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In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 222-222

Abstract: Background: Most patients (pts) diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy in medically fit pts is still the standard practice and a prerequisite for long-term survival, elderly pts have a higher risk of treatment related morbidity and lower remission rates than younger AML pts. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML pts (Niederwieser et al., Blood 2002, abstr. 1337). We present the mature final results of a randomized-controlled trial comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA). Patients and Methods: In the 60+ trial of the Study Alliance Leukemia (SAL), AML pts 〉 60 years and medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). All pts in CR after DA received intermediate-dose cytarabine plus amsacrine (MAMAC) as consolidation treatment, whereas pts in CR after IMA were consolidated with standard-dose cytarabine plus mitoxantrone (2+5). Primary study endpoint was the CR rate with an expected difference of 15% in favor of IMA. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: Between February 2005 and October 2009, 852 pts were screened for study inclusion and 485 pts started study treatment, of which 241 pts were randomized for treatment arm A (DA) and 244 for treatment arm B (IMA). The median age was 69 years. Pt characteristics were equally distributed between the two arms. According to a strict definition, all patients with early death, study drop-out, or failed remission assessment were categorized as being not in CR. The CR rate amongst all 485 pts treated in the study was 47%. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). If all first CRs were taken into account including those achieved after trial discontinuation, the CR rates after DA versus IMA induction were 55% versus 64% (p=0.043). Separate analyses addressing age, cytogenetics, de novo AML, NPM1 and FLT3-ITD confirmed higher CR rates after IMA induction throughout these subgroups. Six-week mortality was 14% in both arms. The median duration of ≥ grade 3 neutropenia was 23 days after DA I and 25 days after IMA (p=0.031). The median duration of thrombocytopenia ≥ grade 3 was 16 versus 20 days after DA I and IMA I, respectively (p 〈 0.001). The incidences of non-hematologic toxicities were not significantly different except for a higher incidence of liver toxicity (odds ratio IMA/DA = 0.52; p=0.001) and gastrointestinal symptoms (OR IMA/DA = 0.62; p=0.041) after DA. In the course of treatment, 11 pts in each arm (5%) received allogeneic stem cell transplantation. After a median follow-up of 66 months, RFS curves are superimposable in the first year with a similar median RFS of 11 months and 10 months after DA and IMA, respectively. However, a separation of RFS curves developed with longer follow up, resulting in 1-year RFS rates of 45% versus 46%, but 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS for all randomized pts was 10 months in both arms; 1-year and 3-year OS rates were 45% and 19% after DA versus 44% and 19% after IMA (p=0.513). Conclusion: The results indicate that elderly AML pts benefit from a dose escalation of cytarabine in induction therapy by significantly higher CR rates and similar toxicity compared to a standard 7+3 approach. In our trial, this did not translate into a survival advantage, most likely due to differences in consolidation treatment of the respective treatment arms. In combination with an effective consolidation strategy such as high-dose cytarabine or allogeneic transplantation, our current results favor the use of intermediate dose cytarabine in induction for pts with a curative AML treatment approach. Figure 1. CR rates depending on induction treatment Figure 1. CR rates depending on induction treatment Disclosures Einsele: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Platzbecker:Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Ehninger:Cellex GmbH: Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.222.222

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 4400-4400

Abstract: Heterotrimeric G proteins mediate intracellular transduction of many hormone-receptor interactions. Activation of the G protein αs subunit (Gαs) upon stimulation of specific G Protein coupled receptors results in increased levels of the second messenger cAMP which has been shown to induce apoptosis in B-cells. On this background we investigated a potential association of a common silent single-nucleotid polymorphism (T393C) in the gene GNAS1 on chromosome 20 encoding Gαs with disease progression in patients with chronic lymphocytic leukemia (CLL). We genotyped the DNA from 109 patients with CLL and 100 healthy controls using PCR amplification followed by restriction analysis. Comparing the CLL patients with healthy controls we found no significant differences in allele frequencies or genotype distributions (CLL patients: 393CC 34 vs CT 51 vs TT 24; healthy controls: 393CC 25 vs CT 50 vs TT 25). However, progression-free survival (PFS) was significantly shorter in 393CC patients compared to T393 allele carriers (median PFS CC: 36 months; T-allele: median PFS not reached; log rank test: p=0.029; adjusted for Binet stage) after 5 years observation time. In multivariate analysis the T393C polymorphism was an independent prognostic factor for PFS. Our data suggest that the GNAS1 T393C polymorphism is not associated with the risk for B-CLL. However, the T393C polymorphism may be a prognostic marker for PFS. It is hypothesized that the 393T-allele is associated with increased cAMP concentrations and, therefore, with higher rates of apoptosis. Further studies assessing differences in the signaling pathway dependent on genotype are underway.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.4400.4400

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 103, No. 1 ( 2004-01-01), p. 136-142

Abstract: Platelet adhesion and activation at the vascular wall are the initial steps leading to arterial thrombosis and vascular occlusion. Prostacyclin and nitric oxide inhibit platelet adhesion, acting via cyclic adenosine monophosphate (cAMP)– and cyclic guanosine monophosphate (cGMP)–dependent protein kinases. A major downstream target for both cAMP- and cGMP-dependent protein kinases is the vasodilator-stimulated phosphoprotein (VASP). To test the significance of VASP for the regulation of platelet adhesion in vivo, we studied platelet–vessel wall interactions using VASP-deficient (VASP–/–) mice. Under physiologic conditions, platelet adhesion to endothelial cells was significantly enhanced in VASP null mutants when compared with wild-type mice (P & lt; .05). Platelet recruitment in VASP null mice involved P-selectin and the fibrinogen receptor glycoprotein IIb-IIIa (GPIIb-IIIa). Under pathophysiologic conditions, the loss of VASP increased platelet adhesion to the postischemic intestinal microvasculature, to the atherosclerotic endothelium of ApoE-deficient mice, and to the subendothelial matrix following endothelial denudation (P & lt; .05 vs wild type). Importantly, platelet adhesion in VASP null mutants was unresponsive to nitric oxide. These data show for the first time in vivo that VASP is involved in down-regulation of platelet adhesion to the vascular wall under both physiologic and pathophysiologic conditions.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2002-11-3417

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4866-4866

Abstract: The biology of myelodysplastic syndromes (MDS) is reflected in aberrant transcription levels of the myeloid lineage. It was the purpose of this study to provide potential novel therapeutic targets by identifying molecular alterations that are pertinent to myelodysplastic syndromes. cDNA from bone marrow-derived CD34+ hematopoietic stem and progenitor cells from 6 healthy persons, and 16 patients with MDS (Table 1) was hybridized to cDNA arrays comprising 1185 well-characterized genes. We used the complete cDNA array expression values to build a dendrogram including all samples under investigation. Interestingly, patient survival had a striking impact on our gene signature for it was the parameter that had the strongest statistical association with the segregation of our MDS patients into 2 sub clusters (Figure 1). We examined whether this segregation of MDS patients was associated with age, gender, MDS-type according to FAB, WHO, IPSS, karyotype or survival. We determined correlation coefficients and found “survival” to be the parameter with the strongest statistically significant association with the segregation of MDS patients into 2 sub clusters (Spearman = 0.697, P = 0.003). The WHO type was less significantly associated (Spearman = 0.537, P = 0.032), and the FAB type did not reach statistical significance (Spearman = 0.492, P = 0.053). Transcriptional changes that are associated with short survival may also indicate to potential novel therapeutic targets. Since median age of patients with MDS is 70 at diagnosis, the majority of patients are not suitable for therapies that are not well tolerated. Moreover, some patients have a nearly normal life expectancy. Ideally, new therapeutic agents should, therefore, be tailored for patients with short survival and be well-tolerated like e.g. Bevacizumab and Cetuximab. But, we could not find increased expression of Bevacizumab and Cetuximab related EGFR- or VEGFR-target genes in CD34+ cells from MDS patients with short survival. In sum, there are transcriptional alterations that are strongly associated with short survival, and thus valuable for prognostication of patients with MDS. Table 1. Classification, and karyotypes of patients with MDS who were analyzed by means of cDNA array analysis Patient No. Age/ Sex FAB (a) IPSS (b) WHO (c) Karyotype (a) FAB, French-American-British cooperative group classification, (b) IPSS, international prognostic scoring system; int, intermediate, (c) WHO, World Health Organization classification 1 61/ F RA int-I RCMD 46, XX, 13q- 2 68/ F RA int-I 5q- 46, XX, 5q-, 12p- 3 62/ M RA int-I RCMD 47, XY, +8 4 50/ M RA int-I RCMD 46, XY, t(X;1) 5 18/ F RA low PRA 46, XX 6 51/ M RA low RCMD 46, XY 7 51 /F RA int-I 5q- 46, XX, 5q-, 12p 8 75/ M RAEB high RAEB II 46, XY, 7q- 9 79/ M RAEB-t high sAML complex 10 68/ M RAEB int-II RAEB-II 46, XY 11 70/ F RAEB-t high sAML 46, XX, 15q- 12 52/ M RAEB-t high sAML complex 13 72/ M RAEB-t high sAML complex 14 75/ M RAEB int-I RAEB-I 46, XY 15 72/ M sAML/MDS - sAML complex 16 76/ M sAML/MDS - sAML 46, XY Dendrogram derived from hierarchical cluster analysis using the 1-correlation distance metrics and an average linkage algorithm. Dendrogram derived from hierarchical cluster analysis using the 1-correlation distance metrics and an average linkage algorithm.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.4866.4866

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2818-2818

Abstract: Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, bone marrow (BM) dysplasia in one or more hematopoietic lineages, and clonal instability with an increased risk to transform to secondary acute myeloid leukemia (AML). In most patients, the erythroid lineage is affected. During the past few years our knowledge about the pathogenesis of MDS, has increased substantially. However, most of these studies focused on CD34+ stem and progenitor cells or granulomonocytic cells, whereas only little is known about genes aberrantly expressed in dysplastic erythroid cells in MDS. In an attempt to define abnormal gene expression patterns and molecular pathways contributing to erythroid dysplasia in MDS and to identify disease-specific phenotypic and molecular abnormalities in dysplastic erythoid cells, we compared gene expression profiles of erythroid progenitor cells (EryPC) in 10 patients with low-risk MDS (IPSS-R score≤7) and 15 control BM samples. EryPC were defined as CD45low/CD105+ cells and purified from BM samples by multicolor flow cytometry and cell sorting (purity 〉 95%). Gene expression levels were analyzed by Affymetrix array technology (GeneChip U133 Plus 2.0 arrays) and confirmed for a panel of select genes by qPCR. A stringent cut-off (p 〈 0.01; fold-change 〉 3.0) was used to define differences in mRNA expression levels. A total number of 1,180 mRNA species were found to be differently expressed in EryPC in MDS (72 up-regulated, 1,108 down regulated) compared to normal BM EryPC. Among these, a number of genes regulating proliferation and differentiation in lymphohematopoietic cells, including TCEB1 transcription elongation factor B (SIII), the transcriptional repressor YY1, E2F3, and the ATP-dependent RNA helicase DDX5, were found to be downregulated in EryPC in MDS compared to normal BM. In the validation phase of our project, we identified the major Coxsackie-Adenovirus Receptor (CAR) as a rather specifically regulated protein-product in dysplastic EryPC. In fact, as assessed by flow cytometry, a significantly lower or even absent expression of CAR was found on EryPC in 20 of 30 patients with MDS (67%), including 3/4 patients with RCUD, 1/4 with RARS, 6/10 with RCMD, 8/9 with RAEB, and 2/3 with 5q- syndrome, compared to normal BM or non-neoplastic controls (p 〈 0.001). In addition, reduced expression of CAR on EryPC was seen in 11/25 patients with myeloproliferative neoplasms (MPN) with dysplastic BM cells, in 4/8 patients with MDS/MPN overlap syndromes, and in 14/19 patients with AML. By contrast, expression levels of CAR on EryPC were normal in almost all non-neoplastic conditions, including renal anemia (n=6), hepatopathy (n=1), drug-related anemia (n=10), folic acid or vitamin B12 deficiency (n=3), intestinal bleeding (n=1), autoimmune hemolytic anemia (n=2), aplastic anemia (n=2), spherocytosis (n=1), chronic inflammation (n=4), and viral infections (n=2). Moreover, CAR expression on EryPC remained normal in most anemic patients suffering from lymphoid malignancies (n=36). Within the group of patients suffering from infection-related anemia, the lowest expression of CAR was observed in a case of adenovirus infection mimicking MDS. An overview of staining results obtained with anti-CAR antibody in various groups of patients and in healthy controls (normal BM, n=20) is shown in Figure 1.Figure 1Expression levels of CAR on EryPC determined by flow cytometry. The level of CAR expression on EryPC is depicted as mean fluorescence intensity and indicated by circle in each individual donor. Horizontal lines represent median CAR expression levels in each group of donors. *, p 〈 0.05, and **, p 〈 0.001, compared to healthy controls, as determined by Mann-Whitney U test.Figure 1. Expression levels of CAR on EryPC determined by flow cytometry. The level of CAR expression on EryPC is depicted as mean fluorescence intensity and indicated by circle in each individual donor. Horizontal lines represent median CAR expression levels in each group of donors. *, p 〈 0.05, and **, p 〈 0.001, compared to healthy controls, as determined by Mann-Whitney U test. In summary, our data show that the major Coxsackie-Adenovirus Receptor CAR is expressed at abnormally low levels on dysplastic EryPC in a substantial subset of patients with MDS and in most patients with related BM neoplasms. Since CAR expression remains normal in almost all reactive conditions, deficiency states and lymphoid malignancies, abnormal CAR expression may contribute as a potential indicator of (clonal) dysplastic erythropoiesis in myeloid malignancies, including MDS. The biochemical basis of abnormal expression and the possible role CAR may play in the pathogenesis of MDS and in related BM neoplasms, is currently under investigation. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2818.2818

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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. 500-500

Abstract: Introduction: Positron emission tomography (PET) assessment early during treatment of advanced stage Hodgkin lymphoma (HL) patients might be suited to determine the individual risk for treatment failure. In the HD18 study, PET was performed after induction therapy with two courses of BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine). Depending on this PET-2 result, patients were either classified as high-risk or low-risk patients and escalation or de-escalation treatment strategies were tested, respectively. To improve the presumably poor progression free survival (PFS) of PET-2 positive patients, we introduced the anti-CD20 antibody rituximab into the BEACOPPescalated regimen (R- BEACOPPescalated). Here, we report the results of the second planned interim analysis for the PET-2 positive patient cohort. Methods: HD18 is an open-label, multicenter, prospective, randomized, phase III study (ClinicalTrials.gov ID: NCT00515554) for patients with newly diagnosed advanced stage HL aged 18–60 years. Patients with PET positive disease (standard uptake value above mediastinal background) after two courses of BEACOPPescalated were randomly assigned to receive additional six courses of BEACOPPescalated (BEACOPP group), or rituximab in conjunction with six cycles of BEACOPPescalated (R-BEACOPP group). We centrally performed a 1:1 randomization by stratified minimization. Primary endpoint was progression free survival (PFS) using an adaptive study design with three interim analyses. Sample size was determined to ensure that an improvement by at least 15 percentage points could be detected by the addition of rituximab to BEACOPPescalated assuming a 5-year PFS rate of 68% for PET-2 positive patients with BEACOPPescalated. Results: Between May 2008 and May 2011, 1,100 patients were enrolled into the HD18 trial, of whom 440 were PET-2 positive and randomized (BEACOPP n=220; R-BEACOPP n=220), corresponding to 43% of all randomized patients. One patient in the BEACOPPescalated group was excluded from intention-to-treat analysis because HL was not confirmed by reference histology. Median age was 30 years (range 18-60), 177 were female (40%). One patient had stage IIA disease, 103 patients (23%) had Ann Arbor stage IIB disease with the risk factors large mediastinal mass or extranodal involvement, the remaining patients had stage III/IV disease. IPS risk groups were distributed as follows: 120 patients 0-1 (28%), 241 2-3 (55%), and 75 4-6 (17%). Overall, grade 4 toxicity occurred in 197/218 (90.4%) and 206/220 (93.6%) of the documented patients in the BEACOPP and R-BEACOPP group, respectively. Grade 4 leukopenia was documented in 193 (88.5%) and 201 (91.4%) patients, grade 4 thrombocytopenia in 112 (51.4%) and 123 (55.9%) patients, anemia in 27 (12.4%) and 31 (14.1%) patients, and grade 4 infections in 9 (4.1%) and 13 (5.9%) patients. Other grade 4 toxicities had a frequency of less than 2%. Treatment related mortality occurred in 1 (0.5%) and 3 patients (1.4%), respectively. Overall, 16 patients died, 6 in the BEACOPPescalated group and 10 in the R-BEACOPPescalated group. With a median follow-up of 35 months, Kaplan-Meier PFS estimates were largely overlapping (log rank p=0.99) with an estimated 3 year PFS of 91.4% for BEACOPP (95% CI: 87.0% – 95.7%) and 93% for R-BEACOPP (95% CI: 89.4% – 96.6%). Accordingly, overall survival was not different (96.5% versus 94.4% at 3 years for BEACOPP versus R-BEACOPP, p=0.31). The data monitoring committee (DMC) recommended publication of this second interim analysis, since a futility analysis indicated a low likelihood of the trial to become successful. Conclusion: Importantly, the definition of PET positivity used in the HD18 study failed to determine a high-risk patient group. PFS in PET-2 positive patients receiving standard treatment with BEACOPPescalated was much better than expected. Accordingly, the chance to improve the overall excellent PFS of these patients with rituximab was low. In fact, we did not observe any benefit. Future analyses of the PET-2 negative patient cohort will show if PET guided risk group allocation allows treatment reduction in advanced stage HL patients. Disclosures Off Label Use: Rituximab for Hodgkin Lymphoma.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.500.500

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. 108, No. 11 ( 2006-11-16), p. 3540-3540

Abstract: Bortezomib has improved the outcome of patients with multiple myeloma. Nevertheless, bortezomib monotherapy achieves responses in less than 50% of patients with advanced disease. Combination therapy can improve response rates but is associated with more adverse events such as neuropathy or myelosuppression. Therefore, we evaluated a step-wise escalation treatment algorithm for patients with relapsed or refractory myeloma. The initial treatment (step1) consisted of bortezomib monotherapy (1.3mg/m2 on day 1,4,8,11). Patients who did not show a at least 25% reduction of paraprotein at the beginning of cycle 2 received an escalated treatment (step2) with bortezomib and dexamethasone (40mg on day 1,4,8,11). The next treatment escalation (step3) was performed by addition of bendamustine (50–100mg/m2 on day 1 + 8) to bortezomib and dexamethasone. Step3 was used for patients who did respond with less than a minor response to one cycle of step2 treatment. We report on 48 patients who have been treated at our institution according to this regimen. Patients median age was 59 years with a median β2-microglobuline level of 3.8 g/dl and median albumine level of 3.7 g/dl. All patients were heavily pre-treated with in median three prior treatment regimen including high-dose therapy and thalidomide in more than 90% of patients. Escalation therapy was applied as planned to 36 (75%) patients, whereas 12 (25%) patients received step2 at the beginning of treatment due to physicians decision because of fulminant disease progression with hypercalcemia or severe tumor burden. Toxicity was as expected for bortezomib monotherapy and was manageable with escalated treatment steps. Response rates for patients in step1 were 11% nCR, 36% PR and 11% MR. In step2 (n=26) response rates were 31% PR, 15% MR and in step3 (n = 7) 43% PR and 29% MR. This results in an overall response rate of 80% for all patients. Patients with fulminant progressive disease who needed upfront treatment with step2 had an inferior overall response rate of 42% in comparison to 90% for patients who were treated according to the planned treatment schedule. With a median follow-up of 26 months the median time to progression and overall survival was 9 months and not reached for patients in the planned program and 2 and 4 months for the patients with upfront escalated therapy. Univariate analysis including several conventional prognostic parameters revealed physicians decision for upfront escalated treatment and age 〉 60 years as the only bad prognostic factors. Interestingly, for patients within the planned treatment schedule, response to previous therapies, the extent of paraprotein reduction and the required escalation step had no impact on response duration. Another interesting observation of our single center study was that re-exposure of step3 treatment at the time of relapse (n=8) resulted in a new remission in 50% and in stable disease in 38% of patients. In conclusion, escalating therapy with bortezomib, dexamethasone and bendamustine induces durable remissions in the majority of patients, even in the presence of poor prognostic parameters. However, this treatment algorithm is not applicable for patients presenting with fulminant disease progression, as these patients need more aggressive regimens.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.3540.3540

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3120-3120

Abstract: Fludarabine-refractory CLL has a poor prognosis with a median overall survival time of less than 12 months despite salvage chemotherapy and intravenous alemtuzumab (Campath-1H) is the approved treatment based on a remission rate of 33% and a median survival time of 16 months (Keating et al., Blood 2002). The CLL2H trial of the GCLLSG was initiated to evaluate the subcutaneous application of 3 × 30 mg alemtuzumab weekly in fludarabine refractory CLL. The current analysis is based on 109 consecutive patients enrolled until completion of the trial in April 2006. Median age was 63 (36–81) years, 71% were male. A median number of 3 (1–9) prior lines of therapy had been given. Subcutaneous treatment was performed on an outpatient basis in all cases and had to be temporarily interrupted in 68 patients due to neutropenia (43%), anemia (6%), thrombocytopenia (3%), infections (40%, CMV reactivations 30%), and was stopped early in 63 cases due to insufficient response (44%), hematotoxicity (16%), infection (17%), and CMV reactivation (13%). The median alemtuzumab dose given was 722 (3–2203) mg. Toxicity was mostly grade I/II apart from hematotoxicity (grade III/IV anemia: 42%, thrombocytopenia: 52%, neutropenia: 54%) and grade III/IV infections (25%). After a median follow up time of 21.4 months, 56 deaths have occurred (due to progression 52%, infections 39%, not CLL related 9%). The overall response rate was 33% (CR 4%, PR 27%), the median progression free survival time was 7.7 months, and median overall survival time was 19.1 months. Genetic high-risk factors were present in the vast majority of cases (unmutated VH 66%, 17p–29%, 11q–19%, TP53 mutation 39%). Responses (CR or PR) were observed in 22% of VH unmutated, 24% of 11q-, 39% of 17p-, and 33% of TP53 mutated cases. Progression free survival and overall survival were not significantly different when comparing the genetic subgroups, particularly TP53 mutated, 11q-, and 17p- (see figure). In conclusion, subcutaneous alemtuzumab is feasible in an outpatient setting in a high-risk population of fludarabine-refractory CLL and appears to be of similar efficacy as by intravenous administration. Most importantly, genetic high risk subgroups with unmutated VH, 11q- or 17p- appear to respond to alemtuzumab. Figure Figure

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.3120.3120

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 879-879

Abstract: Abstract 879 As previously reported, dose-escalated first-line therapy with autoSCT as conducted in the GCLLSG CLL3 protocol is a feasible and effective therapy option for younger patients with poor-risk CLL. Purpose of the present analysis was to study the impact of FISH karyotype according to the hierarchical model, and of IGHV mutational status on progression-free (PFS) and overall survival (OS) in this trial. Trial design and patients: The protocol comprised optional cytoreduction with CHOP, fludarabine, or FC; PBSC mobilization using the Dexa-BEAM regimen; and myeloablative therapy with TBI/CY followed by reinfusion of purged (CD34+) stem cells. Inclusion criteria were age 〈 61 years, stage Binet B/C or poor-risk stage A as defined by short lymphocyte doubling time plus elevated TK, and one line of pretreatment or less. From December 1996 through September 2002, 216 patients were registered with the protocol. As 47 cases had to be excluded due to screening failure (n=21), withdrawn consent (n=19) or other reasons (n=7), 169 patients were eligible for the current analysis. Male to female ratio was 5:1 and the median age at diagnosis was 51 years (range 27-60). Results: SCT was performed in 131 patients (78%) at a median time of 17 months (range 4-159) after initial diagnosis, whereas 38 patients did not proceed to SCT due to mobilization failure (n=14), disease progression (n=4), early death (n=3), patients preference (n=6), or unknown reasons (n=11). At a median follow-up of 99 months (range 4-137) after initiation of first cytoreductive therapy within the protocol, median OS of all 169 patients was 10.5 years, with 10.5 years for those treated with and 6.1 years for those treated without autoSCT, yielding a hazard ratio of 0.26 (95% CI 0.13-0.54; p 〈 .0001). Median PFS was 6.3 years, with 6.8 years for those treated with and 4.8 years for those treated without autoSCT (HR 0.39; 95% CI 0.23-0.67; p=0.0007). The 10-year incidence rate of t-MDS/ t-AML was 9% (1-18%). Diagnostic samples for assessment of the IGHV mutational status were available for 143 of 169 patients (85%). An unfavorable (unmutated of V3-21-containing) IGHV rearrangement was present in 104 patients (73%). Compared to the 39 patients with favorable IGHV, those with unfavorable VH had significantly worse PFS and OS (median PFS 5.1 years vs not reached, hazard ratio (HR) 2.47 (1.56-3.92), p=0.0001; median OS 9.1 years vs not reached, HR 2.0 (1.14-3.68), p=0.017). FISH was possible in 160 patients (95%) with results as follows: del 17p- 4 patients (3%), del 11q- without del 17p 40 patients (25%), trisomy 12 without del 17p- and del 11q- 20 patients (13%), del 13q- as sole abnormality 48 patients (30%), other karyotypes 20 patients (13%), normal karyotype 28 patients (17%). All 4 patients with del 17p- showed progressive disease after Dexa-BEAM mobilization and did not proceed to autoSCT. Whereas PFS (p 〈 0.0001) and OS (p 〈 0.0001) thus was strongly reduced in the 4 patients with del 17p-, no significant differences between the other subsets became evident: median PFS 1.0 years (del 17p-), 5.9 years (del 11q), 4.8 years (+12), 7.5 years (del 13q-), 7.7 years (normal); median OS 1.5 years (del 17p-), 10.5 years (del 11q-), not reached (+12), not reached (del 13q-), 10.3 years (normal). Conclusions: Unmutated IGHV remains an adverse prognostic factor after dose-escalated first-line therapy with autoSCT. In contrast, this strategy may overcome the unfavorable impact of the FISH karyotype del 11q- seen with conventional therapy. Disclosures: Hopfinger: Roche: Honoraria. Schmitz:Roche: Honoraria, Research Funding. Stilgenbauer:BayerScheringAG: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.879.879

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. 114, No. 22 ( 2009-11-20), p. 535-535

Abstract: Abstract 535 Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo). Methods and Patients: 817 treatment-naïve patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (CIRS) score was 1 (range 0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively. A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p 〈 0.001), respectively. 74% (FCR) and 67% (FC) of pts received 6 cycles (p=0.02). The total median cumulative dose applied per pt was 775 mg for F and 7712 mg for C, with no statistically significant difference among the two treatment arms. Pts in Binet stages A and B received more treatment cycles (5.31) than Binet C pts (4.52; p 〈 0.001). Only 57.1% (FC) and 60.3% (FCR) Binet C pts received 6 cycles. Dose reductions by more than 10% were observed in 49% of FCR pts (vs 28% FC (p=0.001). Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p 〈 0.001). Median PFS was 32.8 mo for FC and 51.8 mo for FCR pts (p 〈 0.001, Hazard Ratio (HR) 0.56, CI 95% 0.460-0.689). The largest benefit for FCR was observed in Binet stage A and B for CR, ORR and PFS (Binet A: p=0.08, HR 0.423 CI 95%, 0.157-1.135, Binet B: p 〈 0.001 HR: 0.504 CI 95%, 0.390-0.651, Binet C: p=0.08, HR 0.732 CI 95%, 0.514-1.041). In Binet C, the median PFS was 14 mo for pts treated with up to 3 courses FC, but 44 mo for pts that received 4 courses or more (p 〈 0.001). Median PFS for pts treated with up to 3 cycles FCR was 12.5 mo, while for pts with 4 cycles or more, median PFS has not been reached (p 〈 0.001). Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, CI 95%, 0.023-1.613 p=0.09; Binet B: HR 0.45, CI 95%, 0.296-0.689, p 〈 0.001; Binet C HR1.4, CI 95%, 0.843-2.620, p=0.168). As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity. Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and β2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:Roche: Honoraria, travel grants. Fink:Roche: Travel grants. Mayer:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding. Hensel:Roche: Honoraria, Travel Grants; Bayer: Honoraria. Hopfinger:Roche: Membership on an entity's Board of Directors or advisory committees. Hess:Roche: Honoraria. Bergmann:Roche: Honoraria for monitoring and CRFs. Catalano:Roche: Honoraria, Research Funding, Travel grants. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Berrebi:Roche: travel grants. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants. Trneny:Roche: Honoraria, Research Funding. Westermann:Roche: Travel Grants. Wendtner:Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Staib:Roche: Research Funding. Boettcher:Roche: Honoraria, Research Funding, Travel grants. Ritgen:Roche: Research Funding. Mendila:Roche: Employment. Kneba:Roche: Honoraria, Research Funding. Doehner:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding, travel grants. Fischer:Mundipharma: Research Funding; Roche: travel grants.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.535.535

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7