ALBERT

Description: Key Points The transcription factor NF-E2 is mislocalized in patients with primary myelofibrosis. Immunohistochemical staining for NF-E2 distinguishes essential thrombocythemia from primary myelofibrosis.

Description: Abstract 2840 Background: Pomalidomide in a single arm phase-I/II study and one randomized four arm phase-II study in primary myelofibrosis (MF) and post-polycythemia vera/essential thrombocythemia (post-PV/ET) MF showed efficacy in particular with respect to improvement in anemia. To date, pomalidomide has been evaluated in MF at two dose levels, 0.5mg and 2.0 mg/day. Aims: To evaluate clinical efficacy of pomalidomide alone and in combination with prednisolone (PRED) in patients with primary or post-PV/ET MF and cytopenia. Methods: The main inclusion criteria for primary or post-PV/ET MF patients were red blood cell (RBC)-transfusion-dependence or hemoglobin

Description: Background Pomalidomide (POM) in a 1-arm phase-1/-2 study and a randomized 4-arm phase-2 study in MPN-associated myelofibrosis improved anemia. Pomalidomide was evaluated at doses of 0.5 and 2.0 mg/d. Aims To evaluate efficacy of POM alone at two different doses and combined with prednisolone (PRED) in patients with MPN-associated myelofibrosis and cytopenia (ClinicalTrials.gov No. NCT00949364). Methods Main inclusion criteria were RBC-transfusion-dependence or hemoglobin

Description: In common variable immunodeficiency (CVID) defects in early stages of B-cell development, bone marrow (BM) plasma cells and T lymphocytes have not been studied systematically. Here we report the first morphologic and flow cytometric study of B- and T-cell populations in CVID BM biopsies and aspirates. Whereas the hematopoietic compartment showed no major lineage abnormalities, analysis of the lymphoid compartment exhibited major pathologic alterations. In 94% of the patients, BM plasma cells were either absent or significantly reduced and correlated with serum immunoglobulin G levels. Biopsies from CVID patients had significantly more diffuse and nodular CD3+ T lymphocyte infiltrates than biopsies from controls. These infiltrates correlated with autoimmune cytopenia but not with other clinical symptoms or with disease duration and peripheral B-cell counts. Nodular T-cell infiltrates correlated significantly with circulating CD4+CD45R0+ memory T cells, elevated soluble IL2-receptor and neopterin serum levels indicating an activated T-cell compartment in most patients. Nine of 25 patients had a partial block in B-cell development at the pre-B-I to pre-B-II stage. Because the developmental block correlates with lower transitional and mature B-cell counts in the periphery, we propose that these patients might form a new subgroup of CVID patients.

Description: Introduction: In-depth knowledge about molecular pathogenesis of malignant diseases and rapidly increasing availability of targeted treatment options enables molecularly guided decision-making. We have established a Molecular Tumor Board (MTB) that focuses on patient management based on specific molecular data at the individual patient level. Methods: The MTB has its main focus on hematologic and solid neoplasias progressing during standard treatment, on rare entities and on patients with treatment resistance. The biweekly MTB supports the work of organ-specific boards and external cooperation partners. The MTB multidisciplinary team consists of expert physicians from Hematology, Medical Oncology, Gynecology, Dermatology, Pediatrics and Radiation Oncology as well as Pathology, Molecular biology, Computational Biology and Genetics. Diagnostic and therapeutic recommendations are based on customized diagnostics and a case-by-case literature review. Recommendations are communicated back to the treating physician. Results: In the first year after implementation of the MTB, a total of 92 pts have been discussed in 155 case discussions during 25 MTB meetings. Referred patient cases covered the entire range of malignancies seen by the organ-specific boards including hematologic malignancies. 132 diagnostic recommendations were made in 80/92 (87%) pts, including IHC, ISH or panel sequencing with diagnostic reporting (n=96/72 pts) and exome, genome, transcriptome and/or methylome analysis (n=24/22 pts.). 43 treatment recommendations were made in 39/92 (42%) pts with an implementation rate of 47% (20/43 recommendations in 19/39 pts). Treatment recommendations mainly comprised off-label antibody and tyrosine kinase inhibitor (TKI) therapy (40%) and trial inclusions (28%). Major reasons for non-adherence to recommendations included patient will, death of pts and medical reasons. Objective responses were observed in 5/19 (26%) pts to TKI in- and off-label and antibody off-label treatments. Disease stabilization was achieved in 3/19 (16%) pts. Specifically, the use of PD-(L)1 inhibiting antibodies was suggested in 13 cases (11 off-label) and implemented in 6 cases. Here, 2/6 pts responded or exhibited stable disease upon PD-(L1) blockage. Conclusion: Implementation of a Molecular Tumor Board serves as an interdisciplinary platform for integrating comprehensive molecular data sets as predictive biomarkers in molecular guided, individualized patient care. Our experience demonstrates that individualized treatment recommendation is feasible and effective for a substantial proportion of patients in challenging clinical situations. Disclosures Claus: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Other: Travel Funding.

Description: Introduction Despite broad use of hypomethylating agents (HMAs) in MDS/AML treatment, the number of established outcome predictors is still very limited (Stomper and Lübbert, Sem Hematol 2019). One of them, the early, isolated and sometimes massive increase of platelets, is recurrently observed in patients with MDS treated with HMAs. It is not observed with non-HMA cytidine analogs such as low-dose cytarabine. In HMA-treated MDS patients, an early platelet increase is a predictor of overall and leukemia-free survival (van den Bosch et al., Leuk Res 2004; van der Helm et al., Br J Haematol 2011). HMAs induce cellular differentiation in vitro, by gene reactivation in the malignant cells. However, evidence for HMA-induced in vivo differentiation is still very limited. We hypothesized that the megakaryocytic cell lineage in MDS is a target for HMA-induced cellular maturation in vivo. Methods We systematically analyzed the bone marrow morphology of 34 higher-risk MDS patients (median age: 71.5 years, range 51-79) before and after 1 cycle of treatment with the HMA decitabine (DAC). All patients had been treated at a single center within 3 prospective clinical trials (Wijermans et al., Ann Hematol 2005; Lübbert et al., J Clin Oncol 2011). One treatment cycle consisted of 45 mg/m2 DAC per day (15 mg/m2 intravenously over 4 hours every 8 hours) for 3 consecutive days, repeated 6 weeks later. The early platelet response was evaluated after 1 cycle of DAC treatment. Based on the criteria of the International Working Group, an absolute increase in platelet count of 30x109/l or more compared to the pre-treatment count was defined as a platelet response. The histological analysis of the bone marrow specimens was performed by an experienced hematopathologist blinded to the treatment timepoints. Up to 200 megakaryocytes (MK) per sample were quantified at a magnification of 400 x using chloroacetate esterase staining. Results Thirteen of 34 patients (38%) showed a platelet response already after 1 cycle of DAC treatment, 21 (62%) did not. The median pre-treatment platelet count did not differ in patients with or without an early platelet response (median of 34x109/l in both groups, range 7-169 and 8-265, respectively). After 1 cycle of DAC treatment, patients with a platelet response had a median platelet count of 117x109/l (range 78-281), patients without this response had a median platelet count of 32 x109/l (range 4-155). Overall survival (OS) was measured from the time of early platelet response assessment after completion of 1 treatment cycle, i.e. after 6 weeks. The presence of a platelet response after 1 DAC cycle was associated with a longer OS compared to the absence of this early platelet response: median of 26.6 versus 14.0 months (p=0.04). Both pre- and post-treatment bone marrow biopsies of patients with an early platelet response showed higher numbers of MK, as well as significant differences in MK morphology compared to biopsies from patients without an early platelet response. Regarding MK numbers, increased MK density in specimens of patients with an early platelet response was observed both before (mean MK number per high power field 6.2 vs. 2.6, p=0.02) and after the application of DAC (mean MK number 10.4 vs. 3.1, p=0.01). Regarding MK maturation stage, more pre-treatment juvenile MK (on average 32.4% vs. 20.5% of all MK, p=0.03) and MK with typical myeloproliferative stigmata (present in 5/13 vs. 2/21 biopsies) were observed in patients with an early platelet response, compared to patients without this response. Regarding the induction of megakaryocytic maturation during this early treatment phase, more post-treatment "naked", mature MK nuclei indicative of active platelet shedding (on average 9.5% vs. 3.8% of all MK, p=0.01), were noted in patients with an early platelet response than in patients without an early platelet response. Conclusions This is, to the best of our knowledge, the first systematic hematopathological analysis of changes in quantitative and morphological MK features in bone marrow specimens of MDS patients during HMA treatment. DAC, which has in vitro differentiation-inducing effects on megakaryoblastic cells, induced maturation also of dysplastic MK in vivo in higher-risk MDS patients with an early platelet response to this HMA. The predictive value of an early platelet increase, a very easy-to-determine parameter, during this type of treatment is confirmed. Disclosures No relevant conflicts of interest to declare.

Description: Numerical simulations employing prognostic stable water isotopes can not only facilitate our understanding of hydrological processes and climate change but also allow for a direct comparison between isotope signals obtained from models and various archives. In the current work, we describe the performance and explore the potential of a new version of the Earth system model AWI-ESM (Alfred Wegener Institute Earth System Model), labeled AWI-ESM-2.1-wiso, in which we incorporated three isotope tracers into all relevant components of the water cycle. We present here the results of pre-industrial (PI) and mid-Holocene (MH) simulations. The model reproduces the observed PI isotope compositions in both precipitation and seawater well and captures their major differences from the MH conditions. The simulated relationship between the isotope composition in precipitation (δ18Op) and surface air temperature is very similar between the PI and MH conditions, and it is largely consistent with modern observations despite some regional model biases. The ratio of the MH–PI difference in δ18Op to the MH–PI difference in surface air temperature is comparable to proxy records over Greenland and Antarctica only when summertime air temperature is considered. An amount effect is evident over the North African monsoon domain, where a negative correlation between δ18Op and the amount of precipitation is simulated. As an example of model applications, we studied the onset and withdrawal date of the MH West African summer monsoon (WASM) using daily variables. We find that defining the WASM onset based on precipitation alone may yield erroneous results due to the substantial daily variations in precipitation, which may obscure the distinction between pre-monsoon and monsoon seasons. Combining precipitation and isotope indicators, we suggest in this work a novel method for identifying the commencement of the WASM. Moreover, we do not find an obvious difference between the MH and PI periods in terms of the mean onset of the WASM. However, an advancement in the WASM withdrawal is found in the MH compared to the PI period due to an earlier decline in insolation over the northern location of Intertropical Convergence Zone (ITCZ).

Description: In order to quantify the relative importance of individual boundary conditions and forcings, including greenhouse gases, ice sheets, and Earth's orbital parameters, on determining Last Glacial Maximum (LGM) climate, we have performed a series of LGM experiments using a state-of-the-art climate model AWI-ESM, in which different combinations of boundary conditions and forcings have been applied following the protocol of Paleoclimate Modelling Intercomparison Project phase 4 (PMIP4). In good agreement with observational proxy records, a general colder and drier climate is simulated in our full-forced LGM experiment as compared to the present-day simulation. Our simulated results from non-full-forced sensitivity simulations reveal that both the greenhouse gases and ice sheets play a major role in defining the anomalous LGM surface temperature compared to today. Decreased greenhouse gases in LGM as compared to present day leads to a non-uniform global cooling with polar amplification effect. The presence of LGM ice sheets favors a warming over the Arctic and northern Atlantic oceans in boreal winter, as well as a cooling over regions with the presence of ice sheets. The former is induced by a strengthening in the Atlantic meridional overturning circulation (AMOC) transporting more heat to high latitudes, whilst the latter is due to the increased surface albedo and elevation of ice sheets. We find that the Northern Hemisphere monsoon precipitation is influenced by the opposing effects of LGM greenhouse gases and ice sheets. Specifically, the presence of ice sheets leads to significant drying in the Northern Hemisphere monsoon regions, while a reduction in greenhouse gases results in increased monsoon rainfall. Based on our model results, continental ice sheets exert a major control on atmospheric dynamics and the variability of El Niño–Southern Oscillation (ENSO). Moreover, our analysis also implies a nonlinearity in climate response to LGM boundary conditions and forcings.

Description: Meridional atmospheric transport is an important process in the climate system and has implications for the availability of heat and moisture at high latitudes. Near-surface cold and warm temperature advection over the ocean in the context of extratropical cyclones additionally leads to important air–sea exchange. In this paper, we investigate the impact of these air–sea fluxes on the stable water isotope (SWI) composition of water vapour in the Southern Ocean’s atmospheric boundary layer. SWIs serve as a tool to trace phase change processes involved in the atmospheric water cycle and, thus, provide important insight into moist atmospheric processes associated with extratropical cyclones. Here we combine a 3-month ship-based SWI measurement data set around Antarctica with a series of regional high-resolution numerical model simulations from the isotope-enabled numerical weather prediction model COSMOiso. We objectively identify atmospheric cold and warm temperature advection associated with the cold and warm sector of extratropical cyclones, respectively, based on the air–sea temperature difference applied to the measurement and the simulation data sets. A Lagrangian composite analysis of temperature advection based on the COSMOiso simulation data is compiled to identify the main processes affecting the observed variability of the isotopic signal in marine boundary layer water vapour in the region from 35 to 70◦ S. This analysis shows that the cold and warm sectors of extratropical cyclones are associated with contrasting SWI signals. Specifically, the measurements show that the median values of δ18O and δ2H in the atmospheric water vapour are 3.8 ‰ and 27.9 ‰ higher during warm than during cold advection. The median value of the second-order isotope variable deuterium excess d, which can be used as a measure of non-equilibrium processes during phase changes, is 6.4 ‰ lower during warm than during cold advection. These characteristic isotope signals during cold and warm advection reflect the opposite air–sea fluxes associated with these large-scale transport events. The trajectory-based analysis reveals that the SWI signals in the cold sector are mainly shaped by ocean evaporation. In the warm sector, the air masses experience a net loss of moisture due to dew deposition as they are advected over the relatively colder ocean, which leads to the observed low d. We show that additionally the formation of clouds and precipitation in moist adiabatically ascending warm air parcels can decrease d in boundary layer water vapour. These findings illustrate the highly variable isotopic composition in water vapour due to contrasting air–sea interactions during cold and warm advection, respectively, induced by the circulation associated with extratropical cyclones. SWIs can thus potentially be useful as tracers for meridional air advection and other characteristics associated with the dynamics of the storm tracks over interannual timescales.

Description: Winter (October to March) precipitation δ18OP and δDP values in central Europe correlate with the winter North Atlantic Oscillation index (wNAOi), but the causal mechanisms remain poorly understood. Here we analyse the relationships between precipitation-weighted δ18OP and δDP datasets (δ18Opw and δDpw) from European GNIP and ANIP stations and the wNAOi, with a focus on isotope gradients. We demonstrate that longitudinal δ18Opw and δDpw gradients across Europe (“continental effect”) depend on the wNAOi state, with steeper gradients associated with more negative wNAOi states. Changing gradients reflect a combination of air temperature and variable amounts of precipitable water as a function of the wNAOi. The relationships between the wNAOi, δ18Opw and δDpw can provide additional information from palaeoclimate archives such as European speleothems that primarily record winter δ18Opw. Comparisons between present-day and past European longitudinal δ18O gradients inferred from Holocene speleothems suggest that atmospheric pressure configurations akin to negative wNAO modes dominated the early Holocene, whereas patterns resembling positive wNAO modes were more common in the late Holocene, possibly caused by persistent shifts in the relative locations of the Azores High and the Icelandic Low.