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In: Blood, American Society of Hematology, Vol. 91, No. 4 ( 1998-02-15), p. 1399-1406

Abstract: The ETV6 (also known as TEL) gene on chromosome 12p13 is the target of a number of translocations associated with various hematologic malignancies. The contribution of ETV6 to leukemogenesis occurs through different mechanisms that involve either its helix-loop-helix dimerization domain or its E26 transformation-specific (ETS) DNA-binding domain. Using fluorescence in situ hybridization we characterized seven newETV6 rearrangements in chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma. These aberrations, not always discernible at the cytogenetic level, include a t(5;12)(q31;p13), t(6;12;17)(p21;p13;q25), t(7;12)(p15;p13), t(7;12)(p12;p13), t(7;12)(q36;p13), t(12;13)(p13;q12), and a not completely defined t(12;?)(p13;?). Loss or disruption of the secondETV6 allele by a del(12)(p12p13) or by an intragenicETV6 deletion was detected in two cases. In six cases the 12p13 breakpoint occurred in the 5′ end of ETV6, upstream to exons encoding the HLH domain, whereas the remaining case had a breakpoint between the exons coding for the HLH domain and the exons coding for the ETS domain of ETV6. These observations provide further evidence for the multiple contributions of ETV6 in the pathogenesis of a wide range of hematologic malignancies.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V91.4.1399

Language: English

Publisher: American Society of Hematology

Publication Date: 1998

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2078-2078

Abstract: Abstract 2078 Background: Health-related quality of life profile (HRQOL) of patients diagnosed with high-risk myelodysplastic syndromes (MDS) can be compromised already at the time of diagnosis before receiving any kind of treatment. Clinical decision-making is challenging due to the poor prognosis and no data exist on the possible relationships between patient's HRQOL and the request of prognostic information on survival during consultation. Aim: The main objectives were to assess preferences for prognostic information of patients with high-risk MDS and the relationship between such preferences and patient characteristics including HRQOL. To date no such evidence exists in this population. Patients and Methods: Data were gathered through an ongoing international prospective observational study that recruits newly diagnosed patients with MDS. These patients typically have a limited life expectancy. At the time of diagnosis, and during one of the first clinical consultations in which treatment options were discussed, patients completed the European Organization for Research and treatment of Cancer, Quality of life Questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 is a psychometrically robust generic HRQOL cancer measure assessing both symptoms and functional aspects. Physicians also completed an extensive survey about their patient's preference for involvement in treatment decisions and whether the patient explicitly requested prognostic information for survival. Associations between request for prognostic information, HRQOL socio-demographic characteristics (i.e., living arrangements, age, gender, education) and clinical data including: performance status, comorbidity and disease severity (i.e. IPSS risk category intermediate 2 vs. high risk) were investigated using Fisher's exact test and Wilcoxon-Mann-Whitney test as appropriate. Results: Overall, 184 patients (36% female and 64% male) were analyzed. Mean age of patients was 70 years (range: 31–88). 65% explicitly requested information about expected survival at the time of diagnosis. The symptom profile of patients requesting prognostic information was better than those who did not in 7 out of the 8 symptoms evaluated. The largest clinically meaningful difference was found for fatigue with a mean score of 39 (SD:26) and 52 (SD:28) respectively for those requesting prognostic information versus those who did not. Request for prognostic information was significantly associated with younger age (P=.01) and fewer comorbidities (P=.04). In addition, better physical functioning (P=.009), better role functioning (P=.002) and a lower level of fatigue (P=.002) were also associated with a request for prognostic information during consultation. Additional supportive analysis revealed that patients with a higher overall mean symptom score did not request information about survival (P=.02). Conclusion: These data suggest that the majority of patients with high-risk MDS request prognostic information on survival from their physicians at the time of diagnosis. There is also an indication that patients who are more likely to request such information are those who are in better health condition reporting higher functional abilities and lower symptoms. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.2078.2078

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. 100, No. 3 ( 2002-08-01), p. 1097-1099

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood-2002-03-0867

Language: English

Publisher: American Society of Hematology

Publication Date: 2002

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2993-2993

Abstract: Abstract 2993 High-dose chemotherapy followed by autologous stem cell transplantation is an approved therapeutic intervention in relapsed Hodgkin-lymphoma (HL) and Non-Hodgkin lymphoma (NHL). In multiple myeloma (MM) it remains standard of care in first remission. Unfortunately, a significant portion of patients fail to mobilize and collect a sufficient amount of hematopoietic stem cells, being considered as “poor-mobilizers”. The effectiveness of the hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries and reported to the European Consortium of Stem Cell Mobilization (ECOSM). Here we describe the mobilization success of 580 proven poor-mobilizers (304 male, 276 female) with NHL, HL and MM in Europe between May 2008 and August 2009. Furthermore, we analyzed the mobilization of stem cells in major NHL subgroups. All patients received plerixafor plus granulocyte colony-stimulating factor in standard doses with or without chemotherapy. Two-hundred seventy patients with NHL (138 male, 132 female) with a median age of 56 years (range 12 – 75 years) and a median of two prior chemotherapy regimens (range 0 – 10) were enrolled. Median cell yield was 2.56 × 10 ^6 CD34+ cells/kg BW (range 0 – 17.37). The general accepted minimum of 2.0 × 10 ^6 CD34+ cells / kg bodyweight (BW) for transplantation was reached by 175 patients (64.8%) in a median of two apheresis sessions (range 1 – 4). Thirty-four patients (12.6%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW. There were no significant differences in in stem cell harvests regarding number of prior mobilization attempts or number of prior chemotherapeutic regimens, as well as in comparing patients with diffuse large B cell lymphoma (n=28), follicular lymphoma (n=15), and mantle cell lymphoma (n=24), respectively. Fifty-four HL patients (24 male, 30 female) with a median age of 36 years (range 19 – 76) and a median of three prior lines of therapy (range 1 – 5) were enrolled. Median cell yield was 3.14 × 10^6 CD34 cells/kg BW (range 0 – 32.6). Forty-four patients (81.5%) collected the minimum of 2.0 × 10^6 CD34+ cells/kg BW in a median of two apheresis sessions (range 1 – 4). Twelve patients (22.2%) collected more than 5.0 × 10 ^6 CD34+ cells/kg BW. A total of 256 patients (148 male, 108 female) with a median age of 60 years (range 28 – 76) diagnosed with MM were enrolled. Patients had received a median of two prior lines of treatment and collected a median of 3.60 × 10 ^6 CD34+ cells/kg BW (range 0 – 15.27) in a median of two apheresis sessions (range 1 – 5). The minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was collected by 209 patients (81.6%). Eighty-two patients (32.0%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW allowing tandem transplantation. Overall, the CD34+ cell yield was significantly higher in MM patients than in NHL patients (p 〈 0.0001) and also significantly higher in HL patients than in NHL patients (p =0.013). CD34+ cell yield was not statistically significant between MM patients and HL patients. Furthermore, the number of patients collecting the minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was significantly higher in MM patients compared to NHL patients (p 〈 0.0001) and also significantly higher in HL compared to NHL patients (p =0.017). Analyzing the mobilization strategies and collection success of individual countries demonstrated only minor variations compared to the global results. Chemomobilization and steady state mobilization are used in most countries; however, there is a clear preference for chemotherapy combined with G-CSF/plerixafor in the Czech Republic, Germany, Hungary, Italy and Poland. The data emphasize the role of plerixafor in patients who failed prior mobilization attempts, but the development of improved strategies in poor mobilizers especially with NHL is required. Disclosures: Duarte: Genzyme: Membership on an entity's Board of Directors or advisory committees. Kröger:Genzyme: Membership on an entity's Board of Directors or advisory committees. Mohty:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hübel:Genzyme: 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.V118.21.2993.2993

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. 126, No. 23 ( 2015-12-03), p. 4391-4391

Abstract: Introduction Haploidentical family donors are becoming an effective alternative for patients in need of an hematopoietic stem cell transplantation (HSCT) but lacking an HLA-matched donor. However, to prevent graft-versus-host disease (GVHD), intensive in-vivo or ex-vivo T-cell depletion is often utilised, resulting in slow immune reconstitution, frequent and often lethal infectious complications and/or high relapse rates, thus decreasing overall survival. To overcome these limitations, we have developed a strategy that allows additional donor lymphocytes to be infused post-HSCT without the risk of inducing severe GVHD and maintaining the ability to react against infections and leukemic cells. Patients and Methods In this open-label, multi-centre phase 2 clinical trial (CR-AIR-007; NCT01794299), 23 patients with high-risk AML or ALL were enrolled. Patients underwent myeloablative conditioning and were given a CD34+ selected stem cell graft from a haploidentical family donor. In addition, donor lymphocytes from the same donor were processed using a selective photodepletion technology, creating a donor lymphocyte product depleted of alloreactive T-cells (ATIR101). ATIR101 was to be given to patients at 28-32 days post-HSCT at a fixed dose of 2x106 CD3+ cells/kg. No post-transplant GVHD prophylaxis was administered. The primary endpoint of the study is transplant-related mortality at 6 months post-HSCT. Patients are followed to determine disease-free and overall survival. Patients undergoing a similar T-cell depleted haploidentical HSCT without ATIR infusion (CR-AIR-006; NCT02188290) were used as controls. Most centers providing the historic control data also participate in this phase 2 trial with ATIR101. Results Twenty-three patients, median age of 41 years (range 21 - 64), have been enrolled into this study. Seventeen patients, 7 male and 10 female, had AML, 12 in CR1 and 5 in CR2 at the time of HSCT. Six patients, 5 male and 1 female, had ALL, 4 in CR1 and 2 in CR2 at the time of HSCT. Conditioning regimen consisted of a] TBI (1200 cGy; n=10) or b] melphalan (120 mg/m2; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 5d) and ATG (2.5mg/kg x 4d). No patient experienced graft rejection, with neutrophil and platelet engraftment achieved at a median of 11 and 12 days, respectively (range 8-18, range 9-35). 21 patients to date received ATIR101, at a fixed dose of 2x106 CD3+ cells/kg at a median of 28 days (range: 28-73 days) post-transplant. Median follow-up is 270 Days post-HSCT. No patient developed grade III-IV acute GVHD. Two cases of grade II acute GVHD were reported thus far. The onset of these two acute GVHD cases was delayed, at day 173 and day 247 post-HSCT, 145 and 219 post ATIR respectively. No patient died within the first 100 days post-HSCT. There are 3 deaths as a result of transplant related mortality within 6 months post-HSCT (primary endpoint). When compared to the matched historic control group (N=35), TRM was significantly lower in patients given ATIR101 after a T-cell depleted haplotransplant with a 6-month TRM for HSCT + ATIR101 of 17% versus 34% for HSCT only (Figure 1a). Figure 1a: Kaplan Meier of Transplant related mortality: HSCT + ATIR101 vs HSCT alone (p=0.0075), data as per 3 August 2015. Thus far, in CR-AIR-007 study, only one patient experienced a relapse, which occurred at 90 days post-HSCT and resulted in death of the patient on day 122. The overall survival of patients given ATIR101 is significantly improved, compared to the control group, with a 1-year survival of 67% in the HSCT + ATIR101 group and 20% in the control group (Figure 1b). Figure 1b: Kaplan Meier of Overall Survival: HSCT + ATIR101 vs HSCT alone (p=0.0032), data as per 3 August 2015. Conclusions Addition of ATIR101 to a T-cell depleted haploidentical HSCT protocol significantly improves transplantation outcome, with reduced TRM and improved OS. Specifically, no patient died during the first 100 days post-HSCT. Administration of ATIR101 at the dose of 2x106 cells/kg does not induce severe GVHD, confirming the efficacy of alloreactive T-cell elimination from the donor lymphocyte infusion. We attribute the reduced TRM (mainly infections in the control group) to the additive immunological protection afforded by ATIR101. Moreover, the low number of relapses observed thus far is most encouraging and supports the preservation within ATIR101 of T-cells able to recognize leukemic antigens. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Roy: Kiadis Pharma: Consultancy, Research Funding; Novartis: Honoraria. Rudiger:Kiadis Pharma: Employment. Velthuis:Kiadis Pharma: Employment. Reitsma:Kiadis Pharma: Employment. Gerez:Kiadis Pharma: Employment. Rovers:Kiadis Pharma: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4391.4391

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. 118, No. 21 ( 2011-11-18), p. 257-257

Abstract: Abstract 257 The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) with the same drugs, in previously untreated AML 〈 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) had to receive consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization had to be done after evaluation of consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2. The aim of the trial was to detect an 8% treatment difference (from 35% to 43%) in the 5-yr overall survival (OS) rate, corresponding to a hazard ratio (HR) of 0.80 (alpha=5%, power=95%); secondary endpoints were response to induction, toxicity, disease-free survival (DFS) from CR. Randomization was performed centrally; the 1st randomization was stratified for age ( 〈 46 vs 〉 45 yrs), performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 pts from 68 centers were randomized. Due to insufficient reporting, 3 centers, who recruited 63 patients, have been excluded from the analysis. The remaining 1942 pts (872 pts entered by EORTC-LG and 1070 by GIMEMA) 969 were randomized in SD-AraC and 973 in HD-AraC arm; among them 25 and 28, respectively, were ineligible, but kept in the analysis. Both arms were comparable with respect to gender, age (median=45 yrs), disease history, initial leukocyte count, PS, FAB and cytogenetics. At a median follow up of 6 yrs, 1114 pts had died. Results: After 1 or 2 courses of induction, CR was achieved in 1430 pts (73.6%); 684 (71.9%) pts (SD-AraC group) vrs 746 (78.7%) pts (HD-AraC group): p=0.002. Resistance was documented in 173 (18.2%) vrs 123 (13%), and death during induction in 85 (8.9%) vrs 71 (7.5%) pts, respectively. Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: HD-AraC 〉 SD-AraC. CR rates for pts 〈 46 yrs were 74.7% (SD-AraC) and 81.4% (HD-AraC) and for pts 〉 45 yrs 66.4% (SD-AraC) and 71.8% (HD-AraC). 634 pts (SD-AraC and 686 (HD-AraC) received a consolidation cycle. Among 765 CR-pts 〈 46 yrs 284 pts had an HLA identical sibling ( 〈 46D) and 481 did not or had not been typed ( 〈 46NoD). Among 665 CR-pts 〉 45 yrs 225 pts had an HLA identical sibling ( 〉 45D) and 440 did not or had not been typed ( 〉 45NoD). In the 〈 46D group 211 underwent an allo-SCT and 11 an auto-SCT. In the 〈 46NoD group 274 underwent an auto-SCT and 29 a MUD-SCT; in the 〉 45D group 147 underwent an allo-SCT and 14 an auto-SCT. In the 〉 45NoD group 244 underwent an auto-SCT and 12 a MUD-SCT. Comparisons of treatments arm regarding OS from randomization, DFS and Survival (S) from CR are indicated in the Table. The impact of age on the treatment difference regarding OS was almost significant (p=0.06). In pts 〉 45 who reached CR, the decrease in the relapse rate in the HD-Ara-C arm vrs SD-Ara-C arm (45.5% vs 49.4%) was counterbalanced by an increase in the death in CR rate (18.4% vs 13.2%). Conclusion: The final evaluation of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 6 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C and results in improvement in overall survival but only in pts under the age of 46 years. Disclosures: Muus: Amgen: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.257.257

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. 128, No. 22 ( 2016-12-02), p. 3504-3504

Abstract: Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is a treatment for CLL that can give long disease control. Even with the availability of kinase and BCL2 inhibitors, HCT is still performed in fit patients (pts) with high-risk CLL. Almost exclusively, outcomes on matched related and unrelated donor transplantations in CLL have been published. Recently, mismatched related donors are gaining interest because of the better outcome of haploidentical HCT with post-transplantation cyclophosphamide (PTCY). Methods: All pts with CLL who received a first allogeneic HCT with a mismatched related donor and whose data were available in the EBMT registry were analyzed. Median values and ranges are reported for continuous variables and percentages for categorical variables. The probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and the log-rank test for univariate comparisons. Relapse/progression and nonrelapse mortality (NRM) were analyzed together in a competing risk framework. Statistical analyses were performed using SPSS and R. Results: One-hundred-seventeen pts with CLL (74% males) underwent a mismatched related donor transplantation between 1984 and 2015 (1984-1999: 10, 2000-2004: 18, 2005-2009: 23, 2010-2016: 66). Median follow-up after HCT was 8 months (range 0-187 months). Median age at transplantation was 54 years (yrs) (range 27-71 yrs). Median time from diagnosis to HCT was 67 months (range 4-207 months). Eighteen pts (17%) had previously undergone autologous stem cell transplantation (ASCT). Disease status at HCT was CR in 16% of pts, PR in 39% and SD/PD in 45%. The Karnofsky score was known for 98 pts; 96% had a score of 70% or more at the time of HCT. Fifty-eight percent of pts received reduced-intensity conditioning, 42% myeloablative conditioning. Peripheral blood stem cells were used in 68% of pts, bone marrow in 32%. The HCT was sex matched in 41% of recipient-donor pairs. The relationship of the donor to the patient was known for 34 pts; in 53% the donor was a child, in 38% a sibling and in 6% a parent. Forty pts (38%) received PTCY as GVHD prophylaxis. In the other 77 pts various methods of T-cell depletion (TCD) were used, but not all methods were specified. At least 56% of those pts had in vivo TCD. For the whole cohort of pts OS at 2 and 5 yrs was 46% and 37%, respectively. PFS at 2 and 5 yrs was 38% and 30%, respectively. The use of PTCY did not have a significant impact on OS (49% vs. 42% at 2 yrs, 44% vs. 33% at 5 yrs, p=0.35) and PFS (45% vs. 31% at 2 yrs, 40% vs. 22% at 5 yrs, p=0.15). CI of NRM in the whole group at 2 and 5 yrs were 41% and 45%, respectively. CI of relapse at 2 and 5 yrs were 21% and 25%, respectively. The CI of NRM and relapse at 2 and 5 yrs were not statistically different in pts who received PTCY compared to other types of TCD (NRM: 38% vs. 45% at 2 yrs, 43% vs. 49% at 5 yrs, p=0.45; relapse: 17% vs. 25% at 2 yrs, 17% vs. 29% at 5 yrs, p=0.33). For the whole cohort, the incidence of acute graft-versus-host disease (aGVHD) at 100 days was 34% for grade II-IV and 16% for grade III-IV with a median time of onset of 23 days (range 4-57 days). Conclusions: Mismatched related donor HCT resulted in a 5-year PFS in 30% of the pts. This result seems only slightly inferior to matched donor transplant (5 yrs PFS 37%1). NRM was higher than expected in this cohort, but comparable to other studies on haploSCT with in vivo T-cell depleted grafts. In conclusion, a mismatched related donor HCT may be considered for high-risk chemoimmunotherapy-refractory or 17p deleted/TP53 mutated CLL pts without options for kinase and BCL2 inhibitor therapy. More data are needed to assess the value of PTCY for GVHD prophylaxis in this specific context. References: 1. Schetelig J, de Wreede L, Moreno C, et al. Risk factors for adverse outcome in patients with Chronic Lymphocytic Leukemia (CLL) undergoing Allogeneic Hematopoietic Cell transplantation (alloSCT): a Retrospective EBMT Analysis. Abstract WP024, EBMT meeting 2015. Figure 1 Figure 1. Disclosures Ciceri: MolMed SpA: Consultancy. Foà:Ariad: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Hallek:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Schetelig:Sanofi: Honoraria. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3504.3504

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3740-3740

Abstract: Thrombocytopenia is a common complication in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) that is associated with significant morbidity, a clinically significant bleeding risk, and early death. There are only limited treatment options for this high-risk population. Previous trials (Frey et al. ASH 2012) of thrombopoietin receptor agonists (TPO-RAs) for thrombocytopenia treatment in these pts suggested reduced thrombocytopenia-associated bleeding. ASPIRE (NCT01440374) was a multicenter, phase 2 trial. Eligible pts were ≥18 years, with high-risk MDS or AML, thrombocytopenia (platelets ≤25 x 109/L) due to bone marrow insufficiency, bone marrow blasts ≤50%, and an Eastern Cooperative Oncology Group status of 0-2. Exclusion criteria included platelets ≤10 x 109/L for reasons other than bone marrow insufficiency; leukocyte count ≥25 x 109/L; previous TPO-RA treatment. Pts were severely ill, on no other anti-MDS/AML therapy, with an expected median survival of ~6 months on treatment. Part 1 was an 8-week open-label study of eltrombopag 100 mg/day with dose escalation up to 300 mg/day (Mittelman et al. ASH 2012). Part 2 was a 12-week randomized, double-blind trial, during which pts received eltrombopag or placebo (Mittelman et al. Lancet Haematol 2018). Pts who completed both parts continued to Part 3, an extension phase of 10 months (for pts from Part 1) and 9 months (for pts from Part 2) (Fig. 1A). In ASPIRE Part 2, eltrombopag reduced the frequency of clinically relevant thrombocytopenic events (CRTEs) (one or more ≥Grade 3 hemorrhagic adverse events [AEs], platelets ≤10 x 109/L, or platelet transfusions) compared with placebo during weeks 5-12 in pts with advanced MDS or AML. Here we present data on the long-term durability of clinical benefit, overall survival (OS) and progression-free survival (PFS) for Part 2 pts within Part 2 and Part 3, and safety and tolerability of eltrombopag monotherapy in pts with advanced MDS or AML. Mean pt age was 72.2 years. Pts received a median eltrombopag daily dose of 298.8 mg with a median exposure of 11.1 weeks. At baseline, 40% of pts had an abnormal karyotype and 68% were platelet transfusion-dependent. OS (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.64-1.48) and PFS (HR 0.99, 95% CI 0.68-1.43) were not significantly different between long-term eltrombopag and placebo to eltrombopag switchers in Part 3 (median OS of 4.3 months vs 4.6 months, respectively). Median PFS was 0.94 months and 1.08 months for the placebo and eltrombopag group, respectively. CRTEs were summarized by week with the proportion of pts plotted by visit. Pts experienced large variability in CRTEs during weeks 1-40 with inconclusive results due to low number of pts at some time points (Fig. 1B). Hematological improvement (HI) was defined as improvement (platelets, neutrophils, hemoglobin) on treatment compared with placebo (Cheson et al. Blood 2006). Overall, 33% of pts showed HI with long-term eltrombopag use, compared with 10% during the double-blind phase. However, HI did not reach statistical significance compared with placebo in the double-blind phase. 46% of pts completed treatment. The main reasons for treatment discontinuation were physician decision (24%) and AEs (22%). Overall, 97% of pts experienced an AE during the extension phase plus 30 days. The most common AEs (≥20% of pts) were pyrexia, nausea, diarrhea, and epistaxis. Overall, 56% of pts died, with the disease under study being the most common cause (36%), and 37% of pts had treatment-related AEs. 31% of pts experienced Grade 3 or 4 AEs. The most commonly reported ( 〉 5%) were pneumonia, febrile neutropenia, anemia, hypokalemia, and urinary tract infection. Overall, 66% of pts experienced a serious AE (SAE). The most common (≥10%) were pneumonia, pyrexia, febrile neutropenia, and sepsis. The most common fatal SAEs (≥5%) were sepsis, pneumonia, and cardiac failure. ASPIRE Part 3 did not identify any new safety signals. The most common AEs were consistent with those expected for the disease under study and with eltrombopag treatment. There was no evidence of reduced OS or PFS. More pts met the criteria for HI with long-term eltrombopag use compared with those in the double-blind phase. The large CRTE variability observed with eltrombopag during Part 3 requires further assessment in adequately powered trials of high-risk MDS or AML pts and in a less seriously ill population. Figure 1 Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Portella:Novartis: Employment. Zhu:Novartis: Employment. Selleslag:Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Eltrombopag is used for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is not indicated for the treatment of patients with myelodysplastic syndrome (MDS).

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-130309

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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. 679-679

Abstract: Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count 〈 50 × 109/L. 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; the only treatments not allowed were investigational agents (rituximab was allowed) or other thrombopoietic agents. Patients received romiplostim or SOC for 52 weeks, and those who did not subsequently transfer to another romiplostim study completed a 6-month off-treatment safety follow-up. Co-primary endpoints of the study were: the incidence of splenectomy and the incidence of treatment failure (defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms). Patients who discontinued study during the treatment period were counted as having had splenectomy or treatment failure. To assess the impact of treatment discontinuation on the primary endpoints, a sensitivity analysis was conducted to determine the actual incidence of splenectomy or treatment failure. A total of 234 patients were randomized (romiplostim, 157; SOC, 77); 83% of romiplostim and 66% of SOC patients completed the study. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44 years) and 73% had received ≥2 prior ITP therapies. Patient characteristics were similar between treatment groups. The efficacy of romiplostim was significantly greater than that of SOC in both primary endpoint analyses. The incidence of splenectomy was 9% (14/157) in the romiplostim group compared to 36% (28/77) in the SOC group (OR, 0.17; 0.08, 0.35; p 〈 0.0001), and the incidence of treatment failure was 12% (18/157) in the romiplostim group compared to 30% (23/77) in the SOC group (OR, 0.31; 0.15, 0.61; p=0.0005). Sensitivity analyses confirmed the primary endpoint analyses: the actual incidence of splenectomy was significantly lower in the romiplostim group (2/157, 1%) than the SOC group (15/77, 20%) [p 〈 0.0001], and the actual incidence of treatment failure was significantly lower in the romiplostim group (6/157, 4%) than the SOC group (10/77, 13%) [p=0.009] . The incidence of bleeding events with a worst grade score ≥3 appeared lower for patients in the romiplostim group (3%) than the SOC group (7%). Safety analyses included only patients who received ≥1 dose of romiplostim or 1 type of SOC. During the 52-week treatment period, adverse events occurred in 96% (147/154) of patients receiving romiplostim and 92% (69/75) of patients receiving SOC. Serious adverse events occurred in 23% (35/154) of romiplostim and 37% (28/75) of SOC patients; serious adverse events were considered treatment-related in 5% (7/154) of romiplostim and 8% (6/75) of SOC patients. During the 6-month safety follow-up period, 36% (11/31) of romiplostim and 43% (18/42) of SOC patients experienced an adverse event; treatment-related adverse events occurred in none of the romiplostim patients and 2 of the SOC patients. Overall, 6 patients died: 1 (1%) in the romiplostim group and 5 (7%) in the SOC group. None of the deaths were considered related to study treatment or the underlying ITP. No patients tested positive for neutralizing antibodies to romiplostim or TPO. One romiplostim-treated patient showed an increase in bone marrow reticulin that was still within the normal range (Grade 2). In summary, romiplostim significantly reduced incidences of splenectomy and treatment failure in nonsplenectomized ITP patients compared to SOC. The safety profile of romiplostim was similar to SOC. Disclosures: Kuter: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Rummel:Amgen Inc.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:Amgen Inc.: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Shionogi: Speakers Bureau. Chong:Commonwealth Serum Laboratory (CSL): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Beiβenhirtz:Amgen Inc.: Consultancy. Gehl:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.679.679

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. 126, No. 3 ( 2015-07-16), p. 291-299

Abstract: Azacitidine increased median overall survival by 3.8 months vs current commonly used AML treatments (10.4 vs 6.5 months; P = .1009). Azacitidine safety in patients age ≥65 years with AML ( 〉 30% blasts) was consistent with its known safety profile in other trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-01-621664

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7