanced between both arms. Of the 43 pts evaluable for response and using IWG 06 response criteria, 4 (9%) pts achieved complete remissions (CR): 3 (14%) in the daily schedule and 1 (5%) in the weekly. Two marrow responses (5%), 1 partial response (2%) and 4 hematological improvements (10%) that were equally distributed between both arms were also documented. The overall response rate is 25%, 32% for the daily arm and 19% for the weekly (p=0.3). The media number of course administered so far is 4+ (range 1-11+). The median time to initial and best response is 2 cycles (ranges 2 and 2-4 respectively). No significant non-hematological toxicity has been observed with minimal grade 3 or 4 toxicity with either arm. Mortality during the first 8 weeks due to treatment complications has been 0%. Three pts have transformed to AML including 2 pts that have died due to disease progression. All in the weekly arm. Based on data cut-off by July 10, 2009, 35 pts (81%) remain on study. With a median follow up of 4.5 months (range 0.9-10), median overall survival has not been reached. Despite the trend to increase response rates and transformation with the weekly arm, at the present time no significant advantage to any of the arms has been documented . As a pharmacodynamic end point, induction of global DNA hypomethlytion using the LINE bisulfite pyrosequencing assay has been measured in 8 consenting patients. Induction of global hypomethylation is observed (50% of pts) pts but the data is limited to establish relationships between arm and/or response. In summary, these initial results indicate that lower dose subcutaneous schedules of decitabine in patients with low or int-1 disease are safe and active with significant less myelotoxicity, and related complications, compared to standard 5-day IV schedules of decitabine used in higher risk disease. Disclosures: Garcia-Manero: Celgene: Research Funding; Eisai: Research Funding. Chen:Eisai: Employment. Stein:Eisai: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.119.119

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. 120, No. 21 ( 2012-11-16), p. 4229-4229

Abstract: Abstract 4229 Introduction: Laboratory medicine services are critical to delivering high quality patient care. They operate to internationally recognized standards to ensure the quality and accuracy of their test results. Their responsibilities are wide ranging including enabling the clinician to confirm or exclude the presence of significant diseases, monitoring the progress of chronic conditions, providing expert advice in the management of patients with complex conditions, supporting research and development into new laboratory tests, systems and processes and supporting undergraduate teaching, postgraduate teaching and professional development. In the current economic climate, resources are diminishing in accordance with government austerity measures. At the same time, patients have increasing knowledge and therefore often have increasingly complex demands. To optimize primary care services, it is crucial that primary care physicians have appropriate access to tests. But a balance needs to be struck between a primary care physician's access and a laboratory's ability to limit access so that limited resources can be used to the maximum benefit of patients. Evidence based guidelines are critical. Laboratory tests can broadly be split into two categories: frequently ordered, inexpensive tests such as blood counts and infrequently ordered, expensive tests such as hereditary thrombophillia screens. In our institution, we chose to review vitamin B12 and folate testing as they are frequently requested, relatively inexpensive but time consuming assays. The aims of our study were to review the number of vitamin B12 and folate tests ordered by primary care physicians, to find out why the tests were being ordered and to see if they were being ordered appropriately. Methods: We reviewed our laboratory records to ascertain the number of vitamin B12 and folate assays carried out between 2004 and 2011. To find out why the tests was being ordered, the primary care physicians that use the laboratory in University Hospital Galway were sent out a questionnaire. To review whether or not clinical data was provided, 200 random request forms form March 2012 were reviewed. The literature was then reviewed to look at international guidelines. Results: The number of B12 and folate requests have risen year on year between 2004 and 2011, numbering 33,872 in 2004 and 96,544 in 2011. 69 of 172 primary health care centers responded to the survey. The main reasons given for ordering the test were unexplained neurological symptoms, macrocytosis, anemia and fatigue. 200 random request forms that the laboratory had received from primary care physicians were reviewed. 50% had clinical details. The reasons given for ordering the test were very varied, the most common being rountine screening and fatigue. 50 % had no clinical details provided. If the patient had had a recent full blood count in our laboratory, this was reviewed to see if any indication for the test could be ascertained. The majority (81%) had normal full blood counts. Discussion: According to the central statistics office, the population of our catchment area increased by 17% between 2002 and 2011. This did not account for the 185% increase in testing between 2004 and 2011. As vitamin B12 and folate were invariably requested in association with a ferritin level, this equates to €376,522 per year in assay cost alone. These tests are time consuming (around 40 minutes per batch) and labor intensive, which is increasingly a major factor as the main method for reducing laboratory costs to date has been to reduce the workforce. While the majority of primary care physicians knew the appropriate indications for B12 and folate testing when asked, this was not reflected in their practice. It was also worrying that many seemed unaware of important indications for testing such as unexplained cytopenias. On reviewing the literature, it is clear that there is no current guideline for vitamin B12 and folate testing. The most recent British committee for standards in hematology (BCSH) guideline was published in 1994 and is archived. Conclusion: In the current economic crisis, it is imperative that services are optimized so that patients do not suffer in the setting of decreased resources. This is best achieved when secondary and tertiary care institutions collaborate with primary care to deliver evidenced based health care. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.4229.4229

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7