ALBERT

Description: Introduction: Acquired aplastic anemia (AA) is typically characterized by pancytopenia and bone marrow (BM) failure mostly due to an autoimmune attack against the hematopoietic stem cell compartment. Thus, AA patients frequently respond to immunosuppressive therapy (IST). Hypoplastic myelodysplastic syndrome (hMDS) frequently mimics clinical and morphological features of AA and proper clinical discrimination of hMDS from AA sometimes remains difficult. Interestingly, some cases of hMDS respond at least partially to IST and on the other hand, AA can clonally evolve to hMDS. Telomeres shorten with each cell division and telomere length (TL) reflects the replicative potential of somatic cells. Whereas it is proposed that TL can to some degree discriminate hereditary subtypes of bone marrow failure syndromes from classical acquired forms, the role of TL for disease pathogenesis in hMDS remains unclear. In this study, we therefore aimed to investigate accelerated TL shortening as a possible (bio-)marker to distinguish hMDS from AA. Patients and Methods: TL of BM biopsies at diagnosis of 12 patients with hMDS and 15 patients with AA treated in the University Hospital Düsseldorf were analyzed. Mean age was 45.2 years in AA patients and 65.2 years in patients with hMDS. Confocal Q-FISH protocol was used for TL measurement as published previously (Blood, 2012). TL analysis was performed in single-blinded fashion. 28 patients (range 18-80 years) with newly diagnosed M. Hodgkin without BM affection were used as controls for linear regression and calculation of age-adapted TL difference. For the analysis of the data, we made use of a recently developed mathematical model of TL distribution on the stem cell level allowing us to extrapolate mean TL shortening per year (TS/y) based on the individual TL distributions of captured BM biopsies. Results: Using the controls to adjust for age, we found that age-adapted TL was significantly shortened both in patients with AA (median: -2.96 kb, range -4.21 to 0.26, p=0.001) and patients with hMDS (median: -2.26, range -3.85 to -0.64, p=0.005). In direct comparison, telomere shortening was more accelerated in patients with AA as compared to hMDS (p=0.048). Next, we analyzed the TL shortening per year (TS/y) based on the individual telomere distribution. Calculating the extrapolated TL shortening per year (TS/y), we found significant increased TS/y in AA patients (mean±SD: 235,8 bp/y±202,9, p=0.001) and hMDS patients (120,5±41,7 bp/y, p=0.0001) compared to controls (37,5±18,9 bp/y). Interestingly, the extrapolated rate of TS/y remained stable at different ages in hMDS patients as observed in healthy controls. In contrast, TS/y in AA patients showed a strong age-dependence with a maximum of TS/y in patients younger than 30 years (R²=0.42, p=0.008). Finally, we set to test whether TS/y can be used to identify AA or hMDS patients. Using 150 bp TS/y as a cut-off (4-fold the mean of controls), we found significantly more AA patients (10/15, 66.7%) had accelerated TL shortening compared to hMDS (1/12, 8.3% p=0.005). Conclusion: We provide first retrospective data on TL in patients with hMDS using confocal Q-FISH. Age-adapted TL is significantly shorter in patients with AA compared to hMDS. Interestingly, telomere shortening per year is both significantly increased in AA as compared to hMDS patients as well as in both groups compared to controls. The rate of telomere shortening TS/y might represent a new marker in patients with bone marrow failure syndromes that allows to discriminate AA from hMDS patients pending prospective validation. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1236 Background: Although most patients with early chronic phase CML (ECP-CML) respond to TKI therapy, the depth and speed of response can be different. While it is known that both the Sokal and Hasford scores have an impact on the speed and depth of response, no mechanisms explaining these differences have been identified. Objective: To provide explanations for any potential differences in CML response as a function of the Sokal and Hasford score using a computational model. Methods: We utilize a computational model of hematopoiesis and CML, together with serial quantitative data of disease burden under nilotinib therapy to determine the fraction of CML cells responding to therapy (z) and the impact of TKI on the self-renewal probability of CML cells (e) under therapy. Patients were stratified at diagnosis on both the Sokal and Hasford scoring system. A non-linear least squares method was used to separately fit the model to serial Q-RT-PCR data for BCR-ABL in response to therapy in each cohort. Results: A total of 73 patients were studied. The number of patients with low, intermediate and high risk disease based on the Sokal score was 34, 29 and 10 respectively while the respective distribution of patients on the Hasford score was 29, 43 and 1. Although the impact of nilotinib on the self-renewal probability of CML progenitor cells was similar across all risk groups (there were substantial differences in the fraction of cells responding to therapy: For the Sokal groups, the fraction of cells (z) responding to therapy decreased from 0.09 to 0.086 and 0.069 respectively for low, intermediate and high risk disease. In the case of the Hasford score, the difference in z between low and intermediate categories becomes more pronounced, i.e. z is 0.093 for low and 0.08 for intermediate risk disease. Conclusions: The risk score at diagnosis of CML has a direct impact on the dynamics of response to TKI therapy. Patients with a lower risk score respond faster to the same therapy when compared to high risk patients. The impact of TKI on the self renewal of CML cells appears to be the same regardless of the risk score but the fraction of cells responding decreases as the risk score increases. This suggests that subclones that may be less sensitive to TKI therapy may be emerging. Strategies that increase the fraction of cells responding to therapy in patients with higher risk disease may be indicated. Disclosures: Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Description: Mitigating the detrimental effects of climate change is a collective problem that requires global cooperation. However, achieving cooperation is difficult since benefits are obtained in the future. The so-called collective-risk game, devised to capture dangerous climate change, showed that catastrophic economic losses promote cooperation when individuals know the timing of a single climatic event. In reality, the impact and timing of climate change is not certain; moreover, recurrent events are possible. Thus, we devise a game where the risk of a collective loss can recur across multiple rounds. We find that wait and see behavior is successful only if players know when they need to contribute to avoid danger and if contributions can eliminate the risks. In all other cases, act quickly is more successful, especially under uncertainty and the possibility of repeated losses. Furthermore, we incorporate influential factors such as wealth inequality and heterogeneity in risks. Even under inequality individuals should contribute early, as long as contributions have the potential to decrease risk. Most importantly, we find that catastrophic scenarios are not necessary to induce such immediate collective action.