Tadeusz Robak

Medical University of Łódź, Łódź, Łódź Voivodeship, Poland

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Publications (483)1354.93 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: SMIP-016, a new anti-tumour agent, is a mouse/human chimeric fusion protein built on the ADAPTIR™ (modular protein therapeutic) platform targeting human CD37. In this study, for the first time, we examined pro-apoptotic activity of SMIP-016 in combination with monoclonal anti-CD20 antibody, ofatumumab (HuMax-CD20) in de novo chronic lymphocytic leukaemia (CLL) cells and in different B-cell neoplasm-derived lines. In CLL cells SMIP-016 exerted significant cytotoxicity (versus control - p=0.01). In the in vitro models, SMIP-016 was also distinctly active against Raji line (Burkitt lymphoma; BL) (versus control - p=0.007), Riva-1 line (diffuse large B-cell lymphoma; DLBCL) (versus control - p=0.002) and RPMI 8226 line (multiple myeloma cells; MM) (versus control - p=0.03). In studies combining SMIP-016 and ofatumumab, the cytotoxicity against CLL cells was significantly higher than the agents used alone (p<0.03). Remarkably enhanced cytotoxic activity of SMIP-016 and ofatumumab in combination was also observed in Raji and Riva-1 cell lines (p<0.01 and p<0.003, respectively). Importantly, both agents induced cytotoxicity at very low concentrations which suggests that potential side-effects may be decreased in clinical practice. The mechanism responsible for cytotoxicity of SMIP-016 in all the examined models was connected with caspase-dependent apoptosis. In majority of cell types SMIP-016 induced overexpression of Bax protein, as well as downregulation of Bcl-2, cIAP1 (p<0.03) and Smac/DIABLO (p<0.003) apoptosis-regulating proteins. In conclusion, our study demonstrated high pro-apoptotic activity of SMIP-016, especially in combination with ofatumumab, against ex vivo CLL cells, and BL or DLBCL in vitro cell lines. Thus, further preclinical studies in in vivo models are warranted, as this combination may be a promising therapeutic concept for treatment of those malignancies.
    European journal of cancer (Oxford, England: 1990) 08/2014; · 4.12 Impact Factor
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    ABSTRACT: Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.
    British Journal of Haematology 08/2014; · 4.94 Impact Factor
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    ABSTRACT: In this study Jagged-1 and Dll-1 surface expression as well as Notch-1 receptor intracellular domain (Notch-1-IC) expression were assessed by multi-color flow cytometry in leukemic blasts obtained from 88 patients with acute myeloid leukemia (AML). CD34 + peripheral blood stem cells (PBSCs) were used as a control. The median expression of Jagged-1 and Dll-1 was significantly higher in AML blasts than in PBSCs (p = 0.001 and p = 0.002, respectively). Higher expression of Notch-1-IC was detected in patients with poor-risk karyotype as compared to good- and intermediate-risk groups (p = 0.035). In our study, poor-risk cytogenetics and low (< median) expression of Jagged-1 were the only factors associated with significantly shorter overall survival in intensively treated patients according to multivariate analysis. In conclusion, high Jagged-1 surface level in leukemic cells is an independent favorable prognostic factor in patients with AML. To our knowledge, this is the first study evaluating the prognostic role of Notch-1-IC in AML blasts.
    Leukemia & Lymphoma. 07/2014;
  • Leukemia & lymphoma. 06/2014;
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    ABSTRACT: Addition of rituximab (R) to fludarabine and cyclophosphamide (FC) has significantly improved patient outcomes in chronic lymphocytic leukemia (CLL). Whether baseline gene expression can identify patients who will benefit from immunochemotherapy over chemotherapy alone has not been determined. We assessed genome-wide expression of 300 pretreatment specimens from a subset of 552 patients in REACH, a study of FC or R-FC in relapsed CLL. An independent test set was derived from 282 pretreatment specimens from CLL8, a study of FC or R-FC in treatment-naïve patients. Genes specific for benefit from R-FC were determined by assessing treatment-gene interactions in Cox proportional hazards models. REACH patients with higher pretreatment protein tyrosine kinase 2 (PTK2) mRNA levels derived greater benefit from R-FC, with significant improvements in progression-free survival, independent of known prognostic factors in a multivariate model. Examination of PTK2 gene expression in CLL8 patients yielded similar results. Furthermore, PTK2 inhibition blunted rituximab-dependent cell death in vitro. This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials. REACH (NCT00090051) and CLL8 (NCT00281918) were registered at www.clinicaltrials.gov.
    Blood 06/2014; · 9.78 Impact Factor
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    ABSTRACT: Background In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome. Methods In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. Results At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. Conclusions Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707 .).
    New England Journal of Medicine 05/2014; · 51.66 Impact Factor
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    ABSTRACT: As interleukin (IL)-6 is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab (S) to the VMP (bortezomib-melphalan-prednisone) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP+siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for IgA subtype and 17p deletions. With a CR rate of 27% on S+VMP and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP and at least VGPR rates were 71% and 51% (P=0.0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the two arms. Grade ≥3 adverse event incidence was 92% on S+VMP and 81% on VMP (P=0.09) with trends towards more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve CR rate nor long-term outcomes. This study was registered at http://clinicaltrials.gov as NCT00911859.
    Blood 05/2014; · 9.78 Impact Factor
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    ABSTRACT: Although major advancements in antitumor treatment have been observed, several B cell-derived malignancies still remain incurable. A promising approach that involves targeting RNA either by the use of specific antisense oligonucleotides or cytostatic/cytotoxic ribonucleases (RNases) is being promoted. Two amphibian RNases, onconase (ONC; ranpirnase) and, more recently, r-amphinase (r-Amph), have already been tested, but thus far, mostly on solid tumors. In this study, for the first time we provide comprehensive data on ex vivo and in vivo cytotoxic activity of ONC or r-Amph against cancer cells from different B cell lymphoid malignancies, together with their detailed mode of antitumor action. Our data revealed strong pro-apoptotic activity of ONC and r-Amph in both chronic lymphocytic leukemia and aggressive B cell lymphomas, with less impact on acute lymphoblastic leukemia or multiple myeloma cells. Moreover, the antitumor action of ONC and r-Amph was markedly selective against neoplastic cells sparing normal, healthy control‑derived lymphocytes.
    International Journal of Oncology 04/2014; · 2.66 Impact Factor
  • Tadeusz Robak, Ewa Robak
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    ABSTRACT: Introduction: Antibody-drug conjugates (ADCs) are mAb attached to biologically active drugs through specialized chemical linkers with labile bonds. They deliver the cytotoxic agent and release it at the tumor with limited systemic exposure. Areas covered: In this review, the authors summarize and discuss antibody conjugates in Phase II clinical trials in lymphoid malignancies. Furthermore, the article gives a critical overview of Phase II clinical trials of these therapies. Expert opinion: ADCs have increased selectivity and a longer half-life in comparison to systemic chemotherapy. These agents improve the potency of chemotherapy by increasing the accumulation of the cytotoxic drug within neoplastic cells with reduced systemic effects. Improvements in cytotoxin selection and the use of partial antibodies have further improved the clinical value of ADCs. Newer ADCs currently in Phase II clinical trials show promise as treatments for several lymphoid malignancies, especially lymphoma, multiple myeloma and lymphoid leukemia. In the near future, the addition of ADCs to the armamentarium of anticancer drugs should offer novel and more targeted treatment strategies.
    Expert Opinion on Investigational Drugs 04/2014; · 4.74 Impact Factor
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    ABSTRACT: In the last decade peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous (auto-SCT) and allogeneic (allo-SCT) transplantation. The exact mechanisms of HSC mobilization are still not clear and the efficacy of the procedure is hardly predictable. Ligand- receptor interactions of adhesion molecules such as SDF1/CXCR4, VLA4/VCAM-1 or CD44/osteopontin play important role in homing of HSC in the hematopoietic niche. There is some evidence that disruption of the ligand-receptor complex leads to the egress of HSCs to the peripheral blood. The aim of the present study was the evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in the HSC niche, and their impact on the efficacy of mobilization of HSCs in patients with hematological malignancies. 110 (60 females and 50 males) were enrolled in the study. The median age of the patients was 55 (range 22-69) years. The group consisted of patients with multiple myeloma (74), non-Hodgkin lymphoma (19), Hodgkin lymphoma (15) or acute myeloid leukemia (2). The mobilization procedures comprised chemotherapy and subsequent G-CSF at a dose of 10μg/kg daily. 'Poor mobilizers' group was defined according to GITMO criteria: patients with peak CD34+ in the peripheral blood < 20/μL or total yield <2x 10(6) CD34+ cells /kg body weight in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. The group of patients (N=108) who achieved minimal threshold for collections (CD34+ at least 10/μl) proceeded to aphereses. Median total yield of CD34+ in this group was 5.6x10(6) cells /kg body weight, while median number of cells collected during first apheresis was 3.3x10(6) cells /kg body weight. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for 'poor mobilizer'. The group of 'poor mobilizers' had higher frequency of TT genotype in rs13347 (CD44) gene (CC+ CT vs TT p=0.047). Patients homozygous for T allele had lower total yield of CD34+ cells/kg body weight than the group with allele C (Median=3.7x10(6/)/kg vs. 5.8x10(6/)/kg, p=0.019) and lower number of CD34+ cells gathered during first apheresis (0.95x10(6/)/kg vs. 3.3x10(6/)/kg, p=0.04). Multivariate logistic regression analysis revealed that CD44 TT genotype was the only factor associated with 5 fold higher risk of poor mobilization (p=0.037). Polymorphic variants of CXCR4 and VCAM-1 did not significantly influence the efficacy of HSCs mobilization in our group of patients. our results indicate that among investigated SNPs, only CD44 rs13347 has impact on the efficacy of HSCs mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting 'poor mobilizers' population that may benefit from newer modalities, using adhesion molecules inhibitors.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2014; · 3.15 Impact Factor
  • Tadeusz Robak, Pawel Robak
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    ABSTRACT: Introduction: Immunotherapy using mAbs is a safe and effective method for the treatment of chronic lymphocytic leukemia (CLL) and other lymphoid malignancies. In recent years, mAbs based on selective B-cell depletion - rituximab, ofatumumab and obinutuzumab - have been approved for use in CLL therapy. More recently, CD37, a member of the tetraspanin superfamily of cell surface antigens, has been considered as a target for B-cell malignancies. Areas covered: The results of preclinical and early clinical studies suggest that in patients with CLL, newer anti-CD37 agents, otlertuzumab (formerly known as TRU-016), BI 836826, IMGN529 and (177)Lu-tetulomab can be useful in the treatment of this disease. Expert opinion: CD37 may offer advantages over CD20 as a target for CLL cells. It is selectively expressed on normal mature B cells and by most B-cell malignancies. Anti-CD37 antibodies may be useful for patients resistant or refractory to anti-CD20 mAb therapy or relapsing after such treatment. The development of these agents into a clinically useful therapy for CLL is probably many years away and will be followed with great interest by laboratory investigators and clinicians.
    Expert opinion on biological therapy 02/2014; · 3.22 Impact Factor
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    ABSTRACT: Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) still remains an incurable disease. Major advances have been recently made to understand the molecular pathogenesis underlying CLL, but defects in apoptosis are considered to be the most important factors. Although neoplastic cells are resistant to apoptosis in vivo, they show decreased level of spontaneous in vitro apoptosis, with significant differences among CLL patients. This work compares the level of spontaneous CLL cell apoptosis with prognostic factors and clinical course of the disease. In vitro spontaneous apoptosis of peripheral blood lymphocytes was analyzed using Annexin-V assay (confirmed by TUNEL method) in 135 treatment naïve patients with CLL. Levels of apoptosis after 48h culture in patients with stable disease were found to be significantly higher than in the group with progressive course of the disease (p=0.015). Moreover, the level of spontaneous apoptosis after 24h and 48h of incubation correlated inversely with the progression free survival (p=0.026 and 0.009, respectively). These results suggest that in vitro spontaneous apoptosis of CLL cells may be a simple and cheap prognostic test which is relatively quick to use, and can predict the course of the disease and response to treatment. © 2014 Clinical Cytometry Society.
    Cytometry Part B Clinical Cytometry 01/2014; · 2.23 Impact Factor
  • Tadeusz Robak, Agnieszka Wierzbowska
    Leukemia research 01/2014; · 2.36 Impact Factor
  • Andrzej Hellmann, Tadeusz Robak
    Acta haematologica Polonica 01/2014;
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is predominantly a disease of the elderly, with a median age of 70 years at diagnosis. Appropriate treatment approach requires physical examination, evaluation of performance status, co-morbidities and severity of comorbid conditions, biological age, peripheral, blood count with morphologic examination. In addition, in some patients bone marrow evaluation, serum biochemistry including serum lactate dehydrogenasis and β2-microglobulin, Coombs’ test, imaging of adenomegalies, assessed either by CT scan or by the combination of chest X-ray and abdomen ultrasound should be incorporated into decision-making process with regard to intensity of treatment. In patients requiring therapy, particularly a second-line treatment, del 17p and/or p53 mutations should be also checked. Elderly and/or comorbid patients with CLL may not tolerate more aggressive approach due to high risk of unacceptable toxicity of purine nucleoside analogs, especially in combination with cyclophosphamide and rituximab. Therefore in these patients population, chlorambucil +/- rituximab is still accepted as the first-line treatment and chlorambucil remains the backbone of treatment against which the new protocols should be tested. The results of ongoing trials investigating the role of new immunochemotherapies and the other novel agents will probably modify the treatment of CLL in the following years. In this article we present recommendations for diagnosis, prognosis and therapy of CLL elaborated by by PTH i T and PALG-CLL group.
    Acta haematologica Polonica 01/2014;
  • Journal of Thermal Analysis and Calorimetry 01/2014; · 1.98 Impact Factor
  • edited by D. Ghimishi, 01/2014; Verlag /Publisher:Lambert Academic Publishing, Germany., ISBN: 978-3-659-11163-1
  • Tadeusz Robak
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world, accounting for approximately 30% of all leukemias in Europe and North America. Recently, significant progress in the characterization and understanding of the biology and prognosis of CLL has provided new opportunities for the development of innovative, more effective therapies. Several new anti-CD20 monoclonal antibodies directed against lymphoid cells have been developed and are under investigation in preclinical studies and clinical trials. Currently, the most promising is obinutuzumab, a novel third generation anti-CD20 monoclonal antibody that exhibits superior caspase-independent apoptosis and antibody-dependent cellular cytotoxicity than rituximab. The antibody has shown a safety profile similar to that of rituximab and promising efficacy in patients with CLL. The CD37 antigen may be advantageous over CD20 in diseases in which the level of CD37 expression is higher than that of CD20. The results of recent preclinical and early clinical studies suggest that anti-CD37 antibodies and related agents can be useful in the treatment of CLL, and many small molecule inhibitors targeting B-cell antigen receptor (BCR) signaling pathways have recently been under investigation in patients. Promising clinical results have been observed with a Btk inhibitor, ibrutinib, and a selective inhibitor of PI3Kδ, idelalisib. Several other agents including immunomodulating agents and those targeting the antiapoptotic bcl-2 family of proteins also show promise in treating CLL. Moreover, immune-based treatment strategies intended to augment the cytotoxic potential of T cells offer exciting new treatment options for patients with CLL.
    Acta haematologica Polonica 01/2014;
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology. The results of experimental studies point to the involvement of innate immunity receptors-toll-like receptors (TLR)-in the pathogenesis of the disease. The aim of the study was to assess the expression of TLR3, 7, and 9 in the population of peripheral blood mononuclear cells (PBMC) and in B lymphocytes (CD19(+)), T lymphocytes (CD4(+) and CD8(+)) using flow cytometry. The study group included 35 patients with SLE and 15 healthy controls. The patient group presented a significantly higher percentage of TLR3- and TLR9-positive cells among all PBMCs and their subpopulations (CD3(+), CD4(+), CD8(+), and CD19(+) lymphocytes) as well as TLR7 in CD19(+) B-lymphocytes, compared to the control group. There was no correlation between the expression of all studied TLRs and the disease activity according to the SLAM scale, and the degree of organ damage according to the SLICC/ACR Damage Index. However, a correlation was observed between the percentage of various TLR-positive cells and some clinical (joint lesions) and laboratory (lymphopenia, hypogammaglobulinemia, anaemia, and higher ESR) features and menopause in women. The results of the study suggest that TLR3, 7, and 9 play a role in the pathogenesis of SLE and have an impact on organ involvement in SLE.
    Mediators of Inflammation 01/2014; 2014:381418. · 3.88 Impact Factor
  • Tadeusz Robak
    Blood 12/2013; 122(24):3854-5. · 9.78 Impact Factor

Publication Stats

6k Citations
1,354.93 Total Impact Points

Institutions

  • 1994–2014
    • Medical University of Łódź
      Łódź, Łódź Voivodeship, Poland
    • University of Lodz
      • Department of Cytobiochemistry
      Łódź, Łódź Voivodeship, Poland
  • 2012
    • Institute of Hematology and Blood Transfusion, Warsaw
      Warszawa, Masovian Voivodeship, Poland
  • 2000–2012
    • Medical University of Warsaw
      • Katedra i Klinika Hematologii Onkologii i Chorób Wewnętrznych
      Warsaw, Masovian Voivodeship, Poland
    • Cancer Research Institute
      New York City, New York, United States
  • 2009–2011
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2008
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
    • Instytut Hematologii i Transfuzjologii
      Warszawa, Masovian Voivodeship, Poland
  • 2005
    • Wojewódzki Szpital Specjalistyczny im. M. Kopernika w Łodzi
      Łódź, Łódź Voivodeship, Poland
    • University of Vienna
      • Universitätsklinik für Innere Medizin I
      Vienna, Vienna, Austria
  • 2002–2004
    • Medical University of Gdansk
      Danzig, Pomeranian Voivodeship, Poland
  • 1997–2000
    • Medical University of Lublin
      Lyublin, Lublin Voivodeship, Poland