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  • 1
    Language: English
    In: The New England journal of medicine, 2016-01-07, Vol.374 (1), p.43-53
    Description: Antilymphocyte globulin (ATG) added to the conditioning regimen before allogeneic hematopoietic stem-cell transplantation resulted in a lower rate of chronic graft-versus-host disease at 2 years than the rate without ATG (32% vs. 68%), with no apparent increased risk of relapse. Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic stem-cell transplantation that results in later illness and death and a reduction in quality of life. 1 , 2 Risk factors for chronic GVHD are the use of peripheral blood as a source of stem cells, a history of acute GVHD, and the use of donated stem cells with high numbers of T cells. 3 – 7 In a meta-analysis, the Stem Cell Trialists’ Collaborative Group reported an incidence of extensive chronic GVHD of 47% after peripheral-blood stem-cell transplantation from an HLA-identical sibling. 4 In 2012, more than 70% of the stem-cell transplantations performed in . . .
    Subject(s): Graft vs Host Disease - epidemiology ; Prospective Studies ; Humans ; Immunosuppressive Agents - therapeutic use ; Middle Aged ; Proportional Hazards Models ; Child, Preschool ; Male ; Survival Rate ; Transplantation, Homologous ; Incidence ; Young Adult ; Disease-Free Survival ; Graft vs Host Disease - mortality ; Adolescent ; Antilymphocyte Serum - therapeutic use ; Adult ; Female ; Graft vs Host Disease - prevention & control ; T-Lymphocytes - immunology ; Child ; Chronic Disease ; Prevention ; Treatment outcome ; Graft versus host reaction ; Immunoglobulins ; Dosage and administration ; Analysis ; Graft-versus-host reaction ; Transplants & implants ; Leukemia ; Stem cell transplantation ; Lymphocytes T ; Preventive medicine ; Hemopoiesis ; Globulins ; Risk assessment ; Peripheral blood ; Stem cells ; Bone marrow ; Histocompatibility antigen HLA ; Index Medicus ; Abridged Index Medicus
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Single Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: Reviews of infectious diseases, 1990-01-01, Vol.12 (Supplement_2), p.S157-S160
    Description: The currently accepted empiric antibiotic therapy for bacterial infections in neutropenic patients may not cover the possibility of capnophilic and anaerobic bacteremia. Many of these infections develop in patients with severe mucositis or periodontitis, and the type of organisms recovered also suggests an oral source of infection. We present two cases of bacteremia in neutropenic patients who had been empirically treated with ceftazidime and piperacillin plus amikacin. In the first case a β-lactamase-producing strain of Capnocytophaga ochracea was isolated; in the second case bacteremia was due to a mixture of Leptotrichia buccalis and Fusobacterium nucleatum. These observations emphasize the necessity for a reevaluation of the possible use of antimicrobial agents active against β-lactamase-producing capnophilic organisms and anaerobic bacteria during empiric therapy in neutropenic patients with an oral source of infection.
    Subject(s): Mucositis ; Microbiology ; Antibiotics ; Antimicrobials ; Penicillin ; Leptotrichia ; Infections ; Pathogenesis and Immune Mechanisms of Anaerobic Infections ; Capnocytophaga ; Bacteremia ; Blood ; Biological and medical sciences ; Infectious diseases ; Medical sciences ; Bacterial diseases ; Sepsis - etiology ; Bacteroidaceae - drug effects ; Humans ; Fusobacterium Infections - microbiology ; Male ; Capnocytophaga - isolation & purification ; Capnocytophaga - drug effects ; Fusobacterium Infections - etiology ; Cytophagaceae - isolation & purification ; Fusobacterium - drug effects ; Neutropenia - complications ; Bacteroidaceae - isolation & purification ; Adult ; Female ; Agranulocytosis - complications ; Fusobacterium Infections - complications ; Sepsis - microbiology ; Fusobacterium - isolation & purification ; Index Medicus
    ISSN: 0162-0886
    ISSN: 1058-4838
    E-ISSN: 1537-6591
    Source: Oxford Journals 2016 Current and Archive A-Z Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Blood, 2014-12-06, Vol.124 (21), p.5785-5785
    Description: Abstract Background and Objectives: Recently, knowledge of the specific genetic markers responsible for cancer malignancies and their associated signaling pathways have generated many new targets that promise to increase drug efficacy while reducing side effects such as hematotoxicity. Although hematotoxicity is widely assumed to be the result of depleting hematopoietic progenitors, in particular myeloid progenitors, there are no assays to test new compounds in bone marrow samples to investigate this effect. Because these effects are patient-specific, an assay that identifies those patients risk of severe hematotoxicity by certain treatments could help personalizing patient treatment. Here, we show the ability of our flow cytometry-based automated Exvitech© platform to measure depletion analysis of different subsets of CD34+ progenitors and other cell subsets to potentially establish a new assay to screen drug candidates and combinations for hematotoxicity, as well as personalizing therapy to the individual sensitive patient at risk. So that in multiple myeloma (MM) we can identify at the same time CD34+ cells and pathological plasma cells; we could actually measure depletion of both malignant cells and progenitor cells on the same patient sample. Patients and methods: 16 normal bone marrow (NBM) and 4 MM samples were studied. For a proof of concept to test the hypothesis, we have selected two known cytotoxic drugs (cytarabine and clofarabine: N=10NBM) and two novel drugs with low expected cytotoxicity (ruxolotinib and volasertib: N=6NBM). The whole sample was plated into 96-well assay plates containing 8 concentrations of each drug and incubated for 48-hours for NBM and 12h with Bortezomib for MM samples. A multiple staining (CD45v450/Anexin-FITC/CD117-PE/CD34PerCP/CD38APC/CD19APCya7) was used to distinguish between both populations. Drug response was evaluated as a depletion survival index of each cell population relative to the average of 6 control wells in each plate. Results: As expected, nucleoside induces hematotoxicity in most of the studied NBM samples, but not all. Results reflect that cytarabine has similar activity than clofarabine in terms of efficacy (Ymax: 30% vs 23%) but with less potency (EC50: 6µM vs 0.2µM) in the immature population (N=10; Figure 1). This reflects a lower hematological toxicity which is consistent with clinical practice. Interestingly, for both drugs there is a large range of inter-patient variability inside this population in terms of efficacy (cytarabine, range Ymax: 4%-75% and clofarabine, range Ymax: 10%-37%) and potency (cytarabine, range EC50: 1µM-14µM and clofarabine, range EC50: 0.01µM-2µM) suggesting that in a subsets of vulnerable patients, drug doses could be tailored. By contrast, ruxolitinib and volasertib had little effect (Ymax: 80% vs 73%) in the immature population with minimal interpatient variability confirming the low toxicity expected for these novel drugs even at very high concentrations never achieve in vivo (Figure 1). Figure 2 shows bortezomib activity in MM bone marrow samples measuring both the dose response on malignant and myeloid progenitor cells. For Patient 1 the drug depletes myeloid precursor at lower doses than malignant cells, suggestive of severe hematotoxicity before therapeutic benefit can be achieved. Patient 2 shows the opposite case, where bortezomib depletes malignant cells completely without depleting myeloid precursors, suggestive of a good therapeutic index for this individual patient. Conclusions: These preliminary results show that Vivia Exvitech© platform is able to measure hematopoietic progenitors depletion in addition to other cell populations for novel drugs or before patientxs treatment that could contribute to a more selective drug development or a better clinical management of patients. This approach enables screening for hematotoxicty potential new discovery compounds, new drug candidates, and their synergistic combinations, thus supporting drug discovery and development. This assay could be helpful to both hematological and solid tumor drugs. The platform can measure both malignant and progenitor cells in bone marrow samples of MM and Non Hodgkin's Lymphoma. This simultaneous analysis shown for bortezomib could help guiding the clinical response and possible hematological toxicities associated to drug treatments. Figure 1: Figure 1:. Figure 2: Figure 2:. Disclosures Primo: Vivia Biotech: Employment. Ballesteros:Vivia Biotech: Employment. Robles:Vivia Biotech: Employment. Gorrochategui:Vivia Biotech: Employment. Garcia:Vivia Biotech: Employment. Hernandez:Vivia Biotech: Employment. Martinez:Vivia Biotech: Membership on an entity's Board of Directors or advisory committees.
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
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  • 4
    Language: English
    In: Blood, 2012-11-16, Vol.120 (21), p.4599-4599
    Description: Abstract Abstract 4599 Objective: To prospectively analyze change over time in minimal residual disease (MRD) in a cohort of 84 untreated patients diagnosed with CD20+ B-CLL who received from October 2007 to December 2010 six cycles of R-FC (Rituximab 375 mg/m2 IV in cycle 1 and 500 mg/m2 in cycles 2–6; F: 25 mg/m2, and C: 250 mg/m2 on days 1–3; every 28 days). Patients who achieved response were treated with rituximab 375 mg/m2 every 2 months for 3 years. Materials and methods: EDTA-anticoagulated peripheral blood (PB) and bone marrow (BM) samples were taken at diagnosis, after 3 and 6 cycles of R-FC, and every 6 months during the maintenance phase. MRD was centrally assessed by four-color multiparameter flow cytometry using the following antibody combinations: CD22/CD23/CD19/CD5, CD81/CD22/CD19/CD5, CD20/CD38/CD19/CD5, and CD20/CD79b/CD19/CD5. An acquisition was performed by selection of CD19+ cells/SSC including at least 200,000 events, reaching a sensitivity level of 0.01% (10-4). Results: PB/BM samples for assessing MRD were available from 28 of the 84 patients after 3 cycles of R-FC and from 79 patients after the 6 induction cycles, and 43 (58%) of the 74 patients on maintenance reached the interim study at 18 months of maintenance (9 cycles). Correlation between PB and BM was 57%, 68%, and 86% at the three study time points. After three R-FC cycles, 16 patients (56.8%) had a MRD- in PB, but only 4 patients (14%) also had MRD- in BM. After six R-FC cycles, 58 patients (73.3%) had a negative study in PB, and 41.7% also in BM. Among the 24 patients analyzed after the third cycle with BM+, 11 achieved negativization after 6 cycles, and MRD was negative in PB in 10 of 12 patients. After 18 months of maintenance, 11 patients (26.2%) converted to MRD- in PB/BM, and a single patient (2.4%) converted to MRD+. Conclusion: Six cycles of R-FC achieved better MRD- rates in PB and BM as compared to 3 cycles. Addition of rituximab as maintenance after R-FC increased the number of MRD-negative in BM, and in consequence the MRD-negative CRs. A good correlation was not found between MRD values in blood and bone marrow in the induction phase. However, these levels improved in the maintenance phase due to an increase in the number of cases with RMD-negative in BM witch were negatives in PB during induction phase. Disclosures: Off Label Use: R in Maintenance.
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
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  • 5
    Language: English
    In: Blood, 2010-11-19, Vol.116 (21), p.2448-2448
    Description: Abstract Abstract 2448 Introduction. Combination of Rituximab (R) with fludarabine (F) and cyclophosphamide (C) as first line treatment of B-CLL, results in a high complete response rate, improved progression free and overall survival compared with FC in randomised trials (Hallek et al, Blood 2009). However, more than 30% of patients relapse or show disease progression at 3–4 years after FR or FCR treatment (Byrd et al., Blood 2005; Keating et al., J Clin Oncol 2005). We report on the efficacy and safety results of an interim analysis after one year of Rituximab maintenance (Rm) following FCR in previously untreated CLL patients (pts). Methods and Patients. Between October 2007 and June 2009, a cohort of 84 physically fit pts with CD20 positive CLL received treatment with 6 cycles of FCR (R:375mg/m2 iv cycle-1 and 500mg/m2 iv, cycles 2–6; F:25mg/m2 iv, days 1–3; and C:250mg/m2 iv days 1–3; every 28 days). After 3 months of clinical response evaluation, pts achieving a response were treated with R: 375mg/m2 iv every 2 months for 3 years. Anti-infective prophylaxis included trimethoprim-sulfamethoxazole and acyclovir during treatment and until CD4 positive lymphocyte reached 0.3×109/L. Pts achieving a complete response (CR) and negative minimal residual disease (MRD) in peripheral blood (PB) and bone marrow (BM) after 4 courses of FCR, were allowed to stop FC and complete 2 courses of R and continue with Rm. The median age was 59.5 (range 37–70), 32% were females, 6% were Rai low risk, 69% intermediate risk and 25% high risk stage. IGHV status was unmutated in 64.4%, CD38 positive (〉30%) in 47.6% and ZAP-70 positive (〉20%) in 57.3% of pts. The incidence of genetic abnormalities by FISH for del 6q, del 11q (ATM), trisomy 12, del 13q and del 17p (p53) was 3.5%, 26.1%,15,4%, 50% and 4.7% respectively. MRD was evaluated by multicolor flow cytometry (sensitivity: 1 CLL cell positive in 10000 leukocytes). The primary end point was to evaluate the response rates and adverse events (AEs) profile of FCR and Rm treatments. Secondary endpoints included progression free and overall survival, correlation of response with MRD after FCR and Rm treatments. The mean number of FCR cycles was 5.3, and the complete treatment was administered in 80% of pts. Results. We present the results of a planned interim analysis after 1 year (6 cycles) of Rm following FCR as induction treatment. Of 90 pts screened from 29 centres, 84 were assigned (6 failed eligible criteria) to FCR and were evaluable for response. On an intent to treat analysis, overall response, CR, partial response (PR), non response and progression rates were 95.2%, 73.8%, 21.4%, 3.6% and 1.2% respectively. Of 79 pts evaluable for BM-MRD status, MRD-negative CR, MRD-positive CR, MRD-negative PR and MRD-positive PR rates were 57%, 21.5%, 7.6% and 13.9% respectively. The most common AEs after FCR were rituximab infusion (65.1%), myelotoxicity (33.7%) in 29 pts and infections (34%) with 1 serious AEs (SAEs)(1 exitus by viral myocarditis). In addition, there were 12 non hematological SAEs. Seventy five out of 84 pts continued with Rm treatment, 9 were withdrawn by progression (1), toxicity (5) and investigator decision (3). As of June 2010, 70 out 75 eligible pts had initiated Rm and 37 (49.3%) had completed 1 year of Rm (6 cycles) and were evaluable for response. Of them, 24 (64.8%) pts were in MRD-negative CR and only 1 pts converted to MRD-positive CR; 8 (21, 6%) pts were in MRD-positive CR and 3 converted to MRD-Negative CR, while 5 (13.5%) continued in MRD-positive CR with a sustained decreasing number of CLL cells in BM. Five pts were in MRD-positive PR and of them, 4 were in sustained PR with BM-MRD response and one pts presented clinical progression. In summary, 70.2% reached MRD-negative CR and 97.3% were in sustained response. The most common AEs after Rm were grade 3/4 neutropenia between cycles in 6 (16.7%) pts, infections in 15 (41.7%) pts and there were 2 (5.6%) SAEs (2 pneumonia) reported in this population. Conclusion: Based on these preliminary results, the addition of rituximab maintenance following FCR is feasible and effective in untreated CLL pts and increases the quality of clinical responses by obtaining a higher number of MRD-negative CR cases with an acceptable safety profile. Disclosures: Garcia-Marco: ROCHE: Consultancy, Honoraria, Research Funding. Off Label Use: Rituximab is not approved as maintenance therapy. Leon: ROCHE: Employment.
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
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  • 6
    Language: English
    In: Blood, 2001, Vol.97 (2), p.383-387
    Description: This study analyzed the characteristics of 257 HLA-identical sibling transplants of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells depleted of T cells by CD34(+) positive selection (allo-PBT/CD34(+)) for their effect on the incidence of graft failure. Twenty-four patients developed graft failure (actuarial probability, 11%; 95% confidence interval, 7.1-14. 9). Prognostic factors considered were sex and age of donor and recipient, donor-recipient blood group compatibility, diagnosis, disease status at transplant, conditioning regimen, cytomegalovirus serology, number of CD34(+) and CD3(+) cells infused, and cryopreservation. The major factor associated with graft failure was the number of CD3(+) cells in the inoculum. Twenty-three of 155 patients receiving a T-cell dose in the graft less than or equal to 0.2 x 10(6)/kg experienced graft failure, compared with only one of 102 patients receiving more than 0.2 x 10(6)/kg (actuarial probability 18% vs 1%, respectively; P =.0001). The actuarial probability of graft failure progressively increased as the number of CD3(+) cells in the graft decreased, which was determined by grouping the number of CD3(+) cells in quartiles (log-rank P =.03; log-rank for trend P =.003). In the multivariate analysis by the proportional hazard method, 2 covariates entered into regression at a significant level: CD3(+) cells less than or equal to 0.2 x 10(6)/kg (risk ratio = 17; P 〈.0001), and patients with chronic myelogenous leukemia (CML) conditioned with busulphan-based regimens (risk ratio = 4.8; P =.001). From these results it appears that the number of CD3(+) cells in the inoculum-with a threshold of 0.2 x 10(6)/kg or less-is the most critical factor in maintaining a sustained engraftment in allo-PBT/CD34(+) from HLA-identical siblings. In addition, for patients with CML receiving 0.2 x 10(6)/kg or less CD3(+) cells, total body irradiation might be better than busulphan-based regimens.
    Subject(s): Biological and medical sciences ; Medical sciences ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Bone marrow, stem cells transplantation. Graft versus host reaction ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy ; Hematologic Neoplasms - therapy ; Multivariate Analysis ; Prognosis ; Follow-Up Studies ; Hematopoietic Stem Cell Transplantation - standards ; Cell Count ; Humans ; Middle Aged ; Nuclear Family ; Male ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy ; Blood Donors ; Lymphocytes - immunology ; CD3 Complex - blood ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - diagnosis ; Hematopoietic Stem Cell Transplantation - adverse effects ; Adult ; Female ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - complications ; Hematologic Neoplasms - complications ; Transplantation, Homologous - adverse effects ; Hematologic Neoplasms - diagnosis ; Graft Rejection - etiology ; Actuarial Analysis ; Antigens, CD34 - blood ; Transplantation, Homologous - immunology ; Adolescent ; Graft Rejection - immunology ; Graft Rejection - blood ; Lymphocyte Depletion - standards ; Histocompatibility ; Index Medicus ; Abridged Index Medicus
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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