Krzysztof Warzocha

Publications of Krzysztof Warzocha

• Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study.

  Authors: Jerzy Holowiecki, Sebastian Grosicki, Sebastian Giebel, Tadeusz Robak, Slawomira Kyrcz-Krzemien, Kazimierz Kuliczkowski, Aleksander B Skotnicki, Andrzej Hellmann, Kazimierz Sulek, Anna Dmoszynska [......] Wieslaw W Jedrzejczak, Barbara Zdziarska, Krzysztof Warzocha, Krystyna Zawilska, Mieczyslaw Komarnicki, Marek Kielbinski, Beata Piatkowska-Jakubas, Agnieszka Wierzbowska, Malgorzata Wach, Olga Haus

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 04/2012;

  PURPOSEThe goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acutePURPOSEThe goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML). PATIENTS AND METHODSA cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms.ResultsComplete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% ± 4% at 3 years) compared with the DA arm (33% ± 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 × 10(9)/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02). CONCLUSIONThe addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.

• Chronic eosinophilic leukemia with erythroblastic proliferation and the rare translocation t(8;9)(p22;p24) with PCM1-JAK2 fusion gene - a distinct clinical, pathological and genetic entity with potential treatment target?

  Authors: Monika Prochorec-Sobieszek, Barbara Nasilowska-Adamska, Katarzyna Borg, Izabella Kopeć, Kinga Kos-Zakrzewska, Przemyslaw Juszczyński, Krzysztof Warzocha

  Leukemia & lymphoma. 01/2012;

  Abstract BIK (bcl2-interacting killer) is the founding member of the BH3-only BCL-2 family of pro-apoptotic proteins, which is found suppressed in various cancers. In multiple myeloma (MM), BIK hasAbstract BIK (bcl2-interacting killer) is the founding member of the BH3-only BCL-2 family of pro-apoptotic proteins, which is found suppressed in various cancers. In multiple myeloma (MM), BIK has been shown to be epigenetically silenced in vitro but there is lack of clinical data. We investigated CpG methylation status of BIK promoter in a well-characterized clinical series of multiple myeloma (MM) patients and analyzed for clinical relevance. Forty MM patients (21 male, 19 female, mean age 66) were studied. According to International Staging System (ISS) there were classified to stage-I 16 patients, stage-II 12 patients and stage-III 12 patients. Methylation in the BIK CpG island was assessed by methylation-specific PCR (MSP) assay. Logistic regression analysis was used to investigate for associations between gene methylation and age, ISS stage, performance status, extramedullary disease, bone disease, anemia (Hb10<mg/dl), serum albumin, beta 2 microglobulin levels and relapsed/refractory disease. Methylation in the BIK CpG Island was detected in 16 patients (40%) with a trend favouring male gender (OR=3.08, p=0.09) and the development of bone disease and extramedullary disease (OR=1.6, p=0.35 and OR=3, p=0.14 respectively). MM patients with methylated the BIK CpG island had a statistically significant risk for evolving into relapsed/refractory disease (OR=5.4, p=0.03). This study provides clinical evidence that methylation-induced transcriptional silencing of BIK pro-apoptotic gene may occur in MM, which might serve as a predictor of developing relapsed/refractory MM. These findings warrant validation in larger cohorts of patients and suggest therapeutic utility for agents that enhance BIK expression.

• Palifermin does not influence the incidence and severity of GvHD nor long-term survival of patients with hematological diseases undergoing HSCT.

  Authors: Barbara Nasilowska-Adamska, Richard Szydlo, Piotr Rzepecki, Anna Czyz, Agnieszka Tomaszewska, Miroslaw Markiewicz, Tigran Torosian, Maria Bieniaszewska, Andrzej Hellman, Wieslaw Wiktor Jedrzejczak, Jerzy Holowiecki, Mieczyslaw Komarnicki, Krzysztof Warzocha, Bozena Marianska

  Annals of transplantation : quarterly of the Polish Transplantation Society. 12/2011; 16(4):47-54.

  Palifermin is known as the effective growth factor to reduce the incidence, duration and severity of oral mucositis (OM) following hematopoietic stem cell transplantation (HSCT). However, additionalPalifermin is known as the effective growth factor to reduce the incidence, duration and severity of oral mucositis (OM) following hematopoietic stem cell transplantation (HSCT). However, additional data on the long-term safety of palifermin and its potential influence on graft versus host disease (GvHD) are needed. In this multi-center, non-randomized, matched-control study we assessed early overall survival (OS), incidence and severity of acute/chronic GvHD (a/cGvHD) and incidence of secondary malignancies in 36 patients with hematological diseases treated with allogeneic HSCT and palifermin. The incidence of aGvHD was 28.2% and 38.4% (p=0.34) and cGvHD 41% and 53.8% (p=0.70) in the palifermin and control groups, respectively. The incidence of aGvHD grade 0-IV was 69.2%, 5.1%, 17.9%, 2.5%, 2.5% in the palifermin group and 61.5%, 12.8%, 12.8%, 10.2%, 5.2% in the control group, respectively (p>0.4 for each). The incidence of limited and extensive cGvHD was 17.9% and 23% in the palifermin versus 25.6% and 28.2% in the control group (p=0.32 and p=0.50, respectively). The estimated 3-year OS did not differ significantly between studied groups. We did not observe any secondary malignancies in these patients. Administration of palifermin doesn't seem to influence the incidence and severity of aGvHD/cGvHD, secondary malignancies occurrence and early OS in patients undergoing allogeneic HSCT.

• Haematological parameters in postpartum women and their babies in Poland - comparison of urban and rural areas.

  Authors: Cezary Wojtyła, Przemysław Biliński, Piotr Paprzycki, Krzysztof Warzocha

  Annals of agricultural and environmental medicine : AAEM. 12/2011; 18(2):380-5.

  Anaemia is a serious health problem in the contemporary world which aff ects 24.8% of the total human population. It is especially frequent among pregnant women and children. Anaemia is considered asAnaemia is a serious health problem in the contemporary world which aff ects 24.8% of the total human population. It is especially frequent among pregnant women and children. Anaemia is considered as a risk factor of an unfavourable outcome of pregnancy. More than a half of the cases of anaemia, especially among pregnant women, are caused by iron deficiency. The prevalence of anaemia worldwide is especially high among the rural population. It is estimated that the incidence of anaemia after delivery is 4-27%. Anaemia occurring in pregnant women is the cause of anaemia in newborns after birth. The objective of the study was analysis of the haematological parameters of postpartum women and newborns, with particular consideration of the comparison between urban and rural areas. The studies were conducted with the use of questionnaire forms based on the project undertaken in the USA: Pregnancy Risk Assessment Monitoring System (PRAMS). The survey was carried out on a single day, during the period 9-13 August 2010, in all hospitals in Poland where mothers were hospitalized with their newborns. The presented study was based on the replies concerning the results of whole blood count tests in mothers and their babies. The results of the study did not confirm any significant differences between Hct, Hb and RBC values between urban and rural mothers. In both cases, the Hct levels were at the lower limit of normal. Also, no differences with respect to the above-mentioned values were noted among the newborns, although the babies of urban mothers had a higher Hb level. The results of the studies indicate the lack of differences in the health of mothers and their newborn babies with respect to the urban or rural place of residence. Despite this, anaemia is associated with complications which are life-threatening for the mother and the baby; therefore, efforts should be undertaken in order to minimize this problem.

• Effect of FCGR2A and FCGR3A variants on CLL outcome.

  Authors: David Dornan, Olivia Spleiss, Ru-Fang Yeh, Guillemette Duchateau-Nguyen, Annika Dufour, Jianguo Zhi, Tadeusz Robak, Sergey I Moiseev, Anna Dmoszynska, Philippe Solal-Celigny [......] Javier Loscertales, John Catalano, Boris V Afanasiev, Loree Larratt, Viktor A Rossiev, Isabelle Bence-Bruckler, Christian H Geisler, Marco Montillo, Michael K Wenger, Martin Weisser

  Blood. 11/2010; 116(20):4212-22.

  Polymorphisms of activating Fc-γ receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulatePolymorphisms of activating Fc-γ receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulate antibody-dependent cellular cytotoxicity (ADCC) activity. Whether single-nucleotide polymorphisms of FCGRs correlate with survival of chronic lymphocytic leukemia (CLL) patients treated with a monoclonal antibody containing regimen is unclear. We assessed the FCGR3A and FCGR2A genotype of patients enrolled in the REACH trial, where patients received fludarabine and cyclophosphamide (FC) or rituximab plus FC (R-FC). FCGR3A and FCGR2A polymorphisms did not demonstrate prognostic significance in the FC arm (P = .42 and P = .64, respectively) or R-FC arm (P = .41 and P = .88, respectively) with respect to progression free survival. Patients with intermediate affinity genotypes (FV and HR) benefited significantly from addition of rituximab (hazard ratio = 0.55 [0.37-0.8 CI]; P = .0017 and hazard ratio = 0.63 [0.44-0.9 CI]; P = .011, respectively). Similar benefit was suggested for patients with high- affinity VV and HH (hazard ratio = 0.86 [0.4-1.84 CI]; P = .7 and hazard ratio = 0.7 [0.41-1.18 CI]; P = .18, respectively) and low-affinity FF and RR (hazard ratio = 0.85 [0.56-1.29 CI]; P = .44 and hazard ratio = 0.82 [0.47-1.42 CI]; P = .48, respectively). Overall, our results suggest that FCGR2A and FCGR3A polymorphisms do not significantly influence the outcomes of relapsed or refractory CLL patients treated with FC or the monoclonal antibody regimen R-FC.

• Efficacy and safety of a new intravenous immunoglobulin 10% formulation (octagam® 10%) in patients with immune thrombocytopenia.

  Authors: Tadeusz Robak, Claudia Mainau, Barbara Pyringer, Krzysztof Chojnowski, Krzysztof Warzocha, Anna Dmoszynska, Jan Straub, Paul Imbach

  Hematology (Amsterdam, Netherlands). 10/2010; 15(5):351-9.

  Intravenous immunoglobulin (IVIg) has an established role in the treatment of immune thrombocytopenia (ITP). The safety and efficacy of a new ready-to-use IVIg 10% formulation (octagam(®) 10%) wereIntravenous immunoglobulin (IVIg) has an established role in the treatment of immune thrombocytopenia (ITP). The safety and efficacy of a new ready-to-use IVIg 10% formulation (octagam(®) 10%) were investigated in a prospective phase III study in 116 adult patients with ITP (platelet count ≤20×10(9)/l). Sixty-six patients had chronic ITP and 49 were newly diagnosed. Patients received octagam 10% 1 g/kg/day on two consecutive days; infusion rate was adjusted according to tolerability to a maximum of 0·12 ml/kg/minute. Eighty per cent of patients attained the primary efficacy endpoint of clinical response (platelet count ≥50×10(9)/l within 6 days of dosing). The median time to response was 2 days and the median duration of response was 12 days; mean response duration was 24·1 days. octagam 10% was well tolerated and effective in this population representative of adult patients with ITP, even at the maximum infusion rate of 0·12 ml/kg/minute, without unexpected safety issues.

• Complete remission following treatment with bortezomib, doxorubicin, dexamethasone and autologous stem cell transplant in patient with immunoglobulin E multiple myeloma.

  Authors: Ryszard Pogłód, Maria Kraj, Barbara Kruk, Renata Hagedorna-Tronina, Magdalena Łetowska, Krzysztof Warzocha

  Leukemia & lymphoma. 10/2010; 51(12):2291-4.

• Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia.

  Authors: Tadeusz Robak, Anna Dmoszynska, Philippe Solal-Céligny, Krzysztof Warzocha, Javier Loscertales, John Catalano, Boris V Afanasiev, Loree Larratt, Christian H Geisler, Marco Montillo, Ilya Zyuzgin, Peter S Ganly, Caroline Dartigeas, András Rosta, Jörg Maurer, Myriam Mendila, M Wayne Saville, Nancy Valente, Michael K Wenger, Sergey I Moiseev

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 03/2010; 28(10):1756-65.

  Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone orRituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL. This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276). After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life. R-FC significantly improved the outcome of patients with previously treated CLL.

• Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study).

  Authors: Tadeusz Robak, Krzysztof Jamroziak, Joanna Gora-Tybor, Beata Stella-Holowiecka, Lech Konopka, Bernadetta Ceglarek, Krzysztof Warzocha, Ilona Seferynska, Jaroslaw Piszcz, Malgorzata Calbecka, Aleksandra Kostyra, Jadwiga Dwilewicz-Trojaczek, Anna Dmoszyñska, Krystyna Zawilska, Andrzej Hellmann, Andrzej Zdunczyk, Stanislaw Potoczek, Magdalena Piotrowska, Krzysztof Lewandowski, Jerzy Z Blonski

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 03/2010; 28(11):1863-9.

  PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacyPURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m(2) combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. RESULTS Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. CONCLUSION Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

• Plasma TNF-alpha and IL-10 level-based prognostic model predicts outcome of patients with diffuse large B-Cell lymphoma in different risk groups defined by the International Prognostic Index.

  Authors: Ewa Lech-Maranda, Jacques Bienvenu, Florence Broussais-Guillaumot, Krzysztof Warzocha, Anne-Sophie Michallet, Tadeusz Robak, Bertrand Coiffier, Gilles Salles

  Archivum immunologiae et therapiae experimentalis. 02/2010; 58(2):131-41.

  Tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 are key cytokines involved in lymphoma development. Their pretreatment plasma levels were reported to influence the clinical course ofTumor necrosis factor (TNF)-alpha and interleukin (IL)-10 are key cytokines involved in lymphoma development. Their pretreatment plasma levels were reported to influence the clinical course of non-Hodgkin's lymphoma. In this study the impact of combined elevation of TNF-alpha and IL-10 on disease features and outcome of patients with diffuse large B-cell lymphoma (DLBCL) were investigated. Plasma TNF-alpha and IL-10 levels were determined at the time of diagnosis in a group of 106 DLBCL patients uniformly treated with anthracycline-based regimens. Three risk groups depending on the pretreatment levels of the cytokines were identified: low-, intermediate-, and high-risk groups. In univariate analysis, the cytokine intermediate- and high-risk groups were associated with lower probability of achieving a complete remission (odds ratio [OR] = 0.2, 95% confidence interval [CI] 0.06-0.6, p = 0.006 and OR = 0.05, 95% CI 0.01-0.2, p < 0.0001, respectively) and shorter progression-free survival (PFS) (OR = 4.4, 95% CI 1.9-10.2, p < 0.001 and OR = 9.7, 95% CI 4.1-23.0, p < 0.0001, respectively) and overall survival (OS) (OR = 4.2, 95% CI 1.7-10.1, p = 0.002 and OR = 11.2, 95% CI 4.4-28.4, p < 0.0001, respectively) in comparison with the cytokine low-risk group. In multivariate analysis, the cytokine intermediate- and high-risk groups also correlated with shorter PFS (relative risk [RR] = 4.5, 95% CI 1.9-10.9, p = 0.001 and RR = 5.8, 95% CI 2.2-15.3, p < 0.0001, respectively) and OS (RR = 4.6, 95% CI 1.8-12.0, p = 0.001 and RR = 7.5, 95% CI 2.7-20.9, p < 0.0001, respectively) regardless of the International Prognostic Index (IPI) scoring system. The TNF-alpha and IL-10 level-based index may work as an additional model to the IPI for predicting the survival of DLBCL patients. This model may help to identify patients in a given IPI risk group for whom more accurate and risk-adapted treatment could be advised.

• Frequency of BCR-ABL gene mutations in Polish patients with chronic myeloid leukemia treated with imatinib: a final report of the MAPTEST study.

  Authors: Krzysztof Lewandowski, Krzysztof Warzocha, Andrzej Hellmann, Aleksander Skotnicki, Witold Prejzner, Kajetana Foryciarz, Tomasz Sacha, Michał Gniot, Mirosław Majewski, Iwona Solarska, Grazyna Nowak, Bartosz Wasag, Mikołaj Kobelski, Cezary Scibiorski, Marek Siemiatkowski, Maria Lewandowska, Mieczysław Komarnicki

  Polskie archiwum medycyny wewnȩtrznej. 12/2009; 119(12):789-94.

  INTRODUCTION: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor treatment. OBJECTIVES: The aimINTRODUCTION: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor treatment. OBJECTIVES: The aim of the study was to evaluate the frequency of BCR-ABL gene mutations in patients with CML (the MAPTEST study) treated with imatinib (IM). PATIENTS AND METHODS: Direct sequencing analysis of BCR-ABL gene was performed in 92 patients treated with IM for more than 3 months. The mean time of IM treatment was 18 months. At the time of the analysis, 75 patients were in the first chronic phase (CP), 4 in the second CP, 5 in the acceleration and 8 in the blastic phase. Fifty-seven patients (62%) were treated with IM at a daily dose of 400 mg and 35 patients with higher doses (600 or 800 mg daily). Inclusion criteria were based on the European Leukemia Net definitions for failure and suboptimal response to IM. RESULTS: Twelve mutations were detected in 11 of 92 patients, including 4 mutations (36.7%) diagnosed during CP, 3 (27.3%) in acceleration, and 4 (36.7%) in blast crisis. In 1 patient with lymphoid blast crisis of CML coexisting F359V and Y253F mutations were detected. In the whole group mutations were detected in 2 of 5 patients (40%) with primary resistance (M351T, F359V + Y253F) and in 9 of 87 patients (10.3%) (E255K, T315I-3x, M351T, E355G, F359V-2x) with acquired resistance to IM. CONCLUSIONS: The study confirmed the usefulness of BCR-ABL gene mutation screening in patients with CML resistant to IM therapy.

• Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG).

  Authors: Ewa Lech-Maranda, Marek Seweryn, Sebastian Giebel, Jerzy Holowiecki, Beata Piatkowska-Jakubas, Joanna Wegrzyn, Aleksander Skotnicki, Marek Kielbinski, Kazimierz Kuliczkowski, Monika Paluszewska [......] Barbara Zdziarska, Grazyna Palynyczko, Lech Konopka, Tomasz Szpila, Krzysztof Gawronski, Kazimierz Sulek, Jaroslaw Sokolowski, Janusz Kloczko, Krzysztof Warzocha, Tadeusz Robak

  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 08/2009;

  OBJECTIVES: The addition of cladribine to the standard regimen consisting of daunorubicin and cytarabine has been reported to increase the efficacy of induction therapy in acute myeloid leukemiaOBJECTIVES: The addition of cladribine to the standard regimen consisting of daunorubicin and cytarabine has been reported to increase the efficacy of induction therapy in acute myeloid leukemia (AML). The goal of this study was to determine the effect of this modification on the incidence and spectrum of infectious complications. METHODS: Case report forms of 309 patients with newly diagnosed AML who had been enrolled in the prospective, randomized 'DAC-7 vs. DA-7' trial were reviewed. The frequency, etiology, localization, severity, and outcome of infections were compared for patients receiving only daunorubicin and cytarabine (DA-7) and those additionally treated with cladribine (DAC-7). RESULTS: A total of 443 febrile episodes were reported with no significant difference between the treatment groups. A trend towards a higher frequency of bacteremias was observed among DA-7 patients compared to those in the DAC-7 group (31% vs. 21%; p=0.08). The treatment arms did not differ in terms of the distribution of the isolated Gram-positive, Gram-negative, fungal, and viral organisms. However, when bacteremias were considered, Gram-positive blood cultures tended to be more frequent in the DA-7 compared to the DAC-7 group (16% vs. 8.5%; p=0.07). This difference reached statistical significance when major blood bacteremias were analyzed separately (13% vs. 5%; p=0.02). Complete recovery from infections was observed in the majority of patients across both treatment arms and no significant difference was noted regarding infection-related mortality. CONCLUSIONS: The addition of cladribine to standard induction chemotherapy has no impact on the incidence and spectrum of infectious complications in newly diagnosed AML patients.

• Activity of cladribine combined with cyclophosphamide in frontline therapy for chronic lymphocytic leukemia with 17p13.1/TP53 deletion: report From the Polish Adult Leukemia Group.

  Authors: Tadeusz Robak, Jerzy Z Blonski, Ewa Wawrzyniak, Joanna Gora-Tybor, Aleksandra Palacz, Anna Dmoszynska, Lech Konopka, Krzysztof Warzocha, Krzysztof Jamroziak

  Cancer. 12/2008;

  BACKGROUD:: The 17p13.1 deletion that causes loss of the p53-encoding TP53 gene is the most powerful predictor of a poor response to conventional therapy and shortened survival in patients withBACKGROUD:: The 17p13.1 deletion that causes loss of the p53-encoding TP53 gene is the most powerful predictor of a poor response to conventional therapy and shortened survival in patients with chronic lymphocytic leukemia (CLL). The results of this study have demonstrated that the cladribine and cyclophosphamide regimen may improve treatment results in this poor-risk patient population. METHODS:: In this study, the authors retrospectively analyzed the efficacy and toxicity of 2-CdA with cyclophosphamide combination (the CC regimen) in 20 patients with previously untreated B-cell CLL who had 17p13.1 deletion reported to the Polish Adult Leukemia Group (PALG) registry. The CC regimen consisted of 2-CdA at a dose of 0.12 mg/kg and cyclophosphamide at a dose of 250 mg/m(2) given intravenously for 3 consecutive days. The CC cycles were repeated at 28-day intervals for up to 6 cycles. RESULTS:: Overall, 16 of 20 patients (80%) responded to CC therapy, including 10 patients (50%) who obtained a complete response and 6 patients (30%) who obtained a partial response. The median progression-free survival reached 23 months (95% confidence interval, 5-41 months). The overall survival probability at 2 years was 52.5% (95% confidence interval, 26%-79%). Treatment toxicity generally was acceptable. Infections were the most common grade 3/4 complications and occurred in 6 patients (30%). CONCLUSIONS:: In this retrospective analysis, the results demonstrated that the CC regimen produced a relatively high response rate in patients with previously untreated CLL who had 17p13.1/TP53 deletion, although the response duration and survival were not satisfactory. It is possible that a combination of the CC regimen with p53-independent agents may improve treatment results in this poor-risk patient population. Cancer 2009. (c) 2008 American Cancer Society.

• High incidence of ancestral HLA haplotype 8.1 and monoclonal incomplete DH-JH immunoglobulin heavy chain gene rearrangement in persistent polyclonal B-cell lymphocytosis.

  Authors: Dariusz Wolowiec, Jacek Nowak, Miroslaw Majewski, Olga Haus, Ewa Duszenko, Beata Stella-Holowiecka, Renata Mika-Witkowska, Hanna Makuch-Lasica, Grazyna Nowak, Andzelika Krawcewicz, Kazimierz Kuliczkowski, Krzysztof Warzocha

  Annals of hematology. 08/2008; 87(7):597-8.

• Randomized comparison of cladribine alone or in combination with cyclophosphamide, and cyclophosphamide, vincristine and prednisone in previously untreated low-grade B-cell non-Hodgkin lymphoma patients: final report of the Polish Lymphoma Research Group.

  Authors: Ewa Kalinka-Warzocha, Jaroslaw Wajs, Ewa Lech-Maranda, Bernadetta Ceglarek, Jerzy Holowiecki, Irena Federowicz, Jan Walewski, Jaroslaw Czyz, Tadeusz Robak, Krzysztof Warzocha

  Cancer. 08/2008; 113(2):367-375.

  BACKGROUND.: The objective of this study was to compare the efficacy of 3 regimens, cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisoneBACKGROUND.: The objective of this study was to compare the efficacy of 3 regimens, cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination in previously untreated patients with low-grade B-cell non-Hodgkin lymphoma (LGNHL). METHODS.: For this 3-arm, phase 3 study, 197 patients were randomly allocated to receive 6 monthly courses of cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination. Patients for whom all clinical data were available and 162 patients who completed scheduled chemotherapy were analyzed for the endpoints of this study. RESULTS.: Compared with cyclophosphamide, vincristine, and prednisone combination regimen, cladribine alone or cladribine and cyclophosphamide combination induced higher probability of overall response (odds ratio [OR] = 4.0; 95% confidence interval [CI], 1.7-9,3; P = .002, and OR = 8.5; 95% CI, 3.2-22.7; P < .0001, respectively), complete remission (OR = 5.8; 95% CI, 1.8-18.5; P = .003; and OR = 14; 95% CI, 4.4-44; P < .0001, respectively), progression-free survival (log-rank test P < .0001), but not overall survival. After incorporating the International Prognostic Index in multivariate analysis, treatment with cladribine-containing regimens remained an independent prognostic factor for progression-free survival (chi(2) = 35.94; hazard ratio = 2.38; P < .0002). Incidences of infections were similar in the randomized groups, whereas cladribine and cyclophosphamide combination, but not cladribine alone, induced more frequent neutropenia, anemia, and thrombocytopenia compared with cyclophosphamide, vincristine, and prednisone combination (P < .05 for each). This resulted in a higher frequency of prolongation of intervals between cladribine and cyclophosphamide combination and cyclophosphamide, vincristine, and prednisone combination cycles (P < .05), but dose reductions due to hematological or other toxicity did not differ significantly in cladribine alone, cladribine and cyclophosphamide combination, and cyclophosphamide, vincristine, and prednisone combination groups. CONCLUSIONS.: For patients with LGNHL, first-line cladribine alone or cladribine and cyclophosphamide combination regimens both provided similar treatment responses, acceptable toxicity, and better response rates than cyclophosphamide, vincristine, and prednisone combination. Cancer 2008. (c) 2008 American Cancer Society.

• Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy.

  Authors: Monika Prochorec-Sobieszek, Grzegorz Rymkiewicz, Hanna Makuch-Łasica, Mirosław Majewski, Katarzyna Michalak, Robert Rupiński, Krzysztof Warzocha, Renata Maryniak

  Arthritis research & therapy. 06/2008; 10(3):R55.

  ABSTRACT: INTRODUCTION: The purpose of this study was to analyze the data of patients with T-cell large granular lymphocyte (T-LGL) lymphocytosis associated with inflammatory arthropathy or with noABSTRACT: INTRODUCTION: The purpose of this study was to analyze the data of patients with T-cell large granular lymphocyte (T-LGL) lymphocytosis associated with inflammatory arthropathy or with no arthritis symptoms. METHODS: Clinical, serological as well as histopathological, immuhistochemical, and flow cytometric evaluations of blood/bone marrow of 21 patients with T-LGL lymphocytosis were performed. The bone marrow samples were also investigated for T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangements by polymerase chain reaction with heteroduplex analysis. RESULTS: Neutropenia was observed in 21 patients, splenomegaly in 10, autoimmune diseases such as rheumatoid arthritis (RA) in 9, unclassified arthritis resembling RA in 2, and autoimmune thyroiditis in 5 patients. T-LGL leukemia was recognized in 19 cases. Features of Felty syndrome were observed in all RA patients, representing a spectrum of T-LGL proliferations from reactive polyclonal through transitional between reactive and monoclonal to T-LGL leukemia. Bone marrow trephines from T-LGL leukemia patients showed interstitial clusters and intrasinusoidal linear infiltrations of CD3+/CD8+/CD57+/granzyme B+ lymphocytes, reactive lymphoid nodules, and decreased or normal granulocyte precursor count with left-shifted maturation. In three-color flow cytometry (FCM), T-LGL leukemia cells demonstrated CD2, CD3, and CD8 expression as well as a combination of CD16, CD56, or CD57. Abnormalities of other T-cell antigen expressions (especially CD5, CD7, and CD43) were also detected. In patients with polyclonal T-LGL lymphocytosis, T cells were dispersed in the bone marrow and the expression of pan-T-cell antigens in FCM was normal. Molecular studies revealed TCRB and TCRG gene rearrangements in 13 patients and TCRB, TCRG, and TCRD in 4 patients. The most frequently rearranged regions of variable genes were Vbeta-Jbeta1, Jbeta2 and Vgamma If Vgamma10-Jgamma. Moreover, in 4 patients, additional rearrangements of IG kappa and lambda variable genes of B cells were also observed. CONCLUSION: RA and neutropenia patients represented a continuous spectrum of T-LGL proliferations, although monoclonal expansions were most frequently observed. The histopathological pattern and immunophenotype of bone marrow infiltration as well as molecular characteristics were similar in T-LGL leukemia patients with and without arthritis.

• Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study.

  Authors: Jerzy Hołowiecki, Sebastian Grosicki, Sławomira Kyrcz-Krzemien, Aleksander B Skotnicki, Beata Piatkowska-Jakubas, Krzysztof Warzocha, Ilona Seferynska, Barbara Zdziarska

  Annals of hematology. 06/2008; 87(5):361-7.

  In 1992-1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based onIn 1992-1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based on these findings and encouraging results of the addition of cladribine to standard daunorubicin+Ara-C induction regimen (DAC) in acute myeloid leukemia (AML), the Polish Adult Leukemia Group (PALG) conducted a pilot study on the administration of cytarabine, daunorubicin, and fludarabine (DAF) as a reinduction treatment of AML to assess tolerance, toxicity, and early outcome. The DAF regimen consisted of daunorubicine 60 mg m(-2) day(-1) iv on days 1-3 and fludarabine 25 mg m(-2) day(-1) iv on days 1-5 given before cytarabine 200 mg m(-2) day(-1) in ci on days 1-7. Thirty-four AML patients with median age 39, 24% relapsed and 76% refractory, were included into the study between September 2003 and August 2004. Achieved response rate in the whole study population was 56%; n = 16 patients with complete remission (CR), and n = 3 patients with partial remission (PR). Fifteen of 16 patients achieved CR after the first course of therapy. Only 9% of total population died before the assessment of remission. All patients developed severe neutropenia. Serious infections were observed in 47% of the cases. Severe thrombocytopenia was observed in 72% of the patients. All patients required substitution of platelet concentrates (median 4), and PRBC (median 5). Severe alopecia, mucositis, vomiting were of low frequency. Liver, kidney, or circulatory failure, diarrhea, or polyneuropathy were not observed. The probability of overall survival (OS) for 1 year for the whole study population (34 patients) and the group of 16 patients in CR was: 44% (95% confidence interval [CI] 36-52%) and 69% (95% CI 55-83%), respectively. The probability of leukemia-free survival (LFS) for 1 year was 38% (95% CI 22-54%). Summarizing, DAF regimen used as the induction therapy in relapsed/refractory AML was well tolerated with acceptable toxicity and early efficacy.

• Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study.

  Authors: Jerzy Holowiecki, Malgorzata Krawczyk-Kulis, Sebastian Giebel, Krystyna Jagoda, Beata Stella-Holowiecka, Beata Piatkowska-Jakubas, Monika Paluszewska, Ilona Seferynska, Krzysztof Lewandowski, Marek Kielbinski, Anna Czyz, Agnieszka Balana-Nowak, Maria Król, Aleksander B Skotnicki, Wieslaw W Jedrzejczak, Krzysztof Warzocha, Andrzej Lange, Andrzej Hellmann

  British journal of haematology. 05/2008;

  The treatment of adults with Philadelphia-negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time toThe treatment of adults with Philadelphia-negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4-2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17-60 years), 116 patients were suitable for analysis. MRD level >/=0.1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population (P < 0.0001), as well as in the standard risk (SR, P = 0.0003) and high-risk (P = 0.008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0.1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects (P = 0.001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL.

• Biclonal T-cell receptor gammadelta+ large granular lymphocyte leukemia associated with rheumatoid arthritis.

  Authors: Monika Prochorec-Sobieszek, Monika Chełstowska, Grzegorz Rymkiewicz, Mirosław Majewski, Krzysztof Warzocha, Renata Maryniak

  Leukemia & lymphoma. 05/2008; 49(4):828-31.

• Genetic polymorphisms in the proximal IL-10 promoter and susceptibility to non-Hodgkin lymphoma.

  Authors: Ewa Lech-Maranda, Lucile Baseggio, Carole Charlot, Dominique Rigal, Françoise Berger, Krzysztof Jamroziak, Krzysztof Warzocha, Bertrand Coiffier, Gilles Salles

  Leukemia & lymphoma. 12/2007; 48(11):2235-8.