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Summary Background BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. Methods In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov , NCT02773849 . Findings Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3–4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. Interpretation Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. Funding FKD Therapies Oy.

BACKGROUND CONTEXT Although autogenous iliac crest bone graft (AICBG) is considered the gold-standard graft material for spinal fusion, new bone substitutes are being developed to avoid associated complications and disadvantages. By combining autologous bone marrow mesenchymal stromal cells (MSCs) expanded ex vivo and allogenic cancellous bone graft, we obtain a tissue-engineered product that is osteoconductive and potentially more osteogenic and osteoinductive than AICBG, owing to the higher concentration of MSCs. PURPOSE This study aimed to evaluate the feasibility and safety of implanting a tissue-engineered product consisting of expanded bone marrow MSCs loaded onto allograft bone (MSC+allograft) for spinal fusion in degenerative spine disease, as well as to assess its clinical and radiological efficacy. STUDY DESIGN/SETTING A prospective, multicenter, open-label, blinded-reader, randomized, parallel, single-dose phase I-II clinical trial. PATIENT SAMPLE A total of 73 adult patients from 5 hospitals, with Meyerding grade I-II L4–L5 degenerative spondylolisthesis and/or with L4–L5 degenerative disc disease who underwent spinal fusion through transforaminal lumbar interbody fusion (TLIF). OUTCOME MEASURES Spinal fusion was assessed by plain X-ray at 3, 6, and 12 months and by computed tomography (CT) at 6 and 12 months post-treatment. An independent radiologist performed blinded assessments of all images. Clinical outcomes were measured as change from baseline value: visual analog scale for lumbar and sciatic pain at 12 days, 3, 6, and 12 months posttreatment, and Oswestry Disability Index and Short Form-36 at 3, 6, and 12 months posttreatment. METHODS Patients who underwent L4–L5 TLIF were randomized for posterior graft type only, and received either MSC+allograft (the tissue-engineered product, group A) or AICBG (standard graft material, group B). Standard graft material was used for anterior fusion in all patients. Feasibility was measured primarily as the percentage of randomized patients who underwent surgery in each treatment group. Safety was assessed by analyzing treatment-emergent adverse events (AEs) for the full experimental phase and appraising their relationship to the experimental treatment. Outcome measures, both radiological and clinical, were compared between the groups. RESULTS Seventy-three patients were randomized in this study, 36 from the MSC+allograft group and 37 from the AICBG group, and 65 were surgically treated (31 group A, 34 group B). Demographic and comorbidity data showed no difference between groups. Most patients were diagnosed with grade I or II degenerative spondylolisthesis. MSC+allograft was successfully implanted in 86.1% of randomized group A patients. Most patients suffered treatment-emergent AEs during the study (88.2% in group A and 97.1% in group B), none related to the experimental treatment. X-ray-based rates of posterior spinal fusion were significantly higher for the experimental group at 6 months (p=.012) and 12 months (p=.0003). CT-based posterior fusion rates were significantly higher for MSC+allograft at 6 months (92.3% vs 45.7%; p=.0001) and higher, but not significantly, at 12 months (76.5% vs 65.7%; p=.073). CT-based complete response (defined as the presence of both posterior intertransverse fusion and anterior interbody fusion) was significantly higher at 6 months for MSC+allograft than for AICBG (70.6% vs 40%; p=.0038), and remained so at 12 months (70.6% vs 51.4%; p=.023). Clinical results including patient-reported outcomes improved postsurgery, although there were no differences between groups. CONCLUSIONS Compared with the current gold standard, our experimental treatment achieved a higher rate of posterior spinal fusion and radiographic complete response to treatment at 6 and 12 months after surgery. The treatment clearly improved patient quality of life and decreased pain and disability at rates similar to those for the control arm. The safety profile of the tissue-engineered product was also similar to that for the standard material, and no AEs were linked to the product. Procedural AEs did not increase as a result of BM aspiration. The use of expanded bone marrow MSCs combined with cancellous allograft is a feasible and effective technique for spinal fusion, with no product-related AEs found in our study.

Background aims: Spinal cord injury (SCI) represents a devastating condition leading to severe disability related to motor, sensory and autonomic dysfunction. Stem cell transplantation is considered a potential emerging therapy to stimulate neuroplastic and neuroregenerative processes after SCI. In this clinical trial, the authors investigated the safety and clinical recovery effects of intrathecal infusion of expanded Wharton jelly mesenchymal stromal cells (WJ-MSCs) in chronic complete SCI patients. Methods: The authors designed a randomized, double-blind, crossover, placebo-controlled, phase 1/2a clinical trial (NCT03003364). Participants were 10 patients (7 males, 3 females, age range, 25-47 years) with chronic complete SCI (American Spinal Injury Association A) at dorsal level (T3-11). Patients were randomly assigned to receive a single dose of intrathecal ex vivo-expanded WJ-MSCs (10 x 10(6) cells) from human umbilical cord or placebo and were then switched to the other arm at 6 months. Clinical evaluation (American Spinal Injury Association impairment scale motor and sensory score, spasticity, neuropathic pain, electrical perception and pain thresholds), lower limb motor evoked potentials (MEPs) and sensory evoked potentials (SEPs), Spinal Cord Independence Measure and World Health Organization Quality of Life Brief Version were assessed at baseline, 1 month, 3 months and 6 months after each intervention. Urodynamic studies and urinary-specific quality of life (Qualiveen questionnaire) as well as anorectal manometry, functional assessment of bowel dysfunction (Rome III diagnostic questionnaire) and severity of fecal incontinence (Wexner score) were conducted at baseline and at 6 months after each intervention. Results: Intrathecal transplantation of WJ-MSCs was considered safe, with no significant side effects. Following MSC infusion, the authors found significant improvement in pinprick sensation in the dermatomes below the level of injury compared with placebo. Other clinically relevant effects, such as an increase in bladder maximum capacity and compliance and a decrease in bladder neurogenic hyperactivity and external sphincter dyssynergy, were observed only at the individual level. No changes in motor function, spasticity, MEPs, SEPs, bowel function, quality of life or independence measures were observed. Conclusions: Intrathecal transplantation of human umbilical cord-derived WJ-MSCs is a safe intervention. A single intrathecal infusion of WJ-MSCs in patients with chronic complete SCI induced sensory improvement in the segments adjacent to the injury site. (C) 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

BACKGROUND: Current treatments for several corneal lesions show limited efficacy. Here we report the clinical evaluation of the efficacy of a novel eye drop preparation produced in a public cord blood (CB) bank. MATERIALS AND METHODS: In a multicentre, retrospective, consecutive case study we evaluated 33 patients (46 eyes) unresponsive to conventional treatments who required urgent intervention. The patients were given allogeneic eye drops obtained from cord blood platelet lysate (CBED) to treat severe ocular surface lesions under a compassionate use protocol. The CBED were prepared from CB units donated for haematopoietic stem cell transplantation that did not contain the minimum stem cell dose required for this use. Patients were grouped by acute conditions (neurotrophic ulcers: group I; other corneal ulcers: group II; corneal burns: group III), and chronic conditions (ocular graft-versus-host disease: group IV; severe dry eye syndrome: group V). The patients received one or two drops of the product to the affected eye four to six times per day for 19 days. A further 19-day cycle of treatment could be repeated according to the initial clinical response. RESULTS: Patients received a median of 19 CBED vials (interquartile range 19–57, range 19–442) to complete the therapy. Group I–II–III patients showed full and partial ulcer recovery in 25 (78%) and six (19%) eyes respectively. One eye (3%) did not respond to treatment. For groups IV–V improvement was reported for 12 (85%) eyes and lesions worsened on treatment in both eyes (15%) of one patient. No severe adverse events were directly attributed to CBED. DISCUSSION: Promptly available CBED resulted in a well-tolerated allogeneic treatment that showed evidence of efficacy in this cohort of patients. These positive results support further studies on CBED from platelet lysate as a novel product of CB banks. A prospective clinical trial in neurotrophic keratitis (NCT03084861) is ongoing to confirm these preliminary data.

BACKGROUND: There are many advantages to using cord blood (CB) as a source of therapeutic platelet and plasma derivatives for regenerative medicine. These include availability, universal use, young donor source, and virally safe biological material, rich in tissue regenerative factors. MATERIALS AND METHODS: We aimed to validate a bioprocess design for the production of cord blood-derived platelet concentrates (CBPC) in a public Cord Blood Bank (CBB). CBPC was defined as a product of 10±5 mL, 1,000±200×10(9)/L total platelets, free of erythrocytes and leukocytes. A total of 300 CB units were centrifuged in two steps to enrich for platelets, in compliance with Good Manufacturing Practice. The samples were tested for the degree of platelet activation present, and the levels of growth factor were analysed to evaluate their potential function. CBPC were then activated after thawing with 10% calcium gluconate to generate platelet gels (CBPG) to treat patients with diabetic foot ulcers. RESULTS: After processing, 84% of the products fulfilled the acceptance criteria. Final products contained 1,017±149×10(6) platelets/mL in 10±3mL of plasma. Platelet recovery was 50±9%. The methods described here ensure depletion of white and red blood cells down to a residual concentration of 0.2±0.1×10(6)/mL and 0.03±0.02×10(6)/mL, respectively. Platelets showed low levels of activation during processing, but were significantly activated after thawing, as indicated by an increase in CD62p expression. The growth factors EGF, VEGF, bFGF, PDGF AB/BB and TGF-β1 were at concentrations of 1,706±123 pg/mL; 1,602±227 pg/mL; 314±26 pg/mL; 30±1.5 ng/mL; 24±2 ng/mL (mean±standard error of mean), respectively. For clinical evaluation, a total of 21 CBPG were applied in 3 patients, with no reported adverse events and improvement of ulcers in all of them. DISCUSSION: We designed and validated a highly reproducible, closed system method to manufacture high quality CBPC suitable for clinical applications using CB units not suitable for transplantation in a public CBB.

Pseudoarthrosis is a relatively frequent complication of fractures, in which the lack of mechanical stability and biological stimuli results in the failure of bone union, most frequently in humerus and tibia. Treatment of recalcitrant pseudoarthrosis relies on the achievement of satisfactory mechanical stability combined with adequate local biology. Herein we present two cases of atrophic pseudoarthrosis that received a tissue-engineering product (TEP) composed of autologous bone marrow-derived mesenchymal stromal cells (BM-MSC) combined with deantigenized trabecular bone particles from a tissue bank. The feasibility of the treatment and osteogenic potential of the cell-based medicine was first demonstrated in an ovine model of critical size segmental tibial defect. Clinical-grade autologous BM-MSC were produced following a good manufacturing practice-compliant bioprocess. Results were successful in one case, with pseudoarthrosis resolution, and inconclusive in the other one. The first patient presented atrophic pseudoarthrosis of the humeral diaphysis and was treated with osteosynthesis and TEP resulting in satisfactory consolidation at month 6. The second case presented a recalcitrant pseudoarthrosis of the proximal tibia and the Masquelet technique was followed before filling the defect with the TEP. This patient presented a neuropathic pain syndrome unrelated to the treatment that forced the amputation of the extremity 3 months later. In this case, the histological analysis of the tissue formed at the defect site provided evidence of neovascularization but no overt bone remodelling activity. It is concluded that the use of expanded autologous BM-MSC to treat pseudoarthrosis was demonstrated to be feasible and safe, provided that no clinical complications were reported, and early signs of effectiveness were observed. Copyright © 2016 John Wiley & Sons, Ltd.

Background: Cellular therapies have shown encouraging results in the treatment of chronic osteoarthritis.(OA). Herein, we present the final results of a phase I-II clinical trial assessing the feasibility, safety and efficacy of ex vivo expanded autologous bone marrow Mesenchymal Stromal Cells (MSC, XCEL-M-ALPHA), infused intra-articularly, in patients with knee OA. Methods: Fifteen patients (median age = 52 years) with grade II(9) or III(6) gonarthrosis (Kellgren & Lawrence classification) and chronic pain were treated with an intra-articular infusion of 40.9 x 10(6) +/- 0.4 x 10(6) MSCin a phaseI-IIprospective, open-label, single-dose, single-arm clinical trial. Endpoints were safety and tolerability. Efficacy was measured by the Visual Analogue Scale for pain, algofunctional Health Assessment Questionnaire, Quality of Life (QoL) SF-36 questionnaire, Lequesne functional index and WOMAC score. Cartilage integrity was assessed by Magnetic Resonance Imaging and quantitative T2-mapping at 0, 6 and 12 months. Results: The cell-based product was well tolerated with few reported Adverse Events (mild arthralgia and low back pain). There was a relevant decrease in the intensity of pain since day 8 after the infusion, that was maintained after 12 months. The SF-36 QoL test showed improvement of parameters including bodily pain, role physical and physical functioning at month 12. The health assessment questionnaire revealed a significant decrease of incapacity. Moreover, T2 mapping showed signs of cartilage regeneration in all patients at 12 months post-treatment. Conclusions: Single intra-articular infusion of XCEL-M-ALPHA is a safe and well-tolerated cell-based product, associated with a long-lasting amelioration of pain, improvement of QoL (up to four years), and signs of cartilage repair. (C) 2015 Elsevier B.V. All rights reserved.

BACKGROUND CONTEXT Spinal fusion is a widely used surgical technique for a great variety of spine pathologies. Spinal fusion using the patient's iliac crest is the standard surgical technique, although it is associated with a relevant percentage of failures and local morbidity of the bone donor area. PURPOSE The main objective of this clinical trial was to evaluate the feasibility, safety, and efficacy of implantation of a scaffold of heterologous human cancellous bone tissue seeded with autologous bone marrow mesenchymal cells expanded ex vivo (XCEL-MT-OSTEO-ALPHA) and to compare the resulting intervertebral fusion as evaluated by radiography and computed tomography (CT) with that obtained in patients who received autologous iliac crest graft. STUDY DESIGN/SETTING Multicenter, prospective, open-label, randomized, parallel and single-dose phase I-II study (EudraCT No.2010-023999-12; NCT01552707). PATIENT SAMPLE Sixty-five patients from 5 centers (mean age, 61.05 years; 65.6% female) with degenerative spondylolisthesis (79.4%) and/or disc disease at L4-L5. OUTCOME MEASURES Adverse events were recorded and fusion was assessed by radiography (3, 6, and 12 months) and CT (6 and 12 months). Bone fusion status was evaluated according to previously established qualitative criteria by a radiologist who was blind to treatment allocation. METHODS Patients underwent instrumented circumferential fusion at L4-L5; transforaminal lumbar interbody fusion (TLIF) was performed using an intersomatic cage filled with autologous iliac crest graft, and intertransverse fusion consisted of local bone graft on the TLIF side and randomly assigned XCEL-MT-OSTEO-ALPHA (Group A, treatment) or autologous iliac crest graft (Group B, control) on the contralateral side.Patients underwent follow-up for 1 year. RESULTS Groups A and B comprised 31 and 34 patients, respectively. There were no significant differences in preoperative variables between groups, and no serious adverse reactions were associated with the product. Compared with controls the treatment group showed a significantly higher rate of intertransverse fusion as determined by radiography at 3 (85.7% vs 56.3%), 6 (81.5% vs 48.3%), and 12 months (96.3% vs 51.7%) and by CT at 6 months (96.3% vs 54.8%). One year after surgery the intertransverse fusion rate was higher in the treatment than the control group (86.2% vs 66.7%), although this difference was not significant. CONCLUSIONS XCEL-MT-OSTEO-ALPHA is a viable and safe product for use in lumbar fusion surgery. Radiological fusion rates in the area in which the product was applied were significantly higher than those obtained with autologous iliac crest graft. FDA DEVICE/DRUG STATUS XCEL-MT-OSTEO-ALPHA (Not approved for this indication)

Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid(®) Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581 × 10(9)/L and 411 × 10(9)/L before and after starting hydroxycarbamide + anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400 × 10(9)/L increased from 33 (21.6%) to 74 (48.4%; P

Objective To ascertain the role of patient age as an influencing factor in the pharmacokinetics of anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). Method This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. Results A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. Conclusions To conclude, the differences observed in anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.

EXELS is an ongoing phase IV non-interventional study; 3643 high-risk patients with essential thrombocythemia (ET) were recruited across 13 European countries. We report patient characteristics and cytoreductive treatment patterns of ET across Europe. Hydroxycarbamide (HC; 64.3%) and anagrelide (22.0%) were the two main cytoreductive treatments prescribed. The proportions of patients taking either HC or anagrelide varied across countries, as did the number of patients receiving anti-aggregatory therapy in addition to cytoreductive treatment. This real-world evidence demonstrates that, generally, treatment patterns of ET across Europe adhere to expert recommendations, with some notable variations between countries.

Background Gonarthrosis is the most common cause of pain and disability in middle-aged and elderly people [1,2]. The lack of long-lasting effective treatments for repairing degenerated articular cartilage has spurred research into novel cell-based therapies aiming at reducing pain, slowing the degeneration of cartilage and, ultimately, reverting the natural history of osteoarthritis (OA) [3]. Herein we report the development of a mesenchymal stromal cell (MSC)-based therapy, from conception up to completion of a Phase I/IIa prospective, open-label, single-dose, single-arm clinical trial.

Abstract 2842 Background: As some patients (pts) with essential thrombocythemia (ET) may discontinue their cytoreductive treatment because of drug intolerance/inefficacy, combinations of drugs with different activity/tolerability patterns are being utilized in clinical practice. Objectives: To evaluate the clinical relevance and patterns of cytoreductive combination treatment in ET in Evaluation of Xagrid™ Efficacy and Long-term Safety (EXELS), an observational study in 3643 European pts with high-risk ET. Patients and Methods: Data on pts receiving cytoreductive treatments in combination for ≥30 days (COMB) were collected from a planned data cut in September 2011. This timepoint was 2.5 years after enrollment completed. Results: COMB was recorded in 347 pts (9.5%), the vast majority (87.6%) of whom received anagrelide + hydroxycarbamide (ANA+HC). Other combinations were anagrelide + interferon-α (ANA+IFN), anagrelide + pipobroman (ANA+PIPO; Table). Six patients also received anagrelide + other drugs (ANA+OTH). In 333 pts, the initial drug was HC (n=167; 50.2%), ANA (n=138; 41.4%), IFN (n=14; 4.2%), PIPO (n=9; 2.7%), or OTH (n=5; 1.5%), while the added drug was ANA (n=195; 58.6%), HC (n=123; 36.9%), IFN (n=12; 3.6%), PIPO (n=2; 0.6%), or OTH (n=1; 0.3%). Fourteen pts started ANA+HC concomitantly. The median duration of monotherapy treatment before COMB start was 139 months for HC, 53 months for ANA, 71 months for IFN, and 237 months for PIPO. In pts receiving ANA+HC, the median weekly dose of the initial drug, both before and during COMB, was 10.5 mg for ANA and 7.0 g for HC, while the median weekly dose of the added drug during COMB was 7.0 mg for ANA and 3.5 g for HC. In these pts, the median platelet count ≤6 months before COMB start, during COMB (first test), and during COMB (last test) was 581, 411, and 434 ×109/L, respectively (with counts ≤600 ×109/L in 52.9%, 79.2%, and 77% of cases, respectively); the median white blood cell count was 6.9, 6.8, and 6.8 ×109/L, respectively; the median hematocrit was 38.0%, 36.3%, and 39.0%, respectively; and median hemoglobin was 11.9, 11.6, and 12.0 g/dL respectively. Similar laboratory results were obtained in pts receiving ANA+IFN or ANA+PIPO. Before, during and after COMB, anti-aggregatory treatment, usually low-dose aspirin, was given in 66.3%, 71.8%, and 33.1% of pts, respectively. In the same time periods, thrombotic (3, 11, and 11 cases, respectively) and hemorrhagic events (1, 2, and 5 cases, respectively) occurred. The COMB discontinuation rate was 54.5% globally (186/341 pts). COMB was discontinued by stopping ANA in 67 cases (36.0%), HC in 76 (40.9%), IFN in 8 (4.3%), PIPO in 4 (2.2%), both ANA and HC in 19 (10.2%), both ANA and IFN in 3 (1.6%), both ANA and PIPO in 3 (1.6%), or by adding a third drug in 6 cases (3.2%). In the 158 pts who discontinued ANA+HC, reasons were: intolerance/side effects (n=79, 50.0%), lack of efficacy (n=35, 22.2%), investigator decision (n=34, 21.5%, mainly with switch to ANA monotherapy), patient preference (n=10, 6.3%), missing, other (including economic) or unknown (n=17, 10.2%). Similarly, intolerance/side effects was the most frequent reason for discontinuing ANA+IFN (12/20; 60.0%). Overall, there were 63 patients with suspected severe adverse reactions (SSARs) and 45 with predefined events (PDEs) during COMB. The most frequent SSARs were myelofibrosis, palpitations, myocardial infarction and tachycardia. The most frequent PDEs included cardiovascular symptoms, myocardial infarction, stroke and transformation. Pts on COMB, the majority of whom received ANA+HC, accounted for 3.8% of all pts at registration and 5.0–5.8% of all pts in the following 5 years. Conclusion: COMB was performed in almost 10% of the 3643 pts with ET in the EXELS study, mainly with use of ANA+HC (87.6%). COMB appears to be a useful approach to treating patients for whom monotherapy was not well tolerated or ineffective since platelet levels were reduced to Disclosures: Gugliotta: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Besses:Shire: Honoraria; Novartis: Honoraria. Griesshammer:Shire: Honoraria. Harrison:Novartis: Consultancy, Honoraria, Research Funding; YM Biosciences: Consultancy; S*Bio: Consultancy; Shire: Honoraria, Research Funding; Sanofi Avensis: Honoraria. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Coll:Shire Pharmaceuticals: Employment. Smith:Shire Pharmaceuticals: Employment. Abhyankar:Shire Pharmaceuticals: Employment. Birgegård:Shire Pharmaceuticals: Honoraria; Pharmacosmos: Research Funding; Shire Pharmaceuticals Sweden: Consultancy.