Tadeusz Robak

Medical University of Łódź, Łódź, Łódź Voivodeship, Poland

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Publications (508)1525.42 Total impact

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  • Piotr Smolewski, Tadeusz Robak
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    ABSTRACT: Monoclonal antibodies (MoAbs) were developed in the 1980s in order to treat malignancies. An important target for MoAbs was the CD20 B-cell lineage antigen. Rituximab (RTX) is a chimeric mouse anti-human MoAb that targets the CD20 antigen on the surface of malignant and normal B lymphocytes, and has rapidly become the widest used immunotherapeutic drug. RTX has had a significant impact on how B-cell non-Hodgkin's lymphomas (NHLs) and chronic lymphocytic leukemia is now treated. Areas covered: In this review, the authors demonstrate the mechanisms of action of RTX, and the preclinical data that have led to clinical trials and its final approval for the treatment of B-cell NHLs. Expert opinion: The discovery of RTX opened a new era for treatment of B-cell malignancies and became the starting point for the development of new, more active classes of anti-CD20 agents. Furthermore, it has contributed to the construction of a number of MoAbs specific for other antigens that target different types of neoplastic cells.
    Expert Opinion on Drug Discovery 06/2015; DOI:10.1517/17460441.2015.1045295 · 3.47 Impact Factor
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    ABSTRACT: Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. GlaxoSmithKline, Genmab A/S. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet 04/2015; 385(9980). DOI:10.1016/S0140-6736(15)60027-7 · 45.22 Impact Factor
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    ABSTRACT: Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in CTCL clinical trials there has been little consistency in how responses were defined in each disease "compartment"-some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US FDA for the treatment of CTCL in patients who have received at least 1 prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy, and/or blood involvement. NCT00106431.
    Leukemia & lymphoma 03/2015; DOI:10.3109/10428194.2015.1014360 · 2.61 Impact Factor
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    Haematologica 03/2015; DOI:10.3324/haematol.2014.121459 · 5.87 Impact Factor
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    ABSTRACT: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival. After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group. VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).
    New England Journal of Medicine 03/2015; 372(10):944-53. DOI:10.1056/NEJMoa1412096 · 54.42 Impact Factor
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    ABSTRACT: The role of HLA-G is extensively studied in cancer due to its inhibition of the immune response. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. We, therefore, investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T, and HLA-G 14-base pair, have any influence on the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its clinical course. The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G−725GG or the HLA-G−725GC genotype were lower, and those of the HLA-G ins/ins genotype were higher in the patients compared with the controls. Patients carrying the HLA-G-725CC genotype presented a higher probability of overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (P = 0.003). The homozygous HLA-G del/del had a lower probability of OS than subjects carrying the HLA-G deletion/insertion (del/ins) or the HLA-G ins/ins genotype (P = 0.009). Two HLA-G genotype-based risk groups were defined according to the genotype distribution. The high-risk (HR) group presented a shorter OS than low-risk (LR) patients (P = 0.001). In a multivariate analysis adjusted for International Prognostic Index (IPI) factors, both the intermediate high/high IPI-risk group (P < 0.0001) and the HR genotype group (P = 0.004) independently increased the risk of death. This is the first study indicating an important role of HLA-G polymorphisms for the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibility to DLBCL thus deserves further study. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 03/2015; 54(3). DOI:10.1002/gcc.22235 · 3.84 Impact Factor
  • Tadeusz Robak
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is predominantly a disease of the elderly, with uniquely heterogeneous course. Advanced age has consistently been associated with a poor prognosis in patients with CLL, predominantly due to the frequent occurrence of comorbid conditions. Older and/or comorbid patients with CLL may not tolerate more aggressive approach and in these patients, chlorambucil, especially combined with anti-CD20 monoclonal antibodies, is recommended as the first-line treatment. In physically fit patients without deletion of 17p or TP53 deletion/mutation FCR (fludarabine, cyclophosphamide, rituximab) is the standard first-line therapy. Patients carrying deletion of 17p or mutations of TP53 have a poor response to chemoimmunotherapy. In these patients alemtuzumab-based regimens are frequently used but until recently only allogeneic stem cell transplantation holds the prospect for longer survival. Recently targeted therapies with B-cell receptor pathway inhibitors, ibrutinib and idelalisib or BCL-2 antagonist venetoclax (ABT-199) are associated with remarkable activity in patients with del(17p).
    Acta haematologica Polonica 03/2015; 46(2). DOI:10.1016/j.achaem.2015.02.010
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    ABSTRACT: To improve the efficacy of therapeutic options in chronic lymphocytic leukemia (CLL) an in vitro system to determine the response of mononuclear blood cells from blood of patients was elaborated. The study combines four approaches, i.e., cell viability, apoptosis rate, differential scanning calorimetry (DSC), and immunoblotting to develop personalized therapy protocols based on the cell sensitivity to drug exposure of individual CLL patients. The complementary analyses were performed on 28 peripheral blood samples from previously untreated CLL patients before therapy. The induction and progress of apoptosis in CLL cells exposed in vitro to purine analogs combined with mafosfamide, i.e., cladribine + mafosfamide (CM) and fludarabine + mafosfamide (FM) were assessed using the above approaches. The changes in thermal profiles (decrease/loss of transition at 95±5˚C) coincided with an accumulation of apoptotic cells, a decrease in the number of viable cells, and differences in the expression of the apoptosis‑related protein PARP‑1. No significant changes were observed in the thermal profiles of nuclei isolated from CLL cells resistant to the treatment. The complementary assays revealed a strong relationship between both the in vitro sensitivity of leukemia cells to drugs and the clinical response of the patients, determined usually after the sixth course of treatment (after ~6 months of therapy). As a summary of studies followed by complementary tests, our findings demonstrate the value of in vitro exposure of CLL cell samples to drugs intended to treat CLL patients, before their administration in order to recommend the most suitable and effective therapy for individual patients.
    International Journal of Oncology 01/2015; 46(3). DOI:10.3892/ijo.2015.2823 · 3.03 Impact Factor
  • Tadeusz Robak, Piotr Smolewski
    Blood 01/2015; 125(2):211-2. DOI:10.1182/blood-2014-10-606582 · 10.43 Impact Factor
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    ABSTRACT: Abstract We retrospectively analyzed the rates of significant non-hematological adverse events (AEs) in 105 chronic myeloid leukemia (CML) patients treated with second generation tyrosine kinase inhibitors (TKIs) dasatinib or nilotinib used as second line therapy in Polish tertiary care centers. Our analysis revealed that in a "real life setting", nearly half of CML patients on second generation TKIs suffer from therapy complications. Grade 2-5 non-hematological AEs were observed in 40% of patients treated with nilotinib and in 42% treated with dasatinib (p=0.83). Severe vascular events including PAOD occurred in 11% of patients on nilotinib and 4% on dasatinib (p=0.16). Pleural effusion occurred more often in dasatinib group (26%) than in nilotinib group (2%) (p=003). Importantly, most AEs occurred late, after more than one year of treatment. Since AEs are the most often reason of poor therapy compliance, careful monitoring of tolerability is crucial for an optimal treatment response in CML.
    Leukemia and Lymphoma 01/2015; DOI:10.3109/10428194.2014.994205 · 2.61 Impact Factor
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    ABSTRACT: We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc)+B in patients with relapsed/refractory multiple myeloma in a randomized phase II study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by EBMT criteria. For the 281 randomized patients, median PFS for S+B and plc+B was 8.0 and 7.6 months (HR 0.869, p=0.345), overall response rate was 55% vs. 47% (p=0.213), complete response rate was 11% vs. 7%, and median overall survival (OS) was 30.8 vs. 36.8 months (HR 1.353, p=0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S+B. Siltuximab did not affect B pharmacokinetics. S/plc discontinuation (75% vs. 66%), grade ≥3 neutropenia (49% vs. 29%), thrombocytopenia (48% vs. 34%), and all-grade infections (62% vs. 49%) occurred more frequently with S+B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.
    American Journal of Hematology 01/2015; 90(1). DOI:10.1002/ajh.23868 · 3.48 Impact Factor
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    ABSTRACT: Abstract The IAP family acts as an inhibitor of apoptosis pathways. The potential prognostic value of the expression of selected IAP family members, XIAP, cIAP-1, cIAP-2 and survivin protein was evaluated with regard to treatment response and survival of 56 newly-diagnosed AML adult patients. The presence of these IAP members influenced the achievement of CR. In addition, OS was influenced by low survivin expression in univariate and multivariate analysis (p=0.014 and p=0.013, respectively). A strong correlation was observed between members of the IAP family (XIAP and cIAP-1, XIAP and cIAP-2, cIAP-1 and cIAP-2 p<0.001 for all comparisons), while Smac/DIABLO demonstrated an inverse correlation with XIAP, cIAP-1 and cIAP-2 (p<0.001 for all comparisons). Further studies should be undertaken to better demonstrate the mode of action of IAP members, as well as their prognostic and therapeutic potentials.
    Leukemia and Lymphoma 12/2014; DOI:10.3109/10428194.2014.1003052 · 2.61 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor type A (VEGFA) is a key regulator of angiogenesis and vascular permeability. Chronic lymphocytic leukemia (CLL) cells are able to secrete VEGFA and express VEGFA receptors, thus it can be hypothesized that VEGFA-mediated signaling influences CLL clone survival. In this case-control study we verified whether inherited differences in activities of VEGFA and its main receptor VEGFR2 impact predisposition to CLL or the course of the disease. Four functional single nucleotide polymorphisms (SNPs) including two SNPs in VEGFA gene, namely rs2010963 (+405G>C) and rs3025039 (+936C>T) and two SNPs in VEGFR2 gene including rs7667298 (-271G>A) and rs1870377 (+1719A>T) were genotyped using PCR-based assays in 223 Caucasian CLL patients and 150 matched controls. Regarding VEGF rs2010963 SNP, we observed an association between CLL and allele C distribution with an OR of 1.52 (95% CI, 1.002-2.312), p=0.04. The distribution of other genotypes and alleles was similar in CLL and control groups. No genotype or allele was significantly associated with important prognostic factors in CLL including clinical stage, IgVH mutational status, ZAP-70 expression and FISH cytogenetic abnormalities. In conclusion, the results of our study indicate that genetic polymorphisms in VEGFA mediated pathway may influence the susceptibility to CLL. Copyright © 2014 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 11/2014; 54(2). DOI:10.1016/j.bcmd.2014.11.022 · 2.33 Impact Factor
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    ABSTRACT: ABSTRACT This prospective study has estimated outcomes in 509 elderly AML patients with different treatment approaches depending on ECOG performance status and the Charlson Comorbidity Index (CCI). Patients were stratified into fit (ECOG 0-2 and CCI 0-2) or frail (ECOG >2 and/or CCI >2) groups. The fit patients with CCI 0 received intensive chemotherapy whilst reduced-intensive chemotherapy (R-IC) was given to those with CCI 1-2. The frail patients received the best supportive therapy. The fit patients presented a longer overall survival (OS) than frail subjects but 8-week mortality rates were similar. The CR ratio between fit CCI 0 and CCI 1-2 subgroups was significantly different. Both of the fit subgroups showed similar 8-week mortality rates and OS probabilities. Allocating the fit patients with CCI 1-2 to R-IC enabled to increase the group of elderly patients who could be treated with the intention of inducing remission.
    Leukemia and Lymphoma 11/2014; DOI:10.3109/10428194.2014.985672 · 2.61 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 11/2014; 86(6). DOI:10.1002/cytob.21163 · 2.28 Impact Factor
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    ABSTRACT: Abstract Richter syndrome (RS) or Richter transformation is the development of secondary aggressive lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Most frequently CLL transforms into diffuse large B-cell lymphoma (90%) and rarely (10%) into Hodgkin lymphoma, termed Hodgkin variant of Richter syndrome (HvRS). RS is generally characterized by an aggressive clinical course and poor prognosis. In recent years, major advances have been made in understanding genetic events which relate to progression of CLL or transformation into RS. Better understanding of the molecular pathways has revealed that RS is not a single homogenous entity. The majority of cases are clonally related to the original CLL clone, while a minority develops from an unrelated clone. This review summarizes new data relating to the molecular biology and the genetic/epigenetic changes occurring during Richter transformation, and also considers the clinical features and therapy for both DLBCL-RS and Hodgkin variant-RS. leukemia, DLBCL, Hodgkin lymphoma.
    Leukemia and Lymphoma 10/2014; DOI:10.3109/10428194.2014.979411 · 2.61 Impact Factor
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    ABSTRACT: The bone marrow niche functions are modulated by complicated cytokines network. The aim of our study was to evaluate the levels of VCAM-1, VEGF, MMP-9 and SDF during mobilization of CD34+ cells in patients with hematological malignancies. Thirty four patients were enrolled to the study (19F, 15 M) at median age of 57 years. The group consisted of patients with multiple myeloma (26) and lymphoma (8). The mobilization procedures comprised chemotherapy and then G-CSF. Blood samples were collected before chemotherapy (N = 34) and on the day of the first apheresis (N = 26). Cytokines were evaluated with ELISA assay. We observed significant increase in VCAM-1 levels during mobilization. On contrary, VEGF and SDF levels decreased during mobilization procedure. The levels of MMP-9 were stable during mobilization. We divided patients according to baseline cytokines levels below and above median into “low” and “high” expressors. The group of VEGF “low” expressors had longer median time of G-CSF treatment before first apheresis than ‘high’ expressors. Baseline VEGF levels correlated adversely with duration of G-CSF treatment before first apheresis. Patients were also divided according to median cytokines levels at apheresis into “low” and “high” expressors. “High” VCAM-1 expressors had higher CD34+in peripheral blood as well as higher CD34+numbers collected during first apheresis than “low” expressors. In conclusion, the levels of niche cytokines change significantly during mobilization in patients with hematopoietic malignancies. Baseline VEGF can influence timing of mobilization. Higher VCAM-1 corresponds with higher mobilization efficacy. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 10/2014; DOI:10.1002/jca.21369 · 1.58 Impact Factor
  • Tadeusz Robak
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    ABSTRACT: Anti-CD20 monoclonal antibodies (mAbs), rituximab, ofatumumab and obinutuzumab, have a significant impact in the treatment of chronic lymphocytic leukemia (CLL), particularly in combination with chemotherapy. Over the last few years, several new mAbs have been developed and investigated in CLL. The most promising newer mAbs are directed against CD20, CD19, CD37 and CD40. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib or lenalidomide will probably replace chemotherapy-based combinations in the near future. This review gives a critical overview of established mAbs as well as new antibodies potentially useful in CLL.
    Expert Review of Hematology 09/2014; DOI:10.1586/17474086.2014.963048 · 2.14 Impact Factor

Publication Stats

7k Citations
1,525.42 Total Impact Points

Institutions

  • 1997–2015
    • Medical University of Łódź
      Łódź, Łódź Voivodeship, Poland
  • 1996–2015
    • University of Lodz
      • Department of Cytobiochemistry
      Łódź, Łódź Voivodeship, Poland
  • 2006
    • Jagiellonian University
      Cracovia, Lesser Poland Voivodeship, Poland
  • 2005
    • Wojewódzki Szpital Specjalistyczny im. M. Kopernika w Łodzi
      Łódź, Łódź Voivodeship, Poland
  • 2004
    • Medical University of Gdansk
      Danzig, Pomeranian Voivodeship, Poland
  • 2000
    • Cancer Research Institute
      New York City, New York, United States
  • 1997–2000
    • Medical University of Lublin
      Lyublin, Lublin Voivodeship, Poland