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  • 1
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3281-3281
    Abstract: Abstract 3281 Poster Board III-1 Introduction: In the two consecutive German CML studies III and IIIA (recruitment periods from 1995 to 2001 and 1997 to 2004), eligible patients were assigned to early HSCT by genetic randomization according to availability of a matched related donor. After randomization, 113 patients of study III (84% of 135) and 144 of study IIIA (87% of 166) were eventually transplanted in first chronic phase (CP) using a related donor. Despite comparable transplantation protocols and most centers participating in both studies, survival probabilities in study IIIA were significantly better, even when adjusted for the established EBMT risk score (Gratwohl et al., Lancet 1998 [1]), p + 0.0097. For further explanation, the German Registry for Stem Cell Transplantation (DRST) and the Swiss Transplant Working Group for Blood and Marrow Transplantation (STABMT) were asked for data support. Patients and Methods: The main sample characteristics of the 257 transplanted CML study patients were also applied to the registry patients: diagnosis of CML between 1994 and 2004, first HSCT with a related donor performed in first CP between 1995 and 2004 at an age between 12 and 65 years, and blood or bone marrow as stem cell sources. Thus, additional data of 582 HSCT patients were retrieved from the two registries. Age, recipient sex, donor sex, time between diagnosis and HSCT, calendar year of HSCT, stem cell source, and HLA matching were investigated as potential predictive factors for survival. Then, a sample of patients with the same risk distribution as the 113 patients of study III was randomly drawn from the registry patients. By application of repeated resampling to this new patient group, bootstrap confidence intervals for survival probabilities at various times after HSCT were extractable. This provided the basis to judge whether the survival in study III could be seen as a typical random representation of a sample with an equivalent risk structure or not. The same method was applied to the 144 patients of study IIIA. Results: The 5-year survival probability of all 839 patients resulted in 73% (229 died). Median follow-up time of living patients was 6.7 years. Due to the characteristic plateau of post-transplant survival probabilities, the predictive influence was judged by the Kaplan-Meier method and the log rank statistic. Also consideration of age and time between diagnosis and HSCT as continuous variables seemed less appropriate than working with categorizations. Furthermore, the previously published cut-points “1 year” for time from diagnosis to HSCT ([1] ) and “44 years” for age at HSCT (Maywald et al., Leukemia 2006) were independently confirmed to be the best. Cox model and logistic regression with survival status after 3 years both indicated that age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT had independent statistically significant predictive influence on survival (p 〈 0.05). The first two factors had the strongest effects. Calendar year was only influential when distinction was made between HSCT until and after 1999. All possible combinations of the 4 factors could be summarized in 4 risk groups with significantly different survival probabilities (at 5 years: 87%, 76%, 63%, and 24%). Matched for the risk group distribution of study III [study IIIA], a maximum of 290 [428] registry patients could be drawn. For the 290 [428] patients, 5-year survival was 69% [77%] with a 95% bootstrap confidence interval from 63% to 74% [72% to 81%]. Thus, as for all yearly intervals within the first 5 years, the 5-year survival probabilities of studies III: 65% and IIIA: 79% lied within the corresponding confidence intervals. Conclusions: Along with the registry patients, the study data enabled the identification of age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT as factors with independent predictive impact on survival which led to 4 risk groups with statistically significantly different survival probabilities. More favorable-risk patients in study IIIA stood for a better transplantation strategy. In consideration of these different risks, the survival probabilities in both studies did not significantly vary from those of registry samples with matched risk structures. Accordingly, an improved transplantation strategy along with random variation could be considered as an explanation of the significantly different survival probabilities between the two studies. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Gratwohl:AMGEN, Roche, Bristol-Myers Squibb, Novartis, Pfizer: Research Funding; Novartis: Consultancy. German CML Study Group:Kompetenznetz Leukämie, European Leukemia Net, Roche, Essex, AMGEN: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 339-339
    Abstract: Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR= 〈 0.01% BCR-ABL according to the international scale) was reached with IM 800 after a median of 31.3 months vs. 47.5 and 42.5 months with IM 400 +/- IFN. Also CCR was reached faster with IM 800 (p 〈 0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients with little or no difference in high risk patients. In an analysis “as treated” patients receiving more than 600 mg/day reached remissions faster than those receiving lower dosages (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). At the time of this evaluation, OS (92% at 5 years) and PFS (88% at 5 years) showed no difference. Type and severity of adverse events (AE) at 12 months did not differ from those expected (all grades and grades III/IV). Hematologic (thrombocytopenia 7% vs. 4%) and non-hematologic AEs (gastrointestinal 35% vs. 15-24% and edema 29% vs. 16-19%) were more frequent with IM 800, fatigue (14% vs. 7-13%) and neurological problems (15% vs. 6-7%) more frequent with IM 400 + IFN (all grades). These data show a significantly faster achievement of MMR at 12 months with IM 800 as compared to IM 400 +/-IFN. So far, this faster response rate did not translate into better OS or PFS. Hence IM 400 should still be considered as standard of care. With some individual dose adjustments tolerability of IM 800 was good. Longer observation is required to determine whether this more rapid achievement of MMR and CCR will have a long term impact or not. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; European LeukemiaNet: Research Funding; Kompetenznetz Leukämie: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
    In: Blood, American Society of Hematology, Vol. 109, No. 9 ( 2007-05-01), p. 3812-3819
    Abstract: A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid–free medium restored CTL function. CTLs infiltrating lactic acid–producing multicellular tumor spheroids showed a reduced cytokine production. Pretreatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells, thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 4
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2007
    In:  Journal of Antimicrobial Chemotherapy Vol. 60, No. 1 ( 2007-07-01), p. 180-182
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 60, No. 1 ( 2007-07-01), p. 180-182
    Type of Medium: Online Resource
    ISSN: 1460-2091 , 0305-7453
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2007
    detail.hit.zdb_id: 1467478-6
    SSG: 15,3
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  • 5
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 177, No. 4 ( 2006-08-15), p. 2691-2698
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 177, No. 4 ( 2006-08-15), p. 2691-2698
    Abstract: Activation of alloreactive T cells by APCs such as dendritic cells (DC) has been implicated as crucial step in transplant rejection. In contrast, it has been proposed that macrophages (Mφ) maintain tolerance toward alloantigens. It was therefore the aim of this study to further analyze the T cell-stimulatory capacity of mature DC and Mφ in vitro using the model of allogeneic MLR. There was a strong proliferative response in T cells cocultured with DC, which was further increased upon restimulation in a secondary MLR. In contrast, T cells did not proliferate in cocultures with Mφ despite costimulation with anti-CD28 and IL-2. Cytokine analysis revealed considerable levels of IL-10 in cocultures of T cells with Mφ, whereas high amounts of IL-2 and IFN-γ were present in cocultures with DC. There was only minimal T cell proliferation in a secondary MLR when T cells were rescued from primary MLR with Mφ and restimulated with DC of the same donor, or DC of an unrelated donor (third party), whereas a strong primary proliferative response was observed in resting T cells, demonstrating induction of T cell anergy by Mφ. Functional analysis of T cells rescued from cocultures with Mφ demonstrated that anergy was at least partly mediated by IL-10-producing regulatory T cells induced by Mφ. These results demonstrate that Mφ drive the differentiation of regulatory T cells and mediate anergy in allogeneic T cells, supporting the concept that Mφ maintain peripheral tolerance in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2006
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2007
    In:  Annals of Hematology Vol. 86, No. 8 ( 2007-6-21), p. 575-581
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 86, No. 8 ( 2007-6-21), p. 575-581
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2007
    detail.hit.zdb_id: 1458429-3
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  • 7
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 174, No. 11 ( 2005-06-01), p. 7111-7122
    Abstract: Expression of the mouse transcription factor EC (Tfec) is restricted to the myeloid compartment, suggesting a function for Tfec in the development or function of these cells. However, mice lacking Tfec develop normally, indicating a redundant role for Tfec in myeloid cell development. We now report that Tfec is specifically induced in bone marrow-derived macrophages upon stimulation with the Th2 cytokines, IL-4 and IL-13, or LPS. LPS induced a rapid and transient up-regulation of Tfec mRNA expression and promoter activity, which was dependent on a functional NF-κB site. IL-4, however, induced a rapid, but long-lasting, increase in Tfec mRNA, which, in contrast to LPS stimulation, also resulted in detectable levels of Tfec protein. IL-4-induced transcription of Tfec was absent in macrophages lacking Stat6, and its promoter depended on two functional Stat6-binding sites. A global comparison of IL-4-induced genes in both wild-type and Tfec mutant macrophages revealed a surprisingly mild phenotype with only a few genes affected by Tfec deficiency. These included the G-CSFR (Csf3r) gene that was strongly up-regulated by IL-4 in wild-type macrophages and, to a lesser extent, in Tfec mutant macrophages. Our study also provides a general definition of the transcriptome in alternatively activated mouse macrophages and identifies a large number of novel genes characterizing this cell type.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
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  • 8
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2721-2721
    Abstract: The majority of entities of peripheral (mature) T-cell lymphomas (PTCL) have an unfavourable prognosis as compared to aggressive B-cell lymphomas. This difference has become even more pronounced since the introduction of CD20 antibodies in B-cell lymphoma therapy. The purpose of the present study was to investigate the feasibility and efficacy of the combination of the monoclonal antibody alemtuzumab with chemotherapy consisting of fludarabine, cyclophosphamide and doxorubicin in PTCL. Patients were treated with alemtuzumab 3, 10, 30, 30 mg, days 1–4, fludarabine 25 mg/m2 days 2–4, cyclophosphamide 600 mg/m2 day 3, and doxorubicin 50 mg/m2 day 4. Initially, patients with primary diagnosis, with first relapse, or with primary refractory disease were included. Excluded were patients with primary cutaneous T-cell lymphomas and ALK-positive large cell anaplastic T-cell lymphomas. So far, 37 patients have been included and 30 are evaluable for response and toxicity: 13 patients with PTCL-unspecified, 9 with angioimmunoblastic lymphoma, two with ALK negative anaplastic large cell lymphoma, two with enteropathy-associated T-cell lymphoma, two with nasal-type NK-/T-cell lymphoma, one with an NK-cell lymphoma, and one with a T-PLL. 19/30 patients were enrolled with primary diagnosis of PTCL and 11/30 patients with relapse or refractory disease. The median age was 56 years (range 21–77); 69% of the patients had an intermediate high or high prognostic score according to the international prognostic index. In patients with primary diagnosis the remission rate was 63% (12/19; CR 58%, PR 5%), four patients were primary progressive, and three patients dropped out because of treatment associated complications. Of the 12 responding patients 10 are in ongoing remission at 2+, 2+, 3+, 6+, 12+, 14+, 26+, 27+, 38+, and 39+ months, respectively. Two patients relapsed after being in CR for 23 and 34 months, respectively. In the group of relapsed or refractory patients three CR and two PR (45% overall response) were observed. The main toxicity was leukocytopenia (65% grade III and IV of all evaluable treatment cycles), other grade III and IV toxicities included anemia (17%), thrombocytopenia (35%), infections (16%), pruritus/skin reactions (11%), nausea/emesis (6%), mucositis (4%), and cardiac toxicity (4%, two patients with relapsed disease after pre-treatment with CHOP-like regimens developed severe heart failure and died). 12 (40%) patients reactivated CMV, however, 10 without developing CMV-related disease. In conclusion, the combination is an effective first-line regimen for peripheral T-cell lymphoma, however, regarding the general outcome a longer follow-up period of a larger patient population is required. Because the results were not convincing in relapsed and refractory disease and because of two heart failures in this group, the study was closed for relapsed and refractory patients, but is ongoing for first-line treatment of peripheral T-cell lymphomas.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 9
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 184-184
    Abstract: In spite of favorable response and survival results for the majority of CML patients on imatinib therapy, in a substantial minority imatinib fails or shows suboptimal responses. A treatment optimization study was therefore designed to compare in a randomized fashion standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN (for low- and intermediate-risk patients) or vs. imatinib 800 mg (for high-risk patients). Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase. In July 2005, randomization to the arms imatinib + araC and imatinib after IFN was discontinued and recruitment for imatinib 800 mg was expanded to low- and intermediate-risk patients. Primary goals are: rates of hematologic, cytogenetic and molecular remissions, duration of chronic phase, overall survival, adverse events and analysis of subsequent allografting. Since its activation in 7/2002, 1203 patients have been randomized. The current evaluation represents the first of three designed, statistically adjusted interim analyses of 710 patients randomized by the end of 2005 with a followup of at least 2 years. Analysis was according to intention to treat. 666 patients (545 with primary imatinib, 121 with primary IFN) were evaluable for hematologic, 621 for cytogenetic, and 631 for molecular responses. Median age was 53 years, 60% were male, median values were for Hb 12.5 g/dl, WBC 71.2/nl and platelets 384/nl, 35% had low, 53% intermediate and 12% high risk (Euro score). Median observation time was 3.5 years. Median duration of IFN pretreatment was & lt;4 months. At 1 year, the cumulative incidence of complete hematologic remission (CHR) was 82.3% and 74.4%, of major cytogenetic remission (MCR) 65.6% and 40.6%, of complete cytogenetic remission (CCR) 52% and 19.7%, and of major molecular remission (MMR) 33.2% and 4.7% for primary imatinib and IFN therapies, respectively. At 3 years, the cumulative incidence of CHR was 96.4% and 93.8%, of MCR 89.5% and 89.1%, of CCR 85.2% and 78.5%, and of MMR 79% and 63% for primary imatinib and IFN therapies, respectively. 5-year-survival probability of all patients currently exceeds 90% (94% for imatinib-, 91% for IFN-based therapy, Figure 1). Event free survival after two years (no progression, no death, CCR within the first 18 months, no loss of CHR or MCR) was 80.3%. 36 patients died, 51 patients were transplanted in first chronic phase, and 80 patients progressed, 43 of which were switched to alternative treatments (16 to new drugs, 18 to transplantation, 9 received both). Type and severity of adverse events (AE) did not significantly differ from those reported previously. Hematologic AEs (leukopenia, thrombocytopenia) were most frequent in the imatinib 800 mg arm. Nonhematologic AEs (gastrointestinal) were most frequent in the combination arms and with imatinib 800 mg. In no case recruitment had to be changed due to superiority or inferiority of any arm. This applies also to the high dose imatinib arm where earlier response might translate into better survival. In conclusion, this first interim analysis shows favorable survival and long term response rates. Imatinib in combination with, or after, IFN or with low dose araC are feasible and equally safe treatment alternatives. More definite information will be provided by the next interim evaluation after recruitment has been terminated. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3592-3592
    Abstract: Introduction: Combination of standard chemotherapy with Rituximab led to improved disease control in pts. with B-cell lymphoma and a clearcut survival benefit in diffuse large B cell lymphoma (DLBCL) in a multitude of clinical trials. We wanted to know, if a similar benefit could be demonstrated in the routine follow-up data of the regional population-based cancer registry of the Regensburg cancer center (“Tumorzentrum Regensburg”, TUZ). The TUZ spreads evidence-based treatment recommendations, but beyond this, treatments are performed according to the discretion of individual physicians and institutions. Methods: We searched the registry for B-NHL diagnosed between 1998 and 2005 entered as DLBCL, mantle cell lymphoma (MCL), follicular lymphoma (FL), undefined low grade lymphoma and corresponding terms from the ICD-O3. Furthermore, death certificates were systematically matched to the patient data and additionally searched for the terms C82, 83, 85, 88 of the ICD-10. Using these data, we compared overall survival of patients receiving any first line chemotherapy plus rituximab and patients receiving chemotherapy alone. Results: Comparing registry data to death certificates an 85% coverage of lymphoma patients within the registry can be estimated. In the high grade lymphoma group, 450 patients have been entered into the registry. Of these, 49 were insufficiently documented, 29 patients had a delayed start of their treatment and 41 received no chemotherapy at all. 122 pts. received rituximab-containing chemotherapy resulting in a 2 year survival of 87%, whereas 209 pts. received chemotherapy alone with a significantly inferior 2 year survival of 70%, p=0,004 by log rank test (fig). 307 pts with low grade lymphoma were found. Of these, 31 were insufficiently documented. 84 pts. did not receive any therapy at all during the observation period and showed the best survival as expected (watch and wait). 69 and 123 pts. received first line chemotherapy with or without Rituximab, respectively. Regarding all low grade NHL together, no significant difference was found, however, FL pts. survived longer, when Rituximab was given (2 year survival 91% vs. 72%, p=0,046). Conclusions: A survival benefit comparable to the results within clinical trials can be observed in registry data in an unsupervised community setting for patients with DLBCL treated first line with a Rituximab containing chemotherapy. A strong trend for improved survival was also observed for FL. These data confirm the standard use of Rituximab as first line therapy in DLBCL and FL and they support the collection of an extended set of treatment data containing exact descriptions of systemic therapy in cancer registries in order to answer similar questions in the future. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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