Arnon Nagler

Sheba Medical Center, Gan, Tel Aviv, Israel

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Publications (783)3769.72 Total impact

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    ABSTRACT: Background Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. Methods We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. Results After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). Conclusions The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; number, NCT00678275 .).
    Full-text · Article · Jan 2016 · New England Journal of Medicine
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    ABSTRACT: Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.
    Full-text · Article · Dec 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel.Bone Marrow Transplantation advance online publication, 7 December 2015; doi:10.1038/bmt.2015.300.
    Full-text · Article · Dec 2015 · Bone marrow transplantation
  • Frédéric Baron · Annalisa Ruggeri · Arnon Nagler
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    ABSTRACT: More than 40,000 unrelated cord blood transplantations (UCBT) have been performed worldwide as treatment for patients with malignant or non-malignant life threatening hematologic disorders. However, low absolute numbers of hematopoietic stem and progenitor cells (HSPCs) within a single cord blood unit has remained a limiting factor for this transplantation modality, particularly in adult recipients. Further, because UCB contains low numbers of mostly naïve T cells, immune recovery after UCBT is slow, predisposing patients to severe infections. Other causes of UCBT failure has included graft-versus-host disease (GVHD), and relapse of the underlying disease. In this article, we first review the current landscape of cord blood engineering aimed at improving engraftment. This includes approaches of UCB-HSPCs expansion and methods aimed at improving UCB-HSCPs homing. We then discuss recent approaches of cord blood engineering developed to prevent infection (generation of multivirus-specific cytotoxic T cells (VSTs) from UCB), relapse (transduction of UCB-T cells with tumor-specific chimeric receptor antigens (CARs)) and GVHD (expansion of regulatory T cells from UCB). Although many of these techniques of UCB engineering remain currently technically challenging and expensive, they are likely to revolutionize the field of UCBT in the next decades.
    No preview · Article · Dec 2015 · Expert Review of Hematology
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    ABSTRACT: The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG-PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score ≥3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis.
    No preview · Article · Nov 2015 · Acta Haematologica
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    ABSTRACT: Increasing numbers of patients are receiving reduced-intensity-conditioning regimen allogeneic hematopoietic stem-cell transplantation. We hypothesized that the use of bone-marrow graft might decrease the risk of graft-versus-host-disease compared to peripheral-blood after reduced-intensity-conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced-intensity-conditioning regimen allogeneic hematopoietic stem-cell transplantation from 2000-2012 for acute leukemia and reported to the acute-leukemia-working-party of the EBMT were included in the study. Eight hundred thirty-seven patients receiving bone-marrow grafts were compared with 9011 peripheral-blood transplant recipients after reduced-intensity conditioning regimen. Median follow-up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil≥0.5x109/L at day 60) was lower in bone-marrow recipients, 88 vs. 95% (p<0.0001). Grade II to IV acute graft-versus-host-disease was lower in bone-marrow recipients, 19% vs. 24% for peripheral-blood (p=0.005). In multivariate analysis, after adjusting for differences between both groups, overall survival (HR 0.90; p=0.05) and leukemia-free-survival (HR 0.88; p=0.01) were higher in patients transplanted with peripheral-blood compared to bone-marrow grafts. Furthermore, peripheral-blood graft was also associated with decreased risk of relapse (HR 0.78; p=0.0001). Non-relapse-mortality was not significantly different between recipients of bone-marrow and peripheral-blood grafts, and chronic graft-versus-host-disease was significantly higher after peripheral blood grafts (HR 1.38; p<0.0001). Despite the limitation of a retrospective registry based study, we found that peripheral-blood grafts after reduced-intensity-conditioning regimens had better overall and leukemia-free survival than bone-marrow grafts. However, there is an increase in chronic graft-versus-host-disease after peripheral-blood grafts. Long-term follow-up is needed to clarify if chronic graft-versus-host-disease related deaths might increase the risk of late morbidity and mortality.
    No preview · Article · Nov 2015 · Haematologica
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    ABSTRACT: One of the major projects of the Worldwide Network for Blood and Marrow Transplantation (WBMT) is to promote hematopoietic stem cell transplantation (HSCT) in emerging countries in the world. For these countries, HLA haploidentical HSCT (haplo-HSCT) from family members is an attractive approach because of its cost effectiveness. To learn the current status, including recent trends, of haplo-HSCT, the WBMT invited speakers from major transplant centers in 3 regions (Asia, Europe, and North America) to present at its annual WBMT Joint Session. This article represents the direct reports from these 3 speakers in addition to introductions by 2 WBMT speakers who address data from the Global Transplant Activity survey. It must be emphasized, however, that certain promising results of haplo-HSCT presented in this article were obtained at well-experienced institutes.
    No preview · Article · Nov 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N=37,542; 37%) or autologous (N=65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p<0·0001; HR 0·90;0·85–0·90 per 10years; p<0·001) and autologous HSCT (HR 0·91;0·87–0·96 per 10 patients; p<0·001; HR 0·93;0·87–0·99 per 10years; p=0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2=18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.
    Full-text · Article · Nov 2015 · EBioMedicine
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    ABSTRACT: Background: In the setting of allogeneic human leukocyte antigen (HLA)-matched bone marrow transplantation, transplanting male patients with grafts from female donors has been associated with a higher incidence of graft-versus-host disease (GVHD) and of nonrelapse mortality (NRM). The aim of the current analysis was to compare transplantation outcomes in male patients given female unrelated cord blood (UCB) versus other gender combinations. Patients and methods: Data from 552 consecutive patients with acute myeloid leukemia (AML) given a single UCB transplantation between 2000 and 2014 were included. Results: In comparison with other gender combination, male patients given female UCB (n = 131) had a trend for a higher incidence of grades II-IV acute GVHD (33 versus 25 %, P = 0.08), a trend for a higher incidence of NRM (41 versus 33 %, P = 0.06), and a lower leukemia-free (LFS, 30 versus 41 %, P = 0.01) and overall survival (OS, 33 versus 45 %, P = 0.008). In multivariate analyses, taking into consideration all patients for which data on HLA-matching and cell dose transplanted were fully available (n = 363), male patients transplanted with a female UCB had a trend for a higher incidence of grade III-IV acute GVHD (hazard ratio (HR) = 2.0, P = 0.06), a trend for a higher NRM (HR = 1.5, P = 0.06), and a worse LFS (HR = 1.4, P = 0.04) and OS (HR = 1.3, P = 0.06). Conclusions: Our data suggest that male patients transplanted with female UCB might have higher risk of acute GVHD and of NRM leading to worse LFS and OS. These results should be confirmed in other large cohorts of patients before used for determining the choice of an UCB unit.
    Full-text · Article · Oct 2015 · Journal of Hematology & Oncology
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    ABSTRACT: Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.221.
    No preview · Article · Oct 2015 · Bone marrow transplantation

  • No preview · Article · Sep 2015 · Haematologica
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    ABSTRACT: Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) is limited. Therefore, we performed a retrospective registry analysis on 702 adults with CN-AML undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1(mut)) and FLT3 internal tandem duplications (FLT3-ITD). Double negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. 2y-OS from HSCT was 81±5% in NPM1(mut)/FLT3(wt) (n=68), 75±3% in NPM1(wt)/FLT3(wt) (n=290), 66±3% in NPM1(mut)/FLT3-ITD (n=269) and 54±7% in NPM1(wt)/FLT3-ITD (n=75; p=0.003). Analysis of CEBPα among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients with CEBPα(mut) (n=13, 2y-OS:100%), and with a triple negative genotype (n=138, 2y-OS:77±3%). In a Cox-model of predefined factors, older age, presence of FLT3-ITD and >1 course of chemotherapy to reach CR were associated with inferior outcome. 2y-OS/LFS were 88±3%/79±4% in patients without any, 77±2%/73±3% with one, and 53±4%/50±4 with>=2 risk factors (p=0.002 for LFS, p=0.003 for OS). Hence, FLT3-ITD proofed to be the decisive molecular marker for outcome after HSCT for CN-AML in CR1, regardless of NPM1 mutational status, variations of transplant protocols, or development of GvHD. Age, FLT3-ITD and response to induction chemotherapy allow for a prognostic risk classification.
    Preview · Article · Sep 2015 · Blood
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    ABSTRACT: Human recombinant G-CSF Filgrastim (Neupogen) has been widely used for the mobilization of CD34(+) hematopoietic stem cells (HSC) from healthy donors. The experience with biosimilar G-CSF agents in this area is limited. We performed a prospective study assessing Tevagrastim (biosimilar Filgrastim XMO2) for mobilization of CD34(+) PB HSC in HLA matched normal sibling donors for transplantation in twenty four patients with AML and high-risk MDS (NCT01542944). Results were compared to a historical control group of sibling donors that received filgrastim for stem cell mobilization for allogeneic stem cell transplantations in patients with AML and MDS. The normal donors received tevagrastim or filgrastim in a dose of 10 μg/kg body weight (BW) subcutaneously for 4 days. The target yields of CD34(+) cells was 5 × 10(6) CD34(+) cells/kg BW of the recipient. Median 10.2 × 10(6) (range, 2.52-35.4) and 9.35 × 10(6) (3.7-30.6) CD34(+) cells per kg BW were collected in the tevagrastim and filgrastim groups, respectively. All patients promptly engrafted with a median day of absolute neutrophil count (ANC) of >0.5× 10(9)/L, and of >1× 10(9)/L been 13 days (range, 10-21) and 13.5 days (range, 10-22) in the tevagrastim group, and 12 days (10-18) and 13 days (10-18) in the filgrastim group, respectively. Platelets (PLT) reached counts of >20× 10(9)/L and >50× 10(9)/L within a median of 14 days (range, 11-33) and 17 days (range, 12-33) in the tevagrastim group and 13 (10-29) and 15 (10-32) days in the filgrastim group, respectively. The donors developed only mild and transient side effects which were not different between the tevagrastim study group and the filgrastim historical control group. Similarly the transplant related toxicities and outcome did not differ between the patients transplanted with tevagrastim mobilized grafts and the filgrastim historical controls. In summary, we observed a similar yield of CD34(+) stem cell mobilization in the tevagrastim study group and the filgrastim historical control group with similar engraftment kinetic, hematopoietic reconstitution and transplantation outcome. Tevagrastim administration was safe with minimal side effects and toxicity not different than historical controls. The lack of significant differences for all parameters of stem cell collection, engraftment and safety with the biosimilar XMO2 tevagrastim demonstrate the 'similarity' of the biosimilar and recombinant human G-CSF, in this indication.
    No preview · Article · Sep 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation

  • No preview · Article · Sep 2015
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    ABSTRACT: Background: The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. Methods: We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with, number NCT01191957. Findings: Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). Interpretation: In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. Funding: Agenzia Italiana del Farmaco.
    No preview · Article · Sep 2015 · The Lancet Oncology

  • No preview · Article · Sep 2015
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    ABSTRACT: Autologous hematopoietic stem cell transplantation is the standard therapy for refractory/relapsed aggressive lymphoma. The initial step of the procedure involves mobilization and collection of hematopoietic stem cells. G-CSF fails to achieve mobilization in 15-25% of lymphoma patients. Plerixafor is a novel CXCR4 antagonist that can promote mobilization. It has been used successfully in patients after the failure of G-CSF. It is reasonable to test whether plerixafor should become the mobilizing agent of choice in patients expected to exhibit difficulties in mobilization. We initiated a study to assess the use of plerixafor as a first-line stem cell mobilizer in 20 elderly or heavily pretreated patients with non-Hodgkin or Hodgkin lymphoma. The minimum defined CD34+ cell dose of ≥2 × 10(6) cells/kg was achieved by 90% of the patients, and for 83% of them with one apheresis procedure. The target CD34+ dose of ≥5 × 10(6) cells/kg was achieved by 70% of the patients. The median number of circulating CD34+ cells before and after plerixafor was 14.4 and 42.8 cells/μl, respectively. The post-plerixafor adverse events were mild. All patients promptly engrafted after high-dose chemotherapy treatment. We conclude that plerixafor administration is safe and efficient for upfront mobilization in lymphoma patients predicted to be poor mobilizers. © 2015 S. Karger AG, Basel.
    No preview · Article · Aug 2015 · Acta Haematologica
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    ABSTRACT: Vision incapacitation and blindness associated with incurable retinal degeneration affect millions of people worldwide. In this study, 0.25×10(6) human bone marrow stem cells (hBM-MSCs) were transplanted epiretinally in the right eye of Royal College Surgeons (RCS) rats at the age of 28days. Epiretinally transplanted cells were identified as a thin layer of cells along vitreous cavity, in close proximity to the retina or attached to the lens capsule, up to 6weeks following transplantation. Epiretinal transplantation delayed photoreceptor degeneration and rescued retinal function up to 20weeks following cell transplantation. Visual functions remained close to normal levels in epiretinal transplantation rats. No inflammation or any other adverse effects were observed in transplanted eyes. Our findings suggest that transplantation of hBM-MSCs as a thin epiretinal layer is effective for treatment of retinal degeneration in RCS rats, and that transplanting the cells in close proximity to the retina enhances hBM-MSC therapeutic effect compared with intravitreal injection. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · Stem Cell Research
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    ABSTRACT: Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials. © 2015 by American Society of Clinical Oncology.
    No preview · Article · Aug 2015 · Journal of Clinical Oncology
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    ABSTRACT: Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative for acute leukemia (AL), but carries considerable risk. Machine learning algorithms, which are part of the data mining (DM) approach, may serve for transplantation-related mortality risk prediction. This work is a retrospective DM study on a cohort of 28,236 adult HSCT recipients from the AL registry of the European Group for Blood and Marrow Transplantation. The primary objective was prediction of overall mortality (OM) at 100 days after HSCT. Secondary objectives were estimation of nonrelapse mortality, leukemia-free survival, and overall survival at 2 years. Donor, recipient, and procedural characteristics were analyzed. The alternating decision tree machine learning algorithm was applied for model development on 70% of the data set and validated on the remaining data. OM prevalence at day 100 was 13.9% (n = 3,936). Of the 20 variables considered, 10 were selected by the model for OM prediction, and several interactions were discovered. By using a logistic transformation function, the crude score was transformed into individual probabilities for 100-day OM (range, 3% to 68%). The model's discrimination for the primary objective performed better than the European Group for Blood and Marrow Transplantation score (area under the receiver operating characteristics curve, 0.701 v 0.646; P < .001). Calibration was excellent. Scores assigned were also predictive of secondary objectives. The alternating decision tree model provides a robust tool for risk evaluation of patients with AL before HSCT, and is available online (∼bondi/web1.html). It is presented as a continuous probabilistic score for the prediction of day 100 OM, extending prediction to 2 years. The DM method has proved useful for clinical prediction in HSCT. © 2015 by American Society of Clinical Oncology.
    Preview · Article · Aug 2015 · Journal of Clinical Oncology

Publication Stats

26k Citations
3,769.72 Total Impact Points


  • 2001-2016
    • Sheba Medical Center
      • Cancer Research Center
      Gan, Tel Aviv, Israel
  • 2015
    • University Hospital Centre Zagreb
      • Division of Hematology
      Zagrabia, Grad Zagreb, Croatia
  • 1987-2015
    • Tel Aviv University
      • • Sackler Faculty of Medicine
      • • Department of Pediatrics
      Tell Afif, Tel Aviv, Israel
  • 1992-2013
    • Hebrew University of Jerusalem
      • • Department of Bone Marrow Transplant
      • • Department of Pediatrics
      • • Department of Pharmacology
      Yerushalayim, Jerusalem District, Israel
  • 2012
    • Bank Of Israel
      Yerushalayim, Jerusalem, Israel
  • 2009
    • University of Nantes
      • Faculté de Médecine
      Naoned, Pays de la Loire, France
  • 1986-2008
    • Technion - Israel Institute of Technology
      • Rambam Medical Center
      H̱efa, Haifa, Israel
  • 1999-2006
    • Weizmann Institute of Science
      • Department of Immunology
      Rechovot, Central District, Israel
  • 1991-2005
    • Hadassah Medical Center
      • • Department of Otolaryngology and Head and Neck Surgery
      • • Liver Unit
      Yerushalayim, Jerusalem District, Israel
  • 2002-2004
    • Medical University of Gdansk
      Danzig, Pomeranian Voivodeship, Poland
    • Università degli Studi di Perugia
      • Sezione di Ematologia e Immunologia Clinica
      Perugia, Umbria, Italy
    • Westmead Hospital
      Sydney, New South Wales, Australia
  • 2003
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 1983-2003
    • Rambam Medical Center
      • • Department of Oral and Maxillofacial Surgery
      • • Department of Hematology
      H̱efa, Haifa, Israel
  • 1995-2002
    • Tel Aviv Sourasky Medical Center
      • Hematology
      Tell Afif, Tel Aviv, Israel
  • 2000
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
    • Agricultural Research Organization ARO
      • Institute of Animal Science
      Beit Dajan, Central District, Israel