Malgorzata Kowal

Medical University of Lublin, Lublin, Lublin Voivodeship, Poland

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Publications (12)33.89 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Long-term outcomes following newer therapies for chronic lymphocytic leukemia (CLL) have rarely been reported. This paper presents the results of the final analysis of the Polish Adult Leukemia Group PALG-CLL2 study performed ten years from final patient enrollment. With the extended follow-up time, it was found that cladribine (2-CdA)-based combinations, CMC (2-CdA, cyclophosphamide, mitoxantrone) and CC (2-CdA, cyclophosphamide) administered as first-line treatment of progressive CLL result in significantly longer progression-free survival, but similar overall survival compared to 2-CdA monotherapy. Furthermore, the risk of potentially fatal late adverse events including infections, autoimmune complications and, particularly, secondary neoplasms is comparable among patients treated with CMC, CC or 2-CdA. The results of our analysis support the importance of long-term outcome monitoring of randomized trials in CLL.
    Leukemia & lymphoma 05/2013; · 2.61 Impact Factor
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    ABSTRACT: OBJECTIVES: The relationship between treatment of Chronic lymphocytic leukemia (CLL) with cladribine (2 - CdA) or chlorambucil and immune thrombocytopenia (IT) have not been yet determined. Methods:The records of 777 patients in two randomized PALG (Polish Adult Leukemia Group) CLL programs treated with these agents were retrospectively analyzed. RESULTS: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence was seen between patients on chlorambucil or 2-CdA - based regiments (p=0.33). IT developed at a median time of 0.499 years (0,06 - 4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yrs, 95%CI: 0.06-4.22) in relation to patients treated with 2- CdA- based regiments (0.52 yrs, 95%CI: 0.34-0.69, p=0,049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yrs. vs. 3.2 yrs. p=0.23) but the severity of bleeding was more pronounced in the 2- CdA group. The responses to IT therapy was 35%, 54% and 75% for steroids, chemotherapy and splenectomy respectively. CONCLUSIONS: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2 - CdA-based regiments compared to chlorambucil regimen the clinical course of haemorrhagic diathesis was more severe in 2 - CdA group. Also the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS. © 2013 John Wiley & Sons A/S.
    European Journal Of Haematology 03/2013; · 2.55 Impact Factor
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    ABSTRACT: In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (γH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in γH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis.
    Annals of Hematology 02/2011; 90(2):173-83. · 2.87 Impact Factor
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    ABSTRACT: Despite many therapeutic regimens introduced recently, chronic lymphocytic leukemia (CLL) is still an incurable disorder. Thus, there is an urgent need to discover novel, less toxic and more effective drugs for CLL patients. In this study, we attempted to assess simvastatin, widely used as a cholesterol-lowering drug, both as a single agent and in combination with purine analogs-fludarabine and cladribine-in terms of its effect on apoptosis and DNA damage of CLL cells. The experiments were done in ex vivo short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (named γH2AX) and activated ATM kinase (ataxia telangiectasia mutated kinase), reporters of DNA damage. Results of our study revealed that simvastatin induced apoptosis of CLL cells concurrently with lowering of BCL-2/BAX ratio, and its pro-apoptotic effect is tumor-specific, not affecting normal lymphocytes. We observed that combinations of simvastatin+fludarabine and simvastatin+cladribine had a synergic effect in inducing apoptosis. Interestingly, the rate of apoptosis caused by simvastatin alone and in combination was independent of markers of disease progression like ZAP-70 and CD38 expression or clinical stage according to Rai classification. We have also seen an increase in γH2AX expression in parallel with activation of ATM in most of the analyzed samples. The results suggest that simvastatin can be used in the treatment of CLL patients as a single agent as well as in combination with purine analogs, being equally effective both in high-risk and good-prognosis patients. One of the mechanisms of simvastatin action is inducing DNA damage that ultimately leads to apoptosis.
    Annals of Hematology 05/2010; 89(11):1115-24. · 2.87 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with variable clinical course and prognosis. Therefore, the role of prognostic factors is very important, especially for identifying the group of patients who require intensive treatment. The aim of this study was to assess whether the rate of apoptosis caused by purine analogues differs between patients with better or worse prognostic factors. The experiments were preformed in cultures of blood and bone marrow obtained from CLL patients. The cultures were supplemented with cladribine and fludarabine. We determined the percentage of caspase-3-positive cells and the BCL-2/BAX ratio, and subsequently these apoptosis markers were correlated with the expression of ZAP-70 and CD38, lymphocyte counts, lactate dehydrogenase and beta(2)-microglobulin levels and clinical stage according to the Rai classification. The results showed that bone marrow cells are more sensitive to apoptosis caused by purine analogues than cells derived from blood, supporting the idea that these two compartments have different proliferative statuses. The cells from ZAP-70-positive patients seem to enter apoptosis more readily than those from ZAP-70-negative patients; thus, ZAP-70-positive patients are more likely to benefit from treatment with purine analogues.
    Acta Haematologica 03/2010; 123(3):171-8. · 0.89 Impact Factor
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    ABSTRACT: Given the recent findings on the importance of CD38 signaling in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), we hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to B-CLL risk. We evaluated two potentially functional CD38 SNPs, intronic rs6449182 (184C>G) and missense rs1800561 (418C>T, Arg140Trp) in two hospital-based case-control studies (study A and validation study B). Genotyping was done using PCR-based assays in a total of 460 Polish Caucasian patients with B-CLL and 503 age-matched and gender-matched controls. We found that frequencies of both variant alleles (rs6449182 G and rs1800561 T) were significantly higher in B-CLL. In study A, logistic regression analysis revealed an association between B-CLL and genotypes: rs6449182 CG [odds ratio (OR), 3.57; 95% confidence interval (95% CI), 2.4-5.3], rs6449182 GG (OR, 5.2; 95% CI, 2.36-11.5), and rs1800561 CT (OR, 6.72; 95% CI, 1.5-30.1), although no homozygous rs1800561 TT genotype was detected in either study. These results were confirmed in study B, which showed an association between B-CLL and genotypes rs6449182 CG (OR, 4.00; 95% CI, 2.7-6.0), rs6449182 GG (OR, 12.84; 95% CI, 4.3-38.7), and rs1800561 CT (OR, 10.12; 95% CI, 1.3-81.6), and in the combined analysis of both studies. We also observed that rs6449182 G carriers had more advanced clinical stage (P=0.002) and tended to be younger at diagnosis (P=0.056). Furthermore, we found higher CD38 transcript levels and higher proportions of CD38-positive cells in carriers of rs6449182 G and rs1800561 T alleles (P<0.05 for all comparisons). In conclusion, our data show that CD38 SNPs may affect CD38 expression and contribute to the increased risk of B-CLL carcinogenesis.
    Cancer Epidemiology Biomarkers &amp Prevention 03/2009; 18(3):945-53. · 4.56 Impact Factor
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    ABSTRACT: In this study we attempted to assess interactions of thalidomide with fludarabine in terms of their effect on DNA damage and apoptosis of chronic lymphocytic leukemia (CLL) cells. The experiments were done in ex vivo short-term cell cultures of peripheral blood cells from newly diagnosed untreated patients. We analyzed phosphorylation of histone H2AX on Ser139 (gammaH2AX), reporter of DNA damage, and expression of activated caspase-3, as a marker of apoptosis. Modest increase in expression of gammaH2AX caused by thalidomide was observed in samples of some analyzed patients. The increase in expression of gammaH2AX was also seen in leukemic TK6 cells treated with thalidomide. While treatment of CLL cells with thalidomide alone had no significant effect on apoptosis the treatment with thalidomide+fludarabine had greater than the additive effect on frequency of apoptotic cells. The data suggest that oxidative DNA damage likely induced by thalidomide sensitizes CLL cells to undergo apoptosis in response to fludarabine.
    Leukemia research 11/2008; 33(7):997-1000. · 2.36 Impact Factor
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    ABSTRACT: The status of the immune system of patients with B-cell chronic lymphocytic leukemia (B-CLL) is not yet sufficiently characterized. Clinically, B-CLL patients present immunodeficiency increasing along with disease progression and signs of autoimmunity. In the current study, we evaluated the expression of FOXP3 in CD4+CD25hi T regulatory lymphocytes (Treg) and their influence on immune response against tumor and viral antigens in the complex system of peripheral blood mononuclear cells. In 80 B-CLL patients, the frequency of Treg (CD4+CD25hi FOXP3+) cells was significantly higher in B-CLL patients when compared to healthy volunteers (HV) and increased with the progression of the disease (median: 8.24% in stage A, 11.24% in stage B and 12.57% in stage C according to the Binet classification). The frequency of Treg showed no correlation with prognostic markers such as ZAP-70, CD38 and HLA-G. Notably, Treg frequency correlated with serum levels of TNF (r(2)=0.45, p=0.001). T-cell immune responses against epitopes derived from the tumor-associated antigens survivin, fibromodulin and RHAMM as well as from the influenza matrix protein were evaluated. Functionally, higher frequencies of Treg correlated with decreased T-cell responses against viral and tumor antigens. In conclusion, we detected higher frequencies of Treg in B-CLL patients than in HV. Furthermore, Treg constitute the crucial mechanism of immunosuppression in B-CLL patients.
    Oncology Reports 10/2008; 20(3):677-82. · 2.30 Impact Factor
  • Acta Haematologica 02/2008; 119(3):187-9. · 0.89 Impact Factor
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    ABSTRACT: A 61-year-old man with plasma cell leukemia was treated with thalidomide, lovastatin and dexamethasone. Lovastatin was added to the usual thalidomide/dexamethasone regimen after obtaining the results of shortterm culture, which revealed that thalidomide/lovastatin produced a higher rate of apoptosis, compared with apoptosis induced by each drug alone. Thirty-six months after the beginning of the therapy, the patient is still in complete hematologic remission.
    Clinical Leukemia. 01/2007; 1(3):195-197.
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    ABSTRACT: Zeta-chain associated protein of 70kDa (ZAP-70) is the most promising surrogate marker for the immunoglobulin heavy chain variable region (IgV(H)) mutation status in B-cell chronic lymphocytic leukemia (B-CLL). Crespo et al. proposed the detection of ZAP-70 by flow cytometry. Recently several novel monoclonal antibodies appeared on market. We compared different staining methods utilizing monoclonal antibodies (moAb) against ZAP-70: anti-ZAP-70 PE, clone 1E7.2, anti-ZAP-70 PE, clone 17A/P-ZAP70 directly stained with flourochrome as well as anti-ZAP-70 antibody, clone 2F3.2 stained with Zenontrade mark Alexa Fluor(R) 488 Labeling Kit. Additionally different reagents for permeabilization such as IntraPrep, FIX & PERM, Perm/Wash and 70% ethanol/paraformaldehyde were used to find the most clinically relevant and easy assay to determine ZAP-70 expression in B-CLL. Moreover we compared results of ZAP-70 expression assessed by whole blood protocol with those obtained using-peripheral mononuclear cells isolated from whole blood. Anti-ZAP-70 moAb clone 17A/P-ZAP70 gave elevated results for all B-CLL patients as well as healthy controls. Staining with anti-ZAP-70 moAb clone 1E7.2 and anti-ZAP-70 moAb clone 2F3.2 was effective in distinguishing negative and positive cells for ZAP-70 protein expression. Not statistically significant discrepancies of ZAP-70 expression were noticed between different fixation and permeabilization methods. Basing on results obtained during this study we can recommend use of anti-ZAP-70 PE, clone 1E7.2 moAb utilizing whole blood protocol with commercial kits for permeabilization as an easy method that brings compatible results to the original method proposed by Crespo et al.
    Cytometry Part B Clinical Cytometry 08/2006; 70(4):293-301. · 2.23 Impact Factor
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    ABSTRACT: In this prospective randomized trial, we compared the efficacy and toxicity of cladribine (2-CdA) alone to 2-CdA combined with cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC) in untreated progressive chronic lymphocytic leukemia (CLL). Study end points were complete response (CR), overall response, minimal residual disease (MRD), progression-free survival, overall survival, and toxicity. From January 1, 1998 to December 31, 2003, 508 patients from 15 hematology departments were randomized. Compared with 2-CdA, CMC induced higher CR rate (36% vs 21%, P = .004), and a trend for higher CR rate with CC was observed (29% vs 21%, P = .08). Furthermore, the percentage of patients who were in CR and were MRD negative was higher in CMC compared with 2-CdA (23% vs 14%, P = .042). There were no differences in overall response, progression-free survival, and overall survival among treatment groups. Grade 3/4 neutropenia occurred more frequently in CC (32%) and CMC (38%) than in 2-CdA (20%) (P = .01 and P = .004, respectively). Infections were more frequent in CMC compared with 2-CdA (40% vs 27%, P = .02). In conclusion, CMC used in first-line treatment of CLL results in a higher CR rate and suppresses MRD more efficiently than 2-CdA monotherapy, although associates with increased toxicity. No important differences in efficacy and toxicity were found between CC and 2-CdA regimens.
    Blood 08/2006; 108(2):473-9. · 9.78 Impact Factor

Publication Stats

160 Citations
33.89 Total Impact Points

Institutions

  • 2007–2011
    • Medical University of Lublin
      • Department Hemato-Oncology and Bone Marrow Transplantation
      Lublin, Lublin Voivodeship, Poland
  • 2008
    • Universität Ulm
      • Department of Internal Medicine
      Ulm, Baden-Wuerttemberg, Germany