Academic literature on the topic 'Haematological dynamic assessment'

Since the emergence of high-throughput proteomic techniques and advances in clinical technologies, there has been a steady rise in the number of cancer-associated diagnostic, prognostic, and predictive biomarkers being identified and translated into clinical use. The characterisation of biofluids has become a core objective for many proteomic researchers in order to detect disease-associated protein biomarkers in a minimally invasive manner. The proteomes of biofluids, including serum, saliva, cerebrospinal fluid, and urine, are highly dynamic with protein abundance fluctuating depending on the physiological and/or pathophysiological context. Improvements in mass-spectrometric technologies have facilitated the in-depth characterisation of biofluid proteomes which are now considered hosts of a wide array of clinically relevant biomarkers. Promising efforts are being made in the field of biomarker diagnostics for haematologic malignancies. Several serum and urine-based biomarkers such as free light chains, β-microglobulin, and lactate dehydrogenase are quantified as part of the clinical assessment of haematological malignancies. However, novel, minimally invasive proteomic markers are required to aid diagnosis and prognosis and to monitor therapeutic response and minimal residual disease. This review focuses on biofluids as a promising source of proteomic biomarkers in haematologic malignancies and a key component of future diagnostic, prognostic, and disease-monitoring applications.

Abstract Inhibition of ataxia telangiectasia and Rad-3 related (ATR) kinase offers therapeutic promise for DNA damage response deficient tumors. In addition, ATR inhibitors may offer even broader clinical utility when combined with PARPi’s, chemo, immune or radiation therapy. Flat-fixed dosing of ATR inhibitors alone or in combination has provided clinical benefit but is associated with on target, dose limiting haematological toxicity. Strategies to refine dose selection of this class of medicine may further optimize clinical benefit. The aim of our ongoing investigation is to determine if the dose selection for clinical development of the novel ATR inhibitor ART0380 (IACS-030380) may be optimized based on the degree of PD engagement in both tumor and normal tissue from patients. To do this, we have utilized in vitro and in vivo cancer models to help us understand the dynamic and temporal response to several biomarkers of ATR inhibition and DNA damage. Once established in vitro, we selected key markers, such as γH2AX and pKAP1, to explore in vivo using doses predicted to be biologically effective in man and have shown that these are modulated following exposure to ART0380. To enable the serial assessment of PD engagement in both tumor and normal tissue, we have developed an assay in the phase 1 study of ART0380 (NCT04657068) to measure γH2AX levels in circulating tumor cells (CTC’s) and normal cells (PBMC’s). A significant advantage of this approach is that samples are taken from the same blood draw and at several timepoints following exposure to ART0380. So far, our studies have shown that in patients, who have experienced drug exposures predicted to be biologically effective, γH2AX levels in CTC’s increase by up to 20% respectively from baseline while γH2AX in PBMC’s remains unaffected. This observation may highlight that target engagement has taken place for ART0380 in the tumor without an effect in normal tissue, a phenomena perhaps explained by the pharmacokinetic profile of ART0380. The clinical study is ongoing and we continue to monitor individual patient responses, toxicity, and correlate with PD engagement in tumor and normal tissue circulating biopsies. In addition, we are now expanding our analysis into a multiplexed assay where we will measure pKAP1 as well as γH2AX to build a more detailed assessment of PD activity in patients. Updated data will be presented. Citation Format: Manish Patel, Kathleen N. Moore, Desiree Piscitello, Jayesh Majithiya, Marina Roy Luzarraga, Helen Millward, Sarah V. Holt, Melissa Johnson. A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB520.

Abstract Introduction: Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) may occur following autologous stem cell transplantation (ASCT). The molecular pathogenesis of sMDS/AML is uncertain; moreover, no suitable indicators able to define the risk of sMDS/AML development have been identified so far. A marked though variable telomere loss has been observed in hematopoietic cells following ASCT; meanwhile, shortening of telomere length has been observed to be associated with several neoplasias, including haematological malignancies. Thus, telomere dynamics has been investigated in a series of patients who received ASCT, in order to verify whether the degree of telomere loss in hematopoietic cells might be associated with the risk of sMDS/AML development. Methods: Telomere length (TL) was retrospectively evaluated in bone marrow (BM) cells from 38 lymphoma patients (M/F=24/14; median age=51 years, range 24–68) long-term survivors following ASCT and from 51 healthy donors (M/F=31/20; median age=53 years, range 18–82). Median follow-up since ASCT was 6 years (range 1–10). All patients were in continuous complete remission and displayed normal haematological values at the time of TL assessment. Among 38 autografted patients, 7 developed sMDS/AML (3 AML, 3 sMDS, 1 persistent pancitopenia with cytogenetic abnormalities), at a median of 5 years (range 1–10) following transplant. There were no significant differences in terms of demographical and clinical features not even for the amount of CD34+ve cells reinfused (median values: 5.2 vs 6.8 × 106 CD34+ cells/kg, respectively), between patients developing sMDS/AML and the remaining autografted patients. Samples for TL analysis were obtained and stored at a median of 12 months (range 6–24) before clinical development of sMDS/AML. TL was evaluated by Southern blot analysis. Results: TL of autografted patients was found to be significantly shorter compared to that of age-matched healthy donors, consistently with previous reports (see Figure 1, squares=healthy controls, circles=autografted subjects). A further TL loss was observed in all the 7 patients who subsequently developed sMDS/AML; their TL (Figure 1, black circles) was significantly shorter compared to both healthy subjects and sMDS/AML-free autografted patients (Figure 1, grey circles) (p<0.0005 and p<0.01, respectively). Conclusions. A marked telomere loss seems to be a predictive marker of the development of sMDS/AML following ASCT; TL analysis can now be considered among follow-up assays, in order to early identify patients at high-risk of sMDS/AML occurrence following autograft. Figure 1. TL of BM mononuclear cells in autografted patients vs healthy subjects Figure 1. TL of BM mononuclear cells in autografted patients vs healthy subjects

The use of immunoglobulin preparations for the postexposure prevention of tick-borne encephalitis as the main therapeutic and prophylactic agent fails to have enough high efficiency. For the postexposure prevention and treatment of tick-borne viral encephalitis the use of preparation tioloroin seems to be appropriate. Objective. To determine the expedience of the use of the preparation tiloron for the emergency prevention of tick-borne viral encephalitis and to evaluate its effectiveness in the treatment of patients with febrile and meningeal forms of this infection. Materials and Methods. The evaluation ofpost-exposure prophylaxis of tick-borne was carried out in two groups of individuals (each group was consisted of 100 cases), suffered from the suction of ticks infected by encephalitis virus. Both groups sought for medical help in the first 48 hours after the moment of the tick suction. None of the victims has not been vaccinated against the disease and had no serological markers of infection. According to existing regulations, patients in both groups received post-exposure prophylaxis antiviral tick immunoglobulin in the standard dose. Patients of the second group additionally received an interferon inducer drug tiloron. For the evaluation of the therapeutic efficacy of the drug tiloron there was executed the analysis of clinical and laboratory picture of verified tick-borne viral encephalitis in 40 patients treated at "Republican Hospital for Infectious Diseases" of the city of Syktyvkar in the period from 2010 to 2015. There were studied the dynamics of clinical symptoms, haematological and biochemical markers, CSF, certain immunological indices: CD4, CD8, CD4/CD8, IgM and IgG. For the comparative assessment of the effectiveness of treatment, all the examined patients were divided into 4 groups depending on the clinical diagnosis and ongoing taken causal treatment. Results. Among the patients received post-exposure prophylaxis with inclusion of the preparation tiloron, the disease developed significantly less often, without the formation offocal forms. The use of tiloron in combination therapy reduced the duration of main clinical manifestations in patients with febrile and meningeal forms of the disease, contributed to a more rapid rehabilitation of cerebrospinal fluid, recovery of subpopulations of T-lymphocytes. Conclusions. Immunomodulating inductor tiloron is effective in complex treatment and prevention of tick-borne viral encephalitis.

Introduction: Sickle Cell Disease (SCD) is an autosomal-recessive-genetic disorder that leads to sickling and hemolysis of red blood cells (RBCs). Acute vaso-occlusive pain crisis (VOC) is the predominant pathophysiology faced by SCD patients and the primary reason for emergency medical care. Although neutrophils have been shown to play a role in vaso-occlusion by interacting with sickle RBCs in the cremaster venules of transgenic SCD mice, the cellular, molecular and biophysical mechanisms that promote vaso-occlusion in SS patients is not completely understood. Materials and Methods: Freshly collected heparinized blood from steady-state SS patients and race matched control (AA) subjects was perfused through silicone based microfluidic flow channels with a glass bottom coated a cocktail of recombinant human P-selectin, ICAM-1 and IL-8 at a physiological wall shear stress (6 dyn cm-2). Fluorescent Abs against CD16 and CD49b were added to the blood for in-situ staining of neutrophils and platelets, respectively. Cellular interactions were recorded at a single cell-resolution using quantitative microfluidic fluorescence microscopy (qMFM)1, which allows quantitative assessment of vaso-occlusive events at an unprecedented single cell resolution2. Results: Vaso-occlusion in the microfluidic channel involved neutrophil arrest followed by nucleation of platelets on arrested neutrophils, formation of neutrophil-platelet-aggregates (NPA) and partial occlusion of the microfluidic flow channel. Remarkably, the number of platelet-neutrophil interactions and the lifetime of these interactions were several folds higher in SS patient than control AA blood. Surprisingly, preincubation with 250 ng/ml of bacterial lipopolysaccharide (LPS) led to a significant increase in the number and lifetime of platelet-neutrophil interactions in SS but not AA blood. This enhanced NPA formation in SS patient blood was attenuated to the level observed in AA blood by simultaneous blockage of P-selectin on platelets and Mac-1 on neutrophils as well as pretreatment with a small molecule inhibitor of toll-like-receptor-4 (TLR4) signaling pathway. Conclusion: Our data shows that the vaso-occlusive pathophysiology in SCD involves sequential steps of neutrophil arrest, nucleation of platelets on arrested neutrophils, formation of large NPAs and obstruction of blood flow. Platelet-neutrophil aggregation can be ameliorated by the simultaneous blockage of P-selectin on platelets and Mac-1 on neutrophils. The inflammatory milieu of SS patient blood sets a lower threshold for bacterial endotoxin induced neutrophil-platelet aggregation than control blood. The enhanced platelet-neutrophil aggregation in SS blood is dependent on activation of TLR-4 pathway. Understanding the molecular mechanism of vaso-occlusion will enable the development of therapeutics to prevent VOC in SS patients. References: 1 Jimenez MA, Tutuncuoglu E, Barge S, Novelli EM, Sundd P. Quantitative microfluidic fluorescence microscopy to study vaso-occlusion in sickle cell disease. Haematologica. 2015;100(10):e390-e393. doi:10.3324/haematol.2015.126631. 2 Sundd, P. et al. Quantitative dynamic footprinting microscopy reveals mechanisms of neutrophil rolling. Nat Methods7, 821-824, doi:10.1038/nmeth.1508 (2010). Disclosures Kato: Mast Therapeutics: Consultancy; Bayer: Research Funding.

Abstract Abstract 3234 Background. Wilms' tumor 1 (WT1) gene encodes a transcriptional factor involved in normal cellular development. It is over-expressed in most cases of acute myeloid leukemia (AML). Aim. To estimate the usefulness of WT1 expression quantitative assessment for monitoring MRD and for relapse prediction in acute lymphoblastic leukemia (ALL) patients. Methods. Real time quantitative RT-PCR was made according to the Europe Against Cancer Protocol. WT1 transcript level was determined in bone marrow (BM) samples of adult patients with AML (except acute promyelocytic leukemia) and ALL. We examined the samples of 77 patients with AML and 34 patients with ALL at diagnosis. We also analyzed 190 specimens of AML patients and 150 specimens of ALL patients during follow-up. The obtained WT1 copy numbers were normalized with respect to the β-GUS transcripts. Results. The median value of WT1 level at diagnosis was 581 (range 1,0-8462) in AML patients and 1161 (range 1,5-14879) in ALL patients (no statistical difference in Student's t-test). The median value of WT1 level of patients in complete remission was 4,3 (range 1,1-9,7) for AML and 5,2 (range 1,0-16,8) for ALL. At diagnosis 84% of AML patients and 61% of ALL patients showed the expression of WT1 one log higher than the median values in complete remission. In 7 assessed T-ALL patients the over-expression of WT1 at diagnosis was observed (the median value 1188, range 206–6972). The B-ALL patients with high WT1 expression at diagnosis (range 441–14879) and the B-ALL patients with low WT1 expression at diagnosis (range 1,5-63) differ in fusion genes. There were 2 patients with BCR-ABL (one p190 (7%) and one p210) within the B-ALL subgroup with high WT1 expression at diagnosis whereas within the B-ALL patients with low WT1 expression at diagnosis were 7 ones (6 patients with p190 (46%) and 1 with p210) (7% versus 46%, p=0,033 by Fisher Exact test). In the patients bearing a fusion gene transcript we performed a simultaneous analysis of WT1 and fusion gene transcript expression: in 19 patients with AML (8 AML1-ETO, 2 CBFβ-MYH11, 2 BCR-ABL, 1 DEK-CAN, 1 MLL-AF6, 1 MLL-AF9, 4 MLL duplications) and in 15 patients with ALL (9 BCR-ABL, 3 MLL-AF4, 1 MLL-ENL, 2 E2A-PBX1). It was found the parallelism between the dynamics of WT1 level and fusion-gene transcript level during follow-up. The haematological relapse was correlated with the increase of WT1 expression: 8 AML patients had a median of 1545 (range 140–2578) and for 6 ALL patients a median value was 1050 (range 31–2665) in relapse (no statistical difference in Mann-Whitney U test). We observed the increase of WT1 level was occurred earlier than the relapse was stated for AML patients and for ALL patients with high WT1 expression at diagnosis. Conclusion. The level of WT1 expression may be used as additional nonspecific marker for MRD detection and for imminent relapse prediction during follow-up in patients without additional molecular markers in ALL with high WT1 expression at diagnosis. Disclosures: No relevant conflicts of interest to declare.

Introduction Telomere length is shortened in patients with idiopathic aplastic anemia (AA) and other bone marrow failure disorders (BMFD) and predicts risk of clonal evolution (CE), relapse and overall survival (OS). Telomereopathies predominantly cause bone marrow failure, are multi-systemic disorders with variable penetrance, and may involve inter-play of other factors in disease manifestation and organ affliction. Telomere length (TL) in AA and other hypocellular BMFD, independent of mutations in telomere genes (TGC), has not been studied as a scoring tool, as well predicting the risk of affliction of other organ/systems in these disorders. We systematically review a large cohort of 472 patients in a single centre with AA/BMFD using TL and TGC analysis as a discriminator, to study risk of CE and OS, manifesting with liver/lung and skin complications, cancer predisposition and likelihood of a family member presenting with cytopenias. Methods We screened 1060 consecutive patients at a single centre from the years 2011-18, with AA or unexplained cytopenias for telomere length (TL) analysis using a multiplex qPCR methodology as described by Cawthon et al. 472 (44.5%) patients had TL less than the 25th centile, of whom 243 had <1st centile, 122 had <10th and 107 had TL between the 10-25th centile. These 472 patients underwent TGC mutation analysis on a customised panel of 12 TGC genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, RTEL1, CTC1, USB1, WRAP53, ACD and PARN) using deeply parallel sequencing and were studied alongside their clinical parameters, disease progression, treatments and OS. Results Table attached. The median age and gender across the 3 cohorts studied (TL 10-25th centile, <10th centile and <1st centile) were comparable, with a median age of 43 for the entire cohort. 127 (26.9%) of patients were detected to have a total of 142 mutation in the TGC. A third of patients with BMFD and TL<1st centile had a TGC mutation, but the prevalence did not statistically differ with the other cohorts of TL <10th centile and between 10-25th centile. Patients with TL<1st centile can have mutations in 2 telomere genes, but this is less frequently seen when TL<10th centile and not seen in the cohort with TL between 10-25th centile. TL does not correlate with the manifestation and presence of liver, respiratory and skin problems of telomere disease. TL in BMFD does not associate with increased predisposition to cancer, as their presence was not statistically significant across the 3 groups. Disease manifestation with bone marrow failure, haematological indices, need for blood transfusions, presence of a PNH clone and karyotypic abnormalities, including complex and monosomal karyotype were not dissimilar across the 3 TL cohorts. Not surprisingly, there were more family members with features of cytopenias and BMFD, on screening of patients with a confirmed TGC mutation. TL did not predict a difference in treatment strategies used across the 3 groups, although more patients with a TGC mutation received anabolic steroids. The risk of clonal evolution to PNH or MDS/AML and overall survival was again similar across the 3 TL cohorts with an OS of 93% at 1078 days follow-up for the entire cohort. Conclusion TL can reliably be used as a screening tool to investigate patients for further TGC mutation analysis in patients with AA or BMFD. Heterozygous state mutations in TERT are the commonest, and can be associated with mutations in other TGC genes, particularly RTEL1 and TERC. This may cause a compounding factor in shortening the TL further. However, TL<1st centile does not associate with more severe cytopenias (BMFD) or predict more multi-system manifestation or increased cancer pre-disposition. Indeed, in our cohort it failed to show an increased risk of clonal evolution or decreased OS. Telomere biology is a dynamic process and assessments at different time points, from diagnosis to the time point of progression and transformation, may yield better understanding in pathogenesis of BMFD. TL and TGC mutation analysis in a single centre study from 2011-18. Table Disclosures Kizilors: Incyte biosciences: Research Funding. Mufti:Celgene: Consultancy, Research Funding.

Abstract Sickle cell disease (SCD) is caused by a mutation in the β-globin gene that produces abnormal hemoglobin (HbS), leading to clinical manifestations such as painful vaso-occlusive crises, anemia, and shortened lifespan due to organ damage. SAR445136 (BIVV003) is a zinc finger nuclease ex vivo gene editing therapy in Ph1/2 clinical development for treatment of SCD (PRECIZN-1; NCT03653247). SAR445136 targets the erythroid specific enhancer (ESE) region of the transcription factor BCL11A, which controls the switch from fetal hemoglobin (HbF) to adult forms (HbA in healthy subjects and HbS in SCD subjects). By expressing increased levels of HbF, SAR445136-edited cell progeny exhibit reduced HbS polymerization which is expected to ameliorate RBC sickling and the SCD phenotype. To better understand the dynamics and variability of clinical response to SAR445136, we developed a Quantitative Systems Pharmacology (QSP) model of SCD to describe both key elements of disease biology and the mechanism of action of SAR445136. The QSP approach provides a cohesive representation of the key disease processes in SCD by leveraging additional data sources (e.g. published and internal, clinical and preclinical) to complement data from ongoing clinical trials. The QSP model is applied to help assess mechanism-related questions, such as the observed inter-patient variability with respect to SAR445136 cellular dose, indels, and induced HbF and F cells. To explore the clinical factors that could influence the response to SAR445136, we centered the structure of the QSP model on a realistic representation of erythropoiesis that can describe hematopoietic stem and progenitor cells and erythroid progenitors in the bone marrow and the periphery, including regulation by cytokines EPO, IL-3, and stem cell factor (SCF) (Figure 1A). We first confirmed that the model recapitulates published bone marrow aspirate and blood cell sorting data from healthy individuals (Figure 1B). Next, we modified the model to describe stress erythropoiesis in SCD by incorporating published data on clinical, natural history, and in vitro assessments of SCD progenitor cells, and the resulting reticulocyte and erythrocyte levels (Figure 1B). The updated model describes key features of the SCD disease state, including reduced lifespan of HbS erythrocytes, elevated plasma reticulocytes (Steinberg MH, et al. Blood. 1997;89: 1078-1088), and altered levels of erythroid progenitors (Hoss SE, et al. Haematologica. 2020 Aug 27. doi: 10.3324/haematol.2020.265462) and cytokines, as well as the protective effects of endogenous HbF. Finally, we applied the SCD erythropoiesis model to describe the mechanism of action of SAR445136 by representing ablation followed by the introduction of CD34+ cells containing indels with enhanced HbF expression. The model captures the SAR445136 clinical data and simulates the therapeutic effects of increased total Hb and increased proportion of HbF due to the progeny of SAR445136 cells (Figure 1C). The model provides a quantitative framework for evaluating the effects of treatment parameters including cellular dose, mobilization and engraftment variability, indel quality (i.e., variable editing and HbF expression in erythroid progeny [Lessard S, et al. Blood. 2019;134(Supplement_1):97]) and assessing the pan-cellularity of the response. Due to its mechanistic structure, the model also enables exploration of inter-patient variability in terms of cytokine effects on erythropoiesis. In summary, the QSP model is a computational tool to provide mechanistic insight into emerging SAR445136 clinical data in the context of current understanding of SCD disease biology. The model is intended to provide both qualitative and quantitative support for the clinical development and competitive differentiation of SAR445136. For future development, the model can be expanded to include additional data representing the SCD bone marrow microenvironment to further explore patient heterogeneity. Figure 1 Figure 1. Disclosures Kaddi: Sanofi: Current Employment. Holz: Sanofi: Current Employment. Tao: Sanofi: Current Employment. Galeon: Sanofi: Current Employment. Reiner: Sanofi: Current Employment. Rendo: Sanofi: Current Employment, Other: May hold shares and/or stock options . Zaph: Sanofi: Current Employment.

Abstract The JAK1/2 inhibitor ruxolitinib (RUX) is effective in decreasing symptomatic splenomegaly, and constitutional symptoms in patients with myelofibrosis (MF). Long-term data suggest that treatment with RUX is associated with a survival benefit, and may delay/reverse bone marrow fibrosis. Further, a ≥ 20% reduction in JAK2 V617F allele burden with RUX has been described (Vannucchi et al. Blood. 2012). Yet, many uncertainties surrounding the full clinical potential of RUX persist. The conceivable disease-modifying impact including the achievement of a JAK2 V617F molecular remission under sustained JAK1/JAK2 inhibition in a patient with primary myelofibrosis (PMF) is presented. Patient and Methods: the diagnosis of JAK2 V617F-positive PMF according to the 2008 WHO criteria was made in a 50-years old caucasian male in February 2009. On the first consultation in November, 2009, he complained of fatigue and night sweats. Spleen was 12 cm below costal margin by palpation. Laboratory results were: Hb 153 g/L, WBC 18.9 x109/L, platelets 268 x109/L, peripheral blasts 2%, a leucoerythroblastic blood picture, LDH 10.6 µkat/L [2.8x upper limit of normal]. With an IPSS of 2 points (night sweats and peripheral blasts > 1%) the IPSS risk category for survival was intermediate-II. After signing informed consent, the patient was included in the phase 3, multicenter COMFORT-II trial and randomized to treatment with RUX at a dose of 20mg bid based on platelets count. By week (w) 4, the dose was increased to 25mg bid per protocol (< 40% reduction is palpable spleen length). For efficacy and safety evaluations, serial clinical, spleen volume [by magnetic resonance imaging (MRI)], blood picture, blood chemistry, bone marrow trephine biopsy, and JAK2 V617F allele burden from both peripheral blood samples as well as bone marrow assessments were conducted. The histology of the biopsies was evaluated according to the WHO criteria by experienced pathologists (Table). The JAK2 V617F allele burden was measured from blood samples using allele-specific oligonucleotide quantitative real-time polymerase chain reaction (qPCR) with a dynamic detection range from 0.1 to100% mutated allele (Lange et al. Haematologica 2013) and from bone marrow samples via qPCR followed by pyrosequencing for determining the allelic burden with a sensitivity of 5% of mutated DNA. If necessary, blocking of the non-mutated allele for sensitivity enhancement from 5% up to 0,001% of mutated DNA was done (Siebolts et al. J Clin Pathol 2010). Results: After a follow-up of 240 weeks, treatment with 25mg bid is ongoing. No dose modification/interruption because of adverse events was required. Clinical response was rapid with a 52% reduction in baseline spleen volume from 3.77 L to 1.8 L and improvement in constitutional symptoms at w 12. This was followed by a further decline in spleen volume. By w 216, spleen volume was 0.5 L which corresponded to 85.5% reduction from baseline (Figure). WBC and LDH normalized by w 24 and w 84 respectively. Histologic improvement in marrow cellularity, megakaryocytic, and granulocytic lineages was first evident at w 126 with further reversal of MF-related abnormalities including marrow fibrosis by w 216 (Table). JAK2 V617F allele burden of < 10% in a peripheral blood sample and < 1% in the bone marrow were first documented at w 108 and w 132 respectively. As of w 216, an allele burden <1% was sustained in both blood and marrow samples (Figure). Conclusions: The rapid symptomatic improvement with ruxolitinib could be followed by a considerable MF-modifying response with the potential to alter the course of disease and prognosis. Unlike targeted therapy for chronic myeloid leukemia, ruxolitinib-delivered molecular and histologic remissions could be gradual, and progressive. Whether such deep long-term responses are dose-dependent is not yet known. Thus, the full potential of a sustained JAK1/JAK2 inhibition needs to be elucidated by carefully analyzing the possible correlation between dose, short-term spleen responses and long-term molecular and histologic responses; both in retro- and prospective studies. Changes in marrow histology and spleen volume under ruxolitinib Table 1. Marrow Cellularity % Megakaryocyte Granulocytic ProliferationG:E Marrow Fibrosis (EUMNET) Spleen volume (L)ProliferationAtypiaBaseline100%+++++++++8:1PMF13.8Week 4880%+++++++5:1PMF21.2Week 12630%+++-1:3PMF10.6Week 21640%-+-3:1PMF00.5 Figure 1 Figure 1. Disclosures Al-Ali: Novartis: Honoraria, Research Funding. Lange:Novartis: Consultancy, Honoraria, Research Funding. Prashanth:Novartis: Employment. Niederwieser:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Introduction Survivorship has increased significantly in cancer patients with the advent of novel therapies. However, this improvement has been at the cost of higher rates of cardiotoxicity. Cardiovascular disease has become the main cause of death or cancer therapy interruption in many of these patients. The need for specialist services to deal with these emerging problems has led to global development of many Cardio-Oncology services. Objectives To describe how a Cardio-Oncology service has grown and evolved over a 10 year period in response to the constantly changing oncological landscape. Methods and results Prospective, single center, study of cancer patients referred to our service from February 2011 to December 2021. 1499 patients were referred to the service. Mean age was 60 years (SD: 15) and 60% were female. CV risk factors including hypertension (32%), dyslipidaemia (12%) and diabetes (6%) were common. The most frequent primary tumour location was breast (427 patients, 28%), followed by haematological (151, 10%) and gastrointestinal tract (114, 8%). The average number of referrals per month increased 6 fold from 2011, from 3.3 patients per month to 21 patients in 2021. In the last 5 years there was a 10 fold increase in the number of outpatient consultations from 189 consultations in 2016 to 1988 consultations in 2021. The most frequent reason for referral was pre-treatment assessment (39%), followed by cancer therapy related cardiac dysfunction (CTRCD) (33%) and other acute cancer therapy related CV diseases (CTR-CVDs) (22%). From 2011 to 2017 CTRCD was the main CTR-CVD due to anthracycline and trastuzumab. This ratio changed in 2018 when other CTR-CVDs became the most frequent referral reason following pre-treatment assessment. Patients referred to our service were or had been, mostly under medical therapy alone or in combination with surgery or radiotherapy (1058 patients, 70%), anthracyclines being the predominant treatment (435 patients, 40%). Targeted therapies and immune check point inhibitors became more popular in the last two years (2020–2021). A multivariable logistic regression model was built to assess the relation between the medical treatment and the prevalence of CTRCD vs other CTR-CVDs. Anthracyclines and HER2 therapy are independently associated with a higher prevalence of CTRCD while tyrosine kinase inhibitors and immune checkpoint inhibitors increase the risk of other CTR-CVDs e.g. hypertension, arrhythmias and myocarditis. Conclusions Cardio-Oncology has rapidly evolved from its origin as a subspecialty of heart failure medicine, to a diverse medical specialty that encompasses many different domains of cardiology. Future cardio-oncology services should reflect this and be dynamic, collaborating with cardiac sub-specialities as necessary. Provision of cardio-oncology services requires a considerable knowledge and understanding of the ever growing and changing oncology therapies. Funding Acknowledgement Type of funding sources: None.