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In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 112-112

Abstract: To develop a prognostic scoring system tailored for therapy-related myelodysplastic syndromes (tMDS), we put together a database containing 1933 patients (pts) with tMDS from Spanish, German, Swiss, Austrian, US, Italian, and Dutch centers diagnosed between 1975-2015. Complete data to calculate the IPSS and IPSS-R were available in 1603 pts. Examining different scoring systems, we found that IPSS and IPSS-R do not risk stratify tMDS as well as they do primary MDS (pMDS), thereby supporting the need for a tMDS-specific score (Kuendgen et al., ASH 2015). The current analysis focuses on cytogenetic information as a potential component of a refined tMDS score, based on this large, unique patient cohort. Of the 1933 pts, 477 had normal karyotype (KT), 197 had missing cytogenetics, while 467 had a karyotype not readily interpretable. Incomplete karyotype descriptions will be reedited for the final evaluation. Of the remaining 1269 pts the most frequent cytogenetic abnormalities (abn) were: -7, del(5q), +mar, +8, del(7q), -5, del(20q), -17, -18, -Y, del(12p), -20, and +1 with 〉 30 cases each. Frequencies are shown in Table 1. Some abn were observed mostly or solely within complex KTs, such as monosomies, except -7. Others, like del(20q) or -Y, are mainly seen as single or double abn, while del(5q), -7, or del(7q) are seen in complex as well as non-complex KTs. The cytogenetic profile overlapped with that of pMDS (most frequent abn: del(5q), -7/del(7q), +8, -18/del(18q), del(20q), -5, -Y, -17/del(17p), +21, and inv(3)/t(3q) (Schanz et al, JCO 2011)), with notable differences including overrepresentation of complete monosomies, a higher frequency of -7 or t(11q23), and a more frequent occurrence of cytogenetic subtypes in complex KTs, which was especially evident in del(5q) occurring as a single abn in 16%, compared to 70% within a complex KT. IPSS-R cytogenetic groups were distributed as follows: Very Good (2%), Good (35%), Int (17%), Poor (15%), Very Poor (32%). Regarding the number of abn (including incomplete KT descriptions) roughly 30% had a normal KT, 20% 1, 10% 2, and 40% ≥3 abn, compared to pMDS: 55% normal KT, 29% 1, 10% 2, and 6% ≥3 abn. To be evaluable for prognostic information, abn should occur in a minimum of 10 pts. As a single aberration this was the case for -7, +8, del(5q), del(20q), del(7q), -Y, and t(11;varia) (q23;varia). Of particular interest, there was no apparent prognostic difference between -7 and del(7q); del(5q) as a single abn was associated with a relatively good survival, while the prognosis was poor with the first additional abn; t(11q23) occurred primarily as a single abn and was associated with an extremely poor prognosis, and prognosis of pts with ≥4 abn was dismal independent of composition (Table 1). To develop a more biologically meaningful scoring system containing homogeneous and prognostically stable groups, we will further combine subgroups with different abn leading to the same cytogenetic consequences. For example, deletions, unbalanced translocations, derivative chromosomes, dicentric chromosomes of 17p, and possibly -17 all lead to a loss of genetic material at the short arm of this respective chromosome affecting TP53. Further information might be derived from analyses of the minimal common deleted regions. For some abn, like del(11q), del(3p), and del(9q), this can be refined to one chromosome band only (table 1). Conclusion: Development of a robust scoring system for all subtypes of tMDS is challenging using existing variables. This focused analysis on the cytogenetic score component shows that favorable KTs are evident in a substantial proportion of pts, in contrast to historic data describing unfavorable cytogenetics in the majority of pts. Although complex and monosomal KTs are overrepresented, this suggests the existence of distinct tMDS-subtypes, although some of these cases might not be truly therapy-induced despite a history of cytotoxic treatment. The next steps will be to analyze the prognosis of the different groups, develop a tMDS cytogenetic score, and examine minimal deleted regions to identify candidate genes for development of tMDS, as well as to describe the possible influence of different primary diseases and treatments (radio- vs chemotherapy, different drugs) on induction of cytogenetic subtypes. Our detailed analysis of tMDS cytogenetics should reveal important prognostic information and is likely to help understand mechanisms of MDS development. Disclosures Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sole:Celgene: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Steensma:Amgen: Consultancy; Genoptix: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Millenium/Takeda: Consultancy; Ariad: Equity Ownership. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Valent:Amgen: Honoraria; Deciphera Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Deciphera Pharmaceuticals: Research Funding. Giagounidis:Celgene Corporation: Consultancy. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Lübbert:Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.112.112

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2759-2759

Abstract: Beside cytogenetic aberrations, additional gene mutations are powerful predictors of outcome in myeloid diseases. Moreover, myelodysplastic syndromes with isolated deletion (5q) (MDS del(5q)) have been regarded as one of the most favorable entities among MDS. However, a substantial proportion of MDS del(5q) patients experience transformation into AML soon after diagnosis (Germing et al. Leukemia. 2012;26:1286-1292). Mutations of TP53 gene have early been recognized as an unfavorable prognostic biomarker in MDS in general and recent data suggest a role of TP53 mutations in the transformation of MDS del(5q) into AML. Lenalidomid (Len) is now approved in the US as well as in Europe for the treatment of MDS del(5q) it is of particular interest whether Lenalidomide can alter the course of pretreatment TP53 mutated MDS del(5q). Methods The Le-Mon-5 trial investigated the safety and efficacy of Len in patients with MDS and isolated deletion (5q). All patients gave their written informed consent to the clinical trial and to additional molecular genetic analyses. Bone marrow aspirates were performed at screening prior treatment initiation and during follow-up every 6 months. Only freshly extracted, high-quality DNA from ficollized mononuclear cells was used for next-generation deep-sequencing analysis. For generation of PCR amplicon libraries TP53 oligonucleotide primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) research study network. Amplicon deep-sequencing of TP53 (exons 4-11) was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden. Results Central cytological, histological and cytogenetic review was performed in all patients establishing the diagnosis of MDS with isolated deletion (5q). A total of 68 patients (male: n=9) were analyzed with a median age of 71 years (range 41-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). Mean mutation frequency was 38%. Notably, we did not find mutation frequencies lower than 15%. Of 4 evaluable patients, three patients became transfusion independent within 4 months of Len treatment. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4 and 17 months on Len treatment (27% and 51%, respectively). Noteworthy, one the two patients achieved a complete cytogenetic remission despite maintaining his TP53 mutation frequency. Conclusion Using freshly extracted DNA we achieved high-quality NGS results with a high mean coverage of the relevant coding region of TP53. However, prevalence of TP53 mutations in our patient cohort was lower as compared to previously published data and we did not find low-level allele burdens as published by other groups, which might be due to the different sample sources used. Transfusion independence as well as cytogenetic remissions can be achieved in patients with TP53 mutations who are treated with Lenalidomide. Disclosures: Platzbecker: Celgene: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Götze:Celgene Corp.: Honoraria. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Hofmann:Celgene: Research Funding. Germing:Celgene: Honoraria, Research Funding. Nolte:Celgene: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2759.2759

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 485-485

Abstract: Abstract 485 In order to assess the relative value of major treatment variables for AML and subgroups in a representative setting 2693 patients were treated in a multicenter trial. To avoid a selection during treatment and to provide intention-to-treat conditions in a factorial design patients were randomized up-front in one step to receive TAD-HAM versus HAM-HAM induction, G-CSF priming with all chemotherapy courses during the 1st year versus no G-CSF, and for postremission therapy TAD consolidation followed by monthly myelosuppressive maintenance versus autologous stem cell transplantation instead of maintenance (TAD, thioguanine, araC standard dose and daunorubicin; HAM, araC 3 (age 〈 60) or 1 (age 60+) g/m2 × 6 with mitoxantrone; G-CSF 150μg/m2/day from 48h before until the end of the chemotherapy course; maintenance, 5-day standard dose araC with daunorubicin or with thioguanine or with cyclophosphamide alternatingly). The median age was 61 (range 16-85) years with 55% of patients 60 years or older, 27% patients had AML secondary to cytotoxic treatment or myelodysplasia. Favorable, intermediate, and unfavorable cytogenetics were found in 7.5%, 67% and 25.5% of patients, respectively. Among 956 patients with normal cytogenetics the mutation status was availabel with NPM1 mut/ FLT3-ITD neg in 33% and other combinations in 67%. The median observation time for the entire patients was 4.4 years . In the patients 〈 60 years the overall survival (OS) at 5 years is 40%. 65% went into complete remission (CR). Their relapse rate (RR) at 5 years is 52%. Patients of 60+years show an OS of 13% at 5 years, a CR rate of 54%, and a RR of 81% at 5 years. There were no significant differences in these parameters with respect to randomizations between TAD-HAM versus HAM-HAM, G-CSF priming versus no G-CSF, maintenance versus autologous stem cell transplantation. In a multivariate analysis including all patients and ages the main determinants of OS were age 60+y (HR 2.00; 95% CI 1.82-2.21), de-novo AML (0.79; 0.71-0.88), unfavorable karyotype (2.05; 1.84-2.28), favorable karyotype (0.47; 0.37-0.60), day 16 b.m. blast clearance (0.66; 0.61-0.74), and LDH (1.36; 1.19-1.54). Corresponding factors for the RR were age 60+ (1.90; 1.65-2.18), unfavorable karyotype (1.83; 1.54-2.17), favorable karyotype (0.41; 0.30-0.55), LDH (1.33; 1.11-1.59), and day 16 b.m. blast clearance (0.79; 0.68-0.93). In patients with normal karyotype the main determinants of OS were age 60+ (2.12; 1.77-2.54), NPM1mut/ FLT3-ITD neg (0.45; 0.36-0.56), and for the RR age 60+ (1.87; 1.49-2.35), and NPM1mut/ FLT3-ITD neg (0.37; 0.29-0.48). Even in patients 〈 60 years age older than the median (47y) is a major risk factor for OS (1.56; 1.33-1.82) and RR (1.35; 1.10-1.66). Conclusion: In a prospective analysis of representative and unselected patients with AML the outcome of therapy is mainly determined by chromosomal and molecular abnormalities and by older age as an own risk factor. The influence of treatment variables such as substantial increase in high-dose araC, G-CSF priming, or autologous SCT is neglectable. Present data may contribute a basis for novel molecular and immunologic approaches. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.485.485

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3818-3818

Abstract: Abstract 3818 Poster Board III-754 Lenalidomide consistently induces transfusion independence and complete cytogenetic response in patients with low and intermediate risk myelodysplastic syndromes (MDS) with 5q deletion. Only limited information on long-term outcome of patients treated with this novel approach is currently available. We performed a long-term follow-up analysis of 42 patients with low or intermediate risk MDS and 5q deletion treated with lenalidomide. At a median follow-up of 40 months, 58% of the patients achieved an erythoid response and 48% a cytogenetic response. 36% of patients progressed into acute myeloid leukaemia (AML). Most of them (87%) acquired chromosome aberrations in addition to the 5q deletion, i.e. underwent clonal evolution during leukaemogenesis. There were no clinical, cytological or cytogenetic markers at study entry that allowed prediction of an increased risk of leukaemic transformation. However,erythroid and cytogenetic responders had a significantly decreased risk of progression to AML (p=0.001 and p=0.009, respectively) compared to non-responders. 3 and 5 years after study entry, the cumulative incidence of AML for patients with a cytogenetic response was 10% and 21%, respectively, and for patients without cytogenetic response, it was 46% and 60%. Patients with del(5q) MDS who fail to achieve erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression. In refractory, or relapsing, patients, genetic instability and clonal evolution seem to be the driving forces of leukaemic transformation. Regular follow-up investigations of del(5q) MDS patients treated with lenalidomide may help identifying patients needing alternative treatment strategies. Disclosures: Göhring: Celgene Corp.: cytogenetic reference lab for Celgene MDS-004 study. Giagounidis:Novartis Pharma: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo SmithKline: Consultancy; Johnson & Johnson: Consultancy; Celgene Corp.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Büsche:Celgene Corp.: histology reference lab for MDS-004 study. Kreipe:Celgene Corp.: histology reference lab for MDS-004 study. Hellstrom-Lindberg:Celgene Corp.: Research Funding. Schlegelberger:Celgene Corp.: cytogenetic reference lab for Celgene MDS-004 study.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3818.3818

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4008-4008

Abstract: Abstract 4008 Introduction: Loss of the Y chromosome has been reported to be associated with hematopoietic diseases (Wiktor et al., 2000), but it was also described as an age-related phenomenon in males (UKCCG, 1992). Determination of clonality and prediction of prognosis and treatment outcome might benefit from a differentiation between age- and MDS-associated Y loss. The aim of this study was to evaluate if Y loss was an age- and/or MDS-associated phenomenon by retrospectively analyzing our multicenter, international DACH-, ICWG- and IMRAW-database and by testing the established hypotheses in an experimental study. Patients and Methods: In our multicenter MDS-database of 2901 patients, 101 primary, untreated MDS patients (3.5%) with loss of the Y were identified. We analyzed them according to age, clone size, and the presence or absence of additional chromosomal aberrations and assessed the prognostic relevance of the aberrations using univariate and multivariate models. Additionally, by immunomagnetic cell sorting, we enriched clonal CD34+ cells and CD3+ T-cells not belonging to the MDS clone from peripheral blood of three patients and compared the percentage of cells with -Y using FISH. Results: Isolated loss of Y was observed in 65.3% (n=66) of the 101 patients identified in the multicenter MDS-database, 14.9% (n=15) of the patients displayed one additional aberration and in 19.8% (n=20) -Y occurred as part of complex abnormalities. Overall survival of patients with -Y as a sole change was significantly better compared to patients with a normal karyotype (60.8 vs. 47.4 months; hazard ratio = 0.50, p 〈 0.01). Loss of the Y chromosome as isolated aberration was significantly less frequent in younger ( 〈 60 years) than in older patients (1.9% vs. 4.0%. p 〈 0.01). Patients showing -Y as single aberration were older at time of first diagnosis as patients with any other abnormalities or a normal karyotype (71.5 vs. 66.7 years, p 〈 0.01). There were no differences in clone size between patients with -Y and patients with 5q-, -7/7q-, 20q- or complex karyotypes. Studying sequential karyotypes of some patients, we observed -Y occurring during karyotype evolution. We also identified a patient with -Y at first diagnosis in a mosaic karyotype with normal cells that later developed additional aberrations in the cells with -Y during the course of the disease. These data strongly suggest that -Y is MDS-associated in these patients. To demonstrate that -Y is occurring in the clonal CD34+ cellular compartment as a somatically acquired event we studied the loss of the Y chromosome in CD34+ and CD3+ cells separately in 3 patients. The percentage of cells with -Y was significantly increased in CD34+ cells (69%, 74%, 47%) compared to CD3+ cells (8%, 7%, 2%; p=0.01). Until now, it is not clear whether the low proportion of loss of the Y chromosome in CD3+ cells that exceed in two cases only slightly our laboratory threshold of 3.8% is due to an age related loss of the Y chromosome in T-cells or to contamination of the CD3+ cells with clonal cells. Conclusion: The frequency of loss of Y chromosome in MDS karyotypes is associated with age. However, the evidently better prognosis of MDS patients with loss of the Y chromosome as the sole aberration compared to MDS patients with normal karyotype, the occurrence of Y loss during karyotype evolution, the acquisition of additional abnormalities in cells with -Y as primary aberration, and the observation of -Y in clonal CD34+ cells but not in CD3+ cells suggest a clonal nature of this karyotype anomaly at least in a subset of patients with MDS. In other patients this finding is clearly age-related. The preliminary data of our experimental study will be tested by analyzing a larger cohort of patients. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.4008.4008

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3819-3819

Abstract: Abstract 3819 Transfusion-dependent anemia is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) chromosome abnormality. Background appears to be a haplo-insufficiency of the RPS-14 gene located within the CDR. Lenalidomide has improved the treatment of MDS with 5q deletion inducing a hematologic (erythroid) and cytogenetic response in the majority of patients. The exact mechanisms of action of lenalidomide explaining its effects on erythropoiesis and their possible prognostic relevance are not clear so far. PATIENTS: We present the first data on in-vivo changes at the level of hematopoietic stem cells (SC), erythroid committed SC (SC-e), maturation of SC-e to erythroblastic islands and normoblasts observed during lenalidomide therapy within the bone marrow from a total of 39 transfusion-dependent patients with low- or intermediate-1-risk MDS with del(5q) chromosome aberration (MDS.5q-) who were recruited and treated with lenalidomide (10 mg / d) at the European site of the MDS-003 study and whose bone marrow samples (aspirates and biopsies) were taken prospectively at 6-month intervals after start of treatment. Mature erythroid precursors were marked by anti-hemoglobin-A-antibody (HbA); immature, HbA- erythroid precursors by anti-glycophorin-C-antibody (GPC), and the SC compartment by anti-CD34 antibody. Due to their low number, the numerical densities of SC-e were estimated indirectly by the numerical density of erythroblastic islands within bone marrow whereas the total number of SC was estimated by a statistical approach assuming that SC give rise to clusters of CD34+ precursors. The results were correlated with lenalidomide dose, RPS-14, SPARC, and glycophorin A (GPA) gene expression, degree of anemia, transfusion dependence, cytogenetic and molecular (FISH) response, clonal evolution, AML-free and overall survival of patients. RESULTS: Lenalidomide therapy resulted in a marked increase of SC-e, differentiation of SC-e to GPC+HbA- erythroid precursors, pronounced production of HbA+ precursors and erythrocytes resulting in transfusion independence in 54 % of patients. Lenalidomide-induced increase of SC-e did not correlate with a rise in the total number of SC. It was more pronounced in patients with a cytogenetic response, but it occurred also in patients without a cytogenetic remission. 17 / 39 patients with a minimal therapy effect on erythropoiesis achieving the 1% percentile of normal healthy marrow and continuing for 〉 12 months showed an excellent prognosis with a probability of survival 〉 90 % 60 months after start of treatment and 120 months after diagnosis of disease irrespective of their hematologic response whereas the median survival time of the patients without minimal effect on erythroid precursors (n = 22) was shorter than 20 months after start of treatment (P 〈 0.0002). In multivariate survival analysis, changes of erythropoiesis occurring during lenalidomide treatment, clonal evolution of disease, and age of patients were the only variables providing independent prognostic information (P 〈 0.00005). Classification of disease (FAB, WHO, IPSS, WPSS), changes of peripheral blood cell counts, transfusion independence, cytogenetic and molecular response, RPS-13, SPARC, or GPA gene expression did not provide additional independent prognostic information (P 〉 0.05). CONCLUSIONS: Lenalidomide promotes erythroid differentiation at stem cell level as well as at more mature stages of erythropoiesis affecting both, the neoplastic clone as well as non-neoplastic hematopoiesis. The anti-neoplastic effect of lenalidomide does not seem to be relevant for the prognosis of the patients; (1) genetic instability of neoplastic SC / precursor resulting in clonal evolution on the one and (2) the capacity of neoplastic SC / precursors to respond to lenalidomide therapy with the production of SC-e and more mature erythroid precursors on the other hand appear to be significant. By combining both variables, three groups can be discriminated allowing for a therapy-specific prognostic scoring: one group with excellent prognosis (100 % survival 5 years after start of therapy) comprising ∼ 33 % of patients, another with poor prognosis (0 % survival 5 years after start of therapy) comprising ∼ 28 % of patients, and a third group with intermediate prognosis (53 % dying during this period of observation) comprising ∼ 39 % of patients (P 〈 0.000001). Disclosures: Buesche: Celgene Corp.: reference pathologist of the MDS-004 and the MDS-Le-Mon-5 studies. Giagounidis:Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Göhring:Celgene Corp.: reference cytogeneticist of the MDS-004 study. Schlegelberger:Celgene Corp.: reference cytogeneticist of the MDS-004 study. Knight:Celgene Corp.: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3819.3819

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 391-391

Abstract: Introduction: The predictive value of 18-fluorodeoxyglucose PET performed after a few cycles of chemotherapy has been questioned in aggressive lymphomas. Inconsistent study results, however, may be due to procedural differences rather than an inability of the method to predict outcome. Whether changing treatment in pts. with an unfavorable interim PET (iPET) improves outcome, has not been determined in a randomized study. The PETAL trial (EudraCT 2006-001641-33, NCT00554164) was initiated to resolve these issues. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd R-CHOP cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve objectivity of evaluation (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20-positive lymphomas and a favorable iPET were randomized to receive 4 additional cycles of R-CHOP or the same treatment plus 2 extra doses of R (Part A of the trial). Pts. with an unfavorable iPET were randomized to continue standard R-CHOP for 6 additional cycles or receive 6 blocks of a more complex and more intensive protocol yielding excellent results in Burkitt and other aggressive lymphomas (Part B). Its main components were hyperfractionated alkylating agents (C, ifosfamide) and high doses of methotrexate and cytarabine, with dose reductions in pts. 〉 60 yrs. Other constituents were R, H, O, vindesine, etoposide and dexamethasone (Blood 120: abstr 667, 2012). R was omitted in pts. with CD20-negative lymphomas. Sample size was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in Part A and from 30 % to 45 % in Part B (alpha=0.05, power=0.8). Complete remission (CR), overall survival (OS) and toxicity were secondary endpoints. Results: From 2007 to 2012 926 pts. were recruited by 57 participating oncological centers and analyzed by PET in 23 nuclear medicine institutions. With a median follow-up of 33 months 853 pts. are currently evaluable in the intent-to-treat population. 757 pts. had CD20-positive B cell lymphomas (80 % diffuse large B cell [DLBCL], 3 % primary mediastinal B cell, 8 % follicular lymphoma grade 3), 13 had CD20-negative B cell lymphomas and 83 had peripheral T cell lymphomas. Interim PET was favorable in 746 pts. (87 %) and unfavorable in 107 (13 %). It was highly predictive of outcome, time to TF being significantly higher in Part A than Part B (2-year probability: 79 % vs. 47 %; hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 2.6 – 4.6, p 〈 0.0001; Figure). On multivariate analysis iPET response, International Prognostic Index and B vs. T cell lineage independently predicted TF. Interim PET was also predictive of OS (HR 3.9, CI 2.7 – 5.7, p 〈 0.0001). In pts. with CD20-positive lymphomas and a favorable iPET, addition of 2 extra doses of R failed to improve TF (HR for 2 extra doses 1.2, CI 0.8 – 2.1) and all secondary endpoints. Likewise, in pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt-type regimen showed no beneficial effect on TF (HR for Burkitt 1.6, CI 0.9 – 2.7), CR rate (50 % vs. 31 %, p=0.10) or OS (HR 1.0, CI 0.5 – 2.1). Similar results were obtained, when the analysis was restricted to DLBCL, and for covariate adjusted Cox regression of all survival endpoints. Although treatment related deaths (3 vs. 2 pts.) were comparable in both treatment arms, the Burkitt protocol was associated with more severe grade 3/4 leukopenia (84 % vs. 67 %, p=0.043), thrombocytopenia (63 % vs. 35 %, p=0.007) and mucositis (41 % vs. 12 %, p=0.002). Conclusion: Applying strict rules to the procedure and its interpretation iPET proved highly predictive of outcome in pts. with aggressive lymphomas in this large multicenter trial. Because switching to a more aggressive protocol failed to improve outcome, our results do not support a change in cytotoxic regimen in poor iPET responders. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Duehrsen: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Klapper:Roche: Research Funding. Hoelzer:Amgen: Speakers Bureau; Medac: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.391.391

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 171-171

Abstract: Abstract 171 The 5q- syndrome is the most distinct of all myelodysplastic syndromes with a clear genotype/phenotype relationship. Haploinsufficiency of the ribosomal protein gene RPS14 underlies the erythroid defect found in the 5q- syndrome. The 5q- syndrome is a disorder of aberrant ribosome biogenesis and we have recently demonstrated that erythrocytes obtained from patients with the 5q- syndrome show impaired translation. This defect in translation may represent a potential therapeutic target in the 5q- syndrome and other ribosomopathies, and there are some indications that the use of the translation enhancer L-leucine may have some efficacy. L-leucine is a branched chain amino acid that has been shown to improve haemoglobin levels and transfusion independence in patients with the ribosomopathy Diamond Blackfan Anemia (DBA). Moreover, the treatment of zebrafish models of DBA and the 5q- syndrome with L-leucine has recently been shown by others to result in partial reversal of the anemia. To model the RPS14 haploinsufficiency observed in the 5q- syndrome, we used lentivirally delivered shRNA sequences to reduce the expression of RPS14 in human bone marrow CD34+ cells from healthy controls. We have recently shown that treatment of cultured human erythroid cells derived from CD34+ cells of healthy controls with RPS14 knockdown and cultured erythroid cells derived from the CD34+ cells of patients with the 5q- syndrome with L-leucine results in an increase in cell proliferation, erythroid differentiation and mRNA translation. There is evidence to suggest that L-leucine activates the mTOR (mammalian target of rapamycin) signaling pathway that controls many cellular processes including cell growth and mRNA translation. In order to investigate the mechanism of action of L-leucine, we have studied the phosphorylation levels of S6K1 and 4EBP1, the key downstream targets of mTORC1 (mTOR Complex 1), by sandwich ELISA, Human Phospho-kinase Antibody Array and flow cytometry in RPS14-deficient human erythroblasts. We have shown a significant increase in the levels of phospho-S6K1 and phospho-4EBP1 following L-leucine treatment of cultured erythroid cells derived from CD34+ cells of healthy controls with RPS14 knockdown. The effects of L-leucine on phospho-S6K1 and phospho-4EBP1 were abrogated by rapamycin (an mTOR inhibitor), suggesting that L-leucine has a specific action on the mTOR signaling pathway. Consistent to the results observed in the RPS14 knockdown model, treatment with L-leucine also increased the level of phospho-S6K1 in cultured erythroid cells derived from the bone marrow cells of 5q- MDS patients. These data suggest that L-leucine activates the mTOR pathway in RPS14-deficient human erythroblasts. Our studies support the evaluation of L-leucine as a potential therapeutic agent in the treatment of the 5q- syndrome, and provide evidence on its mode of action through activation of the mTOR signaling pathway. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.171.171

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3276-3276

Abstract: Background: Thrombocytopenia in MDS occurs in ~50% of pts with low/int-1 MDS and is associated with reduced survival; few therapies are available for these thrombocytopenic MDS pts. In a randomized PBO-controlled study, 250 pts with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events (HR romiplostim vs. PBO 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88, P 〈 0.001), and increased IWG HI-P incidence (OR 15.6, 95% CI: 4.7, 51.8, P 〈 0.001). Increases in peripheral blast counts to 〉 10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.7%), and in most cases resolved after discontinuation. Due to concerns of the safety data monitoring committee that the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that transient increases in blast cell counts might put pts at risk for diagnosis of and treatment for AML, treatment with study drug was discontinued in February 2011. Pts were then moved into the long-term follow-up (LTFU) portion of the study. Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was romiplostim: 6.0% (10 pts), PBO: 4.9% (4 pts), HR 1.20 (95% CI: 0.38, 3.84). This report provides additional data on LTFU of these pts up to March 2014, with a particular emphasis on AML incidence. Methods: Eligible pts had IPSS low/int-1 MDS and platelets 1) ≤20x109/L or 2) ≤50x109/L with a history of bleeding, and were receiving only supportive care. Disease progression to AML was defined as 1) ≥20% blasts in the bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim, 2) pathology consistent with leukemia including chloroma or leukemia cutis, or 3) anti-leukemic treatment initiation. Results are presented by treatment group. Results: Of 250 pts in the study, 210 entered LTFU, and 83 of these pts remained on study as of March 2014; the median (Q1, Q3) follow-up was 27.5 (10.8, 41.2) months. Reasons for discontinuation during LTFU were similar in the romiplostim and PBO groups and included death, lost to follow-up, and withdrawal of consent. During the active study period or during LTFU, death was reported in 50.9% (N = 85) of pts in the romiplostim group and 48.2% (N = 40) of pts in the PBO group (HR romiplostim vs. PBO 1.04, 95% CI: 0.71, 1.52) (Figure); mortality rates were greater in those with int-1 vs. low IPSS status for both the PBO and romiplostim groups (Table 1). AML was reported in 11.9% (N = 20) of pts in the romiplostim group and 9.8% (N = 8) of pts in the PBO group (HR 1.21, 95% CI: 0.53, 2.76). The proportions of pts who either died or developed AML were 52.7% (N = 88) in the romiplostim group and 48.2% (N = 40) in the PBO group (HR 1.10, 95% CI: 0.75, 1.60) (Figure). Fourteen of the 28 AML cases occurred in pts who were RAEB-1 at screening (none were RAEB-2) and 5 cases were diagnosed due to anti-AML treatment use alone (Table 2). In LTFU, the rate of pt-reported use of MDS therapy (e.g., azacitidine or cyclosporine) in the romiplostim group was 42.8% (N = 59, 95% CI: 34.4%, 51.5%) and 28.2% (N = 20, 95% CI: 18.1%, 40.1%) in the PBO group. Reported use of AML therapy (e.g., chemotherapy) occurred at a rate of 10.2% (N = 14) in the romiplostim group and 8.5% (N = 6) in the PBO group. Conclusion:Following the 2011 decision to stop study drug, results have been updated with more observational time on study. Specifically, the HRs for death or progression to AML (romiplostim vs. PBO) are 1.04 (95% CI: 0.71, 1.52) and 1.21 (95% CI: 0.53, 2.76), respectively, compared with 2013 HRs of 1.04 (95% CI: 0.70, 1.54) and 1.14 (95% CI: 0.49, 2.62), respectively. As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. Table 1: Survival by Baseline IPSS n (%) RomiplostimN = 167 PBON = 83 Low 14/46 (30.4%) 3/23 (13.0%) 95% CI (%) 17.7, 45.8 2.8, 33.6 Int-1 71/121 (58.7%) 37/60 (61.7%) 95% CI (%) 49.4, 67.6 48.2, 73.9 Table 2: Progression to AML to Date Study-defined AML, n (%) RomiplostimN = 20 PBON = 8 TotalN = 28 Baseline WHO classification RAEB-1/2 11 (55%) 3 (37.5%) 14 (50%) Non-RAEB 9 (45%) 5 (62.5%) 14 (50%) AML diagnosis by Bone marrow/peripheral blast 〉 20% 17 (85%) 6 (75%) 23 (82.1%) Anti-AML therapy alone 3 (15%) 2 (25%) 5 (17.9%) Figure Figure 1 Figure 1. Disclosures Kantarjian: Amgen Inc.: Research Funding. Off Label Use: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in myelodysplastic syndromes is under investigation.. Mufti:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Szer:Sandoz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Amgen Inc.: Honoraria. Kuendgen:Celgene: Research Funding. Gaidano:Amgen Inc.: Consultancy, Honoraria. Wiktor-Jedrzejczak:Amgen Inc.: Research Funding. Orejudos:Amgen Inc.: Consultancy. Lopez:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3276.3276

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1311-1311

Abstract: Abstract 1311 Poster Board I-334 Background Chronic ITP is an autoimmune disease characterized by low platelet counts and increased risk of bleeding that may be severe or even fatal. Rescue medications, most commonly intravenous immunoglobulins, are used to treat or prevent bleeding but produce only transient increases in platelet counts in most cases and may have issues with toxicity. Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor, and is approved for the treatment of adult chronic ITP. Objective To determine the effects of romiplostim treatment on bleeding outcomes during a phase 3b, randomized, open-label study, in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). We have developed a clinically-relevant composite endpoint, termed bleeding-related episode (BRE). A BRE was considered to be either an actual bleeding event, and/or the use of rescue medication to treat or prevent bleeding. Methods Patients were randomized (2:1) to romiplostim or SOC. Eligible patients were required to have either a platelet count 〈 50×109/L or have had their platelet count fall to 〈 50×109/L during or after a clinically-indicated taper or discontinuation of current ITP therapy. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines. Since many types of ITP treatment could be administered in the SOC group, for the purpose of this analysis rescue medication was defined as any use of immunoglobulins (intravenous immunoglobulin or Anti-D), intravenous steroids, or platelet transfusions. In order to collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single clinical episode. Rates of BREs per 100 patient-weeks were calculated from the number of events/episodes divided by the number of patient-weeks on study treatment, multiplied by 100. Results During the 52-week treatment period, the total number of patient-weeks for the romiplostim group (N=154) was 7087, and for the SOC group (N=70) was 2571. During the treatment period, the rate of BREs was lower in the romiplostim group than the SOC group (see Table), with a 67% reduction in the rate of BREs in patients receiving romiplostim compared to SOC (95% CI, 60% to 73%). The rate of BREs involving the use of immunoglobulins was also lower in the romiplostim group, with a 95% reduction in the rate of BREs in patients receiving romiplostim compared to those receiving SOC (95% CI, 92% to 97%). Conclusions Compared to SOC, romiplostim was associated with a reduction in all BREs as well as BREs involving immunoglobulin use. Disclosures Stasi: Amgen Inc.: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau. Giagounidis:Amgen Inc.: Consultancy, Speakers Bureau. Janssens:Roche: Honoraria. Legg:Amgen Inc.: Employment, Equity Ownership. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1311.1311

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7