ALBERT

Description: Abstract 3453 Poster Board III-341 Introduction Increasing insight into the biology of CLL suggests a relevant interplay between tumor cells and the microenvironment. Preclinical data point to the potency of Lenalidomide to favourably modulate such interactions and remarkable clinical activity has been demonstrated in monotherapy trials in pretreated and also in previously untreated CLL patients. However, tumor flare and tumor lysis have been observed as problems and the optimal dose and schedule is still under investigation. In addition, the potential for interaction with effective standard treatment for CLL is unknown. We used a combination of Fludarabine and Rituximab as a backbone to establish a tolerable Lenalidomide dose in a dose escalation design. Study design The study treatment follows two phases: In the induction phase the maximal tolerated dose (MTD) of Lenalidomide in combination with FR should be determined. The protocol combines 6 cycles of Fludarabine (40mg/m2 po d1-3) and Rituximab (375mg/m2 iv day 4 on cycle 1 and 500mg/m2 iv day 1 on cycles 2-6), both in a 28 day cycle. Lenalidomide is given at a starting dose of 2,5 mg daily (day 7-21 of cycle 1) and with dose escalation steps to 5, 10, 15, 20 and 25mg of Lenalidomide from day 1-21 of the following cycles, if toxicity of the combination permits. In a second phase, Rituximab (375mg/m2 iv) at 2, 4 and 6 months after the last cycle is combined with Lenalidomide (day 1-28 of 28 day cycles) at the last tolerated dose for 6 months of maintenance. 40 patients are planned for this study. We herewith present the planned interim analysis for dose finding and safety endpoints for the induction phase of the first 10 patients recruited into the study. Results Mean age of patients was 70 years (range 59-76). Six of 10 patients had stage Rai III/IV and mean WBC count was 159 G/L. Seven of 10 patients had at least one high risk feature from CD38 and FISH analysis or by mutation status. Of the 60 planned cycles 46 (77%) are currently evaluable for this analysis. No systematic toxicity determining MTD was found. 50% of patients proceeded through dose escalation steps as planned. Two patients have already tolerated 25mg of Lenalidomide with their FR cycles. Regarding toxicities, grade 3 and 4 neutropenia was expected in this combination and observed in 7/10 patients. However it was not used as a dose limiting toxicity per se. Still, one 75 year old patient was dose reduced because of febrile neutropenia in the previous cycle. Overall three infectious episodes were observed on treatment. Two patients experienced thrombotic events one of which was then taken off study because of Richter transformation, which might in hindsight have been present from study onset. Surprisingly, 5/10 patients experienced significant skin toxicity, mostly in the form of skin rashes, which was deemed dose limiting in two patients. It was, however, clearly associated with Pneumocystis prophylaxis in one patient, who then went on to receive the full Lenalidomide dose without further rashes. No tumor lysis or flare reaction was observed in the 10 patients reported. Preliminary efficacy data show that all patients achieved at least a PR after 3 cycles of therapy (except for the patient with the Richter transformation). Of the 3 patients currently evaluable after 6 cycles of treatment one CR and two very good PRs were observed before starting the maintenance phase of the study. Conclusions The combination of Lenalidomide with Fludarabine and Rituximab seems clinically feasible and no tumor lysis or flare reaction have been observed, possibly due to the Lenalidomide step up design, as well as the initial tumor load reduction by the chemo-immunotherapy backbone. No clear dose dependent toxicity has emerged as dose limiting for Lenalidomide escalation in this combination. However, 50% of patients had to be dose-limited due to not clearly dose-dependent skin and vascular toxicities. A regime of thromboprophylaxis as well as a delayed start of prophylaxis against pneumocystis have since been amended to improve the management of the patients. In addition, and remarkably, the regimen shows clinical efficacy despite controversial in vitro reports, suggesting a potential negative interaction between Lenalidomide and Rituximab. This might be due to the Lenalidomide pause before each Rituximab cycle or may reflect a difference between in vitro and in vivo. Disclosures Egle: Roche: Research Funding, Speakers Bureau. Off Label Use: Lenalidomide treatment in CLL, Rituximab maintenance in CLL. Greil:Roche: Honoraria, Research Funding; Celgene: Research Funding.

Description: Abstract 292 Introduction: CLL cells derive essential cues from their microenvironment, that may be targets for therapy. To this end the immunomodulatory drug Lenalidomide has shown remarkable clinical activity in monotherapy trials in CLL. However, tumor lysis and tumor flare have been major obstacles in development and marked and unexplained differences in the individual tolerance of the substance remains an unsolved problem. Furthermore, the potential for interaction with standard treatment for CLL is unknown. We employed the combination of Fludarabine and Rituximab for early reduction of tumorload and used it as a backbone to establish a tolerable Lenalidomide dose in combination. Study design: In the induction phase a maximal tolerated dose (MTD) of Lenalidomide in combination with FR was to be determined during 6 cycles of Fludarabine (40mg/m2 po d1-3 q28d) and Rituximab (375mg/m2 iv d4 cycle 1; 500mg/m2 iv d1 cycles 2–6, q28d). In cycle 1 Lenalidomide was added day 7–21 at 2,5 mg. Toxicity permitting, Lenalidomide dose was escalated to 5, 10, 15, 20 and 25mg d1-21 over cycles 2–6. Data from this phase are presented in this planned analysis. Data from a 6 month Lenalidomide/Rituximab maintenance phase will be presented later. Results: The median age of the 45 recruited patients was 66 years (range 43–79). Half of the patients were in stages Rai III/IV and the median β2-MG was 4.4 mg/l. At least one high risk feature from CD38, FISH analysis and mutation status was present in 64% of patients. Five patients stopped treatment during induction (Two due to rashes, two as patient's choice and one due to early Richter's transformation). No systematic toxicity determining an MTD, the primary study endpoint, was found. In striking contrast to a small previous report, 34% of our patients proceeded through dose escalation steps as planned to receive a dose of 25mg of Lenalidomide with their last cycle of FR. The individual MTD was equal or higher than 10mg in 73% of ITT patients and 71% in this group were dose-limited due to individual differences in myelotoxicity. In ITT analysis 27% of patients had an MTD of less than 10mg. Grade 3 and 4 neutropenia was expected in this combination and observed in 88% of patients in any cycle. While it was not used as a dose limiting toxicity per se, 42% of patients were dose-limited due to myelotoxicity at some level. Infectious episodes of grade 3 severity were observed in 5 patients (11%), resulting in a relatively mild rate given the observed myelotoxicity and the phase I/II design. Surprisingly, 1/3 of the patients experienced greater than G2 skin toxicity and this was deemed dose-limiting in nine patients. No tumor lysis or greater than G2 flare reactions were observed. Full response assessment for induction treatment is available for 39 patients. Complete responses were observed in 49% and partial responses in 38% of the ITT population. In 35 patients flow MRD is available and 10 patients have reached MRD negativity. Response quality was not associated with risk factors, age or with lenalidomide dose in those receiving 6 cycles of treatment. Remarkably, one of three patients with deletion 17 achieved an MRD negative CR. Since we could not define a clinical predictor for the patients' tolerance of lenalidomide, we performed extensive immunophenotyping of T cells in pretreatment samples, using markers for functional T cells subsets, their Th polarity and for suppressive or exhausted T cell subsets. Employing a combined endpoint including non-hematological dose-limiting events or MTD 〈 10mg as a comparator, we identified a fraction of non-exhausted memory CD4 cells as highly significant predictor of dose-limiting non-hematologic events (p

Description: Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naïve and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct) 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of 300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of 〉80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

Description: Abstract 1238 Poster Board I-260 Regulatory T cells (Treg) are thought to be potent suppressors of anti-tumor immunity and increased Treg frequencies are correlated with poor prognosis in patients suffering from various tumor types. In the current study we analysed Treg (CD3+CD4+CD25+CD127−) in the peripheral blood of 101 previously untreated chronic lymphocytic B-cell leukemia (B-CLL) patients as well as 170 healthy volunteers using flow cytometry. Statistical analysis was used for correlation with clinical data. Treg of B-CLL patients expressed high numbers of FOXP3 and efficiently suppressed T cell proliferation. No significant difference in relative Treg numbers between B-CLL patients and healthy controls could be observed, but Treg numbers showed a significant negative correlation with time to initial treatment. Defining a cut-off of 9.75%, patients with higher Treg showed significantly shorter time to initial treatment (median 4.4 yr, 95% CI 2.2 – 6.6 yr) when compared to the lower Treg group (median not reached at 4.25 yr) (logrank P=0.001). Further subdivision of patients into quartiles according to Treg numbers showed a clear dose-dependency (logrank P=0.027). Treg numbers had significant prognostic power for time to initial treatment in univariate (P=0.001) as well as multivariate (P=0.037) Cox-regression analysis including Rai stage, IgVH mutational status, chromosomal aberrations and CD38 expression. In conclusion, higher Treg numbers are significantly and independently correlated with shorter time to initial treatment in B-CLL in a dose-dependent fashion and show significant prognostic power for time to initial treatment. These results provide evidence for the role of Treg in the clinical course of B-CLL. Disclosures No relevant conflicts of interest to declare.

Description: Background: Despite modern chemoimmunotherapy more than a third of patients with diffuse large B cell lymphoma (DLBCL) will experience relapse or refractory disease. Multiple mutations associated with the biology of DLBCL have recently been identified by next-generation sequencing in primary tumor samples, but little is known about their prognostic role. Furthermore, histological comparison of the primary tumor and relapsed disease is often not available in clinical practice due to the lack of centralized assessment and complicated by the difficulties to perform exome-wide sequencing in formalin fixed tissues. Therefore, the role of certain mutations and their mechanisms in clonal evolution during relapse is unknown and the rising of chemo-resistant DLBCL subclones has not been described in the literature so far. Methods: We identified all patients with available histologically confirmed relapsed or refractory DLBCL in our single center cohort of 346 patients with aggressive lymphoma treated at our tertiary cancer center in Salzburg, Austria. Primary formalin fixed paraffin embedded tumor sample, sample of refractory or relapsed disease and matched germ line were available for targeted next generation sequencing in 27 patients. A targeted exon capture and next-generation sequencing of all coding exons of 104 selected genes known to be frequently mutated in lymphoma were performed on a HiSeq 2500. Results: Sequencing was successful in 96.8% of all samples resulting in 25 patients with sequencing of the primary tumor and 24 patients with available pairs of primary lymphoma and histologically confirmed relapse. In these 24 patients two relapse samples were available in 10 patients and three relapse samples in one patient. Non-synonymous mutations were present in 74 of the 104 genes tested. Individual tumor samples showed between 0 and 29 non-synonymous mutations (median: 10). Less than six non-synonymous mutations in the primary tumor were associated with a better median OS than more mutations (28 versus 15 months p=0.031). We also compared the frequency of mutated genes in our cohort consisting of high risk patients defined by actual relapse with the literature containing patients with extensive sequencing but only little clinical data and clinical follow-up. Common mutated genes such as CARD11, CD58, CD79B, CREBBP, EZH2, BTG1 or B2M showed no difference in frequency to our patient cohort indicating no or only small driver function in resistant or refractory disease. Nevertheless, mutations previously reported to be at low frequency in DLBCL were significantly more often observed in our primary samples (NOTCH1, MYC, RB1, FAT2, ATM, SMARCA4, BCL7A) and relapsed samples (TP53, MCL1, ATM, FAT2, MYC, RB1, SMARCA4) of high risk patients when compared to the literature. We also observed the gain and the loss of several mutations between first diagnosis and histologically confirmed relapse. Overall, we observed an increase of the amount of non-synonymous mutations at first relapse in 12, no change in 6 and a decrease in 6 paired cases. A completely stable pattern of non-synonymous mutations was detected in 4 cases, but in the majority of cases relevant dynamic was observed: e.g.: gain of non-synonymous mutations in the p53 gene was seen in 3 patients (5 mutations), in the TNFRSF-14 gene in 2 patients (3 mutations), in the RB1 gene in 1 patient (1 mutation), in the NOTCH2 gene in 3 patients (4 mutations) and in the MYD88 gene in 1 patient (1 mutation) or loss of non-synonymous mutations in the CREBBP gene in 3 patients (3 mutations) or in the CRAD11 gene in 2 patients (2 mutations). Monitoring of subclones during disease was also possible using the allelic fraction over time e.g.: showing an increase of the NOTCH1 mutation burden in 2 biopsies after first diagnosis. Discussion: To the best of our knowledge clonal evolution detected by next generation sequencing has not been reported in DLBCL so far. We demonstrate the feasibility of such an approach from fixed tissue samples and using a curated set of target genes. In analogy to other lymphoid malignancies we can show the increase of allelic burden of certain mutations over time and the loss or gain of several others. While this approach is limited by the bias introduced by the selection of genes in the gene set, we feel that deep sequencing of selected mutations will provide further insights into subclone dynamics, which may be responsible for clonal evolution. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1613 Background: Elderly patients with aggressive B-cell lymphoma are underrepresented in almost all clinical trials and treatment related toxicity mainly due to anthracycline treatment is a major concern. Individual pharmacogenetic settings may influence the prognosis due to altered efficacy and treatment related toxicity. Several single nucleotide polymorphisms (SNPs) involved in metabolization of chemotherapeutic agents have been proposed to influence the clinical course of disease in younger patients. However, no data are available in elderly patients. Methods: We retrospectively analyzed and characterized 83 consecutively diagnosed patients ≥75 years with aggressive B-cell lymphoma (78 cases of diffuse large B-cell lymphoma and 5 cases of follicular lymphoma grade 3) from January 2004 until December 2011 treated at our tertiary cancer center by chart-based review. DNA was extracted from diagnostic tissue samples and analysis for 10 SNPs with previously reported effect on pharmacodynamics of components of the CHOP regimen were performed with commercially available primers (rs1883112 NCF4, rs3957357 GSTA1, rs4673 CYBA, rs1799977 MLH1, rs1045642 ABCB1, rs9024 CBR1, rs1695 GSTP1, rs17222723 ABCC2, rs7853758 SLC28A3, rs1056892 CBR3). Results: The entire cohort of 83 patients had a median age of 80 years (range 75–97 years) and 43 of 83 patients were male. Based on clinical judgment of fitness 82% of all patients received a combination of anthracycline and rituximab based therapy. The median overall survival (OS) in all patients was 43 months. Unsurprisingly, patients deemed eligible for a treatment with an anthracycline and rituximab had a better median OS than patients not eligible for this approach (54 vs 6 months p〈 0.0001). Patients not treated with this combination therapy were significantly older (p

Description: Introduction B-cells express either kappa or lambda light chains but not both. B-cell directed therapies such as anti-CD20 antibodies deplete healthy and malignant CD20+ B-cells but spare CD20- plasma and myeloma cells. Furthermore anti-CD20 antibody mediated B-cell depletion can lead to severe hypoimmunoglobulinemia and thereby predispose for infections. Light-chain specific targeting would allow a more specific therapy of lymphomas and myeloma, with collateral damage limited to only half of healthy B-cells. Due to the heterogeneity of immunoglobulines, lymphoma specific therapy so far required customized solutions for every single patient. Despite having 40 variable and 5 joining regions, the kappa light chain has only 1 constant region (IGKC). Therefore the 5’ IGKC intron is conserved in kappa light chain pre-mRNA, regardless of any recombination or somatic hypermutation in the VJ-region. Spliceosome-mediated RNA trans-splicing allows endogenous pre-mRNA to be converted into a new gene product via exon replacement. This can be achieved by the introduction of an RNA trans-splicing molecule (RTMRTM) that binds to endogenous target RNA and induces trans-splicing between the target gene and the RTM. RTMs contain a binding domain (BD), which defines the target specificity, splicing elements for efficient trans-splicing, and the desired coding sequence. This proof-of-principle study was aimed at demonstrating the feasibility of light-chain specific targeting through spliceosome-mediated RNA trans-splicing. Methods This study was approved by the local ethics committee of the provincial government of Salzburg. Potential RTMs for trans-splicing were identified using a fluorescence screening procedure as previously described (Gruber C et al. Mol Cancer Ther. 2011 Feb;10(2):233-41.). Primary lymphoma and myeloma samples were collected during routine diagnostic testing. Total RNA isolation was performed with RNeasy® isolation kit (QIAGEN) and reverse transcription of RNA using the i-script cDNASynthesis Kit (Bio-Rad). Quantitative real-time polymerase chain reaction was performed using GoTaq® qPCR Master Mix (Promega). For western blotting, cell lysates were separated using 10% sodium dodecyl sulfate/polyacrylamide gel electrophoresis. After transferring the proteins onto a nitrocellulose membrane, immune detection of specific proteins was performed using anti-Green Fluorescent Protein (GFP) antibodies and enhanced chemiluminescence detection. Results BD screening identified RTM 55 as the most efficient trans-splicing molecule and was therefore used for further experiments. Since the light chain locus undergoes substantial physiologic genetic changes in the process of VJ rearrangement and somatic hypermutation, we analysed whether these changes extend to the target sequence of the BD of RTM 55. Sequencing of the complete 5’ IGKC intron in primary kappa+ CLL (N=4), DLBCL (N=3) and myeloma cells (N=3) only showed occasional point mutations. In the following, effective endogenous trans-splicing was confirmed in 2 different kappa+ cell lines, the DLBCL cell line SUDHL4 and the CLL cell line MEC2. We could detect successful trans-splicing on the mRNA level and sequencing of PCR-products confirmed accurate trans-splicing with the last base of the J-region adjoining the first base of the GFP gene. Stable retroviral transfection of SUDHL4 cells also allowed the successful detection of the kappa light-chain-GFP fusion protein by western blotting. Surprisingly, the lambda+ myeloma cell line U266 as well as FACS-sorted healthy lambda+ B-cells showed high expression levels of kappa light chain mRNA. This leaky mRNA expression of the non-dominant light chain could not be seen in kappa+ cells, which may be explained by the programmed sequential activation of the kappa and lambda loci during B-cell development. Conclusions We could show that the kappa light chain can be specifically targeted by spliceosome-mediated RNA trans-splicing. The possibility to reprogram the light chain pre-mRNA offers numerous possible applications, such as suicide gene therapy for lymphoma and myeloma. The unexpectedly high expression of kappa mRNA in lambda+ cells but not vice-versa, raises the question whether the lambda light chain locus would offer an even better, since more specific target Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1715 Twelve participating centers in Austria included 257 unselected, consecutive patients with MDS/CMML or AML, who received azacitidine (AZA) between 02/2007 and 07/2011, in the nationwide Austrian Azacitidine Registry (AAR) of the AGMT-study group. Approval by the national Ethics Committee was obtained. The AAR includes 26 patients with CMML (10 with CMML-1, 16 with CMML-2) and is currently the 2nd largest report on CMML patients treated with AZA, the largest comprising 36 evaluable patients (Costa R. et al., Cancer, June 2011, pp2690). Myeloproliferative CMML (MP-CMML), defined as WBC〉13.000/μl at diagnosis, was present in 16/26 patients, whereas 10/26 had myelodysplastic CMML (MD-CMML). Thus, the AAR includes patients for whom AZA is currently not approved by the FDA/EMEA. The AAR includes a high proportion of very old CMML patients (31% 75–79a, 15% 〉80a). Median age was 75a for both males (n=15) and females (n=11). Patients with various levels of PS were included (ECOG-0 (n=6), ECOG-1 (n=14), ECOG-2 (n=8) and ECOG-3 (n=4)). CMML-patients of the AAR suffered from renal insufficiency (n=8), mild liver disease (n=8), coronary artery disease (n=5), diabetes mellitus (n=5), a prior/concomitant solid tumor (n=3), COPD (n=2) and/or venous thromboembolic disease (n=1), respectively. There was no relevant difference in RBC transfusion dependence (TD) for MP-CMML vs. MD-CMML. However, PLT-TD at diagnosis was lower for MP-CMML (23%) than for MD-CMML (67%). In the 19 patients in whom pretreatment cytogenetics were performed, 15, 4 and 0 could be grouped into IPSS good, intermediate and poor risk categories, respectively. Only 57% of all included CMML-patients were treatment-naïve, whereas the rest were pretreated with ICT (10%), ESA (14%), intensive chemotherapy (21%) and other substances (17%) (mainly hydroxyurea and anagrelide) (numbers add up to more than 100% as several patients were pretreated with more than 1 agent). Thus, this registry more accurately reflects a real-life treatment scenario, than most clinical trials that have strict inclusion/exclusion criteria. Most AZA-cycles were applied s.c. (98%), whereas 2% were applied i.v. Median and mean number of AZA-cycles was 5.5 and 9 (SD 10.61; range 1–43), respectively. The FDA-approved d1-7 schedule was used in 62% of all AZA cycles, whereas the non-approved alternative schedules d1-5, 5-2-2 and ‘others’ were applied in 21%, 12% and 6% of all cycles, respectively. Concerning the number of patients however, 20/26 predominantly received the d1-7 schedule. The FDA-approved target dose (75mg/m2 over 7 days) was achieved in 52% of all cycles and in 17/26 of patients, respectively. Reasons for termination of treatment with AZA were death (33%), disease progression (22%), transformation to AML (11%), no response (6%), toxicity (6%) and other reasons (22%). Any kind of HI was noted in 12/26 (46%) of patients. When looking at each lineage separately, 8/26 had HI-ery, 7/26 HI-PLT and 9/26 HI-neutrophils. 6/14 patients who were RBC-TD and 3/7 patients who were PLT-TD prior to AZA-treatment achieved transfusion independence (TI). In patients, in whom (repetitive) bone marrow aspirations/biopsies were performed for response evaluation (n= 12), the following best marrow responses were observed: CR in 4/12 (33%), marrow CR 1/12 (8%), PR in 2/12 (16%), SD in 4/12 (33%) and primary PD in 1/12 (8%). The OR rate observed prior to 07/2011 was 44% (CR + marrow CR + PR + HI). At the time of writing, 9 patients had received 2 AZA cycles, which is required for achievement of hematologic response by the IWG-criteria, ORR was 66%. These are amongst the highest response rates observed for CMML to date. The median OS was 12.7 months (95%CI 6.9; 19.4). Median OS for patients demonstrating HI was significantly higher than for those who did not (19.4 vs. 5.6 months, p

Description: Background: Ropeginterferon alfa-2b (Ropeg) is a novel long-acting monopegylated IFN-alpha-2b. Due to reduced dosing frequencies, better tolerability and improved compliance, Ropeg may be a favorable treatment option for long-term therapy in patients with polycythemia vera (PV). Study design: PEGINVERA phase I/II (NCT: 2010-018768-18), a prospective, open-label, multicenter study, investigated the efficacy and safety of Ropeg for long-term treatment in 51 patients aged ≥18 years with a confirmed diagnosis of PV, regardless of prior cytoreductive therapy. Following ≥1 year of 2-weekly treatment, patients who responded well to Ropeg were permitted to switch to a 4-weekly dosing regimen. Results: Baseline characteristics of the study cohort and interim safety and efficacy data were presented previously (Gisslinger et al., Blood, 2015). Fifty-one patients were treated: Median exposure to Ropeg was approximately 5.1 years (61 months; range: 0 to 87 months). Patients were treated for a median of approximately 2 years (98.9 weeks; (Q1-Q3: 69.0 - 117.4 weeks) on the 2-weekly regimen and 4 years (207.1 weeks; Q1-Q3: 158.6 - 242.0 weeks) on the 4-weekly regimen. The best observed individual hematological response for patients in the efficacy analysis set (FAS) was a complete hematological response for 27/42 (64.3%) and a partial response for 14/42 (33.3%) patients. Patients required a median of 34 weeks (Q1-Q3: 10-96 weeks) treatment to achieve a complete hematological response, and 10 weeks (Q1-Q3: 10-20 weeks) to achieve any hematological response. Switch from 2 to 4-week dosing regimen had no apparent effect on maintenance of response. With respect to JAK-2 allele burden, the best observed individual molecular response was a complete response for 12/42 (28.6%) patients and a partial response for 19/42 (45.2%) patients. Lowest JAK-2 values relative to baseline are presented by patient in Figure 1. Patients required a median of 82 weeks (Q1-Q3: 44-115 weeks) treatment to achieve a complete molecular response and 34 weeks (Q1-Q3: 18-55 weeks) treatment to achieve any molecular response. Irrespective of dosing regimen, molecular responses tended to increase over time. Most patients reported at least one adverse reaction (AR) to treatment (409 ARs in 48/51 [94.1%]); however, the majority (296 in 44 [86.3%] patients) were mild; 102 (in 34 [66.7%] patients) were moderate and 11 (in 10 [19.6%] patients) were severe. The most frequently reported ARs (frequency 〉20%) were arthralgia, influenza-like illness and fatigue. Twelve serious treatment emergent adverse events (TEAE) reported by 8/51 patients (15.7%) were considered to be treatment related: 2 events of depression, 2 of positive anti-thyroid antibodies, and one each of acute stress disorder, increased antinuclear antibodies, arthralgia, atrial fibrillation, fatigue, influenza-like illness, pyrexia, and increased transaminases. 25 patients completed the trial. The majority of discontinuation due to TEAE (13/21 patients) occurred in the first year, when the recommended slow up-titration of Ropeg could not be applied because of the maximum-tolerated-dose design. After the first year, only 8 additional patients discontinued because of TEAE. Conclusions: The final results of this phase I/II study of Ropeg in patients with PV support the findings of the pivotal phase III clinical trial (Gisslinger et al., Blood 2015) with respect to safety and efficacy as determined by hematological, clinical and molecular parameters. In addition, these data provide evidence that treatment with Ropeginterferon alfa-2b for up to 7 years is efficacious, well-tolerated and disease-modifying at both the 2 week and 4 week maintenance treatment regimens. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Krauth:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Greil:MSD: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zoerer:AOP Orphan Pharmaceuticals: Employment. Empson:AOP Orphan Pharmaceuticals: Employment. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment.