ALBERT

Description: Introduction: Most of the knowledge about treatments and outcome of CML patients originates from clinical studies. To get new and unbiased insights in the epidemiology, treatment and outcome of CML, the EUTOS population-based registry of newly diagnosed CML patients was established, - as part of the European Treatment and Outcome Study (EUTOS) for CML. The aim was to collect the data of all adults with newly diagnosed CML, irrespective of treatment and of enrolment in studies. Patients and Methods: The EUTOS population-based registry collected data of newly diagnosed CML patients, 18 years or older, over a specified period of time from 2008 till 2012 living in defined regions. The data were collected by 22 study groups in 20 European countries. Data were gathered via a web-based CRF-system. For comparison we used the already published data from five Company-sponsored registration studies IRIS (O’Brien et.all, NEJM, 2003), TOPS (Cortes et al, JCO, 2009) ENESTnd (Saglio et al, NEJM, 2010), DASISION (Kantarjian et al, NEJM, 2010) and BELA (Cortes et al, JCO, 2012), from three Investigator-sponsored studies GIMEMA (Castagnetti et al, JCO, 2010 and Gugliotta et al, Blood, 2011), French SPIRIT (Preudhomme et al, NEJM, 2010) and German CML IV (Hehlmann et al, JCO, 2011) and from two single referral centers HAMMERSMITH (De Lavallade et al, JCO, 2008) and MDA (Jain et al, Blood, 2013). Results: Till 15.05.2014 2978 patients were registered in the EUTOS Population-based registry. 94.3% of the patients were diagnosed in chronic phase (CP), 3.6% in accelerated phase (AP), and 2.2% in blastic phase (BP). For the calculation of the prognostic scores 361 patients had to be excluded because they were pretreated. For the comparison we used 2350 patients in Chronic Phase with laboratory values before any treatment. 54% of the patients in the EUTOS Population-based registry were male, less than in all studies (56.6 - 60.6%). The median age at diagnosis was 56 years, higher than in all studies (46 - 55). In EUTOS the proportion of patients more than 60 years and more than 65 years old was 40.4 % and 21.9 % respectively. Similar data were rarely reported in all other studies. Median value of the spleen size below costal margin was 0. 46.1% of the patients had a palpable spleen and 15.2% had a spleen size ≥ 10 (spleen size is always reported in cm under costal margin in this abstract). The % of palpable spleen is only reported by IRIS, 25.0% and by the FRENCH Spirit group, 49.8%. The median spleen is only reported by GIMEMA, 2.0. Spleen size ≥ 10 is reported by IRIS, 6.0%, ENESTnd, 12.4% and HAMMERSMITH 25.5%. While the median values for Platelets and Hemoglobin show no big differences, the median WBC in EUTOS is 83.9 x109/l and in the Company-sponsored registration studies: IRIS 18-20 x109/l , in ENESTnd 23-26 x109/l, in DASISION 23-25 x109/l , and in BELA 22-23 x109/l, in the Investigator-sponsored studies: GIMEMA 55 x109/l , in the FRENCH SPIRIT 83-104 x109/l , in the GERMAN CML IV 75-91 x109/l , and in the single referral center study HAMMERSMITH 140 x109/l, clearly indicating that in company-sponsored, registration studies, the reported values of the WBC were not recorded prior to any treatment. The median values for Blasts, Basophils and Eosinophils show also not so big differences. The % of Sokal low risk patients is in EUTOS with 34.5% lower than in all studies (35.2 - 60%) with the exception of HAMMERSMITH 28.9%. Discussion: The EUTOS Population-based registry provides the first European wide real-world series of patients with newly diagnosed Ph+, BCR-ABL+ CML. The age and sex distribution and some baseline characteristics such as Sokal Score as well as median WBC count in the EUTOS population-based registry are different from many prospective studies. This should be taken in due consideration before extrapolating the results of treatment studies to real life. Spleen size, which is known as an important value for prediction, is only very rarely reported in clinical studies. With further follow-up, this registry will provide a population-based insight on treatment, survival, and causes of death. Disclosures Baccarani: Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Hoffmann:Novartis: Research Funding. Rosti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy. Saussele:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Steegmann:Novartis, BMS, Pfizer: Honoraria, Research Funding. Mayer:Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy. Clark:Novartis Pharmaceuticals Corporation: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Lindoerfer:Novartis: Research Funding.

Description: Introduction Clinical studies clearly show that treatment with tyrosine-kinase inhibitors (TKI) greatly improve the prognosis of patients with CML. Detailed treatment recommendations have since been deduced from clinical trial results by the European LeukemiaNet (Blood 122:872-884). However, little is known about whether these achievements can also be transferred to routine health care. This work investigates if all CML patients are treated in agreement with current standards and wether they achieve outcomes at least as good as those in clinical trials. Methods The web-based registry aimed to collect all newly diagnosed adult patients with chronic phase Ph+ and/or BCR-ABL1+ CML in 20 countries or pre-specified regions covering ~ 92.5 million inhabitants. Overall 2904 patients were registered between 2008 and 2012. Cytogenetic and molecular responses were analyzed using cumulative incidences considering death and progression as competing risks. Survival was analyzed using Kaplan-Meier curves and log rank tests. Results 2342 patients were diagnosed in chronic phase and had follow-up data available. The median age was 55 years (range: 18 to 99 years) and 53% were male; 11% of the patients were at high risk of not achieving complete cytogenetic remission (CCyR) at 18 months according to the EUTOS score. According to the Euro score 10% of the patients were in the high risk group, 51% in the intermediate and 39% in the low risk group. 18% were included in clinical trials. Treatment data of 1701 patients were contributed from 15 countries (85% of 2042 patients registered in those countries). As a first-line therapy 80% of patients received imatinib 15% nilotinib, 3% dasatinib and 3% hydroxyurea (HU). Of the patients receiving nilotinib or dasatinib 56% had been enrolled into clinical trials. There were no significant differences between female and male patients regarding the first-line therapy. More than half of the patients who were treated with HU alone were aged 70 or older. Time to first CCyR is known for 62% of patients. Median time to first CCyR was 10 months; after 12 months 57% (95% CI 54%-60%) and after 18 months 76% (95% CI 74%-79%) had achieved CCyR. Time to first CCyR differed significantly regarding the EUTOS score. Median time to first CCyR was 9 months for the low and 13 months for the EUTOS high risk group (p 〈 0.0001). After 18 months 78% (95% CI 75%-80%) of patients in the low and 69% (95% CI 60%-76%) of patients in the high risk group had achieved CCyR. The patients' age did not have major influence on the time to first CCyR (p=0.8974, median time to first CCyR: 18 to 39 years: 9 months, 40-65 years: 9 months, older than 65 years: 11 months). Time to first major molecular remission (MMR) could be calculated for 54% of patients. Median time to first MMR was 15 months. Cumulative incidence of MMR after 12 months was 41% (95% CI 38%- 44%). The median observation time of living patients was 29 months. 187 patients died (8%). Probability of OS for all patients at 12, 24 and 30 months was 97% (95% CI 96% - 97%), 94% (95% CI 93% - 95%) and 92% (95% CI 90% - 93%), respectively. 108 patients progressed of whom 62 subsequently died, while 125 patients died without prior progression. Probability of PFS for all patients at 12, 24 and 30 months was 95% (95% CI 94% - 96%), 92% (95% CI 91% - 93%) and 90% (95% CI 88% - 91%), respectively. Of the 187 patients who died, 33% died after progression. 67% died without prior progression. The probability of progression and subsequent death was 1% (95% CI 1% - 2%) after 12 months and 2% (95% CI 2% - 3%) after 24 months. The probability of dying without prior progression was 2% (95% CI 2% - 96%) after 12 months and 4% (95% CI 3% - 5%) after 24 months. Discussion The EUTOS population based registry provides the first unselected sample of adult Ph+ and/or BCR/ABL1+ adult CML patients in Europe. It shows that in Europe the success reported from commercial and academic studies is transferred to the general population. The majority of patients were treated first-line with imatinib, which was the only TKI approved for first-line use by the EMA during most of the registration period. Probabilities of PFS and OS in the registry are comparable to those in clinical trials. The importance of calculating both overall survival and leukemia-related survival is highlighted, since many patients die from different causes related or unrelated to leukemia and to treatment, but without progression. Disclosures Hoffmann: Novartis Oncology Europe: Research Funding. Baccarani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hasford:Novartis: Research Funding. Lindoerfer:Novartis Oncology Europe: Research Funding. Burgstaller:Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Mayer:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding. Koskenvesa:GSK: Consultancy; Pfizer: Consultancy; Ariad: Other: funding of travel, accomodations or expenses; BMS: Consultancy, Other: funding of travel, accomodations or expenses; Novartis: Consultancy, Research Funding. Castagnetti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Sacha:Angelini: Consultancy; Adamed: Consultancy; Novartis: Consultancy; BMS: Consultancy. Hellmann:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau. Turkina:Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis Pharma: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy. Sninska:Novartis: Consultancy. Simonsson:Novartis Pharma: Research Funding. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant; BMS: Honoraria, Other: Travel grant, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

Description: Background Most randomized clinical trials (RCT) evaluating 2nd generation tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) used as comparator the 'standard' dose of 400 mg of imatinib daily (IMA 400). When major molecular remission (MMR) after 12 months of therapy is used as primary endpoint to measure short term outcome this might however not be the correct comparator. Several studies showed that treatment with a dose of 800mg of imatinib per day (IMA 800) achieves higher rates of MMR at 12 months compared to IMA 400. The objective of our work is to systematically review randomized trials comparing IMA 400 and IMA 800, to calculate a pooled estimator and to compare the result to a pooled estimator of trials evaluating a 2nd generation TKI in comparison to IMA 400. Patients and Methods We searched Medline for RCTs of IMA 400, IMA 800 and 2nd generation TKIs. We extracted data on study designs, treatments, patient numbers and characteristics, statistical analysis methods and MMR at 12 months. Relative risks and respective 95% confidence limits were calculated and pooled using a random effects model. Forest plots were printed to visualize the results. The Jadad score was used to assess the quality of the trials. Results We identified three RCTs [1,2,3] comparing patients treated with IMA 400 and IMA 800 and reporting on MMR at 12 months. Overall 1284 patients were included in the trial arms of interest - 554 were randomized into the IMA 400 arm and 730 into the IMA 800 arm. One trial used the Sokal and two used the Euro prognostic score as a stratum for randomization to allocate patients with different prognosis equally into the treatment arms. Percentage of Euro score high/intermediate risk patients in the IMA 800 arms was 14% / 49% in [1] and 49% / 30% in [3] and in the IMA 400 arms 12%/53% in [1] and 49%/31% in [3]. The percentage of Sokal score high/intermediate risk patients in [2] was 27%/34% in the IMA 400 arm and 23% / 35% in the IMA 800 arm. Median age of the patients in the IMA 400 / IMA 800 arms in [1,2,3] was 54/52, 45/48 and 50/52 years, respectively. Relative chance of being in MMR after 12 months of treatment in [1,2,3] was 1.78 (1.47 to 2.15), 1.15 (0.91 to 1.45) and 1.47 (1.01 to 2.14), respectively. The pooled estimate over all three studies was 1.45 (1.10 to 1.92) and thus indicates a significantly higher rate of MMR after 12 months by treatment with IMA 800 (Fig. 1, p = 0.0088). We identified four RCTs comparing IMA 400 to a TKI of the 2nd generation [4,5,6,7]. In [4] an IMA 400 arm was compared to treatment with two doses of 300mg nilotinib daily. Trials [5] and [7] each compared an IMA 400 arm with 100 mg/d of dasatinib, while [4] compared IMA 400 to 500mg of bosutinib daily. The percentage of Sokal high/intermediate risk patients in [4] and [6] was 28%/36% and 18%/ 47% in both the 2nd generation and the IMA 400 trial arm. Relative chance for MMR at 12 month for the respective 2nd generation TKI treatment arm compared to the IMA 400 arm was 2.00 (1.55 to 2.59) for [4], 1.64 (1.24 to 2.17) for [5], 1.56 (1.22 to 2.00) for [6] and 1.34 (1.05 to 1.75) for [7]. The pooled estimate for the relative chance was calculated as 1.61 (1.37 to 1.91) (Fig. 2, p

Description: Background The German AML Intergroup conducted two randomized studies in younger (

Description: 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.