ALBERT

Description: Abstract 2891 Poster Board II-867 Thalidomide maintenance therapy after completion of induction therapy plus ASCT and also after conventional therapy yielded conflicting results with some trials showing improvement in overall survival and others not. This study evaluates the efficacy of Thalidomide plus Interferon a2b (Thal-IFN) in comparison to interferon a2b (IFN) as maintenance therapy in elderly pts with multiple myeloma. For induction therapy, 289 pts had been randomized to either Thalidomide-Dexamethasone or to Melphalan-Prednisolone; results of this part of the study had been reported previously (BLOOD, 113, 3435-3442, 2009). 137 pts who had completed 9 cycles of induction therapy and had achieved stable disease or better were eligible for maintenance treatment, and 128 (median age 72 years, range 54 - 86 years) had finally been randomized to either Thal (starting dose: 200mg/day) in combination with IFN-a2b (Schering-Plough, 3 Mega U, TIW) or IFN a2b (IFN) at the same dose/schedule only. All pts were scheduled for zoledronate 4mg, q 4 weeks. Median follow up from randomization to maintenance: 35 mos. Median duration of maintenance therapy: 13.2 mos and 8.3 mos for pts randomized to Thal-IFN or to IFN, respectively (logrank test p=0.20). Maintenance therapy with Thal-IFN resulted in an improvement in the depth of response from PR to VGPR or CR in 5 (8%) and with IFN in 2 (3%) pts, respectively. Progression-free survival (PFS) was significantly longer in the Thal-IFN (27.7 mos) compared to the IFN only maintenance group (13.2 mos), (HR, 0.55; 95% 95% CI, 0.36-0.86; log-rank test, p=0.0068). Analysis of PFS by either Thal-Dex or MP induction therapy showed a significantly shorter PFS in pts started on Thal-Dex and subsequently randomized to IFN maintenance only (7.8 mos, log-rank test, p=0.037). PFS was 27.7 mos in pts started on Thal-Dex followed by Thal-IFN, 20.2 mos in those with MP induction therapy followed by IFN, and 27.6 mos in pts with Thal-IFN maintenance after MP induction therapy. Overall survival (OS) was similar in both groups (Thal-IFN 52.6 mos and IFN 51.4 mos, HR: 0.93, 95% CI: 0.53-1.66, log-rank test; p=0.81). OS by induction therapy did not vary significantly between the four treatment groups (logrank test, p=0.99). No significant difference in OS was seen between pts younger than 75 years and those aged 75 years or older (logrank test, p=0.39). Survival after progression of disease tended to be longer in pts who received IFN maintenance therapy only compared to those started on Thal-IFN (HR: 1.75, 95% CI, 0.97 – 3.14, logrank test: 0.056), while OS was similar between both groups when analyzed from termination of maintenance therapy (HR: 1.20, 95% CI, 0.65 – 2.20, log rang test 0.57). Baseline scores of the EORTC QLQ C30 items general health (Thal-IFN, mean 56; IFN, mean 59) and overall quality of life (Thal-IFN, mean 58; IFN, mean 60) were markedly below the score obtained in an healthy population (mean 75.3 and 73.3 respectively), but did neither differ at baseline between both groups nor did they vary significantly during the course of the maintenance (statistics will be provided). Cytogenetic data were available in 66 pts. PFS tended to be longer in pts with adverse FISH findings [t (4; 14), t (14; 20) Del 17p and abnormalities of 1q21] compared to the standard risk group, but differences were not significant (median: 31.5 vs. 21.6 mos, HR: 1.69, 95% CI, 0.13 – 3.07, log-rank test 0.084). The median of OS was 72.3 mos in those with standard risk and 39.6 mos in those with high risk features (HR: 1.94, 95% CI 0.91-4.13, log rank test: 0.082). In multivariate analysis (Cox model) only Thal-IFN maintenance therapy was shown to correlate significantly with PFS (HR: 0.61, 95% CI: 0.39-0.89, p=0.04) while for poor performance status, low hemoglobin, and low albumin a statistically non-significant correlation with survival was noted. Hematologic toxicity was similar between both groups. Pts on Thal-IFN maintenance experienced significantly more neuropathy (p=0.0024), constipation (p=0.0007) and skin toxicity (p=0.0063) and increase in renal impairment (p=0.037). In addition, there was a tendency for more dyspnea (p=0.40) and more fatigue (p=0.11) in pts on Thal-IFN maintenance therapy. Other non-hematological toxicities were similarly distributed in both therapy arms. In conclusion, Thal-IFN maintenance therapy resulted in increased PFS compared IFN maintenance treatment only, but OS was similar between both groups. Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Hajek:Janssen-Cilag: Honoraria. Kuhn:Schering-Plough: Employment.

Description: Abstract 1239 Background. Imatinib (IM), a selective BCR-ABL tyrosine kinase inhibitor (TKI), is a treatment of choice for newly diagnosed chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP) as it was shown in the IRIS trial. The treatment strategy and response evaluation is based on NCCN or ELN guidelines. Only limited “real life” data of IM impact on pts outcome as well as ELN (European LeukemiaNet) recommendations applicability in daily practice has been published. In the Czech as well as in the Slovak Republic (15 million inhabitants), the treatment of CML patients is centralized in overall 13 centers, capable carrying on both the treatment and laboratory monitoring. There are two CML prospective projects CAMELIA and INFINITY focused on CML pts analysis. Aims. To analyze the treatment response and long-term outcome in consecutive, unselected patients with CP-CML treated with IM and to evaluate the prognostic role of ELN 2006 and 2009 response evaluation. To analyze molecular response in more detail. Methods. Altogether 458 consecutively included patients in INFINITY (152 pts) and CAMELIA projects (306 pts) were assessed. For the treatment response evaluation the ELN 2006 and ELN 2009 definitions were used. We assessed rates and the cumulative incidences of complete hematologic responses (CHR), complete cytogenetic responses (CCyR), major (MMoR) and complete molecular responses (CMoR). Overall survival (OS) was defined as the time from the start of IM to death from any cause, overall survival CML-related death (OSCML), transformation-free survival (TFS) as survival without evidence of AP or BP or death from any cause, progression-free survival (PFS) as survival without evidence of AP or BP, loss of CHR, MCyR, increasing white blood cell count or death fron any cause while on IM treatment and event-free survival (EFS) –events defined as a progression (the same as in PFS, as described above), loss of CCyR, failure to achieve CHR at 6 months, MCyR at 12 months and CCyR at 18 months, or intolerance of IM as the cause its discontinution. The patient survival according to MMoR achievement and the cumulative incidence of MMoR according to different BCR-ABL ratio within the first 3 months of IM therapy was analysed. Kaplan-Meier cumulative incidence methods and log rank test were used for survival statistic analysis. Results. A total of 458 patients (median age 52 year;17-81) treated with IM between 2003–2009 were analysed.The median follow-up was 33.1 months (1.4-82.1). At 2 and 4 years the cumulative incidence of CHR was 90.9% and 94.7%, CCyR 64.9% and 76%, MMR 52.4% and 68.1% and CMR 24.5% and 43%, respectively. In 4 years estimated OS was 91.1%, OSCML 96.6%, TFS 93.9%, PFS 83.2% and EFS 66%. According to ELN 2006 criteria the optimal response (OR) by 6 months (defined as PCyR) and by 12 months (defined as CCyR) resp. had significant impact on PFS (p=0.04 and p

Description: Thalidomide-Dexamethasone (TD) is an active regimen both in patients (pts) with relapsing/refractory and in untreated pts with multiple myeloma (MM). Here we compare TD with standard Melphalan-Prednisone (MP) in previously untreated elderly pts with MM. 274 pts have been enrolled (median age: 72 yrs, stage I: 9 (3%), stage II: 84 (31%), stage III: 179 (65%). Pts were randomized to T 200mg/day and D 40mg, days 1–4 and 15–18 (on odd cycles) and days 1–4 (on even cycles) or M 0.25mg/kg days 1–4 and P2mg/kg days 1–4, q 4–6 weeks. T should be dosed up to 400mg/day, if feasible. Pts achieving response or SD were randomized to maintenance therapy either with T (≤200mg/day)-Interferon-a2b (IFN, 3Mega U, TIW) or IFN (3Mega U/TIW). Zoledronic acid (4mg) was administered monthly to all pts during the entire treatment period. Response is defined according Blade’s criteria, plus nCR defined as IF positive or 〉90%↓ in PP and VGPR defined as 〉75% ↓reduction in PP. 231 pts are evaluable per protocol. Best response to TD: CR (14%) nCR 17%, VGPR 17%, PR 21%, yielding an ORR (CR-PR) of 68%. Best response to MP: CR 7%, nCR 8%, VGPR 14%, PR 22%; ORR 51% (ORR in TD vs. MP p=.0044). Time to response and time to best response were shorter in the TD (6, 16 weeks, respectively) compared to the MP group (16, 25 weeks, respectively; p

Description: Abstract 5064 Background: In 2001 Thromboreductin® was registered in Austria as the first EU country for the treatment of Essential Thrombocythemia (ET). Due to the low incidence of ET authorities demanded to establish a patient registry to evaluate safety and efficacy of anagrelide in the long-term treatment of ET. Following market authorization in several EU countries the patient registry is now being maintained in 10 Central European countries. Whereas most clinical trials have only a relatively short follow-up, a patient registry is able to provide long-term data. Patients and Methods: This multinational, multi-center post-marketing observational registry is conducted to assess long-term efficacy and safety of anagrelide in patients with ET under “real-life” conditions. The clinical information is entered into the registry by the treating physicians. Besides relevant clinical data such as risk factors, past thrombotic as well as bleeding events, disease symptoms classified as “major” and “minor” events and previous ET therapies including anticoagulation, laboratory values including renal and liver function parameters as well as blood counts are monitored regularly. Results: This evaluation of the Thromboreductin® Patient Registry database includes 1572 ET patients (median age: 59 years), 1059 (67%) were women and 513 (33%) were male patients; 62% of patients were pretreated with cytoreductive agents, 38% were treatment naïve. The median observation period was 1.9 years (range: 7 days – 10 years), with 168 patients (11%) being followed for at least 5 years. Treatment with anagrelide lowered the platelet count from a median of 742 × 109 /l (95%CI 717/757) to a median of 415 × 109 /l (95%CI, 397/435). Eighty-four percent of patients achieved platelet counts 〈 450 × 109 /l, no differences between pretreated (85%) and treatment-naïve /82%) patients were observed. During the 3464 patient years (PY) included in this evaluation a total of 338 ET-related events (including both thrombotic and bleeding events) were reported of which 102 (2,9% per PY) were considered as “major”. Of the 220 patients with a history of ET-related events, 178 patients (81%) have so far remained event-free under anagrelide therapy. Adverse effects were lower than those previously reported in clinical trials with headache, palpitations and diarrhea being the most frequent side effects (all 〈 3%) leading to treatment discontinuation in 43 patients (2,7%). No new toxicities have been observed. Conclusion: We consider anagrelide to be safe and effective in terms of lowering platelet counts and reducing disease-related events in unselected ET patients treated outside clinical trials under “real-life” conditions. Based on our favourable long-term data we suggest that anagrelide may be considered a first-line agent in the management of ET. Disclosures: Steurer: AOP Orphan Drugs: Honoraria. Petrides:AOP Orphan Drugs: Consultancy.

Description: Thalidomide-Dexamethasone (TD) is an active regimen in patients with relapsing/refractory multiple myeloma (MM). Recent phase II and III studies revealed an even higher response rate in previously untreated patients. In the present trial we compare TD with standard Melphalan-Prednisone (MP) in previously untreated elderly patients with multiple myeloma. The trial is designed to include 350 pts with MM, 190 patients have been enrolled so far (median age: 72 years, stage I: 9 (5%), stage II: 61 (32%), stage III: 120 (63%). Patients are randomized to Thalidomide 200mg/day and Dexamethasone 40mg, days 1–4 and 15–18 (on odd cycles) and days 1–4 (on even cycles) or Melphalan 2.5mg/kg day 1–4 and Prednisone 2mg/kg days 1–4, q 4–6 weeks. Thalidomide should be dosed up to 400mg/day, if feasible. Patients achieving response or stabilization are randomized to maintenance treatment either with Thalidomide (maximal dose 200mg/day)-Interferon alpha-2b (3Mega U, TIW) or Interferon alpha-2b (3Mega U/TIW). All patients are scheduled for monthly Zometa (4mg) during the entire period. Response is defined according Blade’s criteria, statistical results are given by intend to treat analysis. 125 patients are evaluable for response as yet. Best response to TD was: CR 6 (10%), NCR 7 (12%), and VGPR 9 (15%) PR 9 (15%), MR 10 (16%) yielding an ORR of 67%. Four pts had SD (7%) and 16 PD or failure (26%). The respective results in pts on MP were: CR 2 (3%), NCR 4 (6%), VGPR 5 (8%), PR 13 (20%), MR 7 (11%), ORR 48% (p

Description: Abstract 4439 Background: Most results on the treatment of chronic myeloid leukemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive CML patients at ten major centers during 2000–2010. Patients and methods: Data reporting was retrospective in 2000– 2004 and prospective from 2005 on. A total of 295 patients (137 women and 158 men; median age 49 [range, 15–81]) with Ph+ CML were registered. The median follow-up was 45.4 months (0–113,5). Results: Most patients were treated with first- (169; 57.28%) or second-line (84; 28.5%) imatinib, part of patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (28; 9,5%), but 4,7 % were treated with other modalities (14 patients; median age 66 [range, 32–83]). The probability of overall survival (OS) according to Kaplan and Meier at five years was 88.9%, 77.5% and 68.7% for chronic phase patients treated with first-, second-line imatinib and first-line AHSCT, respectively, but only 25.2% for patients receiving other modalities. OS was dependent on the disease phase and Sokal, Hasford and EBMT risk scores (p〈 0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression-free survival as the younger. There was a trend for inferior results of AHSCT performed after failure of imatinib (p=0.075), probably due to differences in EBMT risk scores (p〈 0.001). Conclusions: Ability to achieve results comparable to previous clinical studies in our CML cohort was influenced by centralized care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly. Disclosures: No relevant conflicts of interest to declare.

Description: This phase 3, multicenter, open-label study evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients (≥70 years) with newly diagnosed, de novo, or secondary acute myeloid leukemia. A total of 457 patients were enrolled with 24% 80 years of age or older. Tipifarnib 600 mg orally twice a day was administered for the first 21 consecutive days, in 28-day cycles. The primary endpoint was overall survival. The median survival was 107 days for the tipifarnib arm and 109 days for the BSC arm. The hazard ratio (tipifarnib vs BSC) for overall survival was 1.02 (P value by stratified log-rank test, .843). The complete response rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. The results of this randomized study showed that tipifarnib treatment did not result in an increased survival compared with BSC, including hydroxyurea. This trial was registered at www.clinicaltrials.gov as #NCT00093990.

Description: Introduction: With the onset of tyrosine kinase inhibitors (TKI) to treat patients with CML, the number of patients and overall survival increased and quality of life significantly improved. The basic principle of therapy was also changed, according to the clinical practice now it is aimed at early induction of deep molecular response. Objective: To characterize the CML patient population and TKI treatment results in clinical practice in CML patients in Slovak republic (SR). Methods: The observational study "Slovak registry of chronic myeloid leukemia" (CAMELIA SK) was launched in 2005 by Novartis. Patients with Ph+ CML were enrolled into study after signing the informed consent. Thus the study has a retrospective part (131 patients) and prospective group of 586 CML patients. By June 2016, the Registry contained information about 717 patients from 7 centers of SR. The annual increase of newly diagnosed CML cases ranged from 2 to 56 people per year (median 35.5). Characteristics of patients in the Registry: in June 2016, 489 (68.2%) were alive, 181 (25.2%) dead and 47 (6.6%) lost to follow-up. Median follow-up in alive patients was 79 months (1 to 324 months). Median age at CML diagnosis was 50 years (range 15 - 86 years); male 52.7%. Chronic phase (CP) was in 664 (92.6%), accelerated phase in 37 (5.2%) and blast crisis in 16 (2.2%) patients. Sokal risk group's ratio was 35.8%/34.3%/25.7%/4.2% for low, intermediate, high risk and unknown, respectively. Hasford risk group's ratio was 41.6%/40.6%/13.4%/4.5% for low, intermediate, high risk and unknown, respectively, and EUTOS risk group's ratio was 83.8%/11.7%/4.5% for low, high risk and unknown, respectively. Results: The data for this analysis were available for 594 patients (82.8% of patients in the Registry) treated by tyrosinkinase inhibitors (TKI). First line TKI treatment was initiated in 467 patients: 363 (77.7%) started imatinib (IM), 101 (21.6%) nilotinib (NIL) and 3 (0.7%) dasatinib (DAS). Higher line TKI treatment was initiated in 127 patients, mostly after interferon-alpha or allogeneic stem cell transplantation (SCT), 125 (98.4%) of them started IM and 2 (1.6%) NIL. Time from diagnosis until first line TKI treatment was 0-112.7 months (median 1.1). One TKI drug was used in 388 (65.3%) patients, 2 drugs in 146 (24.6%), 3 drugs in 57 (9.6%) and 4 drugs in 3 (0.5%) patients. From these 594 patients, 448 (75.4%) are alive, 28 (4.7%) are lost to follow-up and 118 (19.9%) died, mostly because of other diseases - 50%; 30.5% died because of CML, 17.8% because of disease progression and 1.7% by SCT. From 363 patients who started first line IM (93.7% in CP), optimal treatment response from evaluable patients according to ELN2013 achieved 57.8%, 49.2%, 17.3%, 27.9% and 36.5% after 3, 6, 12, 24 and 48 months, respectively. Median length of treatment was 39.6 months (0.2-149.1). Change of treatment to 2ndline was performed in 155 (42.7%) patients. In total, 264 (72.7%) patients are still on TKI treatment, 3 (0.8%) progressed to advanced phase, 5 (1.4%) underwent SCT and 42 (11.6%) patients are lost to follow up, had adverse events (AE) or discontinued treatment from other reasons. The death occurred in 49 (13.5%) patients. From 101 patients who started first line NIL (98% in CP), optimal treatment response from evaluable patients according to ELN2013 achieved 82.4%, 82.6%, 59.3%, 66.6% and 83.3% after 3, 6, 12, 24 and 48 months, respectively. Median length of treatment was 18.4 months (0.2-97). Change of treatment to 2ndline was performed in 11 (10.9%) patients. In total, 87 (86.4%) patients are still on TKI treatment, nobody progressed to advanced phase and 10 (9.7%) patients are lost to follow up, had AE or discontinued treatment from other reasons. The death occurred in 4 (3.9%) patients. 53 patients in accelerated or blastic phase started mostly IM treatment (18, 34%), combined chemotherapy (12, 22.6%) or interferon-alpha (9, 17%). 4 patients underwent SCT, 2 started NIL, 2 DAS and 6 another treatment. In total, 35.8% patients are alive, 52.8% died and 11.3% are lost to follow up. Conclusions: The observational study "CAMELIA SK" is the largest registry of hematological diseases in Slovakia, providing information about CML patients receiving TKI therapy more than 10 years. We approved the efficacy and safety of second generation TKI nilotinib in newly diagnosed CML patients as first line therapy. More patients achieved optimal response in short period than on imatinib. Disclosures No relevant conflicts of interest to declare.

Description: We compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon α-2b thrice weekly or to 3 MU interferon α-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P = .006) and overall responses (68% vs 50%; P = .002) compared with MP. Time to progression (21.2 vs 29.1 months; P = .2), and progression-free survival was similar (16.7 vs 20.7 months; P = .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P = .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.

Description: Background: Autologous stem cell transplantation (ASCT) plays an important role in the treatment of multiple myeloma (MM) patients (pts). In this report, we describe the longterm outcome of cohort of 185 pts with newly diagnosed symptomatic MM treated with ASCT. Median follow-up from the start of therapy was 102.8 months (range 67.2–150.4). We have specifically analyzed benefit from the newer drugs used in the relapsed setting. Methods: A total of 185 MM pts underwent ASCT in the clinical trial 4W of Czech Myeloma Group in 18 centres in Czech Republic and Slovak Republic between 1996 and 2001. The conditioning regimen was high dose melphalan (200mg/m2) in all pts. At diagnosis of MM 72.4% (134/185) of pts had stage III according to Durie- Salmon, 18.4% (34/185) stage II and 9.2% (17/185) stage I. Clinical stages according to ISS were the following: stage 1 in 42.5% (74/174) of pts, stage 2 in 36.8% (64/174) and stage 3 in 20.7% (36/174) pts. Types of monoclonal immunoglobulin were as following: 67.6% (125/185) IgG, 21.1% (39/185) IgA, 9.7% (18/185) light chain, 1.6% (3/185) IgD. Renal insufficiency was presented in 5.9% (11/185) of pts. Median age at transplantation was 54.8 years (range: 28.3–69.2). When the symptomatic relapse of MM after ASCT was occurred, 34.6% (45/130) of pts were treated by conventional chemotherapy (CC) alone, 22.3% (29/130) by thalidomide based regimen, 10.7% (14/130) by bortezomib based regimen, 22.3% (29/130) pts underwent re-transplantation and 10% (13/130) of pts received combination of newer drugs and re-transplantation. Results: Following ASCT, overall response rate (ORR) was 93.5% (173/185), 29.2% (54/185) of pts were in CR, 38.4% (71/185) of pts were in VGPR, 25.9% (48/185) of pts in PR. Median of overall survival (OS) from start of treatment was 77.9 months (9.6 – 147.3), median of TTP was 39.8 months (7.0–146.9). Total of 23.2% (43/185) of pts are alive and disease free, 20.5% (38/185) of pts are alive with relapse and 56.3% (104/185) of pts died with median follow-up 8.3 years from the start of therapy. Significant prognostic parameters for better OS after ASCT were: ISS stage 〈 III (p