ALBERT

Description: Background and Aims: Myelodysplastic syndromes (MDS) are mainly diagnosed in the elderly with an increasing burden on healthcare systems. As a consequence, population-based studies are important in order to estimate the evolution of this emerging disease in different countries. Objectives: The objective of this study was to provide trends ofannual case frequency, morphological subtypes, incidence, mortality and survival of patients diagnosed with MDS in Switzerland between 2001 and 2012. Methods: A retrospective, population-based, epidemiological study was carried out on MDS cases reported to the Swiss Cantonal Cancer Registries and aggregated by the National Institute for Epidemiology and Cancer Registration. The Swiss Federal Statistical Office provided mid-year population estimates and cause of death statistics. Due to changes in the WHO classification of MDS, data was stratified for two time periods 2001-2007 and 2008-2012, respectively. 56 million person-years (py) were observed, covering 60%-65% of the Swiss population, during a time period of 12 years. Results: 2138 MDS cases were reported with a median age of 77 years (range of means: 75-78 years). The estimated annual case frequency increased from 263 to 316 (+20%) but the overall age-standardized (adjusted) incidence-rate did not change between the time periods (Table 1). A substantial increase in incidence was only visible for men aged 80-84 (+57.7%), men aged 85+ (+29.3%) and women aged 85+ (+13.4%). With respect to mortality rates, a 10% decline was observed for men aged 85+. Incidence and mortality were very low below the age of 60 years but the rates steeply increased thereafter (Figure 1a). Irrespective of time period, incidence- and mortality-rates were almost twice as high among men compared to women (Figure 1b). Classification in MDS subtypes was poor and improved only modestly from 20% to 39% with a higher awareness for diagnosis of higher-risk diseases. Relative survival at 5 years (RS at 5y) for all patients was 37% in 2008-2012 with better survival for younger patients 〈 65 years (61%) compared to older patients 〉 65 years (24-37%). No differences in survival could be observed between the two time periods (Figure 2). Conclusions: In this study we provide the first population-based, epidemiologic data from MDS patients in Switzerland. The analysis showed a 20% increase of annual incidence mainly due to population aging and not explained by increase in age-specific risk. This observation will impact on the future prevalence of the disease and its burden on healthcare systems.The age-specific incidence-ratesin patients 〉 75 years increased markedlyconsistent with the general increase of cancer-incidence in the elderly population. An increased diagnostic awareness of higher-risk disease seems to shift the population-based data for MDS sub-classification. We observed that younger patients without classified MDS subtypes have a similar survival like lower-risk disease, indicating that lower-risk MDS is underreported. Unsurprisingly, our data showed that younger patients have a better survival than elderly patients. This is most likelyrelated to higher frequency of lower-risk diseases in younger patients and their eligibility for allogeneic HSCT. However,the lack of a survival benefit observed in elderly patients on population-based level, after introduction of hypomethylating agents as standard treatment for transplant ineligible patients, is intriguing. The underlying reasons require further health-service research investigations. Relevance: The currently available data from CCRs in Switzerland is insufficient for detailed health service research on MDS patients, since important data is lacking on treatment, side effects and outcomes. A new cancer registration law with mandatory notification of cancer cases will be implemented in Switzerland by 2018. Moreover, the Swiss MDS Study Group has launched a Swiss MDS Registry that has started recruitment in 2016. Both initiatives will be of great value to improve data collection in order to foster future health service research of MDS patients in Switzerland with international collaborators. Table 1 Incidence and Mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Table 1. Incidence and Mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Figure 1 Incidence and mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Figure 1. Incidence and mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Figure 2 Age-specific relative survival of MDS patients diagnosed in 2001-2007 and 2008-2012 Figure 2. Age-specific relative survival of MDS patients diagnosed in 2001-2007 and 2008-2012 Disclosures Bonadies: Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ruefer:Novartis: Consultancy; Celgene: Consultancy, Research Funding. Gerber:Celgene: Consultancy. Benz:Celgene: Consultancy. Lehmann:Novartis: Consultancy.

Description: Introduction : Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with a very indolent clinical course and patients may survive for many decades. First-line treatment with purine analogues such as cladribine (Cld) is considered standard of care since it is very efficient and induces profound remissions. However, patients with HCL often relapse after purine analogues and repeated treatment may increase morbidity and mortality. Despite good clinical evidence of long term control of the disease by several mainly single center studies of patients treated with purine analogues, there is only one study analyzing mainly subcutaneous (sc) treated patients based on registry data. We therefore performed a pooled long-term follow-up analysis of our prospective multicenter studies treating patients with sc Cld focusing on survival, secondary malignancy and retreatment. Materials and Methods : The SAKK included patients treated for HCL in 4 studies between 1993 and 2005. Three studies focused on first-line regimens with sc Cld, whereas the fourth protocol focused on the effect of Rituximab monotherapy in patients pretreated with Cld. Classical morphologic, immunohistochemistry and flow cytometry criteria were used as inclusion criteria and response was assessed by established criteria. Treatment algorithms in the 4 studies were as follows: 1) 5 days of Cld 0.14mg/kg sc followed by max 2 cycles of 7 days of Cld 0.1mg/kg sc in case of minor response or no response (SAKK 32/93); 2) Single shot of Cld 0.25mg/kg sc followed by a maximum of 2 cycles of 0.14mg/kg sc for 5 day in case of minor response, no response or relapse (SAKK 32/95); 3) 5 consecutive days of Cld 0.14mg/kg sc versus the same dose in 5 weekly applications (SAKK 32/98); 4) Rituximab 375 mg/m2iv weekly for 4 weeks in relapsed patients (SAKK 31/98). SAKK 32/93 included 63, SAKK 32/95 74 and SAKK 32/98 100 patients. Of the 26 patients registered in 31/98 20 were already in SAKK 32/93, 32/95 and 32/98. Therefore, we also included the treatment information and follow-up data of these 20 patients. All patients were subject to life-long follow-up within the clinical trials. Further information including secondary malignancies and retreatments were obtained by sending out questionnaires to the treating physicians of the study patients. Of the 237 patients 4 patients were in two of the studies and 10 patients have been excluded because of non-classical HCL phenotype. Therefore, a total of 223 patients were included in the analysis. Overall survival and follow-up time were assessed by Kaplan-Meier and reverse Kaplan-Meier method, respectively. Results : The median age of patients at the time of diagnosis was 55 (range 21 to 96) years, 50 patients were female (22.4%) and 173 (77.6%) male. At the time of data analysis, the median follow-up time was 12.1 (95%-CI 10.0 to 14.0) years. A total of 129 (57.8%) patients had the last follow-up information more than two years prior to the data cut-off in May 2016, however, the available information of all patients was used for the sub-analyses including secondary malignancies or retreatment. By the cut-off date, 49 patients have died, 14 (28.6%) due to secondary malignancies and 7 (14.3%) due to HCL progression. Median overall survival from diagnosis was 31.6 (95%-CI 31.6 to 37.8) years. Retreatment was necessary in 53 (23.7%) patients after a mean of 6 (0.2 to 20.4) years and first retreatment was mainly Cld (64%), rituximab (19%) or Cld and rituximab (13%). 21 patients (9.4%) required more than one retreatment with a mean number of 1.57 (range 1 to 5) treatments. A total of 42 (18.8%) patients developed secondary malignancies with an average time to occurrence of 7.1 (range: 0.1 to 17.7) years. The majority of the secondary malignancies were of non-hematological origin (85.9%), most frequently skin cancer (31.0%), followed by prostate cancer (19.0%) and colorectal cancer (16.7%). Six patients (14.4%) developed hematological secondary malignancies with a predominance of B-lymphoid neoplasms. Conclusion : Long-term overall survival in HCL patients treated with sc Cld was excellent and comparable to studies using iv Cld. Despite the long follow-up, sc Cld had a curative potential and relapses requiring re-treatment were observed only in a minority of patients. Secondary malignancies were predominantly non-hematological. These data indicate that patients need to be followed carefully with a special focus on secondary malignancies. Disclosures Chalandon: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Description: Background:In 2016 WHO recognized the provisional entity refractory anemia with ring sideroblasts and thrombocytosisas a distinct entity and renamed it myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). The disease presents hallmarks of both myelodysplastic and myeloproliferative features. Although the diagnostic criteria are well defined and there are several studies of the molecular landscape of the disease, the treatment regimen of these patients remains inconsistent. Due to lack of clinical trials, treatment options are chosen either on MDS- or MPN-based regimens and individual preferences such as patients characteristics and clinical presentation. Prevention of thromboembolic events is a reasonable goal. However, the use of platelet-lowering drugs is still not well studied and treatment related anemia leading to transfusions with accelerated iron overload limits a general use of cytoreductive treatment. To avoid worsening of the anemia while efficiently reducing thrombocytosis we treated 3 patients with pegylated interferon (pIFN) and provide insight in JAK2-allele burden measurement and additional mutations obtained with next generation sequencing (NGS). Results:Three patients with diagnosis of MDS/MPN-RS-T were treated with 135µg pIFN during an observation period between 8 and 34 months. All 3 patients had a JAK2V617F mutation, 〉15% ringsideroblasts and a thrombocyte count above 600G/l. In the additional NGS analysis, two patients showed a mutation in the SF3B1 gene, one with an additional DNMT3A mutation. In the third case, NGS results revealed a mutation in the splicing factor U2AFI, which is a rare finding in patients with MDS/MPN-RS-T. JAK2-allelel burden was obtained at the beginning and showed a decrease of a mean value of 38% as measured by digital droplet PCR. Anemia was present at initial diagnosis in two patients. During observation period, none of the patient became transfusion dependent, in one case even an improvement in hemoglobin levels was achieved. Side effects of the treatment were only minimal and no thromboembolic as well as major bleeding event occurred under additional acetylsalicylic acid medication. Conclusion: In summary we show that in patients with MDS/MPN-RS-T a therapy with pIFN achieved rapid decrease of thrombocyte values without lowering hemoglobin levels at a maximal dose of 135µg per week. JAK2-allele burden reduction and a low side effect profile further demonstrate the value of this treatment option for these often elderly patients. However, larger studies are needed to confirm our data. Disclosures No relevant conflicts of interest to declare.

Description: Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by aberrant proliferation of erythroid, megakaryocytic and myeloid lineages. They are associated with decreased survival, thromboembolic complications, hemorrhage and leukemic transformation. MPN can be subdivided into polycythemiavera(PV), essentialthrombocythemia(ET) and primary myelofibrosis (PMF). The JAK2-V617F mutation is present in 70-80% of all MPN patients. MPN is initiated and maintained by mutated hematopoietic stem and progenitor cells (HSPC). Bone marrow mesenchymal stem cells expressing the intermediate filament proteinnestin(nestin+ MSCs) that are innervated by sympathetic nerve fibers constitute an important component of the stem cell niche and regulate normal HSCs. Thesenestin+ MSCs are strongly reduced in bone marrow of JAK2-V617F positive MPN patients and in mice expressing JAK2-V617F due to damage of the sympathetic nerve fibers triggered by cytokines from the mutant cells. In a JAK2-V617F mouse model of MPN, treatment with a beta-3sympathicomimeticagonist corrected the damage inflicted by the MPN clones on their niches and ameliorated the MPN phenotype. To test the potentially beneficial effect on disease-control by modulating bone marrow niche cells in patients with MPN, we performed a phase II trial with the beta-3sympathicomimeticagonistmirabegron. Patients and Methods: The trial consisted ofmirabegrontreatment with 25 mg daily during the first week, followed by 50 mg daily for at least 24 weeks. Patients with acytohistologicallyconfirmed diagnosis of MPN and a JAK2-V617F allele burden 〉20% in granulocytes at study entry were eligible, if not treated with JAK2 inhibitors or interferon. Reduction of the JAK2-V617F mutant allele burden ³50% in granulocytes was defined as the primary end point. Secondary end points included changes in blood counts or MPN related symptoms. As a side study, bone marrow biopsies were quantified fornestin+ MSCs, fibrosis and CD34+ HSPCs. N=39 patients have been accrued in 10 institutions in Switzerland. Eight (21%) had ET, 22 (56%) PV, and 9 (23%) PMF. N=27 (69%) were male, the median age was 62 (Q1-Q3 53-72) years. Median mutated allele burden at study onset was 52% (Q1-Q3 33-73%). All patients had prior treatment, N=28 (72%) patients hadcytoreductivetreatment, the remaining patients hadantiaggregation, anticoagulation or phlebotomy. Results: No patient reached the primary endpoint of 50% reduction in allele burden, one patient achieved a 25% reduction by 24 weeks of treatment. Adverse events were mostly grade I or II on the CTCAE scale. Three patients had grade III events: two were considered to be at least possibly related to study medication. In the side study, 24 patients agreed to bone marrow biopsy prior to and at the end ofmirabegrontreatment and for 20 patients both measurements are available. In these patients an increase in thenestin+ MSCs cells from a median of 1.09 (Q1-Q3 0.38-3.27)/mm2 to 3.95 (Q1-Q3 1.98-8.79)/mm2 (p50% in patients with MPN. However, an increase in thenestin+ MSCs in bone marrow and a slight decrease of myelofibrosis were found, which will be further investigated. Figure 1 Bone marrow histology of a patient before (week 0) and at the end ofmirabegron treatment (week 24). Upper panel,reticulin fibers are stained black by silver impregnation (Gomori). Lower panel, immunohistochemistry staining with antibodies against humannestin protein (brown staining). Note decrease inreticulin fibrosis and increase innestin+ cells after 24 weeks of treatment. Magnification: 200x. Figure 1. Bone marrow histology of a patient before (week 0) and at the end ofmirabegron treatment (week 24). Upper panel,reticulin fibers are stained black by silver impregnation (Gomori). Lower panel, immunohistochemistry staining with antibodies against humannestin protein (brown staining). Note decrease inreticulin fibrosis and increase innestin+ cells after 24 weeks of treatment. Magnification: 200x. Disclosures Theocharides: Novartis: Consultancy, Honoraria. Rüfer:Novartis: Consultancy, Speakers Bureau. Benz:Celgene: Consultancy. Tzankov:Novartis: Speakers Bureau; Abbott: Speakers Bureau. Skoda:Novartis: Consultancy, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Consultancy, Speakers Bureau.