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Prabhala, Rao H., Paola Neri, Jooeun E. Bae, Pierfrancesco Tassone, Masood A. Shammas, Charles K. Allam, John F. Daley, et al. "Dysfunctional T regulatory cells in multiple myeloma." Blood 107, no. 1 (January 1, 2006): 301–4. http://dx.doi.org/10.1182/blood-2005-08-3101.
Повний текст джерелаАнотація:
Abstract Multiple myeloma (MM) is characterized by the production of monoclonal immunoglobulin and is associated with suppressed uninvolved immunoglobulins and dysfunctional T-cell responses. The biologic basis of this dysfunction remains ill defined. Because T regulatory (Treg) cells play an important role in suppressing normal immune responses, we evaluated the potential role of Treg cells in immune dysfunction in MM. We observed a significant increase in CD4+CD25+ T cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and in patients with MM compared with healthy donors (25% and 26%, respectively, vs 14%); however, Treg cells as measured by FOXP3 expression are significantly decreased in patients with MGUS and MM compared with healthy donors. Moreover, even when they are added in higher proportions, Treg cells in patients with MM and MGUS are unable to suppress anti-CD3–mediated T-cell proliferation. This decreased number and function of Treg cells in MGUS and in MM may account, at least in part, for the nonspecific increase in CD4+CD25+ T cells, thereby contributing to dysfunctional T-cell responses.
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Sutherland, Wayne H. F., Sylvia A. de Jong, and Robert J. Walker. "Effect of Dietary Cholesterol and Fat on Cell Cholesterol Transfer to Postprandial Plasma in Hyperlipidemic Men." Lipids 42, no. 10 (August 7, 2007): 901–11. http://dx.doi.org/10.1007/s11745-007-3101-1.
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Demirci, Selami, Ayşegül Doğan, Hüseyin Apdik, Emre Can Tuysuz, Sukru Gulluoglu, Omer Faruk Bayrak, and Fikrettin Şahin. "Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells." Molecular and Cellular Biochemistry 437, no. 1-2 (June 15, 2017): 133–42. http://dx.doi.org/10.1007/s11010-017-3101-2.
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Micallef, Ivana, Patrick J. Stiff, John F. DiPersio, Richard Thomas Maziarz, John M. McCarty, Jennifer Angell, Gary Bridger, and Gary Calandra. "Successful Stem Cell Mobilization Rescue by AMD3100 (Plerixafor)+G-CSF for Patients Who Failed Primary Mobilization: Results from the Phase III (3101-NHL) Study." Blood 110, no. 11 (November 16, 2007): 602. http://dx.doi.org/10.1182/blood.v110.11.602.602.
Повний текст джерелаАнотація:
Abstract Background: AMD3100 (plerixafor)+G-CSF (A+G) was generally safe and more effective in mobilizing CD34+ hematopoietic stem cells compared to placebo+G-CSF (P+G) in a Phase III, multicenter, randomized, double-blind, placebo controlled study conducted in patients with non-Hodgkin’s lymphoma (NHL). In the intent-to-treat analysis, 78/148 (53%) patients in the P+G group and 20/150 (13%) patients in the A+G group failed to mobilize ≥ 2 x 106 CD34+ cells/kg, p<0.0001. Of these failure patients, 52 in the P+G group and 10 in the A+G group consented to enter into the rescue arm of the study. This abstract reports the outcomes of these rescue patients. Methods: Patients enrolled in the Phase III study who failed to mobilize ≥2 x 106 CD34+ cells/kg could enter into the rescue arm of the study and receive A+G. The patient’s treatment assignment in the study remained blinded. Following a rest period of ≥7 days, patients were given G (10 μg/kg/day) subcutaneously (SQ) for 4 days. In the evening around 10PM on Day 4, patients were given a dose of A (240 μg/kg SQ). On Day 5, all patients returned to clinic to receive a morning dose of G before apheresis. Patients continued to receive the evening dose of A followed by morning dose of G and apheresis the next day for up to a total of 4 aphereses or until ≥5 x 106 CD34+ cells/kg were collected. Pooled cells were allowed for transplantation. Results: After rescue therapy, 33/52 (63%) patients who previously failed P+G and 4/10 (40%) patients who previously failed A+G collected ≥2 x 106 CD34+ cells/kg. Seven of the 33 patients who previously failed with P+G collected ≥ 5 x 106 CD34+ cells/kg. Six of the ten A+G patients and 46/52 P+G patients were transplanted. Median time to PMN engraftment was Day 10 and Day 11 for the A+G and P+G groups, respectively. Median time to platelet engraftment was Day 22 and Day 20 for the A+G and P+G groups, respectively. One patient in the P+G group never had platelet counts > 50,000 and was counted as a failure to engraft, even though the patient was clinically stable through 6 months post-transplant. In the re-mobilized group, 9 patients died (2 patients were never transplanted and 7 patients had disease progression). Grafts were durable for ≥100 days in all 6 rescued A+G patients and all 41 rescued P+G patients who engrafted. The predominant adverse events were mild gastrointestinal effects (diarrhea, nausea, vomiting, and abdominal pain) and injection site reactions. There were no drug-related serious adverse events reported in these re-mobilized patients. Conclusions: The addition of AMD3100 to G-CSF successfully mobilized sufficient stem cells for transplant in 63% of NHL patients who previously failed mobilization with G-CSF alone. The high success rate is consistent with the Compassionate Use Protocol experience. AMD3100 was generally well tolerated. The 40% success rate in the patients who previously failed AMD3100+G-CSF suggests that re-mobilization with the same combination is a potentially useful strategy for similar patients.
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Yamasaki, Sho, Eri Ishikawa, Masayuki Kohno та Takashi Saito. "The quantity and duration of FcRγ signals determine mast cell degranulation and survival". Blood 103, № 8 (15 квітня 2004): 3093–101. http://dx.doi.org/10.1182/blood-2003-08-2944.
Повний текст джерелаАнотація:
Abstract Immunoglobulin E (IgE) bound to multivalent antigen (Ag) elicits mast cell degranulation but not survival; on the contrary, IgE in the absence of Ag (IgE(-Ag)) induces survival only but not degranulation. Although these distinct responses are mediated through the same receptor, FcϵRI, the molecular mechanism generating the divergence is largely unknown. We recently showed that the signals through FcRγ chain are essential for IgE(-Ag)–induced mast cell survival as well as IgE(+Ag)–induced degranulation. To determine whether the cellular output is regulated by the quantity of FcRγ signal, we expressed CD8/FcRγ chimeras (CD8/γ) in bone marrow–derived mast cells (BMMCs) from FcRγ-/- mice to manipulate the strength of FcRγ signals by anti-CD8 cross-linking. Cross-linking of CD8/γ induced mast cell survival and degranulation. Survival was induced by weaker stimulation than needed for degranulation in terms of anti-CD8 concentration and the valency of chimera. However, sustained extracellular signal-regulated kinase (Erk) activation seems to regulate survival even when the activation signal was strong enough to elicit degranulation. Generation of sustained Erk activation by active mitogen-activated protein kinase kinase (MEK) induced BMMC survival. These results suggest that the duration and the magnitude of FcRγ signals may determine mast cell survival and degranulation, respectively. (Blood. 2004;103:3093-3101)
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Delvino, P., F. Sardanelli, S. Monti, P. Cohen, X. Puéchal, C. Montecucco, L. Mouthon, L. Guillevin, and B. Terrier. "AB0467 REMISSION AND LOW DISEASE ACTIVITY STATE IN PATIENTS WITH GRANULOMATOSIS WITH POLYANGIITIS AND MICROSCOPIC POLYANGIITIS: PREVALENCE AND IMPACT ON DAMAGE ACCRUAL." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1531.1–1532. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3101.
Повний текст джерелаАнотація:
Background:Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) require glucocorticoids (GCs) and immunosuppressants (IS) to induce and maintain remission. At the era of highly active drugs and treat-to-target strategies, defining the goal to achieve in terms of remission could be beneficial for the long-term management.Objectives:To assess the impact of prolonged remission or low disease activity state (LDAS) in GPA and MPA patients and its relationship with damage accrual.Methods:Patients diagnosed with GPA and MPA, according to ACR criteria and/or Chapel Hill definitions, seen in two vasculitis centers and followed-up for ≥5 years were included. Disease activity was assessed by BVAS, and damage accrual by the VDI. Three levels of remission were defined: complete remission (CR): BVAS=0 and negative ANCA in GCs-free and IS-free patients; clinical remission off therapy: no disease activity and positive ANCA in GCs-free and IS-free patients; clinical remission on therapy: no disease activity in patients with low dose GCs (≤5 mg/d) and/or IS. LDAS was defined as 0<BVAS≤3 without major organ activity, no new disease activity, low-dose GCs (≤7.5 mg/day) and well-tolerated IS. We defined remission or LDAS as prolonged when lasting ≥2 consecutive years. The effect of prolonged remission and LDAS on damage accrual was evaluated.Table.Prevalence of vasculitic affection of respective arteries in patients with giant cell arteritis and polymyalgia rheumatica and patients with giant cell arteritis only.Affected arteryGroupPMR-GCA-group (n=27)GCA-group (n=18)UnilateralBilateralNoneUnilateralBilateralnoneAxillary artery9 (33%)12 (45%)6 (22%)5 (28%)7 (39%)6 (33%)Common superficial temporal artery3 (11%)21 (78%)3 (11%)5 (28%)13 (72%)0 (0%)Frontal branch6 (22%)17 (63%)4 (15%)3 (17%)11 (61%)4 (22%)Parietal branch5 (18%)21 (78%)1 (4%)3 (17%)13 (72%)2 (11%)Facial artery7 (26%)17 (63%)3 (11%)4 (22%)11 (61%)3 (17%)PMR-GCA-group: patients with diagnosis of giant cell arteritis and consecutive polymyalgia rheumaticaGCA-group: patients with diagnosis of giant cell arteritis onlyResults:167 patients were included: 128 (76.6%) GPA, mean age 51.0±16.7 years. At 5-years, mean VDI was 2.7±2.0, mainly because of AAV-related items (2.0±1.7) rather than treatment-related items (0.7±1.0). During the 5-year follow-up, 10 (6.0%) patients achieved prolonged CR, 6 (3.6%) prolonged clinical remission off therapy, 89 (53.3%) prolonged clinical remission on therapy, 42 (25.1%) prolonged LDAS and 20 (12.0%) never achieved LDAS. Damage accrual at 5-years in patients with prolonged CR, clinical remission off therapy, clinical remission on therapy, LDAS or those never achieved LDAS was 1.6±1.1, 1.8±1.7, 2.3±1.9, 3.8±2.0 and 3.3±2.0, respectively (P<0.0001). Damage was comparable between patients in prolonged remission off therapy and those in remission on therapy (P=0.3). In contrast, patients in prolonged LDAS or those never in LDAS had significantly more damage accrual (P<0.0001 and P=0.01, respectively) than those in prolonged remission off therapy. Eighty-one patients (49%) reached a VDI ≥3 at 5-years. The inability to achieve prolonged remission was associated with a VDI ≥3 at 5-years (OR 5.07, 95% CI 2.53-9.84, P<0.0001), and considering only prolonged CR or clinical remission off therapy did not had any benefit on damage accrual. In contrast, achieving prolonged LDAS had no benefit compared to spending no time in LDAS (P>0.99). Compared to patients achieving prolonged remission, those not able to achieve prolonged remission were younger (46±16.0 vs. 53.5±16.6, P=0.001), had more frequent GPA (P=0.0003), had more PR3-ANCA (P=0.006), had more ENT and lung involvement (P<0.0001 and P=0.036, respectively).Conclusion:Sixty percent of GPA and MPA patients achieved prolonged remission, which was associated with a better outcome in terms of damage accrual. In contrast, prolonged LDAS was associated with increased damage and was not a sufficient target to achieve in GPA and MPA.Disclosure of Interests: :None declared
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D'Souza, Anita, Francis K. Buadi, Martha Q. Lacy, Morie A. Gertz, Suzanne R. Hayman, Shaji Kumar, David Dingli, Steven R. Zeldenrust, and Angela Dispenzieri. "Relapse of POEMS Following Autologous Stem Cell Transplantation: A Single Center Experience." Blood 118, no. 21 (November 18, 2011): 3101. http://dx.doi.org/10.1182/blood.v118.21.3101.3101.
Повний текст джерелаАнотація:
Abstract Abstract 3101 The POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare paraneoplastic disorder secondary to a clonal plasma cell process. The most experience with successful outcomes in POEMS with disseminated disease has been with high dose chemotherapy followed by autologous stem cell transplantation (ASCT). However, the risk of relapse of POEMS following an ASCT or the outcome of the patients who relapse is not known. We therefore performed a retrospective review of POEMS patients who underwent ASCT at our center and subsequently relapsed or progressed. Over the past 12 years, 58 patients with POEMS underwent autologous stem cell transplantation at the Mayo Clinic, Rochester between Mar 18, 1999 and Jun 22, 2011. With a median follow up of 40 months (1–147 months), 12 patients have relapsed. The median time to relapse was 41 months. The 1, 2, and 5 year PFS rates were 98%, 94%, and 75%, respectively (Figure 1), and the 1, 2, and 5 year OS rates were 98%, 98%, and 94%. Of the 12 patients with documented relapse, 7 had baseline PET/CT scans all of which had FDG avid lesions. By 1 year, the FDG avidity had not resolved in 4 of these patients who then went on to either develop additional lesions or increasing SUV of existing lesions. Of the 12 patients with documented relapse, 8 had baseline VEGF measurements, and all but 1 had normalization by 1 year. The first sign of relapse was a clinical deterioration in 2, a rising M-protein in 3, and a rising plasma VEGF level in 5 patients. All of these patients had new or worsening of existing lesions on PET/CT scan (n= 9) or x-ray imaging (n= 3). The symptoms of clinical relapse included pain at the site of the lytic lesion and generalized pain with swelling. Of the patients who relapsed, 5 were treated with radiation therapy, 4 received lenalidomide or thalidomide, 2 had alkylator based therapy and 1 had bortezomib based therapy. One patient was treated with surgical resection of his hepatic plasmacytoma and 2 patients have been observed without needing definitive treatment as of yet. One patient also received anti-VEGF treatment with bevacizumab unsuccessfully after failing cyclophosphamide therapy. In this large cohort of POEMS patients treated with high dose chemotherapy and autologous stem cell transplantation in a single center, a relapse rate of 21% was noted. Not every patient who relapsed has been deemed to need further treatment, and most patients could be salvaged with chemotherapy or radiation. Only one patient died from relapsed POEMS following stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.
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Johnson, Emhonta, Christopher S. Theisen, Keith R. Johnson, and Margaret J. Wheelock. "R-cadherin influences cell motility via Rho family GTPases. Vol. 279 (2004) 31041-31049." Journal of Biological Chemistry 279, no. 42 (October 2004): 44229–30. http://dx.doi.org/10.1016/s0021-9258(20)68100-5.
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van Heijst, Jeroen W. J., Izaskun Ceberio, Lauren B. Lipuma, Dane W. Samilo, Gloria D. Wasilewski, Anne Marie R. Gonzales, Jimmy L. Nieves, Marcel R. M. van den Brink, Miguel A. Perales, and Eric G. Pamer. "Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation." Nature Medicine 19, no. 3 (February 24, 2013): 372–77. http://dx.doi.org/10.1038/nm.3100.
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Cubas, Rafael A., Joseph C. Mudd, Anne-Laure Savoye, Matthieu Perreau, Julien van Grevenynghe, Talibah Metcalf, Elizabeth Connick, et al. "Inadequate T follicular cell help impairs B cell immunity during HIV infection." Nature Medicine 19, no. 4 (March 10, 2013): 494–99. http://dx.doi.org/10.1038/nm.3109.
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Bolwell, Brian J., Auayporn P. Nademanee, Patrick Stiff, Edward Stadtmauer, Richard T. Maziarz, Ivana N. Micallef, Sachin Marulkar, Pritesh Gandhi, and John F. DiPersio. "Mobilization with Plerixafor (Mozobil ®)Plus G-CSF Results in Superior Day 1 Collection of CD34+ Cells Compared to Placebo Plus G-CSF: Results From Two Randomized Placebo-Controlled Trials in Patients with Multiple Myeloma or Non-Hodgkin's Lymphoma." Blood 114, no. 22 (November 20, 2009): 3224. http://dx.doi.org/10.1182/blood.v114.22.3224.3224.
Повний текст джерелаАнотація:
Abstract Abstract 3224 Poster Board III-161 Background While most centers use 2 × 106 CD34+ cells/kg as the minimal cell dose for autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT), infusion of higher CD34+ cell dose is associated with better outcomes in patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL). Recent evidence suggests a correlation between CD34+ cell yield on Day 1 of collection and total CD34+ cell yield as well as post-transplant outcomes. This analysis was designed to: 1) compare Day 1 collection between patients with NHL or MM mobilized with plerixafor plus G-CSF or placebo plus G-CSF; and 2) determine whether Day 1 CD34+ cell yields correlated with the total mobilization yield and number of apheresis days. Methods Data were obtained from two prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trials that compared the safety and efficacy of plerixafor (0.24 mg/kg/day SQ) plus G-CSF (10 μg/kg/day) with placebo plus G-CSF for mobilization of HSC for auto-HSCT in patients with NHL (3101 Study) or MM (3102 Study). Pearson correlation coefficient was used to evaluate the association of day 1 CD34+ cell collection with total CD34+ cell yield and the number of days of apheresis. Results In the NHL trial, 150 patients were mobilized with plerixafor plus G-CSF and 148 patients underwent mobilization with placebo plus G-CSF. More than half the patients (55.3%) in the plerixafor group collected ≥2 × 106 CD34+ cells/kg on Day 1 of apheresis (Figure 1A). In contrast, 19.6% patients in the placebo group collected ≥ 2 × 106 CD34+ cells/kg on Day 1 of apheresis (p< 0.001). In the MM study, 148 patients were mobilized with plerixafor plus G-CSF and 154 patients were mobilized with placebo plus G-CSF. More than half the patients (52.7%) in the plerixafor group collected ≥6 × 106 CD34+ cells/kg on the first day of collection compared to only 16.9% patients in the placebo group (p<0.001; Figure 1B). There was a strong positive correlation between day 1 collection and the total CD34+ cell yield in patients with NHL (r= 0.86, p-value= <0.0001) or MM (r= 0.87, p-value= <0.0001) in both the plerixafor and placebo groups. For NHL patients, the median Day 1 collection was higher in the plerixafor group compared to the placebo group: 2.66 × 106 vs. 0.77 × 106 CD34+ cells/kg (p<0.001) and this translated into higher total CD34+ cell yields in the two groups respectively: 5.69 × 106 vs. 1.98 × 106 CD34+ cells/kg (p<0.001). Similarly, for MM patients, the median CD34+ cells/kg collected on Day 1 was higher in the plerixafor group compared to the placebo group: 7.01 × 106 vs. 2.29 × 106 CD34+ cells/kg (p<0.001) and this translated into better overall collection in the plerixafor vs. placebo groups: 10.96 × 106 vs. 6.18 × 106 CD34+ cells/kg (p<0.001). A negative correlation was observed between CD34+ cells collected on Day 1 and the number of days of apheresis performed in patients with NHL (r= -0.67, p-value=<0.0001) or MM (r= -0.50, p-value= <0.0001) in both the plerixafor and placebo groups. Consequently, better Day 1 collection in plerixafor-treated NHL or MM patients translated into significantly fewer apheresis days to achieve the target collection compared to placebo treated patients. Conclusions These data support previous reports demonstrating a strong correlation between day 1 CD34+ cell collection and total CD34+ cell yield and apheresis days. These data also demonstrate that addition of plerixafor to G-CSF allows significantly more patients to achieve the target cell collection within 1 day of apheresis compared to G-CSF alone. These findings support the observation that mobilization with plerixafor plus G-CSF reduces the number of apheresis days required to achieve the minimal or optimal cell dose to proceed to transplantation. Disclosures Bolwell: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nademanee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stadtmauer:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Genzyme Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Micallef:Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Gandhi:Genzyme Corporation: Employment, Equity Ownership. DiPersio:Genzyme: Honoraria.
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Irfan, Syed Mohammed, Sadia Sultan, Syeda Alia Abbas, and Sana Ashar. "Insight into Donor Deferral Pattern Based on Peripheral Blood Counts: An Experience from Southern Pakistan." Blood 128, no. 22 (December 2, 2016): 5042. http://dx.doi.org/10.1182/blood.v128.22.5042.5042.
Повний текст джерелаАнотація:
Abstract Introduction: American association of blood banking (AABB) recommends screening of all potential donors by a copper sulphate technique, but this method has chances of false acceptance as well as false deferral. Additionally others valuable blood parameters remain undetermined. Yet this is practically applicable in developed countries with low prevalence of anemia and community infections. In Pakistan anemia's secondary to nutritional deficiency or infectious diseases are much common. It makes the application of this crude method questionable. With this background we determined the whole peripheral blood counts by automated hematology analyzers in all prospective blood donors. This is to provide the pre-donation deferral rate of the healthy blood donors based on peripheral blood counts. The basic knowledge about frequency, types and severity of anemia among donors will help to plan a strategy to promote donor recruitment and overall national health. Methods: Prospective records of all the reported donors were collected from January-2014 to December-2015 at Liaquat National Hospital, Karachi. Results: Overall 36954 potential donors reported to the blood bank, out of which 33853 were selected and 3101 were deferred, which makes the deferral rate of 8.39%. Of total, 264 (0.71%) donors were excluded based on history whereas 174 (0.47%) donors were excluded due to examination findings while majority [n=2663 (7.20%)] of donor were deferred based on complete blood counts. Based on peripheral blood counts; anemia (91.8%) represents the major cause of deferral, followed by raised total leukocytic count (3.7%) and polycythemia (3.3%) respectively and thrombocytopenia (1.0%) was the least potential cause. Microcytic-hypochromic anemia was found in 58.5% donors followed by normocytic and macrocytic anemias in 38.9% and 2.4% respectively. Mild anemia was seen in 78.2% followed by moderate and severe anemias in 20.5% and 1.18% respectively. Conclusion: In view of frequently anemic donors in the present study, it is strongly recommended to have a full blood counts rather to rely on semi-quantitative methods which led to acceptance of anemic donors. High prevalence of anemia among Pakistani blood donors signifies deteriorating health status not only in donor population but also in general population as well. Astonishingly high TLC (sub clinical infections) turned out as second important cause of deferral. This situation recalls for strenuous efforts to overcome as it entails that we will likely to face more dearth of donors in future. Disclosures No relevant conflicts of interest to declare.
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Hou, Jian Q., Jun He, Zi X. Chen, Xiao J. Bao, Li Yao, Wen Y. Di, Hui Zhang, and Jian Zhang. "The Gene Locus Distribution of HLA in the Chinese Population by High Resolution Typing of HLA-A,B,C,DR,DQ and Its Effect on Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 3037. http://dx.doi.org/10.1182/blood.v108.11.3037.3037.
Повний текст джерелаАнотація:
Abstract Allogeneic hematopoietic stem cell transplantation (AHSCT)can potentially cure a variety of hematopoietic and congenital metabolic disorders. Ideally, one would hope to find identical unrelated donors who are genotypically identical to the patients at all HLA loci. To explore distribution of HLA gene subsites in the Chinese population and its effect on AHSCT. High resolution typing of HLA-A,B,Cw,DR,DQ were performed on 101 cases from the data base of China Marrow Donor Program (CMDP) donors and 76 patients (ALL 23cases, CML 32cases, AML 23cases)by using PCR-SSP and PCR-SSO. The HLA subsites with highest gene frequency were A*0201, A*0207, A*1101, A*2402, B*4001,B*4601, C*0102, C*0702, DR*0901, DR*1202,DQ*0301and DQ*0303(PF>0.2). The subsites with secondary high frequency were A*3101,A*3303,B*1301,B*1302,B*1501, B*5101,B*5801,C*0303,C*0304,C*0602,C*0801, DR*0405, DR*0406,DR*0701,DR*0803, DR*1501,DQ*0202,DQ*0302,DQ*0401, DQ*0502, DQ*0601(PF>0.1). The phenotypic frequency of A*1101,B*4601,C*0102,DR*0901, DQ*0303 in the Chinese population was as high as 0.38, Among which B*4601and DR*0901 were the single allele with highest frequency. The gene locus in HLA with linkage disequilibrium were A*0207-B*4601- DR*0901-C*0102-DQ*0301or0303;A*0201-B*4601-DR*0405 or DR*0803- C*0102-DQ*0302orDQ*0502;A*3001-B*1302-DR*0701-C*0602-DQ*0202 and A*3303- B*5801-DR*0901-C*0302-DQ*0303 or DQ*0302, respectively. CMDP demonstrated the effect of HLA-A and B allele matching on the development of severe acute GVHD and on the overall survival rate. HLA-DR matching are less effective than classIfor clinical outcomes. Additionally, the HLA-C mismatch was found to have a synergistic effect on the acute GVHD and survival rate when another HLA locus mismatch coexisted. Our results demonstrated that the frequency distribution of HLA gene subsites is important for selecting more suitably matched donor for HSCT and is helpful for making donor recruitment strategy. As the HLA-Cw played important role on aGVHD occurrence and the failure of BMT, more attention should be paied on HLA-Cw allele in clinical HSCT.
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Zeng, Yi, Hanping Feng, Michael W. Graner, and Emmanuel Katsanis. "Tumor-derived, chaperone-rich cell lysate activates dendritic cells and elicits potent antitumor immunity." Blood 101, no. 11 (June 1, 2003): 4485–91. http://dx.doi.org/10.1182/blood-2002-10-3108.
Повний текст джерелаАнотація:
Abstract We have utilized a free-solution isoelectric focusing technique (FS-IEF) to obtain chaperone-rich cell lysate (CRCL) fractions from clarified tumor homogenates and have previously reported on their vaccinating potential. To better understand the underlying mechanisms as well as to improve on the immunizing efficacy of tumor-derived chaperone complexes, in the present study we examined the effects of CRCL-loaded dendritic cells (DCs) against 12B1, an aggressive bcr-abl+ murine leukemia tumor. We found that DCs incubated with 12B1-derived CRCL had higher expression of CD40 and major histocompatibility complex class II (MHC-II) on their cell surface, produced more interleukin-12 (IL-12), and had superior immunostimulatory capacity in a mixed leukocyte reaction (MLR) when compared with DCs exposed to unfractionated tumor lysate or purified heat-shock protein 70 (HSP70). Vaccination of mice with 12B1 CRCL–pulsed DCs significantly prolonged their survival, with more than 80% of mice rejecting their tumors following a lethal challenge with live 12B1 compared with those immunized with tumor lysate or HSP70-loaded DCs. The protective immunity generated was tumor specific, long lasting, and both CD4+ and CD8+ T-cell dependent. Moreover, immunization with CRCL-loaded DCs resulted in a 75% cure rate in mice with pre-existing 12B1 tumors. Our findings indicate that CRCL has prominent adjuvant effects and is a very effective source of tumor antigen for pulsing DCs. FS-IEF–derived CRCL-pulsed DCs are a promising anticancer vaccine that warrants clinical research and development.
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Smith, David F. "Tetratricopeptide repeat cochaperones in steroid receptor complexes." Cell Stress & Chaperones 9, no. 2 (2004): 109. http://dx.doi.org/10.1379/csc-31.1.
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Xu, Hong, Ziqiang Zhu, Yiming Huang, and Suzanne T. Ildstad. "The CXCR4 Antagonist AMD 3100 Induces Rapid Mobilization of Facilitating Cells and Hematopoietic Stem Cells in Mice." Blood 118, no. 21 (November 18, 2011): 4694. http://dx.doi.org/10.1182/blood.v118.21.4694.4694.
Повний текст джерелаАнотація:
Abstract Abstract 4694 Bone marrow transplantation (BMT) offers great promise for treating red blood cell disorders, inherited disorders of metabolism, autoimmune diseases, and inducing donor-specific tolerance to organ transplants. However, the widespread application of this approach is dependent upon the development of less toxic strategies for BMT and avoidance of graft-versus-host disease (GVHD). CD8+/TCR− facilitating cells (FC) facilitate engraftment of highly purified hematopoietic stem cells (HSC) across major histocompatibility complex barriers without causing GVHD. We previously reported that Flt3 ligand (FL) and granulocyte colony-stimulating factor (G-CSF) synergistically mobilize FC and HSC into the peripheral blood (PB). Recently, AMD 3100 has been found to be a rapid mobilizing agent whose effect occurs within hours after injection. It is a macrocyclic compound and potential fusion inhibitor that antagonizes CXCR4 alpha-chemokine receptor for its effect on HSC mobilization. CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1), are important in HSC homing and maintenance in the bone marrow microenvironment. Here, we investigated the effects of AMD 3100 on the mobilization of FC and HSC into PB in combination with FL and G-CSF. A dose titration of AMD 3100 was first performed. B6 mice were injected subcutaneously with AMD 3100 with the doses ranging from 1.25 mg/kg to 10 mg/kg. PB was obtained 0.5, 1, 3, and 6 hours post-injection. After individual count of peripheral blood mononuclear cells (PBMC), cells were stained for flow cytometric analysis to enumerate FC (CD8+/TCR−). The numbers of PBMC significantly increased even 0.5 hour after AMD 3100 treatment and peaked at 1 h. The maximal mobilization of PBMC was noted at 1 h with 5.0 mg/kg AMD 3100. Treatment with 5.0 mg/kg AMD 3100 caused a 3.1-fold increase of WBC at 1h compared with saline treated controls. An increase of FC was detectable with all doses of AMD 3100. The numbers of FC peaked between 1 and 3 h, and declined rapidly to resemble saline-treated controls at 6 h after. A 5.9-fold increase of FC was observed at 1 h with 5.0 mg/kg AMD 3100 (P = 0.012). These data suggest that AMD 3100 is a potent cell mobilizer from bone marrow to PB. We next investigated the effect of AMD 3100 in combination with FL and G-CSF on the mobilization of FC and HSC into PB. B6 mice were injected with FL (day 1 to 10), G-CSF (day 4 to 10), and AMD 3100 (day 10). PB was obtained 1 h after injection on day 10. After performing a count of peripheral WBC, cells were stained for flow cytometric analysis to enumerate FC (CD8+/TCR−) and HSC (Lin−/Sca-1+/c-kit+) mobilization. The maximal mobilization of PBMC was observed when animals were treated with AMD 3100/FL/G-CSF. The numbers of PBMC with AMD3100/FL/G-CSF treatment increased with 17.2-fold and 6.4-fold when compared with controls treated with saline or AMD 3100 alone (P < 0.00001), respectively. A maximal elevation of both FC and HSC was detected when AMD 3100 was added to FL/G-CSF treatment and reached 1.91 ± 0.42 × 103/μl (Figure 1A) and 1.89 ± 0.35 × 103/μl (Figure 1B), respectively. The increase of FC and HSC was significant. There was a 10.1-fold increase in FC and 230.8-fold increase in HSC when compared with recipients treated with AMD 3100 alone (P < 0.00001). AMD 3100/FL/G-CSF treatment resulted in a 1.7-fold of FC and 2.2-fold increase of HSC when compared with recipients treated with FL/G-CSF (P < 0.05). In summary, AMD 3100, FL, and G-CSF show a highly significant synergy on the mobilization of FC and HSC. This study may be clinically relevant in efforts to mobilize immunomodulatory FC and HSC to PB for transplantation, especially to induce tolerance for organ transplant recipients. Disclosures: Ildstad: Regenerex, LLC: Equity Ownership.
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Li, Carrie J., Yang Liu, Taylor Bell, Jack Wang, Hui Guo, Makhdum Ahmed, Hui Zhang, et al. "Novel Bruton's Tyrosine Kinase Inhibitor Bgb-3111 Demonstrates Potent Activity in Mantle Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 5374. http://dx.doi.org/10.1182/blood.v128.22.5374.5374.
Повний текст джерелаАнотація:
Abstract Background: Aberrant B-cell receptor signaling is an important contributor to lymphomagenesis in mantle cell lymphoma (MCL). Bruton's Tyrosine Kinase (BTK), a component of the BCR signaling axis, has been validated as a clinically relevant target, and BTK inhibitor ibrutinib received FDA approval for treatment of MCL in 2013. Growing concerns that single agent ibrutinib exerts off-target effects that interfere with other treatments such as rituximab-induced antibody-dependent cell cytotoxicity limit its utility in combination treatments. In this study, we assessed the in vitro and in vivo effects of BGB-3111in MCL models. Methods: We performed cell viability assays with BGB-3111 treated MCL cell lines to determine inhibition of cellular proliferation. The same assays were conducted on primary human MCL cells and patient-derived xenograft (PDX) tumor samples. Dose-dependent inhibition of BTK auto-phosphorylation and inhibition of downstream targets such as PLC-γ were determined by phospho-protein immunoblotting and immunoprecipitation. A reverse-phase protein assay (RPPA) was conducted on BGB-3111-treated Mino cells to evaluate changes in MCL oncogenic signaling. Induction of apoptosis in MCL cells treated with increasing doses of BGB-3111 was quantified using flow cytometry. For in vivo experiments, an ibrutinib-sensitive MCL PDX mouse model was treated with 50 mg/kg/day BGB-3111 and monitored for mean tumor burden and survival. Results: BGB-3111 potently inhibited cell viability in a panel of MCL cell lines, with an activity range of 1-10 uM, and induced apoptosis in a dose-dependent manner in several MCL cell lines.BGB-3111 treatment of MCL cells demonstrated a dose-dependent decrease in p-BTK (Y223) and inhibition of downstream effectors without impacting total protein levels, while RPPA revealed upregulation of the PI3K-Akt signaling axes. In addition, BGB-3111 treatment did not impact phosphorylation of off-target kinases affected by ibrutinib treatment. In vivo, BGB-3111 suppressed tumor growth and prolonged tumor survival in BGB-3111 treated mice. Conclusion: The second generation BTK inhibitor BGB-3111 demonstrates selectivity for BTK in vitro and BTK inhibition in vivo. BGB-3111-treated PDX mouse models examining survival, tumor growth, and other factors point to BGB-3111 as an effective single agent BGB-3111 is being investigated in Phase I clinical trials. Disclosures Wang: Beigene: Employment. Wang:Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Acerta: Consultancy, Research Funding; Kite Pharma: Research Funding; BeiGene: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding.
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Lee, Ha Yeon, Mi Ran Lee, Won Seog Kim, and Seok Jin Kim. "Side Population Cells of Human B-Cell Non-Hodgkin Lymphoma Cell Lines May Contain Lymphoma-Stem Cells Responsible for Lymphoma Initiation." Blood 116, no. 21 (November 19, 2010): 3105. http://dx.doi.org/10.1182/blood.v116.21.3105.3105.
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Abstract Abstract 3105 Background: Cancer stem cells are considered to initiate cancer development, and such populations might be related with the resistance to treatment and relapse. There are accumulated data supporting the presence of cancer stem cells in several human cancers such as breast and colon cancers. In hematologic malignancy, the presence of cancer stem cells was supported by the previous studies from leukemia. However, there are few reports regarding the possibility of lymphoma stem cells. Side population cells are defined as cells that efficiently extrude the Hoechst 33342 dye, and hence remain negative for this fluorescent marker in flow cytometric analysis. The isolation of SP cells from total tumor cells has been used as a tool for cancer stem cell research. Methods: We performed the side-population analysis to isolate a stem-like cell population. The side population analysis was based on the modified Hoechst 33342 dye efflux assay. Thus, cells expressing ATP binding cassette (ABC) transporter subfamily G number 2 (ABCG2) on their surface efflux Hoechst 33342 dye. On the other hand, cells without ABCG2 expression cannot efflux dye. According to this different nature, we discriminated side population from non-side population. We isolated side population from three lymphoma cell lines, 1A2 (B-cell lymphoblastic lymphoma cell line), Raji (Burkitt lymphoma cell line), and Toledo (Diffuse large B-cell lymphoma cell line). We compared the SP cells with NSP cells from each cell line via in vitro propagation and colony forming assay. We also evaluated the ability of tumorigenesis in NOD/SCID mice and compared the gene expression via performing microarray. Results: We isolated a subset of cells (side population) from three cell lines. The number of side population was extremely small, so the ratio of SP to NSP was from 0.01% to 0.25% regardless of the type of lymphoma cell lines. The in vitro propagation for 3 weeks showed that the growth rate of the side population was significantly higher than non-side population in three cell lines. The life span of non-side population was limited while side population could continuously proliferate. Thus, non-side population could not be cultured over four weeks, and the proportion of viable cells was higher in the side population (≥95%) than non-side population (≤80%). The RT-PCR and confocal microscopy demonstrated the higher expression of ABCG2 in the side population compared to the non-side population. The inoculation of lymphoma cells (200 – 1000) into NOD/SCID mice showed the tumor formation in mice inoculated with side population cells while there was no tumor in non-side population. The hierarchical clustering of differentially expressed genes showed the different pattern of gene expression between side and non-side population in each cell line. Conclusion: This study suggests that the side population may contain a cell population highly capable of proliferation, and this population may have the characteristics of lymphoma stem-like cells. Disclosures: No relevant conflicts of interest to declare.
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Gruhn, Bernd, Juliane Sanft, Nadine Pfaffendorf, Ilona Wolff, Dietlinde Fuchs, Felix Zintl, and James Beck. "Clinical Relevance of Minimal Residual Disease and Chimerism for the Detection of Relapse after Hematopoietic Stem Cell Transplantation." Blood 112, no. 11 (November 16, 2008): 338. http://dx.doi.org/10.1182/blood.v112.11.338.338.
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Abstract The clinical relevance of both minimal residual disease (MRD) and chimerism after hematopoietic stem cell transplantation (HSCT) for the detection of impending relapse has not yet been extensively studied. We investigated MRD in 119 consecutive children (median age, 12 years) with ALL (n=56), AML (n=36), MDS (n=20), or CML (n=7) who underwent bone marrow (n=80) or peripheral blood stem cell (n=39; T-cell depleted: n=18) transplantation in a single center. Thirteen patients received autologous HSCT and 106 patients underwent allogeneic HSCT. The donor was HLA-matched unrelated in 58 patients and HLA-identical related in 48 patients. The Wilms’ tumor gene (WT1) expression was used for the detection of MRD because WT1 gene is overexpressed in the vast majority of patients with leukemia. In contrast, WT1 gene is not expressed in normal peripheral blood mononuclear cells (PBMCs) and only weakly expressed in normal bone marrow (BM) cells. We performed a quantitative reverse transcriptase-polymerase chain reaction (PCR) to examine the level of WT1 gene expression. For the present study, we followed up MRD in both BM and PB after HSCT. In the 119 patients, a median of 11 analyses (range, 3–27 analyses) covering a median period of 708 days (range, 29–3101 days) was performed. Analysis of 25 paired BM and PB samples revealed that the level of MRD in BM was on average 9 times higher and paralleled that in PB. All 85 patients with continuous normal WT1 expression levels in BM and continuous undetectable WT1 expression levels in PB remained in complete remission without relapse at a median of 1884 days (range, 58–5905 days) after HSCT. In contrast, all 32 patients who suffered from hematological relapse after a median of 152 days (range, 28–1104 days) presented with high levels of WT1 gene expression in BM and PB (P < .001). In 19 patients, we observed a gradual or rapid increase of WT1 expression levels at a median of 31 days (range, 12–119 days) before hematological relapse. In 14 of these 19 patients, DNA was available at the time of increase of WT1 expression level to perform analysis of hematopoietic chimerism using a semi-quantitative short-tandem-repeat PCR. Interestingly, 10 of the 14 patients (71%) revealed a complete donor chimerism, whereas only 4 of the 14 patients (29%) showed a mixed chimerism. In two patients, we diagnosed a molecular relapse using WT1 gene expression at 161 and 360 days after transplantation. At the time of molecular relapse, both children revealed a complete donor chimerism. In both patients, molecular remission was achieved by withdrawal of cyclosporin A and by donor lymphocyte transfusion, respectively. Both children are alive and well without relapse at 10 and 9 years after transplantation. In conclusion, quantitative analysis of WT1 gene expression is a valuable tool for monitoring of MRD in patients with ALL, AML, CML, and MDS after HSCT. Increasing levels of WT1 gene expression strongly predict hematological relapse. Therefore, this approach is very useful for early diagnosis and treatment of molecular relapse after HSCT. MRD measurement using WT1 gene expression is more sensitive for the detection of impending relapse than the analysis of hematopoietic chimerism.
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Blasius, Amanda, William Vermi, Anne Krug, Fabio Facchetti, Marina Cella, and Marco Colonna. "A cell-surface molecule selectively expressed on murine natural interferon–producing cells that blocks secretion of interferon-alpha." Blood 103, no. 11 (June 1, 2004): 4201–6. http://dx.doi.org/10.1182/blood-2003-09-3108.
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Abstract Natural interferon (IFN)-producing cells (IPCs) recognize certain viruses and DNA containing deoxycytidylate-phosphatedeoxyguanylate (CpG) motifs through the toll-like receptor (TLR) 9, resulting in secretion of IFN-α, interleukin 12 (IL-12), and proinflammatory chemokines. Human IPCs are found mainly in inflamed lymph nodes, where they are presumably recruited from the blood to activate both innate and adaptive responses to microbial infections. Demonstrating IPC recruitment and function in murine infection models has been difficult because multiple antibodies are required to distinguish IPCs from other immune cells and very few IPCs can be recovered from lymph nodes. Here we describe a monoclonal antibody (mAb) that exclusively detects murine IPCs in all lymphoid organs under both normal and inflammatory conditions. Using this antibody, we demonstrate that IPCs are normally present in the T-cell zone of lymph nodes and spleen and that inoculation of peripheral tissues with inflammatory stimuli triggers recruitment of IPC into sentinel lymph nodes, whether the stimuli are able to directly stimulate IPCs through TLR or not. Remarkably, we show that incubation of IPCs with the antibody in vitro or administration of the antibody in vivo dramatically reduce secretion of IFN-α in response to CpG DNA without causing IPC depletion. Thus, the antibody identifies an IPC-specific surface molecule that, when engaged, inhibits IFN-α secretion. (Blood. 2004;103:4201-4206)
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Cai, Ann, Derin Keskin, Anselmo Alonso, David DeLuca, Wandi Zhang, Naa Lokko, Valentina Nardi, et al. "Peptides Derived From Mutated BCR-ABL Elicit T Cell Immunity In CML Patients." Blood 116, no. 21 (November 19, 2010): 887. http://dx.doi.org/10.1182/blood.v116.21.887.887.
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Abstract Abstract 887 Over 20 BCR-ABL mutations have been identified that result in imatinib resistance and relapse of chronic myelogenous leukemia (CML). CML is highly responsive to immunological manipulations and we therefore hypothesized that mutated BCR-ABL-derived peptides could serve as immunogenic tumor-specific targets. Herein, we present a multi-step strategy for identifying tumor-specific T cell epitopes generated from gene mutation. We first investigated whether peptides derived from 24 frequent BCR-ABL mutations could potentially bind 8 common class I MHC molecules by applying the well-validated prediction servers IEDB and NetMHC to tiled 9- and 10-mers around each mutation. More than 60 peptides were predicted to bind to one or more of the following alleles with IC50<1000: A*0201, A*0301, A*1101, B*0702, B*0801, B*1501, A*0101 or A*2402. From NetMHC, 24 of 84 (29%) were predicted as high (IC50<50), 42 (50%) as intermediate (IC50=50-500), and 18 (21%) as weak binders (1000> IC50>500). From IEDB, 9 of 61 (15%) were predicted as high, 35 (57%) as intermediate and 17 (38%) as weak binders. 24 of 84 mutated peptides (29%) and 24 of 61 mutated peptides (39%) were predicted as binding with at least two-fold higher affinity compared to parental peptides, using NetMHC and IEDB, respectively. These predictions indicated that cells from 7 of 9 imatinib-resistant CML patients had the potential to present at least one mutated BCR-ABL derived peptide by binding autologous HLA alleles (with IC50<1000). CML cells from 3 of the 5 patients had an E255K mutation and expressed HLA-A3, and were predicted to generate two promising candidate peptides: E255K-A247-255 (KLGGGQYGK, IEDB IC50=113; NetMHC IC50=192) and E255K-B255-263 (KVYEGVWKK, IEDB IC50=29; NetMHC IC50=28). Both peptides were predicted to bind HLA-A*0301 at least ten-fold more tightly than parental peptides. Using a competitive MHC binding assay, we confirmed that E255K-A and –B were high binders with IC50 scores of 208nM and 17nM, respectively and that they both had at least ten-fold fold greater affinity than parental peptides. In addition, E255K-B also bound to the other HLA-A3 superfamily members HLA-A*1101, HLA-A*3001, HLA-A*3101, HLA-A*6801 (IC50: 39–603nM). We next successfully generated T cell lines against E255K-B but not E255 K-A from a normal HLA-A3+ donor that demonstrated greater specificity against the mutated peptide (2330±325 SFC/million cells, by IFNγ-ELISPOT) than the parental peptide (1270±42 SFC/million cells). E255K-B is endogenously processed and presented since E255K-B reactive T cells also responded to HLA-A3+ antigen-presenting cells (APCs) that were transfected with a minigene encompassing 227 base pairs surrounding the E255K mutation (1900±85 SFC/million cells). Finally, we assessed the potential for E255K-B to stimulate T cell responses in CML patients. E255K-B elicits T cell immunity in vivo in that we could detect antigen-specific CD8+ T cell reactivity from two HLA-A3+ CML patients bearing the E255K mutation by IFNγ-ELISPOT and by antigen-specific tetramer staining. T cell responses could be abrogated in the presence of class I blocking antibody w6/32. For both patients, reactive T cells were polyfunctional, expressing GM-CSF, IP10 and TNFα in response to APCs pulsed with mutated peptide or expressing the E255K minigene. For Patient 2, E255K reactivity developed only in the setting of donor-derived engraftment following curative allogeneic stem cell transplantation. Further analysis to explore the kinetics of mutated peptide-specific immunity in relationship to burden of mutation-expressing leukemia cells is in progress. Our studies have demonstrated that leukemia-driven genetic alterations can provide immunogenic tumor-specific antigen targets associated with clinical response in vivo. Importantly, even though BCR-ABL mutations generate resistance to imatinib, they also create novel epitopes that can be effectively recognized by cytotoxic CD8+ T cells. Our studies support the development of specific, nontoxic and personalized vaccination strategies for eradication of drug-resistant CML. Disclosures: No relevant conflicts of interest to declare.
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Fujiwara, Hideaki, Yoshinobu Maeda, Yuichiro Nawa, Masayuki Yamakura, Daisuke Ennishi, Yukihiro Miyazaki, Katsuji Shinagawa, Masamichi Hara, Mitsune Tanimoto, and Kosei Matsue. "Utility of Positron Emission Tomography/Computed Tomography In Extranodal Natural Killer/T-Cell Lymphoma." Blood 116, no. 21 (November 19, 2010): 3101. http://dx.doi.org/10.1182/blood.v116.21.3101.3101.
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Abstract Abstract 3101 Background: Natural killer (NK/) T-cell lymphoma, nasal type, is an aggressive form of extranodal lymphoma that is common in Asia, but rare in Europe and North America. Although NK/T-cell lymphoma involves upper aerodigestive sites such as the nasal cavity and nasopharynx, it frequently involves other extranodal sites, including the gastrointestinal tract, bone marrow, adrenal gland, and skin. Because of the frequency of extranodal site involvement, pretreatment evaluation of disease extension is important for staging and treatment. Recently, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was evaluated for its usefulness in the prognosis and treatment response of aggressive B-cell lymphoma and Hodgkin's lymphoma, and relevant results were obtained. Many studies have evaluated the value of PET/CT for various types of B-cell lymphomas, but other similar studies involving T-cell and NK-cell lymphomas are rare. In the present study, we compared the utility of PET/CT and conventional modalities, particularly CT, in extranodal NK/T-cell lymphoma. Patients and Method: From January 2006 to April 2010, 19 untreated patients with extranodal NK/T-cell lymphoma (11 males and 8 females; median age 61 years; range 13–90 years) were included in the study. PET/CT and conventional procedures (e.g., CTs and biopsies) were compared and evaluated for their abilities to detect tumor lesions and their influence in staging and treatment strategies. PET/CT was performed as an initial staging procedure. In addition to PET/CT, all patients underwent initial staging workups, including whole-body CT with contrast media, biopsies from the bone marrow and other sites, and panendoscopies of the upper aerodigestive tract. Patients were evaluated for clinical stage by both evaluation modalities (PET/CT and conventional modalities) according to the Ann Arbor Staging System, and treatment strategies were first planned based on staging results. Following PET/CT, the clinical stage was reevaluated in each patient, and treatment strategies were decided based on the re-staging results. Result: Seven patients (37%) had bone marrow involvement, eight (42%) were in Ann Arbor stage I–II, and 11 (58%) had a systemic dissemination. Most patients with systemic dissemination (9/11, 82%) had cutaneous lesions. The median number of disease sites was 4 (range, 1–15). The median number of positive lesions was 3 (range, 1–15) by PET/CT compared to 2 (range, 0–14) by CT (p = 0.12). Using PET/CT, 108 lesions (93%) were detected, and at least one FDG-avid lesion was observed at initial staging workups in all patients. In contrast, 70 lesions (60%) were detected by CT, and three patients (16%) did not show any positive lesion. Two lesions (2%) at the nasal cavity that were detected by biopsy were undetectable by either PET/CT or CT. The nodal and extranodal regions were separately evaluated by PET/CT and conventional modalities. In total, 28 nodal lesions were detected: all (100%) were positive by PET/CT and 26 (93%) by CT. Conversely, 89 extranodal lesions were detected, and 83 (93%) and 44 (49%) were positive by PET/CT and CT (p = 0.003), respectively. For the detection of upper aerodigestive lesions, PET/CT and CT demonstrated similar results: 23 lesions (92%) vs. 17 (68%), respectively. Notably, PET/CT was superior to CT in detecting cutaneous lesions [31 lesions (100%) vs. 19 lesions (61%), respectively; p = 0.026]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT and none by CT. Using conventional modalities, 11 patients (58%) were in the localized stage and eight (42%) were in the advanced stage. Using PET/CT, eight (42%) were in stage I–II and 11 (58%) were in stage III–IV. Most patients received chemotherapy plus local irradiation in stage I–II, and intensive chemotherapy with or without hematopoietic stem cell transplantation in stage III–IV. One patient did not receive treatment because of unwillingness for treatment and older age. PET/CT findings altered the stage and treatment strategy in four (21%) and two cases (11%). Conclusion: In extranodal NK/T-cell lymphoma, PET/CT demonstrated a high detection rate for nodal and extranodal lesions, except in the bone marrow. PET/CT may have an impact on treatment strategy and is essential for risk-adapted treatment. Disclosures: No relevant conflicts of interest to declare.
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Kapp-Schwoerer, Silke, Renate Looser, Franz Schaub, Michael Hummel, Manfred Olschewski, Jens Hasskarl, Michael Lübbert, Ulrich Germing, Radek C. Skoda, and Annette H. Schmitt-Graeff. "Acute Panmyelosis with Myelofibrosis: Clinicopathological and Molecular Features of a Rare Malignant Bone Marrow Disease." Blood 114, no. 22 (November 20, 2009): 3101. http://dx.doi.org/10.1182/blood.v114.22.3101.3101.
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Abstract Abstract 3101 Poster Board III-38 Background Acute panmyelosis with myelofibrosis (APMF) is listed among the category of “AML, not otherwise specified” in the actual WHO classification of hematopoietic tumors. Since specific genetic alterations have not yet been defined, this myeloid neoplasm (MN) remains clinicopathologically assigned. The WHO classification addresses the difficulties concerning the differential diagnosis between APMF, myelodysplastic syndromes (MDS) with excess of blasts and concomitant fibrosis (RAEB-F) and acute megakaryoblastic leukaemia (AMGL). Methods Our files were searched for patients with rapid-onset MN without a prior history of a myeloproliferative neoplasm or a MDS fulfilling the 2008 WHO criteria of APMF. An age- and gender-matched control group of RAEB-F cases with multilineage dysplasia was retrieved for comparison. Our approach included: i) the careful review of morphological, clinical and laboratory data with special regard to the proportion of immature CD34 + precursors/blasts in bone marrow (BM) biopsies; ii) the grading of BM fibrosis according to the European consensus guidelines; iii) the analysis of the JAK2-V617F, the MPL W515L and the GATA1 mutational status, the cytoplasmic localization of nucleophosphamin1 (NPM1) in BM blasts, and the expression the inhibitor of differentiation protein-2 (Id2) in hematopoietic and stroma cells; iv) the evaluation of the prognostic relevance of these parameters. Results Fifty-four patients (32 males, 22 females) with a median age of 66, 9 years from our institutions were diagnosed APMF. Sufficient DNA for allele specific PCR for JAK2 genotyping was obtained from paraffin-embedded EDTA-decalcified BMB specimens from 22 APMF and 14 RAEB-F patients. In addition, an analysis of MPL W515L and GATA1 mutations was performed on 15 APMF cases. The relevant clinicopathological and molecular data are summarized in the table. Semiquantitative evaluation revealed a decreased expression level of Id2 in erythropoiesis of the APMF samples, while Id2 was increased in the stromal compartment. Within the total APMF cohort, patients aged ≤60 years had a longer OS (p=0,013). A comparison between the Kaplan-Meier curves of the APMF patients who underwent hematopietic cell transplantation (HCT) with those treated by conventional chemotherapy clearly showed that HCT significantly improved OS (median survival 6,1 vs. 11,1 months, p=0,005). Within the non-transplanted group, a bone marrow blast count ≤25% was associated with a longer OS (p=0,006). Conclusions Our results point to significant differences between APMF and RAEB-F with regard to OS, MCV, LDH, BM fibrosis and BM blast cells. We detected a higher frequency of mutated JAK2 V616F in the MB samples than generally reported in the literature for other categories of AML or MDS. However, the JAK2 V617F mutation status or an aberrant cytoplasmic NPM1 localization were both not predictive of outcome. In contrast to data published for AMGL, no association between a MPL W515L mutation and APMF was observed. Survival was significantly worse in APMF than in RAEB-F. A rapid diagnosis based on a multiparameter approach and a proper management including the option of HCT even in elderly patients seems mandatory for APMF patients. Targeting the fibrotic BM microenvironment which is characterized by an increased Id2 expression may be considered for future therapeutic strategies. Disclosures Skoda: Genentech Inc.: Consultancy.
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Hennemann, H., E. Dahl, J. B. White, H. J. Schwarz, P. A. Lalley, S. Chang, B. J. Nicholson, and K. Willecke. "Two gap junction genes, connexin 31.1 and 30.3, are closely linked on mouse chromosome 4 and preferentially expressed in skin." Journal of Biological Chemistry 267, no. 24 (October 1992): 17225–33. http://dx.doi.org/10.1016/s0021-9258(18)41916-3.
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Theer, Patrick, Cyril Mongis, and Michael Knop. "PSFj: know your fluorescence microscope." Nature Methods 11, no. 10 (September 29, 2014): 981–82. http://dx.doi.org/10.1038/nmeth.3102.
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Trentin, Livio, Anna Cabrelle, Monica Facco, Davide Carollo, Marta Miorin, Alicia Tosoni, Paola Pizzo, et al. "Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas." Blood 104, no. 2 (July 15, 2004): 502–8. http://dx.doi.org/10.1182/blood-2003-09-3103.
Повний текст джерелаАнотація:
Abstract This study investigated the role of several chemokines and their receptors on malignant B lymphocytes recovered from 13 patients with chronic lymphocytic leukemia (CLL), 9 with hairy cell leukemia (HCL), 5 with mantle cell lymphoma (MCL), 5 with marginal zone B-cell lymphoma (MZL), 6 with small lymphocytic lymphoma (SLL), and 5 with follicular cell lymphoma (FCL). Flow cytometry analysis demonstrated that CXCR4 and CXCR5 were expressed on all malignant and normal B cells. Considering CC receptors, CCR1 was expressed in 70% of patients with CLL and 40% of those with HCL but was lacking in patients with MCL, MZL, SLL, and normal B cells. CCR2 showed a heterogeneous pattern of expression. CCR3 was found in almost all patients with CLL and in the majority of those with HCL, whereas it was usually lacking in patients with MZL and SLL and in healthy subjects. CCR5 was expressed in patients with HCL and MCL. Migration assays showed that different chemokines, mainly CXCL12 and CXCL13, are able to trigger migration of malignant B lymphocytes. Some of these chemokines induce calcium mobilization. These data indicate that different patterns of chemokine receptor expression identify different malignant B-cell subsets and that these receptors are functional and might play a role in malignant B-cell circulation. (Blood. 2004;104:502-508)
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Sarde, Aurelien, Sterling Eckard, Li Mei, Curtis Ruegg, Patrick Chun, and Victoria Smith. "Selectivity of T Cell Engager AMV564 Against Different Leukemic Blast Populations and Potential Application for Patient Selection." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-141475.
Повний текст джерелаАнотація:
Introduction AMV564 is a bivalent T cell engager that targets CD33 on leukemic blasts and myeloid-derived suppressor cells (MDSC). In a phase 1 study in relapsed/refractory AML patients, AMV564 administered by continuous intravenous infusion for 14 consecutive days over a 28 day cycle was well-tolerated and demonstrated anti-leukemic activity including bone marrow blast reductions in 17 of 35 efficacy evaluable patients (Westervelt P et al. Blood. 2019;134:834). In a phase 1 study in solid tumor patients, AMV564 administered by subcutaneous route via a daily injection was well tolerated with evidence of clinical activity (Starodub A et al. J Clin Oncol. 2020;38:3101) and a preliminary half-life of 58 hours, supporting transition to a more patient-friendly daily injection for future clinical studies in selected AML patients. The bivalent structure of AMV564 promotes more potent binding to clustered CD33, such as that found in lipid raft regions or active signaling configurations. CD33 is an active signaling molecule on immature and immune suppressive myeloid cells such as MDSC (Chen CL et al. J Clin Invest. 2013;123:4595-611) with no apparent role on differentiated myeloid cells, but less is known about the configuration of CD33 on leukemic blasts. While CD33 is broadly expressed by leukemic blasts, the degree and homogeneity of expression can vary. The binding of AMV564 to leukemic blasts and primary human myeloid cells and impact on T cell mediated cytotoxicity was thus further explored, and novel assays for evaluation of patient samples were developed. Methods AML cell lines, primary human cells, and patient samples were analyzed using flow cytometry with appropriate marker panels including AMV564, which was directly labeled (phycoerythrin) or detected with labeled anti-AMV564 antibodies. T cell cytotoxicity assays were conducted using primary human T cells and leukemic blasts or other target cells (3:1 ratio) for 48 or 72 hours. Results Results from flow cytometry assays of cell binding by AMV564 were similar whether using phycoerythrin-labeled AMV564 or a labeled anti-AMV564 antibody. AMV564 showed consistent binding characteristics for many leukemic blast lines (largely of M2 FAB subtype); however, substantial differences in binding were detected between the KG1 myeloid cell line (M2 FAB subtype) and the KG1a cell line (M0 FAB subtype) that represents a morphologically and functionally less mature state than the parental KG1. At saturating concentrations (10 nM), there was >10-fold less binding of AMV564 to KG1a vs KG1, whereas a reagent CD33 antibody (WM53) had a similar binding profile for each cell line (Figure 1). The difference in AMV564 binding between these two cell lines is reflected in the cytotoxic potency of AMV564, with a 17.6-fold difference in EC50 (0.42 pM for KG1 vs 7.39 pM for KG1a, Figure 2). AMV564 can engage CD8 and CD4 T cells to drive target-dependent killing and the difference in potency against KG1 vs KG1a was observed using both CD8 and CD4 T cells. Similarly, whereas purified naïve CD8 T cells killed KG1 effectively with AMV564, there was almost no cytotoxicity against KG1a. T cell proliferation was proportional to cytotoxicity in these assays, with much larger increases in proliferating cells apparent with KG1 target cells. There was little or no detectable AMV564 binding or killing of autologous monocytes or neutrophils. The AMV564 binding assay is compatible with primary human samples and analysis of residual samples from patients enrolled in the phase 1 AML study is underway to assess the degree of CD33 clustering on leukemic blasts and associations with response. Conclusions AMV564 demonstrated a high degree of selectivity across the myeloid lineage in a novel binding assay using labeled drug, and there was little or no evidence of cytotoxicity against differentiated myeloid cells such as neutrophils and monocytes. Furthermore, significant differences in potency across AML blasts were observed, which could be further impacted by the available T cells. While AMV564 has demonstrated anti-leukemic activity across an unselected relapsed/refractory AML population, this novel assay could be used to select patients in whom blasts are expressing CD33 in a predominantly clustered configuration, and thus identify patients most likely to experience deeper and more durable responses with AMV564 monotherapy. Disclosures Sarde: Amphivena Therapeutics: Current Employment, Current equity holder in private company. Eckard:Amphivena Therapeutics: Current Employment, Current equity holder in private company. Mei:Amphivena Therapeutics: Current Employment, Current equity holder in private company. Ruegg:Amphivena Therapeutics: Current Employment, Current equity holder in private company. Chun:Amphivena Therapeutics: Current Employment, Current equity holder in private company. Smith:Amphivena Therapeutics: Current Employment, Current equity holder in private company.
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Opat, Stephen, Robert Marcus, Craig A. Portell, William Reed, Chris Tankersley, Jane Huang, and Judith Trotman. "Phase 2 Study of Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Marginal Zone Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5256. http://dx.doi.org/10.1182/blood-2019-122629.
Повний текст джерелаАнотація:
Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including marginal zone lymphoma (MZL). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may be co-administered with strong or moderate CYP3A4 inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib has been generally well tolerated amongst patients with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1 study demonstrated responses in 7 of 9 patients with relapsed/refractory (R/R) MZL treated with zanubrutinib (Tam et al. ASH 2017); the remaining 2 patients had stable disease indicating an encouraging rate of overall disease control. Study Design and Methods: This ongoing global phase 2, single-arm, open-label study (MAGNOLIA; NCT03846427) is examining zanubrutinib monotherapy in patients with R/R MZL who have received 1 or more prior lines of systemic therapy (Figure). Eligible patients must have histologically confirmed diagnosis of MZL including splenic, nodal, and extranodal subtypes, have received prior anti-CD20 antibody therapy, and have measurable disease. Patients must have documented clinical need for therapy as well as adequate marrow and organ function. Patients are treated with oral zanubrutinib at 160 mg twice daily until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary efficacy endpoint is ORR according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014) measured by computed tomography and bone marrow assessment data as determined by an independent review committee (IRC). A 2-sided Clopper-Pearson 95% CI for ORR will be calculated. Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), overall survival, safety, and patient-reported outcomes. All patients are tested for the MYD88 mutation at study entry. Recruitment is ongoing. Disclosures Opat: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy. Marcus:Gilead: Consultancy; Roche: Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Other: Travel, Accommodations, Expenses; Roche-Genentech: Honoraria. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy. Reed:BeiGene: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Tankersley:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Trotman:Pharmacyclics: Research Funding; Roche: Research Funding; BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US
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De Franceschi, Lucia, Simona Sada, Annalisa Andreoli, Andrea Angheben, Stefania Marocco, and Zeno Bisoffi. "Sickle cell disease and hyperreactive malarial splenomegaly (HMS) in young immigrants from Africa." Blood 106, no. 13 (December 15, 2005): 4415–17. http://dx.doi.org/10.1182/blood-2005-08-3109.
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Ou, Ying, Kun Wang, Lucy Liu, Ashutosh Jindal, Yuying Gao, and Sri Sahasranaman. "Exposure-Response Relationship of the Bruton Tyrosine Kinase Inhibitor, Zanubrutinib (BGB-3111) in Patients with Hematologic Malignancies." Blood 134, Supplement_1 (November 13, 2019): 5063. http://dx.doi.org/10.1182/blood-2019-129580.
Повний текст джерелаАнотація:
Background: Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible inhibitor of Bruton tyrosine kinase (BTK), currently in phase 3 development for the treatment of hematologic malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM). In a dose escalation study evaluating doses of 40, 80, 160, and 320 mg once daily and 160 mg twice daily, no dose limiting toxicities were observed and maximum tolerated dose (MTD) was not established. Objective responses have been observed in patients with various B-cell malignancies (including CLL, MCL, WM) at all tested dose levels. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (Tam et al. Blood 2016;128:642). To support dose selection, this exposure-response (E-R) analysis evaluated exposure-safety and exposure-efficacy (in MCL) relationships in patients with B-cell malignancies receiving zanubrutinib monotherapy. Methods: A population pharmacokinetic (PopPK) model was developed from 600 subjects enrolled in 9 clinical studies in patients with B-cell malignancies and healthy volunteers. Exposure data such as steady-state area under the plasma concentration time curve (AUC0-24,ss), maximum observed plasma concentration (Cmax ) or steady state trough concentration (Cmin) derived from the PopPK analysis were used in the E-R analysis. Exposure-efficacy analyses were performed using exposure metrics and overall response rate (ORR) data from two studies in patients with relapsed/refractory (R/R) MCL (n=51), including Study 206, a pivotal Phase 2 study conducted in China and study AU-003, a global Phase 1, dose escalation/cohort expansion study. The efficacy endpoint evaluated was ORR, as assessed by an independent review committee (IRC) as well as by investigators, according to 2014 Lugano Classification. Exposure-safety analyses were conducted using data from 4 studies in patients with B-cell malignancies (n=372) receiving zanubrutinib as monotherapy at a total daily dose from 40 mg to 320 mg. The safety endpoints evaluated included Grade ≥ 3 adverse events (AE) and AEs of interests, including neutropenia, thrombocytopenia, anemia, infections/infestations, all events of secondary primary malignancies, all events of atrial fibrillation and flutter, major bleeding events, and any bleeding events. Results: PopPK analysis demonstrated that race, body weight, age, CrCL, sex, tumor type, and use of acid-reducing agents did not show a statistically significant impact on the PK of zanubrutinib. The PK profile of zanubrutinib was comparable between Asians and non-Asians, which allows for bridging of clinical efficacy and safety data across the pivotal studies conducted globally (AU-003) and in China (206). The analysis showed that the median AUC0-24,ss and Cmax values were 1736 ng·h/mL and 275 ng/mL in responders compared with 1326 ng·h/mL and 175 ng/mL in nonresponders, respectively. Although overall median exposure (AUC0-24,ss, Cmax) was higher in responders compared with nonresponders, no significant E-R relationship was identified for efficacy based on probability of observing ORR and logistic regression model (Fig 1). The E-R relationships based on investigator assessments were consistent with those based on IRC assessments. For the exposure-safety analysis, the exposure ranges were similar in patients experiencing adverse events of interests relative to those who were not. There were no evident E-R relationships between PK exposure (AUC0-24,ss, Cmax, or Cmin) and the probability to have adverse events of interest (eg., Fig. 2). Conclusion: E-R analyses indicate that higher plasma exposures of zanubrutinib were not associated with higher probability to have adverse events across the dose range of 40 mg to 320 mg in patients with B-cell malignancies. This result supports the recommended dose of 160 mg twice daily in patients with MCL, based on high rates of objective response in patients with R/R MCL, generally favorable safety and tolerability profiles, and complete and sustained BTK occupancy in PBMCs and target tissues at this dose. Disclosures Ou: BeiGene: Employment. Jindal:BeiGene: Employment. Sahasranaman:BeiGene: Employment, Equity Ownership.
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Debatin, KM, A. Fahrig-Faissner, S. Enenkel-Stoodt, W. Kreuz, A. Benner, and PH Krammer. "High expression of APO-1 (CD95) on T lymphocytes from human immunodeficiency virus-1-infected children [letter]." Blood 83, no. 10 (May 15, 1994): 3101–3. http://dx.doi.org/10.1182/blood.v83.10.3101a.3101a.
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Davi, G., C. Giammarresi, G. Vitale, and S. Mansueto. "Enhanced thromboxane biosynthesis in patients with Mediterranean spotted fever [letter; comment]." Blood 83, no. 10 (May 15, 1994): 3101. http://dx.doi.org/10.1182/blood.v83.10.3101b.3101b.
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Matsuda, Jennifer L., Qianjun Zhang, Rachel Ndonye, Stewart K. Richardson, Amy R. Howell та Laurent Gapin. "T-bet concomitantly controls migration, survival, and effector functions during the development of Vα14i NKT cells". Blood 107, № 7 (1 квітня 2006): 2797–805. http://dx.doi.org/10.1182/blood-2005-08-3103.
Повний текст джерелаАнотація:
AbstractVα14i natural killer T (NKT)–cell function has been implicated in a number of disease conditions. The molecular events that drive Vα14i NKT-cell development remain elusive. We recently showed that T-bet is required for the terminal maturation of these cells. Here we identify some of the genetic targets of T-bet during Vα14i NKT-cell lineage development. Microarray gene-expression analyses on developing Vα14i NKT cells were performed and provide a molecular framework to study these maturation events. In vitro ectopic expression of T-bet in immature Vα14i NKT cells, which do not yet express T-bet, was sufficient to promote Vα14i NKT-cell maturation, driving the expression of multiple genes, including those that participate in migration, survival, and effector functions. By regulating the expression of T-helper 1 (Th1)–associated cytokines, chemokines, chemokine receptors, and molecules involved in cytolysis, T-bet defines the unique lineage attributes of mature Vα14i NKT cells and acts to link these attributes to a developmental process.
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Calviño, Eva, M. Cristina Tejedor, Pilar Sancho, Angel Herráez та José C. Diez. "JNK and NFκB dependence of apoptosis induced by vinblastine in human acute promyelocytic leukaemia cells". Cell Biochemistry and Function 33, № 4 (23 квітня 2015): 211–19. http://dx.doi.org/10.1002/cbf.3105.
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Li, Shirong, Rentian Feng, Huihui Ma, G. David Roodman, Markus Y. Mapara, and Suzanne Lentzsch. "Lenalidomide Upregulates CXCR4 on CD34+ Hematopoietic Cells Resulting In Increased Binding to Bone Marrow Niche and Inhibiting Mobilization Into Peripheral Blood In Multiple Myeloma Patients." Blood 116, no. 21 (November 19, 2010): 4079. http://dx.doi.org/10.1182/blood.v116.21.4079.4079.
Повний текст джерелаАнотація:
Abstract Abstract 4079 Background: In multiple myeloma (MM), lenalidomide has impressive clinical activity in patients with both relapsed/refractory and newly diagnosed disease. Nevertheless hematopoietic stem cell transplantation (HSCT) is still the “backbone” in the treatment of newly diagnosed MM patients and very often lenalidomide treatment (as induction therapy) is combined with HSCT in order to achieve high response rates. Clinical data have shown that in up to 43% of those patients, standard mobilization of CD34+ cells with G-CSF alone failed to mobilize significant numbers of hematopoietic progenitors into peripheral blood, raising concerns about potential stem cell toxicity of lenalidomide (Mazumder et al, Leukemia 2008). Interestingly mobilization of hematopoietic progenitors with AMD-3100 (Plerixafor) overcomes mobilization failures in almost all patients previously treated with lenalidomide. The fact that AMD-3100 antagonizes the binding of chemokine stromal- cell–derived factor-1α (SDF-1α) to CXC chemokine receptor 4 (CXCR4) suggests a potential role of the CXCR4/SDF-1α axis in mediating mobilization failure after lenalidomide treatment. Subsequently, the findings noted above raised questions on: 1) the stem cell toxicity of lenalidomide; 2) the underlying mechanism that mediates the development of G-CSF resistance; and 3) the mechanism of the modulation of the CXCR4/SDF-1α axis by lenalidomide. In our previous work we showed the following. 1) Lenalidomide neither inhibited colony formation in standard colony assays nor the development of cobble stone area forming cells (CAFC) in LTC-IC assays, suggesting that lenalidomide is not stem cell toxic (Koh et al, Blood 2005). 2) We further showed that lenalidomide significantly upregulated G-CSF secretion of CD34+ cells (600%), suggesting that the high levels of G-CSF may mediate a relative resistance towards G-CSF-induced mobilization (Pal et al, Blood, 2010). Results and Methods: We analyzed why blocking CXCR4 by AMD-3100 overcomes mobilization failure to G-CSF. We first examined the CXCR4 expression profile of CD34+ cells treated with lenalidomide. Lenalidomide treatment significantly upregulated the expression of CXCR4 on cell surface after 48h treatment measured by flow cytometry. Increased expression of CXCR4 onCD34+ cells remained high with continuous treatment. Western blot assay of the hydrophobic (membrane) and the hydrophilic (cytosol) cell fraction confirmed our data showing that lenalidomide increases the expression of CXCR4 on CD34+ cell surface. Confocal microscopy showed that lenalidomide inhibited SDF-1α induced CXCR4 internalization. In accordance with the increased CXCR4 surface expression, transwell migration assay revealed that the SDF-1α-induced migration of CD34+ cells in the presence of lenalidomide significantly increased by 52% in comparison to control. Quantitation of SDF-1α showed that CXCR4 had no significant effect on the secretion of SDF-1α by CD34+ cells and in human stromal cells. Result: In conclusion, our data show that lenalidomide is not toxic to hematopoietic progenitors. The strong increase of G-CSF secretion by CD34+ cells might contribute to a desensitization of CD34+ cells to G-CSF mobilization. Primarily our data indicate that increased expression of CXCR4 followed by blocked internalization, increases binding to SDF-1α secreted by the bone marrow niche. This subsequently prohibits the mobilization of CD34+ cells. These data suggest that blocking the CXCR4 receptor by AMD-3100 disrupts this circle and finally permits the mobilization of hematopoietic cells from the bone marrow niche into peripheral blood. This study provides novel insights into the effects of lenalidomide on CD34+ cells relevant for HSCT in MM. Disclosures: Roodman: Amgen: Consultancy; Celgene Corp: Consultancy; Acceleron: Consultancy; Millennium: Consultancy. Mapara:Gentium: Equity Ownership. Lentzsch:Celgene Corp: Research Funding.
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Delgado, Elina, Charles F. LeMaistre, Carlos Bachier, Brad Smith, Guillermo López-González, Maureen Hougham, Shawn Kaleel, and Paul Shaughnessy. "Cost Analysis of Mobilization and Autologous Transplantation in Patients Who Received AMD 3100 after Failing Standard Mobilization." Blood 112, no. 11 (November 16, 2008): 2151. http://dx.doi.org/10.1182/blood.v112.11.2151.2151.
Повний текст джерелаАнотація:
Abstract AMD3100 administered with G-CSF has been demonstrated to mobilize hematopoietic stem cells in patients (pts) who do not collect sufficient cells for autologous transplant following other mobilization regimens. This retrospective study evaluated the difference in clinical outcomes and costs of mobilization and transplant between pts who achieved sufficient CD34+ cells to proceed to transplant using a standard mobilization regimen (control group) versus pts who had failed previous mobilization regimens and were remobilized with AMD3100 and G-CSF in the compassionate use protocol (CUP). Between 2005 and 2008, a total of 88 pts in the control group and 36 pts in CUP were evaluated. In the latter group, mobilization data were available for 35 pts, post-transplant care information was obtainable for 28 pts, and 23 pts had cost data. Prior mobilization attempts in this group included cyclophosphamide plus G-CSF (67%) or G-CSF alone (33%). Following AMD3100 administration, 33 (94%) pts achieved successful mobilization of > 1.9 million/kg CD34+ cells. A median of 3.36 x106 CD34+ cells/kg (range, 0.51–13.05) were collected in a median of 3 (range, 1–4) apheresis days. In comparison, control pts collected a median of 10.8 x106 CD34+ cells/kg (range, 1.95–69.32) in a median of 2 (range, 1–6) apheresis days. Twenty-eight CUP pts went on to transplant and received a median of 3.71 x106 CD34+ cells/kg (range, 1.91–13.05) compared to a median of 5.5 x106 CD34+ cells/kg (range, 1.95–18.76) infused into the control group. The CUP pts had a median day to ANC > 500/μl of 11 days (range, 9–17) and platelets > 20,000 /μl of 27 days (range, 13–37). At day 100, 92% of the CUP pts reached engraftment and there were no transplant related mortalities. The control population had a median day to ANC > 500/ ul of 11 days (range, 8–14) and platelets > 20,000/μl of 18 days (range, 9–83). The control group experienced 100% engraftment and one transplant related fatality. Relapse occurred in 14% of the CUP pts and 32 % of the control pts. With a median follow up of 385 days (range, 55–992) in the CUP pts and 560 days (range, 156–867) in the control pts, 86% of CUP pts and 91% of control pts are alive (p=NS). The median cost of remobilization with AMD3100 was $2,959 less in the CUP pts than the median cost of initial mobilization for the control group, but this was not significantly different between the groups. As expected, the median total cost of mobilization in the CUP pts, including initial mobilization costs, was $16,927 more than in the control pts (p<0.0001). Total cost of mobilization in the CUP pts does not include the cost of AMD3100 as drug was administered on study. In both groups of pts, greater than 95% of total transplant costs occurred in the first 30 days of the transplant course. The difference in the total median transplant costs at day 30 in the CUP pts was $7,373 more than in the control pts. (p=0.0024). The primary difference in cost between the groups was reflected in total inpatient costs; CUP pts incurred 91% of total costs and control pts 57% of total costs in the first 30 days. In conclusion, this single center review shows remobilization with AMD3100 + G-CSF allowed a high percentage of patients who failed standard mobilization to subsequently mobilize adequate CD34+ cells and proceed to autologous transplant with acceptable clinical outcomes. Pts who required remobilization also had an increased cost of transplantation because of increased inpatient costs. Additional pharmacoeconomic studies that compare the costs of utilizing AMD3100 in the first-line setting and comparing it to costs of cytokines with or without chemotherapy are warranted.
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Carelli-Alinovi, Cristiana, Bruno Giardina, and Francesco Misiti. "Amyloid beta peptide (1-42)-mediated antioxidant imbalance is associated with activation of protein kinase C in red blood cells." Cell Biochemistry and Function 33, no. 4 (April 23, 2015): 196–201. http://dx.doi.org/10.1002/cbf.3103.
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Park, Su-Jin, Jae Ho Park, Anna Han, Munkhtugs Davaatseren, Hyun Jin Kim, Myung-Sunny Kim, Haeng Jeon Hur, et al. "Euphorbiasteroid, a component ofEuphorbia lathyrisL., inhibits adipogenesis of 3T3-L1 cells via activation of AMP-activated protein kinase." Cell Biochemistry and Function 33, no. 4 (April 23, 2015): 220–25. http://dx.doi.org/10.1002/cbf.3107.
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Hailemichael, Yared, Zhimin Dai, Nina Jaffarzad, Yang Ye, Miguel A. Medina, Xue-Fei Huang, Stephanie M. Dorta-Estremera, et al. "Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion." Nature Medicine 19, no. 4 (March 3, 2013): 465–72. http://dx.doi.org/10.1038/nm.3105.
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Cooper, Todd Michael, Sharyn D. Baker, Jennifer Direnzo, Tanya M. Trippett, Lia Gore, Aru Narendran, Keith J. August, et al. "Chemosensitization and Mobilization Of AML/ALL/MDS With Plerixafor (AMD 3100), a CXCR4 Antagonist: A Phase I Study Of Plerixafor + Cytarabine and Etoposide In Pediatric Patients With Acute Leukemia and MDS." Blood 122, no. 21 (November 15, 2013): 2680. http://dx.doi.org/10.1182/blood.v122.21.2680.2680.
Повний текст джерелаАнотація:
Abstract Background The protection afforded to leukemic blasts by the bone marrow microenvironment has been identified as an important mechanism of chemoresistance. Interaction between stroma-derived growth factor-1 alpha (SDF-1α) and its receptor, CXC chemoreceptor 4 (CXCR4) are implicated in chemotaxis, homing, and survival/apoptosis of normal and malignant hematopoietic cells in the bone marrow. Preclinical data demonstrates that plerixafor (AMD3100), a CXCR4 antagonist, disrupts tumor-stroma interactions and mobilizes leukemia cells from their protective stromal environment. Combinations of CXCR4 antagonists with chemotherapy have demonstrated preclinical synergy. Chemosensitization using plerixafor prior to cytotoxic chemotherapy has been tested in adults with acute leukemia. We report the first Phase I study of plerixafor (NCT01319864) delivered prior to chemotherapy in children with relapsed/refractory acute leukemia and MDS. Study Design Patients > 3 and < 30 years of age with relapsed or refractory AML, ALL, MDS or mixed phenotype acute leukemia were eligible for enrollment. Plerixafor was administered intravenously (IV) once daily followed 4 hours later by cytarabine (1 gm/m2 every 12 hours) and IV etoposide (150 mg/m2 daily) for a total of 5 days of therapy. Plerixafor pharmacokinetic studies were performed on days 1 and 5. Correlative biology studies included measurement of peripheral blood mobilization of leukemic blasts by flow cytometry, quantitative expression of CXCR4 on leukemic blasts, and the change in surface expression of CXCR4 on residual blasts after course 1 of therapy. Results Eighteen evaluable patients (11 AML, 6 ALL, 1 MDS) were treated at 4 dose levels of plerixafor (6, 9, 12, and 15 mg/m2/dose) utilizing a Rolling 6 design. The median number of prior regimens was 2.8 (range 1-7) for ALL and 2.1 (range 1-4) for AML. Six patients had high risk cytogenetics (3 ALL, 2 AML, 1 MDS). Three patients with ALL and 4 with AML had prior hematopoietic stem cell transplant (HSCT). Toxicities were consistent with intensive relapsed leukemia regimens. The most common Grade 1 and 2 toxicities attributed to plerixafor occurring in >10% of patients were anorexia, nausea, vomiting, diarrhea, fatigue, and dizziness. There were no dose limiting toxicities and no delay in count recovery attributable to plerixafor. There were responses in 3 (2 complete response (CR), 1 complete response with incomplete hematologic recovery (CRi)) of 11 AML patients (27%) and no responses in those with ALL or MDS. Peripheral leukemia-specific blast counts (measured by flow cytometry before and 4 hours after the first dose of plerixafor) demonstrated mobilization of leukemic blasts in 14 of 16 patients with samples available, with median fold increase of 3.4 (range 1.3 to 17). The degree of leukemic blast mobilization correlated positively with quantitative leukemia blast surface CXCR4 protein expression (expressed as median fluorescence index relative to isotype control), with a Pearson’s correlation co-efficient of 0.56, p=0.02. Mean ± SD plerixafor AUC values at 12 and 15 mg/m2 were 5074 ± 380 and 5732 ± 573 ng*h/mL, respectively. Drug clearance was similar between days 1 and 5 (p=0.195). Conclusion The favorable safety profile of plerixafor and biologic rationale demonstrated in this clinical trial support further clinical study of chemosensitization using CXCR4 antagonists in overcoming chemoresistance. Disclosures: Off Label Use: Plerixafor is not approved for chemosensitization in the treatment of acute leukemia.
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Numata, Ayumi, Katsumichi Fujimaki, Naoto Tomita, Masatsugu Tanaka, Chizuko Hashimoto, Rika Oshima, Kenji Matsumoto, et al. "Retrospective Study of the Utility of Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 In Patients with Follicular Lymphoma Uniformly Treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristin, and Prednisone." Blood 116, no. 21 (November 19, 2010): 3100. http://dx.doi.org/10.1182/blood.v116.21.3100.3100.
Повний текст джерелаАнотація:
Abstract Abstract 3100 The Follicular Lymphoma International Prognostic Index (FLIPI) is the most useful prognostic index for follicular lymphoma (FL). FLIPI was developed from retrospective data, which was based on treatment without rituximab (R) therapy and did not contain β2-microglobulin data of some cases. Recently the working group that had suggested FLIPI proposed FLIPI2, based on prospectively collected data. However, FLIPI2 contains data on several different treatment methods, such as treatment with or without R therapy. The present study aimed to retrospectively analyze the prognosis of FL uniformly treated with the combination of R, cyclophosphamide, doxorubicin, vincristin, and prednisone (R-CHOP). This study involved 114 patients consecutively diagnosed with FL who were treated with R-CHOP and were registered in the data-base of the Yokohama City University Hematology Group between January 2001 and October 2009. All the parameters required for FLIPI and FLIPI2 calculation were present in 108 patients (men, 53; women, 55, median age; 57 years [34- 78 years]). The median follow-up period was 31.7 months (0.8- 97.5 months). According to the FLIPI score, 50 patients (46.3%) were in the high-risk group (HR); 31 patients (28.7%), the intermediate-risk group (IR); and 27 patients (25.0%), the low-risk group (LR). On the basis of the FLIPI2 score, 45 patients (41.7%) were in HR; 52 patients (48.1%), IR; and 11 patients (10.2%), LR. According to FLIPI, the 5-year overall survival (5yOS) was 74.1% (95% CI, 58.1– 94.4%) for HR, 89.5% (95%, CI, 76.6– 100%) for IR, and 100% for LR (p = 0.0049); the 5-year time to failure (5yTTF) was 42.3% (95% CI, 26.0– 68.9%) for HR, 39.1% (95% CI, 22.7– 67.3%) for IR, 66.4% (95% CI, 47.2– 93.4%) for LR (p = 0.244). According to the FLIPI2 score, 5yOS was 71.3% (95% CI, 53.2– 95.6%) for HR, 85.6 % (95% CI, 72.0– 100%) for IR, and 100% for LR (p = 0.197), the 5yTTF was 35.8% (95% CI, 20.0– 64.2%) for HR, 46.7% (95% CI, 31.1– 70.3%) for IR, and 76.2% (95% CI, 52.1– 100%) for LR (p = 0.075). In conclusion, in FL patients treated with R-CHOP, FLIPI provided a more accurate OS than that provided by FLIPI2; however, FLIPI2 provided a more accurate TTF than that provided by FLIPI. Disclosures: No relevant conflicts of interest to declare.
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Michaelis, Sebastian, Markus Mezger, Martin Bornhauser, Rudolf Trenschel, Gernot Stuhler, Matthias Stelljes, Lutz P. Mueller, et al. "KIR Haplotype B Donors but Not KIR-Ligand Mismatch Result in a Reduced Risk of Relapse After Haploidentical Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning and a CD3/CD19 Depleted Graft." Blood 120, no. 21 (November 16, 2012): 3101. http://dx.doi.org/10.1182/blood.v120.21.3101.3101.
Повний текст джерелаАнотація:
Abstract Abstract 3101 Natural killer (NK) cell alloreactivity, after allogeneic hematopoietic cell transplantation (HCT) is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and human leukocyte antigen (HLA) class I ligands on recipient cells. Recently, a positive influence of KIR haplotype B versus haplotype A donors on the outcome of HLA-matched allogeneic HCT was demonstrated (Cooley et al., Blood 2010). Previously, Ruggeri et al. (Science 2002) reported the positive influence of KIR-ligand mismatch (MM) on outcome of haploidentical HCT (HHCT). Here we investigated the influence of the donor KIR haplotype and KIR-ligand MM on relapse of 57 patients with hematologic malignancies receiving HHCT after reduced intensity conditioning and graft CD3/CD19 depletion. 36 patients with AML, eight with ALL, four with multiple myeloma, four with NHL and one with MCL, CML, CMML, MDS, CLL, respectively (median age 45 years, range 19–61 years) were evaluated. Patients were “high risk” because of relapse (n=8), prior HCT (n=23), refractory disease (n=20) or cytogenetic risk (n=6). At HHCT, 29 patients were in complete remission (CR) and 28 in partial remission (PR). 15 KIR genes were determined by real-time PCR as described (Vilches et al., Tissue Antigens 2007, Alves et al., Tissue Antigens 2009), and donors were assigned the A/A or B/x haplotype. Patients and donors were HLA-typed by high-resolution molecular methods. Of the 57 donors, 17 had KIR haplotype A (29.8%) and 40 KIR haplotype B (70.2%). A KIR-ligand MM was found in 34 of 57 patients (59.6%). Cumulative incidence adjusted for competing risk showed no difference between KIR haplotype A or B patients regarding non-relapse mortality (NRM) (Gray's test: p=0.200), but a significantly reduced incidence of relapse for patients with a haplotype B donor (p=0.001). In particular, patients in PR benefited more from a haplotype B graft (p=0.008) than patients in CR (p=0.297). This resulted in a trend in the Kaplan-Meier estimated event free (EFS) at 3 years of 26.8 % for KIR haplotype B and 11.7 % for KIR haplotype A (HR=1.33 [CI=0.66–2.70], log rank test: p=0.422). In detail, all patients in PR died within 1.2 years when haplotype A donor cells were transplanted whereas 25% of haplotype B recipients were still alive after 3 years (HR=1.27 [CI=0.49–3.30], p=0.631). In comparison, 16.6% of haplotype A and 28.1% of haplotype B recipients in CR survived for more than 3 years (HR=1.46 [CI=0.54–3.94], p=0681). Surprisingly, KIR-ligand MM cumulative incidence curves were not statistically different for relapse (p=0680) or NRM (p=0.579). In addition, KIR-ligand MM resulted in a trend for decreased EFS rate for MM patients (17.6%) in contrast to matched patients (33.7%; HR=1.47 [CI=0.89–2.75], p=0.230). These effects were even more pronounced when analyzing the patient cohort with AML. Of the 36 donors, 10 showed KIR haplotype A (27.8%), 26 KIR haplotype B (72.2%) and KIR-ligand MM was present in 25 patients (69.4%). EFS at 3 years was prolonged for KIR haplotype B graft recipients (EFS: HR=2.29 [CI=0.88–5.96], p=0.087). In addition, cumulative incidence adjusted for competing risk analysis revealed a reduced incidence of relapse for patients with a haplotype B donor (all AML patients: p=0.079, AML in PR: p=0.049), but not for NRM (all AML patients: p=0.806, AML in PR: p=0.674). Again, KIR-ligand MM cumulative incidence curves were not significantly different for both relapse (p=0.126) and NRM (p=0.535). In line, KIR-ligand MM led to decreased EFS rate for MM patients (16.0%) in contrast to matched patients (53.0%; HR=2.27 [CI=1.08–5.06], p=0.045). Taken together, in the setting of RIC and CD3/CD19 depleted HHCT we could not confirm the positive data with KIR-ligand MM but observed a significant lower risk of relapse with a KIR haplotype B donor. We therefore conclude from our results that a donor KIR B haplotype should be favored as donor for HHCT using RIC and CD3/CD19 depletion in patients with hematological malignancies, particularly if no complete remission has been achieved prior to HHCT. Disclosures: Off Label Use: off lable use of drugs for conditioning.
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Herbst, Friederike, Claudia R. Ball, Oksana Zavidij, Annika Mengering, Sylvia Fessler, Manfred Schmidt, Christof von Kalle, and Hanno Glimm. "Overexpression of EVI1 Causes Genomic Instability and Cell Cycle Arrest in Hematopoietic Cells." Blood 120, no. 21 (November 16, 2012): 2398. http://dx.doi.org/10.1182/blood.v120.21.2398.2398.
Повний текст джерелаАнотація:
Abstract Abstract 2398 Deregulated expression of the zinc finger transcription factor ecotropic viral integration site 1 (EVI1) is an independent poor prognostic marker for patients with acute myeloid leukemia. Moreover, we have recently shown that in clinical gene therapy of chronic granulomatous disease (cGD) the activation of this gene locus by strong promoter and enhancer elements within the gamma-retroviral vector LTR has led to clonal dominance and malignant transformation. Physiologically, EVI1 is essential for embryonic development and in regulating hematopoietic stem cell self-renewal. As very little is known about its molecular mechanism driving hematopoietic transformation towards leukemia, we aim to systematically analyze the role of deregulated EVI1 expression and its larger splice form MDS1/EVI1 in hematopoiesis. Lentiviral vector particles encoding for EVI1 (E) or MDS1/EVI1 (ME) and eGFP as marker protein were produced to stably overexpress the transgenes. Transgene expression was verified in myeloid HL60 cells by western blotting and immunofluorescence staining. Analysis of growth kinetics of human HL60 cells in suspension cultures revealed 1.5 – 3 folds lower cell counts of ME and E expressing cells as compared to eGFP control vector transduced cells. We further analyzed the expression of transferrin receptor CD71 which is mainly expressed on proliferating cells to promote iron uptake. Both, E and ME transduced cells, down-regulated CD71 during seven days in culture as compared to eGFP-transduced control cells. 64.2 ± 0.4% of ME cells and 31.1 ± 1.6% of E cells expressed CD71 compared to untransduced (97.4 ± 0.0%) and control vector cells (94.8 ± 0.8%) (p<0.001). For further analyzing the transgene effect on cell cycle activity, 3 populations with different intensity of transgene expression (negative, intermediate and high eGFP+ cells) were isolated. With raising ME expression a 5-fold decrease in the percentage of cells in sub-G1 phase but a 1.3-fold increase in the percentage of cells in G1/G0 phase of the cell cycle was detected. In the highly EVI1 expressing fraction 91.4% arrested in G1/G0 phase of the cell cycle (50.4% in G1/G0 phase in eGFP− E cells). Moreover, almost 1/3 of these transcription factor expressing cells (29.8 ± 8.3% of ME and 27.2 ± 1.6% of EVI1 positive cells) could be detected in G0 phase as compared to 5.0 ± 1.3% of control vector transduced cells. In human CD34+ hematopoietic cells, E and ME overexpression led to a decrease of eGFP+ cells from 8% at day 3 after transduction to 0.5 – 2.5% at day 14 in suspension culture. In contrast, the proportion of eGFP+ human primary cells remained stable for the time period analyzed after transduction with the control vector. We then asked if the cell cycle arrest in G0/G1 is associated with genetic instability, as patients with insertional activation of EVI1 developed a myelodysplastic syndrome with monosomy 7. Analyzing global gene expression comparing mock and eGFP control vector transduced cells with EVI1 expressing hematopoietic cells revealed more than 2000 differentially regulated genes. Genes involved in cell cycle regulation, recombination, replication and DNA repair were significantly downregulated upon EVI1 expression compared to control cells. For further studying DNA damage repair capacity, we irradiated EVI1- and eGFP-control vector transduced cells. Staining of γ-H2AX, an indirect marker for DNA double strand breaks (DSB), revealed that EVI1+ γ-H2AX+ cells were enriched almost 2-fold in G0/G1 phase of the cell cycle as compared to control vector transduced cells. The number of DSB positive cells decreased within 6 hours without apoptosis indicating that most of the double-strand breaks were repaired by non-homologous end-joining. In summary, our data show that EVI1 overexpression causes G0 cell cycle arrest of hematopoietic cells possibly associated with genetic instability. DSB repair in EVI1+ cells may subsequently lead to the accumulation of additional mutations. Systematic investigation of EVI1 and MDS1/EVI1 overexpression in human hematopoietic cells will gain insights into mechanisms leading to clonal dominance and malignant transformation. Disclosures: No relevant conflicts of interest to declare.
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Tam, Constantine S., Michael Wang, David Simpson, Stephen Opat, Gavin Cull, Javier Munoz, Tycel J. Phillips, et al. "Updated Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 1592. http://dx.doi.org/10.1182/blood-2018-99-117224.
Повний текст джерелаАнотація:
Abstract Background: Investigational Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity vs other TEC and EGFR family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642). A recent update of clinical data suggested that complete and sustained 24-hour BTK occupancy is associated with durable responses in patients with non-Hodgkin lymphomas (Tam et al. Blood 2017;130:152). Here, we present updated safety and efficacy data from patients with mantle cell lymphoma (MCL). Methods: Study AU-003 is a global, open-label, multicenter, phase 1b trial investigating zanubrutinib in patients with B-cell malignancies. After dose escalation, the expansion phase enrolled disease specific cohorts at the recommended phase 2 dose of zanubrutinib (320 mg/day once daily or 160 mg bid). Treatment emergent adverse events (TEAEs) were summarized according to NCI CTCAE v4.03 and response was assessed per International Conference on Malignant Lymphoma criteria (Cheson et al. J Clin Oncol 2014;32:3059). Positron-emission tomographic (PET) scan was not required for response assessment. Results: As of 28 Feb 2018, 43 patients were enrolled: 38 relapsed/refractory and 5 treatment-naïve (Table). Median follow-up was 10.3 months (range, 0.1-39.2). Twenty patients have discontinued treatment (12 due to progressive disease; 8 due to TEAEs). Most common TEAEs of any cause (≥15% of patients) included diarrhea (30.2%), petechiae/purpura/contusion (30.2%), upper respiratory tract infection (27.9%), constipation (18.6%), fatigue (18.6%), and rash (16.3%). Two cases of atrial fibrillation/flutter (4.7%) and 3 cases of major hemorrhage (7.0%; renal hematoma, gastrointestinal hemorrhage, and tumor hemorrhage, all grade 3) were reported. Most common grade ≥3 TEAEs of any cause (≥2 patients) included anemia (7.0%), cellulitis (7.0%), pneumonia (7.0%), myalgia (7.0%), neutropenia (4.7%), back pain (4.7%), peripheral edema (4.7%), hypertension (4.7%), and acute kidney injury (4.7%). Fourteen patients experienced ≥1 serious TEAE (SAE) of any cause; SAEs occurring in >1 patient included pneumonia (7.0%) and cellulitis (4.7%). Nine TEAEs led to discontinuation of zanubrutinib in 8 patients: pneumonia, cognitive disorder, antineutrophil cytoplasmic antibody-positive vasculitis and acute kidney injury (same patient), joint effusion, and myelodysplastic syndrome; 3 of the 9 were fatal TEAEs designated by the investigator as unrelated to zanubrutinib including pneumonia, congestive cardiac failure, and cerebral infarction. Three patients who had not yet reached their first response assessment were not evaluable for response. As shown in the Table, overall response rate was 90.0% (n=36/40) including 20.0% (n=8) with complete response. Response was based on computed tomography (CT) scan alone for the majority of patients as PET was not required. The 4 non-responders included 1 with progressive disease, 1 with stable disease, and 2 patients who discontinued because of TEAEs (pneumonia, congestive cardiac failure) before the first response assessment. Median progression-free survival was 18.0 months (Table, Figure). Conclusions: Zanubrutinib monotherapy was demonstrated to be highly active in patients with relapsed/refractory MCL, with a safety profile consistent with that of previous reports of zanubrutinib. Disclosures Tam: Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding. Wang:MoreHealth: Consultancy; Novartis: Research Funding; Dava Oncology: Honoraria; Kite Pharma: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Simpson:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Research Funding; BeiGene: Research Funding; Merck: Honoraria, Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria. Opat:Gilead: 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, Other, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Amgen: Research Funding; Mundipharma: Honoraria; Beigene: Other: Clinical Trial Support; Epizyme: Other: Clinical Trial Support; Merck & Co., Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support and travel expenses; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Munoz:Alexion: Consultancy; Kite: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Juno: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Honoraria; Bayer: Consultancy, Speakers Bureau; Genentech: Consultancy, Honoraria. Phillips:Gilead: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Consultancy. Kim:Novartis: Research Funding; Roche: Research Funding; Celltrion: Research Funding; Takeda: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; J&J: Research Funding. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Trotman:PCYC: Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding.
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Dedeken, Laurence, Phu-Quoc Le, Nadira Azzi, Cecile Brachet, Catherine Heijmans, Sophie Huybrechts, Christine Devalck, Ngalula Mujinga Malou, and Alina Ferster. "Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Childhood: A Single Center Experience with 45 Patients." Blood 118, no. 21 (November 18, 2011): 3103. http://dx.doi.org/10.1182/blood.v118.21.3103.3103.
Повний текст джерелаАнотація:
Abstract Abstract 3103 Despite improvement in medical management, sickle cell disease (SCD) is still associated with high risk of morbidity, chronic disability and early death. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative approach. Since November 1988, 45 patients (median age: 8.3 years; range: 1.7–15.3 years) with severe SCD underwent related HSCT in our unit. Thirty-five received bone marrow transplant, 3 cord blood, 6 bone marrow and cord blood and 1 peripheral blood stem cells. Two donors result from preimplantation genetic diagnosis with HLA selection. All were HLA-identical sibling except one who had one class II mismatch. All had one or more severe manifestations: 24 patients presented more than 2 vaso-occlusive crises per year, 11 recurrent acute chest syndrome, 19 cerebral vasculopathy and 4 erythroid alloimmunisation. Conditioning regimen consisted of the standard combination of busulfan, cyclophosphamide and from November 1991 antithymocyte globulins (ATG) were added: ATG Fresenius first and from July 2000 ATG Merieux. Since 1995 all patients were treated with hydroxyurea (HU) prior to transplantation for a median duration of 2.7 years (range: 0.8–10.7 years). Acute graft versus host disease (GVHD) was observed in 11 patients (3 grade III and 2 grade IV). Ten patients were treated for CMV reactivation and 4 for EBV reactivation. Only one patient had presented a probable invasive fungal disease. After median follow-up of 6.5 years, 10 patients had presented chronic GVHD, none was extensive. Only one required therapy beyond 2 years from transplant. Engraftment was successful in 42/45. One rejection occurred 15 months after transplantation. Since HU introduction before transplant (1995), no graft failure occurred. Important mixed chimerism is present in 2 patients (AA donor) who remain free of any sickle cell disease symptoms. Two deaths occurred: 1 unexplained death 6 years after HSCT in a child free of any treatment and 1 cerebral hemorrhage 18 days after transplant in a child with severe cerebral vasculopathy. Growth was normal after transplant. As expected, gonadal function was impaired in the majority of girls. However 3 girls had spontaneous normal puberty and one had two spontaneous pregnancies with normal outcome. Our results are very encouraging showing excellent outcomes. Both the overall survival (OS: 95.6%) and the event-free survival (EFS: 86.7%) are comparable to the other published studies, ranging from 93 to 97%, and 82 to 86 % respectively. Since 1995, all the 33 patients engrafted successfully. Previous treatment with HU may have contributed to successful engraftment. After 5.3 years of follow-up, their OS and EFS are both at 96.9%. The difference in outcome before and after 1995 is strongly significant for EFS (58.3% vs 96.9%, p=0.003). Severe cerebral vasculopathy with its risk of CNS hemorrhage remains a true challenge. Disclosures: No relevant conflicts of interest to declare.
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Schnurr, Max, Qiyuan Chen, Amanda Shin, Weisan Chen, Tracey Toy, Corinna Jenderek, Simon Green, et al. "Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery." Blood 105, no. 6 (March 15, 2005): 2465–72. http://dx.doi.org/10.1182/blood-2004-08-3105.
Повний текст джерелаАнотація:
AbstractDendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.
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Chen, Christiane I., Holden T. Maecker, Rhoda Falkow, and Peter P. Lee. "Disturbed NK Cell Compartment in CML Patients with Anti-Leukemia Immune Responses Under Treatment with Imatinib Mesylate." Blood 112, no. 11 (November 16, 2008): 3202. http://dx.doi.org/10.1182/blood.v112.11.3202.3202.
Повний текст джерелаАнотація:
Abstract Imatinib mesylate has revolutionized the treatment of CML and, as an oral agent with few side effects, became the first-line therapy for patients with CML. However, patients who discontinue the drug invariably relapse. Currently, the only curative treatment for CML is allogeneic stem cell transplantation (ABMT). A major mechanism of ABMT is immunological as evidenced by the poor clinical outcome with T cell-depleted ABMT. To determine anti-leukemia immune responses in patients in remission on imatinib, blood and bone marrow samples before (12 samples) and serially after treatment (59 samples, range 10 months – 35 months) were collected and analyzed. The NK cell (CD56+CD3−) compartment in the 12 CML patients were significantly decreased before treatment (median 3,4 % vs 10 %, p<0.01) and remained low in patients in remission on imatinib (5 % vs 10 %, p< 0.01) compared to 32 age matched healthy donors. Within the CD8+ T cell compartment, naïve T cells (CD45+CD27+) were significantly higher before treatment (55.5 % vs 37.7 %, p=0.04) and decreased slowly to normal levels after successful treatment (41.5 % vs 37.7 %, p=0.28), whereas memory (CD45−CD27+) T cells presented the opposite way. They were significantly lower before treatment (21.7 % vs 31.1 %, p=0.03) and increased slowly to normal levels after successful treatment (27.5 % vs 31.1 %, p=0.39). However, the percentage of T cells (CD4+, CD8+, CD4+CD25+ regulatory T cells) and B cells were not significantly different. These results correlated (p<0.01) with T cell responses to autologous leukemia cells at the same time points, analyzed by IFN-g ELISPOT assay (median 36 SFCs vs 5 SFCs, p<0.01), and were confirmed by cytokine flow cytometry (IFN-g 3.6 % vs 0.29 % and TNF-a 6.6 vs 0.1 %). These results suggest that a significant portion of CML patients in remission with imatinib develop an anti-leukemia T cell response, whereas the NK cell compartment is disturbed. Mechanisms by which imatinib treatment leads to anti-leukemia immune responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge will be useful in the development of immunotherapy strategies against CML and may, in combination with imatinib, lead to eradication of residual leukemia cells for a durable cure.
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Verheyden, Sonja J., Michel Bernier, and Christian J. Demanet. "Identification of Natural Killer Cell Receptor Phenotypes Associated with Leukemia." Blood 104, no. 11 (November 16, 2004): 2997. http://dx.doi.org/10.1182/blood.v104.11.2997.2997.
Повний текст джерелаАнотація:
Abstract Introduction: Natural Killer (NK) cells play a key role in defense against tumor cells that have the capacity to downregulate Human Leukocyte Antigen (HLA) class I expression. It has been reported that leukemic cells can have down-regulated expression of HLA class I molecules. Apparently, the NK cells of these patients are not able to destroy these leukemic cells and may allow malignant cells to escape from innate immune control. This failure may be due to the fact that NK cells are part of the malignant clone and therefore might have a decreased function. An alternative hypothesis could be that these patients may display a NK cell Receptor (NKR) genotype incapable of destroying leukemic cells with aberrant expression of HLA class I molecules. The polymorphic nature of the NKR genes generates diverse repertoires in the human population, which display specificity in the innate immune response. Materials and Methods: In the present study, 11 Killer cell Immunoglobulin-like Receptor (KIRs) and 2 CD94/NKG2 receptors were genotyped by PCR-SSP in 96 leukemic patients and 148 healthy Caucasians. Results and Conclusion: We report a significant increased frequency of the more inhibitory AB KIR phenotype in leukemic patients compared to the controls (31.1% in healthy controls vs. 51.0% in leukemic patients, Pc = 0.002), which is related to the high prevalence of the inhibitory KIR2DL2 in this population (Pc = 0.007). Moreover, two specific KIR phenotypes AB1 and AB9, including all inhibitory KIRs, were significantly associated with leukemic patients. Our study suggests that an important percentage of leukemic patients express a KIR phenotype in favor of escape from NK cell immunity.
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Fowler, Nathan H., Judith Trotman, Rebecca Auer, Christopher R. Flowers, William F. Reed, Elena Ivanova, Jane Huang, and Pier Luigi Zinzani. "Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)." Blood 134, Supplement_1 (November 13, 2019): 5252. http://dx.doi.org/10.1182/blood-2019-122628.
Повний текст джерелаАнотація:
Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. First generation BTK inhibitor ibrutinib has limited activity as monotherapy in R/R FL (Gopal et al. J Clin Oncol 2018). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. In preclinical studies, zanubrutinib had minimal inhibitory effects against ITK and did not inhibit ITK-mediated anti-CD20-induced antibody-dependent cell-mediated cytotoxicity (Li et al. Cancer Res 2015). Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma (NHL), Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib was generally well tolerated amongst pts with B cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1b dose-escalation study including 36 pts with R/R FL (median 2 [range, 1-9] prior lines of therapy) treated with the combination of zanubrutinib with anti-CD20 antibody obinutuzumab reported an overall response rate (ORR) of 72.2% including complete response in 14 pts (38.9%); median progression-free survival was 24.9 mo (Tam et al. ICML 2019). Study Design and Methods: This ongoing phase 2, global, randomized, open-label, active-controlled study (ROSEWOOD; NCT03332017) is examining zanubrutinib + obinutuzumab vs. obinutuzumab monotherapy in pts with R/R FL who have received ≥2 prior lines of therapy (Figure). Eligible pts must have histologically-confirmed grade 1-3a B-cell FL and measurable disease, and have received prior anti-CD20 antibody and alkylator-based combination therapy. Pts are randomized 2:1 to receive oral zanubrutinib 160 mg twice daily + obinutuzumab or obinutuzumab alone (both arms in 28-day cycles, at 1000 mg IV on days 1, 8, and 15 of cycle 1; day 1 of cycles 2-6; and then once every 8 weeks) until progressive disease (PD), toxicity or a maximum of 30 mo of obinutuzumab. Pts receiving zanubrutinib should remain on study treatment until PD. Randomization is stratified by prior therapies (2-3 vs >3) and rituximab-refractory status. Disease response is assessed per the 2014 Lugano Classification for NHL. The primary endpoint is ORR by independent review committee (IRC). Response rates will be compared between groups in an intent-to-treat analysis. Key secondary endpoints include ORR by investigator assessment, rate of complete response or complete metabolic response, time to and duration of response, progression-free survival (all IRC and investigator assessments), overall survival, and safety. At the investigator's discretion, pts in the obinutuzumab arm can cross over to the combination arm if they have PD at any time or less than partial response after 12 mo. Recruitment is ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trotman:Celgene: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Janssen: Research Funding. Auer:Hartley Taylor: Honoraria; Janssen: Honoraria, Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees; Celgene: Other: personal fees. Flowers:TG Therapeutics: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; V Foundation: Research Funding; BeiGene: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Optimum Rx: Consultancy; Eastern Cooperative Oncology Group: Research Funding. Reed:BeiGene: Employment, Equity Ownership, Other: Travel & Accommodations. Ivanova:BeiGene: Employment. Huang:BeiGene: Employment, Equity Ownership. Zinzani:TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US
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Shen, Jessica, Naritsara Wongtong, Denis Noubouossie, Laila Elsherif, Qingning Zhou, Jianwen Cai, and Kenneth I. Ataga. "Lack of Difference in Hepcidin Levels in Sickle Cell Anemia and Sickle Cell Beta Thalassemia." Blood 126, no. 23 (December 3, 2015): 4591. http://dx.doi.org/10.1182/blood.v126.23.4591.4591.
Повний текст джерелаАнотація:
Abstract Introduction: Sickle cell disease (SCD) may be associated with iron overload following repeated RBC transfusions. In beta thalassemia major, a disease characterized by hemolysis and ineffective erythropoiesis, iron overload occurs due to both repeated RBC transfusions and hyperabsorption of iron. Hyperabsorption of iron occurs due to ineffective erythropoiesis and subsequent downregulation of hepcidin, the main regulator of systemic iron homeostasis. With the presence of a thalassemia gene, HbSβ-thalassemia patients may have an increased tendency to hyperabsorb iron compared to HbSS patients. The purpose of this exploratory study was to compare hepcidin levels in HbSS and HbSβ-thalassemia as well as the levels of GDF-15 and any associations between hepcidin and ferritin, other measures of iron balance, erythropoietin and markers of inflammation. Methods: Eligible patients with HbSS or HbSβ-thalassemia (HbSβ0-thalassemia or HbSβ+-thalassemia) were evaluated during routine clinic visits. Hepcidin, GDF -15 and erythropoietin were analyzed using commercially available ELISA kits, while plasma cytokines were analyzed by Luminex® multi-analyte profiling technology. Complete blood counts, serum iron, transferrin, transferrin saturation and ferritin, high-sensitivity CRP and routine chemistries were performed at the clinical laboratories of UNC Hospitals. Patients' clinical data, including SCD-related clinical complications and estimates of the number of lifetime RBC transfusions, were obtained at the time of evaluation combined with reviews of their medical records. The levels of hepcidin and GDF-15 were compared in HbSS and HbSβ-thalassemia (and SCD vs. healthy controls) using Wilcoxon rank sum tests, and the association of hepcidin and laboratory covariates was evaluated using Spearman correlation coefficient. Reported p-values are for individual tests, unadjusted for multiple comparisons. Results: Baseline demographic variables were similar in HbSS and HbSβ-thalassemia patients, but platelet counts, lactate dehydrogenase, total bilirubin, direct bilirubin, indirect bilirubin, aspartate transaminase and alkaline phosphatase were significantly higher in HbSS patients (Table 1). No significant differences were observed when hepcidin levels were compared between control subjects (N = 15) and SCD patients (N = 40) (25.2 ± 14.3 ng/mL vs. 19.5 ± 17.3 ng/mL, p = 0.13). In addition, no difference was observed in hepcidin levels (16.1 ± 11.4 ng/mL vs. 23.7 ± 22.2 ng/mL, p = 0.53) or GDF-15 levels (1635.1 ± 1357.7 pg/mL vs. 2051 ± 2385.4 pg/mL, p = 0.9) when HbSS patients were compared with HbSβ-thalassemia. Hepcidin was associated with ferritin (r= 0.57, p = 0.0001) and transferrin (r = -0.46, p = 0.0029) in SCD patients. However, no significant correlations were observed between hepcidin and erythropoietin, high sensitivity CRP, IL-6, IL-8, IL-10 and TNFα. Conclusion: No differences in hepcidin levels were observed in SCD patients compared with healthy controls, and in HbSS patients compared with HbSβ-thalassemia patients. We confirm the association of hepcidin with ferritin, but surprisingly find no association of hepcidin with IL-6. Table 1. Baseline Variables Variable HbSS (N = 22)Mean ± SD (or %) HbSβ-thalassemia (N = 18)Mean ± SD (or %) 95% CI for Mean Difference Age (years) 37.96 ± 12.7 36.4 ± 11.4 (-6.2,9.2) Gender (females) 15 (68.2) 12 (66.7) Weight (kg) 70.8 ± 15.1 74.7 ± 14.8 (-13.7,5.9) Transfusions 0 - 5 6 - 10 11 - 20 21 - 50 9 (23.1) 5 (12.8) 5 (12.8) 2 (5.1) 11 (28.2) 3 (7.7) 3 (7.7) 1 (2.6) White Blood Cell Count (× 109/L) 9.5 ± 3.1 9.4 ± 3.1 (-1.9,2.04) Hemoglobin(g/dL) 9.4 ± 1.7 10 ± 1.99 (-1.7,0.6) Platelet Count (× 109/L) 402.6 ± 134.9 310.1 ± 151.6 (1.8,183.1) Ferritin (ng/mL) 346.3 ± 406.9 174 ± 257.7 (-50.3,395) Reticulocyte Count (× 109/L) 233.5 ± 139.9 215.7 ± 138.9 (-71.8,107.6) Lactate Dehydrogenase (U/L) 954.3 ± 322.95 720.4 ± 174.2 (73.8,394) Total Bilirubin (mg/dL) 3.9 ± 3.1 1.4 ± 0.9 (1.2,3.9) Direct Bilirubin (mg/dL) 0.56 ± 0.5 0.3 ± 0.1 (0.04,0.48) Indirect Bilirubin (mg/dL) 3.3 ± 2.8 1.06 ± 0.8 (1.03,3.5) Aspartate Transaminase (U/L) 46.5 ± 18.8 32.8 ± 11.9 (3.4,23.9) Alanine Transaminase (U/L) 30.7 ± 13.5 28.7 ± 9.7 (-5.6,9.6) Alkaline Phosphatase (U/L) 110.6 ± 45.6 78.1 ± 24.7 (9.7,55.3) Creatinine (mg/dL) 0.67 ± 0.17 1.1 ± 1.25 (-1.07,0.18) Disclosures No relevant conflicts of interest to declare.