Andrzej Hellmann

Publications of Andrzej Hellmann

• 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.

• Microscopic examination of bone marrow aspirates in malignant disorders of haematopoiesis-a comparison of two slide preparation techniques.

  Authors: Krzysztof Lewandowski, Agnieszka Complak, Andrzej Hellmann

  Annals of hematology. 04/2012; 91(4):497-505.

  It is mandatory to perform microscopic examinations of bone marrow aspirates during the diagnosis of many neoplastic haematopoiesis disorders. In 2008, The International Committee for StandardizationIt is mandatory to perform microscopic examinations of bone marrow aspirates during the diagnosis of many neoplastic haematopoiesis disorders. In 2008, The International Committee for Standardization in Hematology recommended the use of two types of slides for the microscopic evaluation of bone marrow: wedge-spread film and crush film slides. Because these techniques have not yet been compared, we performed such a comparison. Routine bone marrow samples from 250 patients diagnosed due to different neoplastic haematological disorders were evaluated. The major differences between the two compared techniques were identified in 13 patients with non-Hodgkin's lymphoma, seven patients with systemic mastocytosis and 11 patients with acute leukaemias or myelodysplastic syndromes or chronic myelomonocytic leukaemia. Differences were noted also in many patients with multiple myeloma, but the clinical significance of these discrepancies was rather modest. The major causes of the differences observed seemed to be the dilution of marrow with blood cells and the focal growth of many neoplastic cells. We believe that the crush technique is more advantageous compared to the wedge-spread films. Therefore, we recommend the use of crush films as the primary method for establishing a diagnosis or for making therapeutic decisions based on the microscopic examination of bone marrow.

• Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study.

  Authors: Myron S Czuczman, Luis Fayad, Vincent Delwail, Guillaume Cartron, Eric Jacobsen, Kazimierz Kuliczkowski, Brian K Link, Lauren Pinter-Brown, John Radford, Andrzej Hellmann, Eve Gallop-Evans, Christine G Dirienzo, Nancy Goldstein, Ira Gupta, Roxanne C Jewell, Thomas S Lin, Steen Lisby, Martin Schultz, Charlotte A Russell, Anton Hagenbeek

  Blood. 03/2012;

  New treatments are required for rituximab-refractory follicular lymphoma (FL). Patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 monoclonal antibody; dose 1, 300New treatments are required for rituximab-refractory follicular lymphoma (FL). Patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 monoclonal antibody; dose 1, 300 mg; doses 2-8, 500 or 1000 mg; N=116). Median age was 61 years, 47% had high-risk FLIPI scores, 65% were chemotherapy-refractory, and median number of prior therapies was 4. Overall response rate (ORR) was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, ORR was 22%. Median progression-free survival (mPFS) was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation; mPFS for these patients was 9.1 months. Most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions; none were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well-tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. This study was registered at www.clinicaltrials.gov as NCT00394836.

• The prophylactic use of granulocyte-colony stimulating factor during remission induction is associated with increased leukaemia-free survival of adults with acute lymphoblastic leukaemia: a joint analysis of five randomised trials on behalf of the EWALL.

  Authors: Sebastian Giebel, Xavier Thomas, Helene Hallbook, Klaus Geissler, Jean-Michel Boiron, Francoise Huguet, Elisabeth Koller, Ulrich Jaeger, Bengt Smedmyr, Andrzej Hellmann, Jerzy Holowiecki

  European journal of cancer (Oxford, England : 1990). 12/2011; 48(3):360-7.

  Granulocyte-colony stimulating factor (G-CSF) is used to prevent febrile neutropenia and support intense chemotherapy. However, its impact on long-term outcome in oncological patients includingGranulocyte-colony stimulating factor (G-CSF) is used to prevent febrile neutropenia and support intense chemotherapy. However, its impact on long-term outcome in oncological patients including adults with acute lymphoblastic leukaemia (ALL) has not been determined so far. In the current study follow-up data from individual patients recruited in five multicentre, prospective, randomised trials were pooled to perform a joint analysis. Among 347 adults and adolescents with ALL, 185 were assigned to receive prophylactically G-CSF along with induction chemotherapy while 162 patients were treated without G-CSF support. With the median follow-up of 5.3years, there was a tendency towards increased 5year probability of the overall survival for the G-CSF arm compared to the controls (32%±4% versus 23%±4%, p=.07), which reached statistical significance in a subgroup of T-ALL (51%±8% versus 29%±9%, p=.01) and among patients aged 21-40years (44%±6% versus 27%±6%, p=.03). The probability of leukaemia-free survival was 38%±4% and 24%±4% (p=.01) while the median remission duration equalled 33 and 17months (p=.007), respectively. In a multivariate analysis the prophylactic use of G-CSF was independently associated with reduced risk of relapse (hazard ratio (HR)=.64, p=.007) and treatment failure (HR=.67, p=.02). The prophylactic use of G-CSF during induction of ALL is associated with improved long-term outcome and should be recommended especially in a setting of T-ALL and in 'young adults'. Our analysis provides the first direct evidence coming from prospective trials for the impact of primary G-CSF prophylaxis on disease-free survival of oncological patients.

• Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma.

  Authors: Andrzej Hellmann, Simon Rule, Jan Walewski, Ofer Shpilberg, Huaibao Feng, Helgi van de Velde, Hamina Patel, Donna M Skee, Suzette Girgis, Vernon J Louw

  Clinical pharmacokinetics. 12/2011; 50(12):781-91.

  Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect theseBortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. Conclusions: In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

• The time is crucial for exvivo expansion of T regulatory cells for therapy.

  Authors: Natalia Marek, Maria Bieniaszewska, Adam Krzystyniak, Jolanta Juscinska, Jolanta Mysliwska, Piotr Witkowski, Andrzej Hellmann, Piotr Trzonkowski

  Cell transplantation. 04/2011;

  Ex vivo expanded CD4+CD25highCD127- T regulatory cells (Tregs) are recognized as a promising candidate for immunosuppressive therapy in humans. However, due to the plasticity of Tregs lineage andEx vivo expanded CD4+CD25highCD127- T regulatory cells (Tregs) are recognized as a promising candidate for immunosuppressive therapy in humans. However, due to the plasticity of Tregs lineage and artificial environment present during ex vivo expansion, Tregs easily lose suppressive activity. Here, we followed expanding CD4+CD25highCD127- Tregs and their naive (CD45RA+) and memory-like (CD45RA-) subsets in order to establish the best conditions of the expansion. We found that, regardless of the phenotype sorted, expanding Tregs were undergoing changes resembling homeostatic proliferation and transformed into effector memory-like cells which produced not only suppressive interleukin(IL) 10 but also IL6, IL17 and interferon(IFN)γ. With the time ex vivo, Tregs were losing the expression of FoxP3 and suppressive activity both when stimulated and when at rest. The only variable which helped preserving suppressive abilities of Tregs was the limitation of the time of ex vivo cultures to the two weeks only. According to our study, the highest number of highly suppressive Tregs could be yielded with CD4+CD25highCD127- Tregs cultured no longer than two weeks. Thorough quality check, preferentially with the assessment of FoxP3 expression and IFNγ suppression assay, should be applied to assess suppressive activity of the cells.

• A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib.

  Authors: Andrzej Mital, Anna Piskorz, Krzysztof Lewandowski, Bartosz Wasąg, Janusz Limon, Andrzej Hellmann

  European journal of haematology. 03/2011; 86(6):531-5.

  Mastocytosis is a myeloproliferative neoplasm characterized by the excessive proliferation of mast cells. Mast cell leukaemia (MCL), the aggressive form of this disease, requires cytoreductiveMastocytosis is a myeloproliferative neoplasm characterized by the excessive proliferation of mast cells. Mast cell leukaemia (MCL), the aggressive form of this disease, requires cytoreductive therapy, such as cladribine, interferon-alpha-2b and, most recently, tyrosine kinase inhibitors - dasatinib or imatinib. We present a case of a 56-yr-old female patient with aleukaemic MCL in whom the typical KIT-D816V mutation was not detected. Sequencing of the entire coding sequence of KIT gene revealed a somatic mutation in exon 9 (p.A502_Y503dup). This mutation was previously reported in patients with gastrointestinal stromal tumours (GIST). Considering the good response to imatinib in such patients, therapy with imatinib was attempted in our patient. The treatment tolerance and outcomes were very good, with reduced mast cell infiltration of the bone marrow, normalization of the serum tryptase concentration and resolution of the clinical signs and symptoms. In the absence of the KIT-D816V in systemic forms of mast cell proliferation, a search for other mutations is indicated, preferably by sequencing the entire KIT gene, as this can influence the choice of treatment. The finding of the p.A502_Y503dup in exon 9, a mutation which has been observed in GIST but not previously reported in any form of aggressive mastocytosis, can be associated with a good response to imatinib in both diseases.

• The early reduction of leukemic blasts in bone marrow on day 6 of induction treatment is predictive for complete remission rate and survival in adult acute myeloid leukemia; the results of multicenter, prospective Polish Adult Leukemia Group study.

  Authors: Sebastian Grosicki, Jerzy Holowiecki, Sebastian Giebel, Slawomira Kyrcz-Krzemien, Kazimierz Kuliczkowski, Marek Kielbinski, Aleksander B Skotnicki, Beata Piatkowska-Jakubas, Andrzej Hellmann, Agnieszka Wierzbowska, Beata Stella-Holowiecka, Barbara Zdziarska, Malgorzata Calbecka

  American journal of hematology. 02/2011; 86(5):437-9.

  The aim of this study was to prospectively evaluate the impact of early bone marrow response on complete remission (CR) rate and long-term outcome in adults with acute myeloid leukemia. Bone marrowThe aim of this study was to prospectively evaluate the impact of early bone marrow response on complete remission (CR) rate and long-term outcome in adults with acute myeloid leukemia. Bone marrow cytology was assessed on day 6 of induction treatment in 164 patients, revealing the presence of ≥5% blasts in 61 cases. In this subgroup the CR rate was significantly lower compared to the remaining patients (P < 0.00001) resulting in decrease of the overall survival (P = 0.002). Persistence of ≥5% blasts in bone marrow on day 6 of induction is an easily available surrogate marker to be used for treatment decisions.

• Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1-2 study.

  Authors: Bertrand Coiffier, Nedjad Losic, Birgitte Biilmann Rønn, Stéphane Lepretre, Lars Møller Pedersen, Ole Gadeberg, Henrik Frederiksen, Marinus H J van Oers, James Wooldridge, Janusz Kloczko, Jerzy Holowiecki, Andrzej Hellmann, Jan Walewski, Tadeusz Robak, Jørgen Petersen

  British journal of haematology. 07/2010; 150(1):58-71.

  The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients withThe purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden.

• Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.

  Authors: William G Wierda, Thomas J Kipps, Jirí Mayer, Stephan Stilgenbauer, Cathy D Williams, Andrzej Hellmann, Tadeusz Robak, Richard R Furman, Peter Hillmen, Marek Trneny, Martin J S Dyer, Swami Padmanabhan, Magdalena Piotrowska, Tomas Kozak, Geoffrey Chan, Randy Davis, Nedjad Losic, Joris Wilms, Charlotte A Russell, Anders Osterborg

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 03/2010; 28(10):1749-55.

  New treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm)New treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL. Patients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24. This planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia. Ofatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis 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.

• 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.

• Ofatumumab, a Novel CD20 Monoclonal Antibody, Is Active in Patients With Fludarabine- and Alemtuzumab-Refractory or Bulky Fludarabine-Refractory Chronic Lymphocytic Leukemia Irrespective of Prior Rituximab.

  Authors: William Wierda, Thomas Kipps, Jirí Mayer, Stephan Stilgenbauer, Cathy D Williams, Andrzej Hellmann, Tadeusz Robak, Richard R Furman, Peter Hillmen, Marek Trneny, Martin J S Dyer, Swami Padmanabhan, Magdalena Piotrowska, Tomas Kozak, Geoffrey Chan, Randy Davis, Nedjad Losic, Joris Wilms, Charlotte Russell, Anders Osterborg

  Clinical lymphoma & myeloma. 12/2009; 9(6):E36.

  Ofatumumab, a novel CD20 monoclonal antibody, produces high response rates regardless of prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulkyOfatumumab, a novel CD20 monoclonal antibody, produces high response rates regardless of prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulky fludarabine-refractory chronic lymphocytic leukemia.Background: Patients with CLL refractory to fludarabine and alemtuzumab (FA-ref ) or refractory to fludarabine with bulky (> 5 cm) lymphadenopathy (BF-ref ) have poor outcomes with current salvage therapy (overall response rate [ORR], 23%; overall survival [OS], 9 months). Ofatumumab is a human monoclonal antibody that binds a distinct membrane-proximal epitope on the CD20 molecule and elicits more efficient in vitro complement-dependent cytotoxicity of B-cell lines and primary tumor cells versus rituximab. We assessed whether prior rituximab exposure impacted outcomes with ofatumumab in patients with FA-ref or BF-ref CLL enrolled in an international, pivotal trial. Patients and Methods: Patients received 8 weekly ofatumumab infusions followed by 4 monthly infusions (infusion, 1300 mg; infusions 2-12, 2000 mg). The primary endpoint was ORR (1996 NCI-WG criteria) assessed by an Independent Endpoint Review Committee over 24 weeks. Secondary efficacy endpoints included progression-free survival (PFS) and OS. Results: In the 59 FA-ref and 79 BF-ref patients at the planned interim analysis, ORR was 58% (95% CI, 40%-74%) and 47% (95% CI, 32%-62%), respectively. Median PFS was 5.7 months (95% CI, 4.5-8.0 months) and 5.9 months (95% CI, 4.9-6.4 months), and median OS was 13.7 months (95% CI, 9.4-[not yet reached] months) and 15.4 months (95% CI, 10.2-20.2 months), respectively. In the subgroup of FA-ref (n = 35) and BF-ref (n = 43) patients who previously received a rituximab-containing regimen, ORR was 54% and 44%, and median PFS was 5.5 months (95% CI, 3.7-8.0 months) and 5.5 months (95% CI, 3.8-6.4 months), respectively. In FA-ref and BF-ref patients refractory to fludarabine in combination with rituximab and cyclophosphamide (n = 16 in each group), ORR was 50% and 44%, and median PFS was 4.6 months (95% CI, 2.3-6.4 months) and 5.6 months (95% CI, 2.1-6.6 months), respectively. Conclusion: Single-agent ofatumumab is active in patients with FA-ref and BF-ref CLL, irrespective of prior anti-CD20 monoclonal antibody therapy with rituximab, including refractoriness to fludarabine-based regimens containing rituximab.

• JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms.

  Authors: Anna Siemiątkowska, Maria Bieniaszewska, Andrzej Hellmann, Janusz Limon

  Leukemia research. 08/2009;

  We report three novel mutations in JAK2 exons 12, 19 and 25 in V617F-negative patients with polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Scanning of JAK2 exons 12-25 andWe report three novel mutations in JAK2 exons 12, 19 and 25 in V617F-negative patients with polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Scanning of JAK2 exons 12-25 and MPL exon 10 revealed the presence of JAK2 alterations in six and MPL W515L/K mutations in five of 34 patients with myeloproliferative disorders. Our results confirm that routine JAK2 analysis should include exon 12 mutations in polycythemia vera patients. MPL gene mutations seem to be associated with thrombocytosis, regardless of the type of myeloproliferative neoplasm.

• 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.

• First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells.

  Authors: Piotr Trzonkowski, Maria Bieniaszewska, Jolanta Juścińska, Anita Dobyszuk, Adam Krzystyniak, Natalia Marek, Jolanta Myśliwska, Andrzej Hellmann

  Clinical immunology (Orlando, Fla.). 07/2009;

  Here, we describe a procedure and first-in-man clinical effects of adoptive transfer of ex vivo expanded CD4+CD25+CD127- T regulatory cells (Tregs) in the treatment of graft versus host diseaseHere, we describe a procedure and first-in-man clinical effects of adoptive transfer of ex vivo expanded CD4+CD25+CD127- T regulatory cells (Tregs) in the treatment of graft versus host disease (GvHD). The cells were sorted from buffy coats taken from two family donors, expanded ex vivo and transferred to respective recipients who suffered from either acute or chronic GvHD. The therapy allowed for significant alleviation of the symptoms and reduction of pharmacologic immunosuppression in the case of chronic GvHD, while in the case of grade IV acute GvHD it only transiently improved the condition, for the longest time within all immunosuppressants used nonetheless.

• Impact of granulocyte colony stimulating factor administered during induction and consolidation of adults with acute lymphoblastic leukemia on survival: long-term follow-up of the Polish adult leukemia group 4-96 study.

  Authors: Sebastian Giebel, Jerzy Holowiecki, Malgorzata Krawczyk-Kulis, Krystyna Jagoda, Beata Stella-Holowiecka, Maria Sadus-Wojciechowska, Andrzej Hellmann, Anna Dmoszynska, Monika Paluszewska, Tadeusz Robak, Lech Konopka, Ilona Seferynska, Aleksander Skotnicki, Slawomira Kyrcz-Krzemien

  Leukemia & lymphoma. 06/2009;

• Outcome of HLA-matched related allogeneic hematopoietic stem cell transplantation for patients with acute leukemia in first complete remission treated in Eastern European centers. Better results in recent years.

  Authors: Sebastian Giebel, Myriam Labopin, Jerzy Holowiecki, Boris Labar, Mieczyslaw Komarnicki, Vladimir Koza, Tamas Masszi, Martin Mistrik, Andrzej Lange, Andrzej Hellmann, Antonin Vitek, Joze Pretnar, Jiri Mayer, Piotr Rzepecki, Karel Indrak, Wieslaw Wiktor-Jedrzejczak, Jerzy Wojnar, Malgorzata Krawczyk-Kulis, Slawomira Kyrcz-Krzemien, Vanderson Rocha

  Annals of hematology. 04/2009;

  The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemiaThe goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid (n = 459) and lymphoblastic (n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 +/- 2%, 19 +/- 2%, and 23 +/- 2%, respectively. The cumulative incidence of NRM decreased from 22 +/- 2% for patients treated between 1990 and 2002 to 15 +/- 3% for transplantations performed between 2003 and 2006 (p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.

• First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial.

  Authors: Anton Hagenbeek, Ole Gadeberg, Peter Johnson, Lars Møller Pedersen, Jan Walewski, Andrzej Hellmann, Brian K Link, Tadeusz Robak, Marek Wojtukiewicz, Michael Pfreundschuh, Michael Kneba, Andreas Engert, Pieter Sonneveld, Mimi Flensburg, Jørgen Petersen, Nedjad Losic, John Radford

  Blood. 07/2008; 111(12):5486-95.

  Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocyticOfatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.

• 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.