A Nagler

Sheba Medical Center, Gan, Tel Aviv, Israel

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Publications (702)3298.26 Total impact

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    ABSTRACT: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.
    New England Journal of Medicine 09/2014; 371(10):895-905. · 51.66 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a very effective therapeutic modality with curative potential in patients with hematological malignancies. The therapeutic efficacy is mainly based on the alloreactive reaction of donor lymphocytes against malignant cells of the recipient named as 'graft-versus-leukemia' or 'graft-versus-tumor' (GVL, GVT) effect. However, besides the beneficial GVL effect, alloreactive reaction attacks normal cells and provokes the deleterious 'graft-versus-host disease' (GVHD) which represents the major limitation of allo-SCT. Current trials have focused on a dual goal: augmentation of GVL and complete abolishment of GVHD. From a theoretical point of view complete dissociation of GVL from GVHD can occur by selecting antigenic targets present on malignant and absent from normal cells. Hematopoietic tissue-restricted minor histocompatibility antigens and leukemia or tumor-associated antigens are ideal candidates for tumor-targeted immunotherapy. Other options for inducing anti-tumor immunity in the absence of GVHD are natural killer (NK) cell immunotherapy, amplification of immune responses by using monoclonal antibodies, and bispecific T and NK-cell engagers. Genetically modified immune effectors such as T-cells armed with chimeric antigen receptors (CAR) or transduced with T-cell receptors with anti-tumor specificity are another exciting field of immunotherapy against malignancies.
    Annals of medicine. 06/2014;
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    ABSTRACT: Three-drug induction regimens have become the standard of care in newly diagnosed transplant-eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms 'VTD' or 'VCD' and 'induction regimens for newly diagnosed multiple myeloma'. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3-4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3-4 adverse events was found in the VCD-treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.
    British Journal of Haematology 05/2014; · 4.94 Impact Factor
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    ABSTRACT: Oral busulfan is the historical backbone of the Busulfan+cyclophosphamide regimen for autologous stem cell transplantation. However intravenous Busulfan has more predictable pharmacokinetics and less toxicity than oral busulfan; therefore, we retrospectively analyzed data from 952 patients with acute myeloid leukemia who received intravenous busulfan for autologous stem cell transplantation. Most patients were male (n=531, 56%), and median age at transplant was 50.5 years. Two-year overall survival, leukemia-free survival, and relapse incidence were 67+/-2%, 53+/-2%, and 40+/-2%, respectively. Non-relapse mortality at 2 years was 7±1%. Five patients died from veno-occlusive disease. Overall leukemia free survival and relapse incidence at 2 years did not differ significantly between the 815 patients transplanted in first complete remission (52+/-2% and 40+/-2%, respectively) and the 137 patients in second complete remission (58+/-5% and 35+/-5%, respectively). Cytogenetic risk classification and age were significant prognostic factors: 2-year leukemia free survival was 63±4% (good risk), 52±3% (intermediate risk), and 37+/-10% (poor risk; p=0.01); patients ≤50 years old had better overall survival (77+/-2% vs. 56+/-3%; p<0.001), leukemia free survival (61±3% vs. 45+/-3%; p<0.001), relapse incidence (35±2% vs. 45+/-3%; p<0.005), and non-relapse mortality (4±1% vs. 10+/-2%; p<0.001) than older patients. The combination of intravenous busulfan and high-dose melphalan was associated with the best overall survival (75±4%). Our results suggest that the use of intravenous busulfan simplifies the autograft procedure and confirms the usefulness of autologous stem cell transplantation in acute myelocytic leukemia. As in allogeneic transplantation, veno-occlusive disease is an uncommon complication after an autograft using intravenous busulfan.
    Haematologica 05/2014; · 5.94 Impact Factor
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    ABSTRACT: BACKGROUND Total body irradiation (TBI) is widely used for conditioning before hematopoietic cell transplantation. Its efficacy and toxicity may depend on many methodological aspects. The goal of the current study was to explore current clinical practice in this field.METHODSA questionnaire was sent to all centers collaborating in the European Group for Blood and Marrow Transplantation and included 19 questions regarding various aspects of TBI. A total of 56 centers from 23 countries responded.RESULTSAll centers differed with regard to at least 1 answer. The total maximum dose of TBI used for myeloablative transplantation ranged from 8 grays (Gy) to 14.4 Gy, whereas the dose per fraction was 1.65 Gy to 8 Gy. A total of 16 dose/fractionation modalities were identified. The dose rate ranged from 2.25 centigrays to 37.5 centigrays per minute. The treatment unit was linear accelerator (LINAC) (91%) or cobalt unit (9%). Beams (photons) used for LINAC were reported to range from 6 to 25 megavolts. The most frequent technique used for irradiation was “patient in 1 field,” in which 2 fields and 2 patient positions per fraction are used (64%). In 41% of centers, patients were immobilized during TBI. Approximately 93% of centers used in vivo dosimetry with accepted discrepancies between the planned and measured doses of 1.5% to 10%. In 84% of centers, the lungs were shielded during irradiation. The maximum accepted dose for the lungs was 6 Gy to 14.4 Gy.CONCLUSIONSTBI is an extremely heterogeneous treatment modality. The findings of the current study should warrant caution in the interpretation of clinical studies involving TBI. Further investigation is needed to evaluate how methodological differences influence outcome. Efforts to standardize the method should be considered. Cancer 2014. © 2014 American Cancer Society.
    Cancer 05/2014; · 5.20 Impact Factor
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    ABSTRACT: In order to explore the mechanism(s) underlying the pro-tumorigenic capacity of heparanase we established an inducible Tet-on system. Heparanase expression was markedly increased following addition of doxycycline (Dox) to the culture medium of CAG human myeloma cells infected with the inducible heparanase gene construct, resulting in increased colony number and size in soft agar. Moreover, tumor xenografts produced by CAG-heparanase cells were markedly increased in mice supplemented with Dox in their drinking water compared with control mice maintained without Dox. Consistently, we found that heparanase induction is associated with decreased levels of CXCL10, suggesting that this chemokine exerts tumor suppressor properties in myeloma. Indeed, recombinant CXCL10 attenuated the proliferation of CAG, U266 and RPMI-8266 myeloma cells. Similarly, CXCL10 attenuated the proliferation of human umbilical vein endothelial cells (HUVEC), implying that CXCL10 exhibits anti-angiogenic capacity. Strikingly, development of tumor xenografts produced by CAG-heparanase cells over expressing CXCL10 was markedly reduced compared with control cells. Moreover, tumor growth was significantly attenuated in mice inoculated with human or mouse myeloma cells and treated with CXCL10-Ig fusion protein, indicating that CXCL10 functions as a potent anti-myeloma cytokine.Leukemia accepted article preview online, 04 April 2014; doi:10.1038/leu.2014.121.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2014; · 10.16 Impact Factor
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    ABSTRACT: Acute lymphocytic leukemia (ALL) is a rare disease with a poor outcome in adults. Over the years different protocols have been developed with the aim of improving the outcome. The German study group protocols (GMALL), which are the most frequently used in our institutions, changed significantly between the periods 1989-93 and 1999-2003.
    The Israel Medical Association journal: IMAJ 04/2014; 16(4):224-8. · 0.98 Impact Factor
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    ABSTRACT: Treatment of traumatic brain injury (TBI) is still an unmet need. Cell therapy by human umbilical cord blood (HUCB) has shown promising results in animal models of TBI and is under evaluation in clinical trials. HUCB contains different cell populations, but to date only mesenchymal stem cells have been evaluated for therapy of TBI. Here we present the neurotherapeutic effect, as evaluated by neurological score, using a single dose of HUCB-derived mononuclear cells (MNCs) upon intravenous (iv) administration one day post-trauma in a mouse model of closed head injury (CHI). Delayed (8 days post-trauma) intracerebroventricular administration of MNCs showed improved neurobehavioral deficits thereby extending the therapeutic window for treating TBI. Furthermore, we demonstrated for the first time, that HUCB-derived pan-hematopoietic CD45 positive (CD45+) cells, isolated by magnetic sorting and characterized by expression of CD45 and CD11b markers (96-99%), improved the neurobehavioral deficits upon iv administration, which persisted for 35 days. The therapeutic effect was in a direct correlation to a reduction in the lesion volume and decreased by pre-treatment of the cells with anti-human-CD45 antibody. At the site of brain injury, 1.5-2 h after transplantation, HUCB-derived cells were identified by near infrared scanning and immunohistochemistry using anti-human-CD45 and anti-human-nuclei antibodies. NGF and VEGF levels were differentially expressed in both ipsilateral and contralateral brain hemispheres, thirty-five days after CHI, measured by ELISA. These findings indicate the neurotherapeutic potential of HUCB-derived CD45+ cell population in a mouse model of TBI and propose their use in the clinical setting of human TBI.
    Journal of neurotrauma 03/2014; · 4.25 Impact Factor
  • Drorit G Merkel, Arnon Nagler
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    ABSTRACT: Transfusion dependent low risk myelodysplastic syndromes (MDS) patients, eventually develop iron overload. Iron toxicity, via oxidative stress, can damage cellular components and impact organ function. In thalassemia major patients, iron chelation therapy lowered iron levels with recovery of cardiac and liver functions and significant improvement in survival. Several noncontrolled studies show inferior survival in MDS patients with iron overload, including an increase in transplant-related mortality and infection risk while iron chelation appears to improve survival in both lower risk MDS patients and in stem cell transplant settings. Collated data are presented on the pathophysiological impact of iron overload; measuring techniques and chelating agents' therapy positive impact on hematological status and overall survival are discussed. Although suggested by retrospective analyses, the lack of clear prospective data of the beneficial effects of iron chelation on morbidity and survival, the role of iron chelation therapy in MDS patients remains controversial.
    Expert Review of Anti-infective Therapy 03/2014; · 2.07 Impact Factor
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    ABSTRACT: The choice of a rituximab-based regimen and the prognostic significance of interim 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in primary mediastinal large B cell lymphoma (PMBCL) are debatable. We evaluated the clinical features and outcomes of 95 consecutive patients with PMBCL who were treated between 1985 and 2009. Forty-three patients received rituximab-based chemotherapy, R-VACOP-B (N = 30) or R-CHOP21 (N = 13), whereas 52 patients were treated with VACOP-B (N = 47) or CHOP21 (N = 5). Radiotherapy was not given. Patients who received rituximab had a 5-year progression-free survival (PFS) of 79 % and overall survival (OS) of 97 % compared with 58 % (p = 0.06) and 88 % (p = 0.2), respectively, without rituximab. Five-year PFS in patients treated with R-VACOP-B, R-CHOP21, VACOP-B, and CHOP21 were 83, 69, 62, and 20 %, respectively (p = 0.039). However, direct comparison showed that the difference between PFS rates in patients receiving R-VACOP-B compared to R-CHOP21 was not statistically significant (p = 0.3). None of the standard clinical risk factors predicted for PFS and OS in patients receiving rituximab (R)-chemotherapy. Mid-interim FDG-PET/CT scans were performed in 30/43 patients who received R-chemotherapy. The negative predictive values of mid-PET activity were high (100 % for R-VACOP-B and 86 % for R-CHOP21) while the positive predictive values (PPV) were relatively low (30 and 75 %, respectively). Despite the low PPV, the 5-year PFS for mid-PET-negative patients (N = 16) was significantly higher (94 %) than that for mid-PET-positive (N = 14) patients (57 %, p = 0.015). This retrospective analysis demonstrates that the superiority of VACOP-B over CHOP21 for treatment of PMBCL disappeared once rituximab was added. The potential benefit of using interim PET activity as a guide for continuing therapy in patients with PMBCL remains unclear due to the relatively low PPV.
    Annals of Hematology 03/2014; · 2.87 Impact Factor
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    ABSTRACT: Functional role of CXCR4 in CML progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of Erk1/2, Akt, S6K, STAT3 and STAT5 pro-survival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with sub-optimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperons and anti-apoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. BM stromal cells markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BM stromal cells elevated proto-oncogene BCL6 expression in the CML cells in response to imatinib treatment, suggesting the possible role of BCL6 in stroma-mediated TKI resistance. BKT140 reversed the protective effect of the stroma, effectively promoted apoptosis and decreased BCL6 levels in CML cells co-cultured with BMSCs. BKT140 administration in vivo effectively reduced the growth of subcutaneous K562-produced xenografts. Moreover, the combination of BKT140 with low-dose imatinib markedly inhibited tumor growth, achieving 95% suppression. Taken together, our data indicate the importance of CXCR4/CXCL12 axis in CML growth and CML-BM stroma interaction. CXCR4 inhibition with BKT140 antagonist efficiently cooperated with imatinib in vitro and in vivo. These results provide the rational basis for CXCR4-targeted therapy in combination with TKI to override drug resistance and suppress residual disease.
    Molecular Cancer Therapeutics 02/2014; · 5.60 Impact Factor
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    ABSTRACT: Abstract FDG-PET/CT scanning is often used for staging and response assessment in Mantle cell lymphoma (MCL); however, the ability of interim and post therapy scans to predict outcome is debatable. We retrospectively evaluated the prognostic impact of interim and post therapy FDG-PET/CT scan on outcome of patients with MCL. Fifty eight consecutive patients diagnosed between 1998 and 2011 were included in the analysis. Scans, performed at diagnosis, mid-therapy, post chemotherapy (prior to ASCT) and post transplantation, were reviewed and outcome was analyzed. Median age was 59. Most patients presented with advanced disease. MIPI was low in 45%, intermediate in 41% and high in 14%. Thirty four patients (58%) received RCHOP or RCHOP-like chemotherapy and 24 (42%) underwent an upfront ASCT. Three years overall (OS) and progression free survival (PFS) were 81% and 45% respectively. No significant differences in OS or PFS between the PET positive and PET negative groups both for interim and post therapy scans were observed. Analysis of chemotherapy only and chemotherapy+ASCT groups separately did not reveal any correlation between interim, post therapy or pre transplant PET result to OS and PFS. We conclude that in patients treated with R-CHOP-21 or R-CHOP- like chemotherapy using the International Harmonization Project criteria to determine whether a scan is positive or negative, there is no role for interim or post therapy PET.
    Leukemia & lymphoma 01/2014; · 2.61 Impact Factor
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    ABSTRACT: The clinical course of polycythemia vera and essential thrombocythemia is potentially associated with long-term severe complications, such as evolution to myelofibrosis or acute myeloid leukemia. Allogeneic stem cell transplantation is currently the only potentially curative treatment for advanced polycythemia vera or essential thrombocythemia. We analyzed 250 consecutive patients with an initial diagnosis of polycythemia vera (n=120) or essential thrombocythemia (n=130), who underwent transplantation due to progression to myelofibrosis (n=193) or acute myeloid leukemia (n=57) and reported to European Group for Blood and Marrow Transplantation registry between 1994 and 2010. The median age was 56 years (range 22-75) and 52% of patients had an interval from diagnosis to transplant of 10 years or more. With a median follow-up from transplantation of 13 months, 3 years overall survival and relapse incidence were 55% and 32%, respectively. In the univariate analysis, the main parameters that negatively affected post-transplantation outcomes were older age (>55 years), a diagnosis at transplant of acute myeloid leukemia and the use of an unrelated donor. The 3 years cumulative incidence of non-relapse mortality was 28%, significantly higher in older patients (>55years, 35% vs. 20%, p=0.032), in unrelated compared to related donor (34% vs. 18%, p=0.034) and in diagnosis of acute myeloid leukemia compared to myelofibrosis (29% vs. 27%, p=0.045). This large retrospective study confirms that transplantation is potentially curative for end-stage polycythemia vera /essential thrombocythemia patients progressing to myelofibrosis or acute myeloid leukemia. Relapse and non-relapse mortality remain unsolved problems for which innovative treatment approaches need to be assessed.
    Haematologica 01/2014; · 5.94 Impact Factor
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    ABSTRACT: Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m(2)/h, 32 mg/m(2)/h or 24 mg/m(2)/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.Blood Cancer Journal (2014) 4, e238; doi:10.1038/bcj.2014.60; published online 15 August 2014.
    Blood Cancer Journal 01/2014; 4:e238. · 1.40 Impact Factor
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    ABSTRACT: The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen (®) ) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.
    Theranostics 01/2014; 4(3):280-9. · 7.81 Impact Factor
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    ABSTRACT: Abstract Differences in the prevalence of Multiple Myeloma across races have been observed, with a two to three fold greater prevalence in African Americans compared with Caucasians. Little is known about the incidence or prevalence of Multiple Myeloma in other populations. The association between father's country of origin and the incidence of Multiple Myeloma was examined in a nationwide population-based cohort. Health-related data on 746,200 16-19 year old Jewish males examined between 1967 and 1998 were linked to the Israel National Cancer Registry to derive Multiple Myeloma incidence up to 2006. During 17,352,349 person-years of follow-up, 109 examinees developed plasma cell dyscrasias. Middle Eastern origin was protective compared to European origin (HR 0.39; 95% CI 0.22-0.68; p=0.001, adjusted for year of birth), and also when restricted to Israeli-born males (HR 0.44; 95% CI 0.24-0.82; p=0.01). In conclusion, second generation adolescents of Middle Eastern origin are at persistently lower risk of developing Multiple Myeloma compared to European origin, supporting a genetic component in the pathogenesis of Multiple Myeloma.
    Leukemia & lymphoma 12/2013; · 2.61 Impact Factor
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    ABSTRACT: The objective of the current study was to investigate the role of postremission consolidation chemotherapy before reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (alloSCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Of the 789 consecutive patients with AML in CR1 who underwent RIC alloSCT from a human leukocyte antigen-matched sibling or matched unrelated donor peripheral stem cell grafts between 2001 and 2010, 591 patients received at least 1 cycle of consolidation chemotherapy and 198 patients did not receive any consolidation chemotherapy before alloSCT. To minimize inherent survival bias in favor of patients who underwent transplant long after achieving CR1, the study focused on 373 patients who underwent transplant within the median time frame between achievement of CR1 and alloSCT (3 months for patients who underwent alloSCT from matched siblings and 4 months for patients who underwent alloSCT from matched unrelated donors). In this subgroup, 151 patients did not receive any consolidation chemotherapy and 222 patients received ≥ 1 consolidation chemotherapy cycle. With a median follow-up of 36 months (range, 2 months-135 months), the 3-year cumulative recurrence incidence (RI) was not significantly different between the groups (36% ± 4% for the group treated without consolidation chemotherapy vs 38% ± 3% for patients who received consolidation chemotherapy; P = .89). In addition, leukemia-free survival was similar between the groups (45% ± 4% and 47% ± 3%, respectively; P = .41). Dose intensity of cytarabine given during consolidation chemotherapy appeared to have no influence on RI. On multivariate analysis, pretransplant consolidation (≥ 1 cycle vs 0 cycles) was found to have no significant impact on RI (hazards ratio, 1.29; 95% confidence interval, 0.84-1.97 [P = .24]) or leukemia-free survival (hazards ratio, 1.00; 95% confidence interval, 0.71-1.42 [P = .99]). The data from the current study suggest no apparent advantage for postremission consolidation chemotherapy before RIC alloSCT, provided a donor is readily available. Cancer 2013. © 2013 American Cancer Society.
    Cancer 12/2013; · 5.20 Impact Factor
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    ABSTRACT: Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of HSPGs, important structural and functional components of the ECM. Cleavage of HS leads to loss of the structural integrity of the ECM and release of HS-bound cytokines, chemokines, and bioactive angiogenic- and growth-promoting factors. Our previous study revealed a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing GVHD. We now demonstrate that HPSE is up-regulated in response to pretransplantation conditioning, followed by a gradual decrease thereafter. Expression of heparanase correlated with the rs4693608 HPSE SNP before and after conditioning. Moreover, a positive correlation was found between recipient and donor rs4693608 SNP discrepancy and the time of neutrophil and platelet recovery. Similarly, the discrepancy in rs4693608 HPSE SNP between recipients and donors was found to be a more significant factor for the risk of aGVHD than patient genotype. The rs4693608 SNP also affected HPSE gene expression in LPS-treated MNCs from PB and CB. Possessors of the AA genotype exhibited up-regulation of heparanase with a high ratio in the LPS-treated MNCs, whereas individuals with genotype GG showed down-regulation or no effect on HPSE gene expression. HPSE up-regulation was mediated by TLR4. The study emphasizes the importance of rs4693608 SNP for HPSE gene expression in activated MNCs, indicating a role in allogeneic stem cell transplantation, including postconditioning, engraftment, and GVHD.
    Journal of leukocyte biology 12/2013; · 4.99 Impact Factor
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    ABSTRACT: Sixty patients with early chronic phase CML (ECPCML) received Nilotinib on a phase II study which included a comparison of the Xpert BCR-ABL Monitor™ PCR system with standardized (IS) BCR-ABL1 real-time quantitative PCR (RQ-PCR). 88% patients achieved MMR with 45% achieving MR4.5. At 3 months BCR-ABL1/ABL1 IS >1% and <10% was associated with a lower likelihood of subsequent MR4.5 compared to patients with lower levels (p=0.018). No significant difference was observed between methodologies in identifying MMR. Nilotinib induces high molecular response rates in ECPCML and the Xpert BCR-ABL Monitor™ system merits further investigation in this setting.
    Leukemia research 12/2013; · 2.36 Impact Factor

Publication Stats

18k Citations
3,298.26 Total Impact Points

Institutions

  • 1996–2014
    • Sheba Medical Center
      • Cancer Research Center
      Gan, Tel Aviv, Israel
  • 1996–2013
    • Hebrew University of Jerusalem
      • • Department of Bone Marrow Transplant
      • • School of Pharmacy
      • • Faculty of Medicine
      • • Department of Pharmacology
      • • Department of Oncology
      Yerushalayim, Jerusalem District, Israel
  • 1991–2013
    • Hadassah Medical Center
      • • Department of Otolaryngology and Head and Neck Surgery
      • • Department of Pediatric Surgery
      • • Department of Surgery
      Yerushalayim, Jerusalem District, Israel
  • 1987–2013
    • Tel Aviv University
      • • Department of Pediatrics
      • • Department of Cell and Developmental Biology
      Tell Afif, Tel Aviv, Israel
  • 2012
    • Maria Sklodowska Curie Memorial Cancer Centre
      Gleiwitz, Silesian Voivodeship, Poland
  • 2009–2012
    • Centre Hospitalier Universitaire de Nantes
      Naoned, Pays de la Loire, France
  • 1997–2012
    • Agricultural Research Organization ARO
      • Institute of Animal Science
      Bet Dagan, Central District, Israel
  • 2011
    • Klinikum Augsburg
      Augsberg, Bavaria, Germany
  • 2004–2011
    • Ministry of Health (Israel)
      Yerushalayim, Jerusalem District, Israel
  • 2002–2011
    • Gamida Cell Ltd.
      Yerushalayim, Jerusalem District, Israel
  • 1999–2011
    • Weizmann Institute of Science
      • • Department of Immunology
      • • Department of Biological Regulation
      Israel
  • 2008–2010
    • University of Nantes
      Naoned, Pays de la Loire, France
    • Institut Paoli Calmettes
      • Cancer Research Center of Marseille (CRCM)
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
    • University of Hamburg
      • Center for Oncology
      Hamburg, Hamburg, Germany
  • 2007
    • Universitätsklinikum Freiburg
      • Allogeneic Stem Cell Transplantation Unit
      Freiburg, Lower Saxony, Germany
    • Ludwig-Maximilian-University of Munich
      München, Bavaria, Germany
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 2006
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 1986–2006
    • Technion - Israel Institute of Technology
      • Rambam Medical Center
      Haifa, Haifa District, Israel
  • 2003
    • Tel Aviv Sourasky Medical Center
      • Intensive Care Unit
      Tel Aviv, Tel Aviv, Israel
  • 2001
    • Edith Wolfson Medical Center, Holon
      Yerushalayim, Jerusalem District, Israel
  • 2000–2001
    • Università degli Studi di Torino
      • Dipartimento di Scienze Cliniche e Biologiche
      Torino, Piedmont, Italy
  • 1987–1999
    • Rambam Medical Center
      • • Department of Oral and Maxillofacial Surgery
      • • Department of Hematology
      H̱efa, Haifa District, Israel
  • 1989–1995
    • Stanford Medicine
      • Department of Medicine
      Stanford, CA, United States
  • 1994
    • Meir Medical Center
      • Department of Obstetrics and Gynecology
      Kafr Saba, Central District, Israel
  • 1988–1990
    • Stanford University
      • • Division of Hematology
      • • Department of Medicine
      Palo Alto, CA, United States