Kooperativer Bibliotheksverbund

In: Hämostaseologie, Georg Thieme Verlag KG, Vol. 40, No. 01 ( 2020-02), p. 119-127

Abstract: Introduction In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years. Methods Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records. Results We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from 〉 70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%. Conclusions Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.

Type of Medium: Online Resource

ISSN: 0720-9355 , 2567-5761

URL: Article

DOI: 10.1055/s-0039-3399493

Language: English

Publisher: Georg Thieme Verlag KG

Publication Date: 2020

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2645-2645

Abstract: The optimal consolidation chemotherapy in AML patients 〉 60 years has yet to be defined in detail. Although age-adjusted induction chemotherapy results in CR rates comparable to those in younger patients, relapse remains the major hurdle to successful treatment. While the role of stem cell transplantation (HSCT) in elderly patients is currently being evaluated in randomized studies, we focus here on the intensity of consolidation chemotherapy. Patients data from the elderly AML trials OSHO 1997 (n=410) and OSHO 2004 (n=733) were pooled and analyzed. These protocols have identical inclusion/exclusion criteria and induction chemotherapy, but differ in the intensity of consolidation therapy. In the OSHO 1997 trial, Ara-C 120 mg/m2 bid was given from day 1-5 and mitoxantrone 10 mg/m2 from day 1-2 as consolidation. In the OSHO 2004 an intensified consolidation using Ara-C 500 mg/m2 bid on day 1/3/5 was applied together with mitoxantrone as used in the OSHO 1997 study. Of the 1143 patients, 689 entered CR (60% in the OSHO 1997 and 61% in the OSHO 2004) and 536 (OSHO 1997, n=242, OSHO 2004, n=294) did not receive HSCT as consolidation. The analysis concentrated on the dose of AraC used in the consolidation for this elderly population and on the cycles of consolidation applied. Patient characteristics were compared using chi-square test for categorical data and Wilcoxon rank sum test for continuous data. OS was analyzed using the Kaplan-Meier method, and univariate comparisons were made by means of the log-rank test. Cox regression was used to find any association between consolidation chemotherapy considered as a time-dependent covariate on Overall Survival (OS) or Relapse Incidence (RI). RI and Non Relapse Mortality (NRM) were calculated using the competing risk method, and the Gray test was applied to compare differences. Multivariate modeling was performed by Cox regression analyses with a forward selection method. Median ages in the AML studies were 66 (60-81) years and 69 (60-85) years for the OSHO 1997 and OSHO 2004, respectively. Patients characteristics were balanced except for age and Karnofsky score (p 〈 .0005) and a trend towards more intermediate and high risk karyotypes, more female and less WBC in the OSHO 2004 compared to the OSHO 1997 study (p=0.06). OS at 15 years was 14±2% in all patients with no difference between the two consolidations, but strong dependence on cytogenetic risk factors. In multivariate analyses risk factors for survival were high/intermediate risk karyotypes, male gender, non de-novo AML and less than two consolidations. Patients with two consolidations had better OS than patients with one or no consolidations in the pooled group and in each of the two protocols with no difference between OSHO 1997 and OSHO 2004. Relapse incidence amounted to 79±2% and NRM 10±04% at 15 years with no difference between the two protocols. Relapse incidence was dependent upon cytogenetic risk and the number of consolidations applied in a multivariate model. There were no risk factors predicting TRM in multivariate analysis. Our analysis of patient characteristics according to the number of consolidations showed the distribution of consolidation therapies to be 15.2%, 28.0%, 56.6% and 14.2%, 32.3% and 53.4% for 0, 1 and 2 consolidations in the OSHO 1997 and OSHO 2004 respectively (n.s.). Higher age, higher risk cytogenetics, non-de novo AML type, less CR after one induction cycle and lower WBC count at diagnosis were characteristic of patients receiving none or one as compared to two consolidation therapies. The multivariate analysis revealed cytogenetics and gender as independent risk factors, but not the application of one as opposed to two consolidation treatments. The increase of AraC dose in the OSHO 2004 was unable to either increase survival or improve relapse incidence in the cohort of elderly patients. TRM was not different between the OSHO 1997 and 2004 studies. However, the application of one or two consolidation cycles had a significant impact on survival that was not due to decreased relapse incidence after normalization for risk factors. Interestingly, just above 50% of patients received 2 consolidations as proposed in the protocol with no statistically significant difference between OSHO 1997 and OSHO 2004. Patients receiving fewer consolidation therapy cycles are older, have more non-de novo AML and lower WBC count. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2645.2645

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. 126, No. 23 ( 2015-12-03), p. 2517-2517

Abstract: Background The German AML Intergroup conducted two randomized studies in younger ( 〈 60 years) and elderly (≥60 years) patients in which the study arms were compared to a common standard arm. Here, we compared the two studies in younger and elderly patients focusing on disease characteristics and outcome. Patients and Methods The East German Study Group (OSHO) and the Acute Myeloid Leukemia Cooperative Group (AMLCG) each entered patients from 18 to 59 years into one study and patients aged 60 years and older into another. Each study group randomized upfront 10% of all AML patients into a common standard arm and 90% in the study group specific arm. All patients with de novo AML or AML after myelodysplastic syndrome or cytotoxic treatment were eligible. Chi-squared and Mann-Whitney-U tests were used to detect significant differences between the age groups regarding demographic, clinical and cytogenetic characteristics at baseline. Complete Remission (CR) at 90 days and cumulative probabilities of death were determined for outcome. To avoid bias due to the higher probability of death in older patients, cumulative probabilities of death were calculated for relapsed patients or those who did not achieve CR after 90 days. Other deaths were considered as a competing risk. Results A total of 2435 AML patients were analyzed, 1132 in the study 〈 60 years and 1303 in the study ≥60 years. Significant differences in patient characteristics were noted between the studies. The elderly patient group contained a higher proportion of males than the younger group (55% vs 49% respectively, p=0.0031) and a higher percentage of secondary AML (40% vs 21% respectively, p 〈 0.0001). In contrast, younger patients had higher median WBC count [13x109/L (range 0.03-798) for 〈 60 years and 6.9x109/L (range 0.23-450) for ≥60 years, p 〈 0.0001] and higher median lactate dehydrogenase [442U/L (range 35-19,624) for 〈 60 years and 350U/L (range 51-9,486) for ≥60 years, p 〈 0.0001]. Cytogenetic risk was similarly distributed in both groups (favorable: 12% in both age groups, intermediate: 66% in 〈 60 years and 63% in ≥60 years, adverse: 22% in 〈 60 years and 25% in ≥60 years, p=0.1672). However, the favorable combination of FLT3-ITDwt and NPM1mut in normal karyotype was more common in the younger (35%) than in the older group (27%; p=0.0212). A higher rate of CR at 90 days was observed in the younger (66%) than in the older (51%) patients (p= 〈 0.0001). Of the younger patients 14.8% died (3.8% with persisting AML, 3.3% without AML and 7.7% without evaluable disease status) while of the older patients 21.8% died (6.2% with persisting AML, 2.5% without AML and 13.1% without evaluable disease status) during this period (p=0.0001). Relapse at 90 days was seen in 1% of the younger and in 2% of the older patients. The cumulative probability of AML-related death was lower in younger patients than in older patients (p 〈 0.0001). Of the younger patients 29% (95% CI: 26% to 31%) and 44% (95% CI: 40% to 46%) died after one and three years due to AML; in the older group the corresponding frequencies were 45% (95% CI: 42% to 48%) and 62% (95% CI: 59% to 65%; Figure 1a). The probability of dying from AML was lowest for the younger patients with de novo AML [27% (95% CI 24% to 29%) at 1 year and 41% (95% CI 38% to 44%) at 3 years] and highest for those with secondary AML [38% (95% CI 32% to 44%) at 1 year and 56% (95% CI 49% to 62%) at 3 years (p=0.0001)] , with similar differences being observed in the older patients (p=0.0001, Figure 1b). In the younger patients, CR at 90 days was lower in the standard (58%) than in the study arm (66%, p=0.0558), while AML related death was 29% and 27% at 1 year and 44% and 39% at 3 years respectively. In the older patients CR at 90 days was 52% vs. 51%, AML related death at 1 year 45% and 45% and at 3 years 63% and 69% for study arm and standard arm, respectively (Figure 1c). Conclusion This analysis reveals significant differences in gender, laboratory characteristics and proportion of secondary AML in elderly compared to younger AML patients. While there was no clear difference in cytogenetic risk groups, favorable molecular markers were more frequent in younger patients. Clear differences in CR rates after 90 days of therapy and AML related death rate were seen in regard to age ( 〈 60 years and ≥60 years) and disease type (de novo and secondary AML). As the common standard arm in both of the studies was age adapted, the differences between the two age groups are likely to be related to disease biology. Disclosures Niederwieser: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Krug:Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees; Sunesis: Speakers Bureau; Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria. Hegenbart:Janssen: Honoraria, Other: travel support. Pfirrmann:Novartis Pharma: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Kraemer:TEVA: Other: travel support. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2517.2517

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: British Journal of Haematology, Wiley, Vol. 143, No. 2 ( 2008-10), p. 191-200

Abstract: Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose‐limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low‐dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high‐dose therapy with stem‐cell support. BPT comprised fixed doses of bendamustine (60 mg/m 2 ) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty‐four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression‐free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non‐haematological side effects were observed and no patient developed dose‐limiting haematotoxicity. Transient grade 3–4 neutropenia was reported in 12 patients, and grade 3–4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study.

Type of Medium: Online Resource

ISSN: 0007-1048 , 1365-2141

URL: Issue

URL: Article

DOI: 10.1111/bjh.2008.143.issue-2

DOI: 10.1111/j.1365-2141.2008.07076.x

Language: English

Publisher: Wiley

Publication Date: 2008

detail.hit.zdb_id: 1475751-5

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1851-1851

Abstract: Outcome of elderly patients with AML is usually poor. Increased incidence of high risk AML and intolerance against dose escalation are the main causes for treatment failure. Pharmacokinetic measurements indicated that intracellular Ara-CTP formation is saturated at much lower infusion rates than used in high dose AraC schedules, probably causing AraC accumulation in the plasma and increased toxicity. Therefore, the East German Study Group (OSHO) used intermediate doses of AraC delivered at the presumptive saturating infusion rate over a prolonged period of time. The same schedule was applied to younger (≤60 years of age, AML 96) and older ( 〉 60 years of age, AML 97) patients with AML. In the present evaluation, determining factors for complete remission rate and hematopoietic reconstitution were identified. Methods: All 690 patients entered in the AML 96 (n=370) and AML 97 (n=320) study of the OSHO and treated with one or two courses of induction therapy (AraC 2 g/m2 iv on day 1,3,5,7 in combination with idarubicine 12 mg/m2 day 1–3 or mitoxantrone 10 mg/m2 iv day 1 to 3) followed by 2 consolidation courses were evaluated. The following baseline variables were studied in univariate analysis for their impact on CR rate: sex (M vs. F), age (≤ 60 years vs. 〉 60 years; continuous variable), cytogenetics at diagnosis (normal, favourable, unfavourable and others), disease classification (de novo or secondary AML), WBC ( 〈 2/2–90/ 〉 90 x 109/l), FAB-classification (M0/M1/M2/M3/M4/M5/M6/M7), LDH (≤ 2 x ULN vs. 〉 2 ULN) and the use of G-CSF (yes or no). Factors significant in this analysis were included in a multivariate model (logistic regression). Hematopoietic reconstitution was defined as the first of two consecutive days with leucocytes 〉 1000/μL and platelets 〉 50000/μL. Results: As shown in the multivariate analysis, the most important and highly significant parameter for CR rate was cytogenetics at diagnosis (p=10−11) followed by disease classification (de novo or secondary AML; p=0,001), WBC (p=0,003) and sex (p=0,018). In contrast, we could not demonstrate any significant influence of age (p=0,64), G-CSF (p=0,16) and FAB classification (p=0,38) on CR rate. Significant factors for the recovery of leukocytes were the use of G-CSF (p= 10−12), cytogenetics (p=10−4) and disease classification (de novo or secondary AML; p=0,04). AML classification (de novo or secondary AML; p=0,00002) and cytogenetics (p=0,001) but not age (p=0,17) were determinants for platelet recovery. Conclusion: Cytogenetics at diagnosis and disease type (de novo vs. secondary) were the most important determinants for CR rate using intermediate dose AraC. We could not demonstrate any influence of age on CR rate and hematological recovery.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.1851.1851

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. e18501-e18501

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2016.34.15_suppl.e18501

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2016

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3564-3564

Abstract: Thalidomide is an active single agent in advanced relapsed or refractory multiple myeloma (MM). The combination of low dose thalidomide with bendamustine and prednisolone might maintain or increase efficacy of the drug while avoiding dose limiting toxicity (DLT). Patients and Methods: The treatment consists of a fixed dose of bendamustine (60mg/qm) day 1, 8, and 15 with prednisolone (100 mg) day 1, 8, 15, and 22. In addition, thalidomide is given in three escalating doses, starting with 50 mg to a maximum of 200 mg daily. At each dose level 8 to 12 relapsed or refractory patients, half of them after conventional chemotherapy and half after high dose therapy with stem cell support, were enrolled. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles either until a maximal response was achieved, or until a DLT or a disease progression were observed. Between March 2004 and May 2006, 28 patients were enrolled: 8 in the first dose level with 50 mg thalidomide; 8 in the second dose level with 100 mg and 12 in the third dose level with 200 mg. All patients had received a minimum of 2 prior treatment regimens. Seven patients had been refractory to the last treatment. Median age was 67 years (range: 40 – 78). All patients completed 2 cycles of BPT-treatment and are therefore evaluable. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). Results: Twentyfive of 28 patients responded after at least 2 cycles of chemotherapy with 3 CR, 1 nCR, 5 VGPR, 15 PR and 1 MR. Two patients had stable disease and one patient was refractory. With a median follow up of 15 months, EFS and OS at twelve months were 34 % and 92 %, respectively. The most common side effects were constipation (11 patients WHO grade 1, 8 patients WHO grade 2), polyneuropathy (15 patients WHO grade 1, 3 patients WHO grade 2) and somnolence (4 patients WHO grade 1). None of the 28 patients developed dose-limiting hematoxicity as defined by an ANC 〈 1,0 Gpt/l for 〉 7 days or an ANC 〈 0,5 Gpt/l for 〉 3 days or platelet count 〈 25 Gpt/l. Transient neutropenia was reported in 9 patients (WHO grade 3 and 4) but no thrombocytopenia was observed. Conclusion: BPT with a dose between 50 and 200 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.3564.3564

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1066-1066

Abstract: Despite recent advances, treatment of elderly patients with AML remains a challenge because of adverse disease biology, comorbidities and therapy related toxicities. The balance between effectivity and toxicity of treatment strategies play a key role. Since comparative studies are lacking, a prospective randomized trial was designed among German AML study groups with different treatment strategies to compare outcome. Patients ≥60 years with all AML subtypes except M3 were randomized up-front to a common standard arm (CSA) (10%) and to study specific arms (90%) of the AMLCG or the OSHO. The CSA consisted of one or two inductions of araC 100 mg/m2/d continuous IV (CI) d 1-7 d and daunorubicin (dauno) 60 mg/m2/d IV d 3, 4, 5 and two courses of araC 1 g/m2/d BID IV d 1, 3 and 5 as consolidation (Mayer RJ et al, NEJM 1994). The AMLCG study arm randomized TAD (araC 100 mg/m2/d CI d1-2 followed by BID d 3-8, dauno 60 mg/m2/d IV d 3-5 and 6-thioguanine 100 mg/m2/d po BID d 3-9) and HAM [araC 1 mg/m2/d IV BID d 1-3 and mitoxantrone (mito) 10 mg/m2/d IV d 3-5] versus two courses of HAM with any 2nd course only given if blasts persisted ± G-CSF. Two courses of TAD were given as consolidation followed by maintenance chemotherapy over three years. The OSHO study arm included araC 1 g/m²/d BID IV d 1 + 3 + 5 + 7 and mito 10 mg/m2/d IV d 1 - 3 for one or two induction courses and ara-C 500 mg/m² BID 1h IV d 1 + 3 + 5 in combination with mito10 mg/m2/d IV d 1 + 2 as consolidation. Pegfilgrastim 6 mg s.c. was applied on day 10 of induction and on d 8 of consolidation. The study was approved by the IRB and registered at clinicaltrials.gov (NCT01497002 and NCT00266136). Written informed consent was obtained from all patients prior to randomization. Between April 1st, 2005 and May 26th, 2015 1286 patients were assigned randomly to the CSA (n=132) or to the study groups arm (n=1154). After excluding 139 patients (10.8%), 1147 patients were eligible for analysis, 1120 with follow-up for overall survival (OS) and 1079 for complete remission (CR) analysis. Baseline characteristics of all eligible patients showed median ages of 68 (60-82) years for the CSA and 69 (60-87) and 70 (60-85) years in the study arms A and B, respectively (p=0.05). Proportions of patients with secondary AML differed significantly between study arms (A: 42%, B: 30%, CSA: 36%; p=0.003). The CSA had less flt3 wildtype/npm1 wildtype patients (31%) vs. arm A (51% p=0.040) and arm B (58%, p=0.0455). No differences were observed with respect to cytogenetic risk groups, white blood cell counts, LDH, and npm1 mutant/ flt3-wildtype or mutant. The primary endpoint event free survival (EFS) did not differ between the CSA and study group strategies. Three-year EFS was 12.4% (95% CI: 6.7 - 19.9%) in the CSA, 15.6% (95% CI: 13.1 - 18.3%) in group A and 11.4% (95% CI, 7.4% to 16.4%) in group B (n.s.;Fig.1). With a median follow-up of 67 months, OS did not differ significantly between CSA and study group regimens. The 3-year survival probability was 22.3% (95% CI: 14.7-30.9%) in the CSA, 24.7% (95% CI: 21.6-27.9%) in group A and 22.4% (95% CI, 16.7% - 18.3%) in group B (Fig.2). CR status after 90 days of therapy was evaluated as secondary endpoint. The proportion of patients in CR in the CSA [51% (95% CI: 42-61%)] was comparable to the 50% (95% CI: 47-54%) and 48% (95% CI: 41-55%) of the study group arms (p=n.s.). Persistent leukemia was seen in 16% (95% CI: 10-24%) in the CSA vs 17% (95% CI: 14-19%) and 12% (95% CI: 8-17%) in groups A and B, respectively (both p= n.s.). A total of 226 patients died within 90 days of treatment, 24% (95% CI: 17-33%) in CSA, 19% in group A (95% CI: 16-22%) and 27% (95% CI: 21-33%) in group B; CSA vs A p=0.1859, CSA vs B p=0.5902). Death without AML was 3% in CSA, 2% in group A and 3% in group B, death with AML was 9% in CSA, 6% in group A and 5% in group B and death from indeterminate cause was 12% in CSA, 11% in group A and 20% in group B. Three-year relapse free survival (RFS) was 21.3% (95% CI: 12.2 - 31.0) in the CSA, 28.9% (95% CI: 24.9 -33.0%) in group A and 24.0% (95% CI: 16.8 - 31.9) in group B (both p=n.s.; Fig.3). In multivariate analysis independent variables for EFS and OS were age, type of disease, cytogenetic group and WBC count, but not the allocation to one of the treatment arms. Age and cytogenetic group were determinants for RFS. Conclusion A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared to a common standard arm. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Niederwieser: Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hegenbart:Pfizer: Other: Travel grant; Janssen: Honoraria, Other: Travel grant. Sayer:Riemser Pharma: Consultancy. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Fischer:Novartis: Consultancy, Honoraria. Dreger:Novartis: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Gilead: Speakers Bureau; Roche: Consultancy; Novartis: Speakers Bureau. Hiddemann:Roche: Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants; Roche: Other: Grants.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1066.1066

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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. 280-280

Abstract: Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients 〈 75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray's test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes. The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p 〈 0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p 〈 0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p 〈 0.0005). Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p 〈 0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p 〈 0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p 〈 0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p 〈 0.0001). Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p 〈 0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p 〈 0.0006), FLT3 mutation status (p 〈 0.03) and HCT (p 〈 0.0005). NRM was influenced by HCT (p=0.002). Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.280.280

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. 122, No. 21 ( 2013-11-15), p. 1409-1409

Abstract: Purpose In patients with relapsed acute myeloid leukemia (AML) 〉 60 years of age we analyzed age at relapse, interval from first complete remission (CR1) to relapse, cytogenetic risk at initial diagnosis, prior allogeneic stem cell transplantation (alloSCT) and FLT3/NPM1 mutational status as possible prognostic factors for overall survival (OS). Introduction After achieving CR1 more than 50% of elderly AML patients eventually relapse. Prognostic factors for OS are poorly defined in this patient population. For younger patients with relapsed AML a risk score has been described including age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis and prior stem cell transplantation (SCT) as prognostic factors. We sought to investigate whether these are also prognostic factors in elderly patients with relapsed AML. In addition, we assessed the prognostic impact of FLT3- and NPM1 mutational status (wild-type (wt) or mutated (mut)) at diagnosis. Patients and methods In the ongoing multicenter OSHO trial #69 for AML patients 〉 60 years we evaluated data of all relapsed patients. Overall survival was calculated from the day of first relapse until the day of death using the Kaplan Meier method. Univariate analysis was performed to test for the influence of age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis, prior alloSCT and FLT3/NPM1 mutational status. Subsequently, independent prognostic factors were defined in a multivariate analysis with age at relapse, time from CR1 to relapse, cytogenetic risk at initial diagnosis and prior alloSCT as covariates. Results From April 2005 until April 2013 904 patients were registered. 733 of these received intensive induction chemotherapy which resulted in CR1 in 447 (61%) pts. In this patient group 260 relapses were observed after a median interval, calculated from the day of CR1, for living patients of 2.7 years (range 0.1 to 7.5). Median age at relapse was 69 years (range 60 – 85) with 129 (49.6%) pts. being 60 to 68 years old, 102 (39.2%) pts. being 69 to 74 years old and 29 (11.1%) pts. being 75 to 85 years old. Median interval from CR1 to relapse was 0.58 years (0.07 – 6.28). 114 (43.8%) relapses occurred up to 6 months after CR1, 119 (45.8%) between 7 and 18 months after CR1 and 27 (10.4%) later than 18 months after CR1. Only five (1.9%) relapsed pts. showed good risk cytogenetics at diagnosis, whereas it was of intermediate risk in 159 (61.1%) pts., of poor risk in 68 (26.2%) pts. and unknown in 28 (10.8%) pts. Forty-one (15.8%) pts. had received prior alloSCT in CR1. Information on FLT3- and NPM1 mutational status at diagnosis was available in 194 (74.6%) pts. 110 (42.3%) pts. had FLT3/NPM1 wt/wt, 48 (18.5%) pts. had FLT3/NPM1 wt/mut, 23 (8.8%) pts. had FLT3/NPM1 mut/wt and 13 (5.0%) pts. had FLT3/NPM1 mut/mut. OS rate at 2 years of all relapsed pts. was 13 ± 2%. For patients younger than 69 years and for those 69 years of age or older OS rate at 2 years was 17 ± 4% and 9 ± 3%, respectively (p=0.03). The interval between CR1 and first relapse also affected 2 year-OS with 7 ± 3%, 15 ± 4% and 36 ± 12% for pts. with relapse up to 6 months, 7 to 18 months and later than 18 months after CR1, respectively ( 18 months: p=0.009). OS rate at 2 years was also influenced by cytogenetic risk at initial diagnosis with 17 ± 3% for pts. having good or intermediate risk cytogenetics and 3 ± 2% for those with poor risk cytogenetics (p 〈 0.0005). Prior alloSCT had a negative influence on OS. Two-year OS rate was 10 ± 5 and 13 ± 3% (p= .015) for patients with prior alloSCT vs. those without prior alloSCT, respectively. FLT3/NPM1 mutational status at diagnosis had no impact on OS. In univariate analysis age at relapse (p 〈 0.04), interval from CR1 to relapse (p 〈 0.0005), cytogenetic risk at initial diagnosis (p 〈 0.02) and prior alloSCT (p 〈 0.02) were shown to be prognostic factors for OS, whereas FLT3/NPM1 mutational status was not significant (p=0.82). In multivariate analysis the same factors remained significant but only interval from CR1 to relapse (p 〈 0.0005) and prior alloSCT (p=0.003) were independent. Conclusion In AML patients 〉 60 years in first relapse OS is poor. Longer interval from CR1 to relapse and no prior alloSCT are independent beneficial prognostic factors for OS. FLT3/NPM1 mutational status at diagnosis has no prognostic impact on OS. Disclosures: Wedding: Roche: Speakers Bureau; Amgen: Speakers Bureau; Chugai: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Novartis: Speakers Bureau; Cephalon: Speakers Bureau; Prostarkan: Speakers Bureau; Pfizer: Speakers Bureau. Niederwieser:Novartis: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1409.1409

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7