A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes
- Registration Number
- NCT02631070
- Lead Sponsor
- Celgene
- Brief Summary
The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.
- Detailed Description
Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 229
Subjects must satisfy the following criteria to be enrolled in the study:
- Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
- Documented diagnosis of MDS according to World Health Organization (WHO)/French American British (FAB) classification that meets IPSS R classification of very low, low, or intermediate risk disease, and:
Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1 mutation is present.
- < 5% blasts in bone marrow
- Peripheral blood white blood cell (WBC) count < 13,000/µL 3. Requires red blood cell RBC transfusions 4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5. Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating agents (ESA) treatment, defined as:
- Refractory to prior - erythropoietin stimulating agents treatment: documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with granulocyte colony stimulating factor (G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent
- Intolerant to prior ESA treatment: documentation of discontinuation of prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event
- ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs
The presence of any of the following will exclude a subject from enrollment:
-
Prior therapy with disease modifying agents for underlying MDS disease.
-
Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
-
MDS associated with del 5q cytogenetic abnormality
-
Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
-
Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
- iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate stain for iron).
-
Prior allogeneic or autologous stem cell transplant
-
Known history of diagnosis of acute myeloid leukemia (AML)
-
Use of any of the following within 5 weeks prior to randomization:
- anticancer cytotoxic chemotherapeutic agent or treatment
- corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS
- iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
- other RBC hematopoietic growth factors (eg, Interleukin-3)
- investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the half-life prior to randomization or within 5 weeks, whichever is longer is excluded.
-
Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
- Basal or squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
-
Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control Arm: Placebo Placebo Subcutaneous injection every 3 weeks Experimental Arm - Luspatercept (ACE-536) Luspatercept Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks
- Primary Outcome Measures
Name Time Method Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24 From Week 1 through Week 24 of study treatment RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24 From Week 1 through Week 24 of study treatment RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48 From Week 1 through Week 48 of study treatment RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24 From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days. The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study.
It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT) Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment Mean change from baseline in mean daily dose of ICT averaged over Week 9 to Week 24 or Week 33 to Week 48. For each participant, the mean change in daily dose of ICT was calculated as the difference of postbaseline mean daily dose and baseline mean daily dose.
Time to Acute Myeloid Leukemia (AML) Progression From randomization to study completion (up to approximately 57 months) Time to AML progression was defined as the time between randomization date and the first diagnosis of AML as per World Health Organization (WHO) classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with a diagnosis of AML were considered to have had an event, participants who did not progress to AML at the time of analysis were censored at the last assessment date which did not indicate progression to AML.
Change From Baseline in Mean Serum Ferritin Baseline and Week 9 through Week 24 and Week 33 through Week 48 Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.
Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML) From randomization to study completion (up to approximately 57 months) Percentage of participants progressing to AML throughout the course of the study
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss) Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Area under the curve steady state was defined as the area under the plasma concentration-time curve for a steady state. calculated by the linear trapezoidal rule.
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) From randomization to 1 year post first dose Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as "treatment-emergent" if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as "preexisting" if the baseline sample was ADA positive and the participant was not qualified for "treatment-emergent."
Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48 Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.
Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period Week 1 through 24 or Week 1 Through Week 48 A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of \<4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.
Overall Survival From randomization to study completion (up to approximately 57 months) Overall Survival was defined as the time from the date of study drug randomization to death due to any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for those who discontinued from the study or were lost to follow-up.
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F) Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2) Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax) Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Tmax was defined as the observed time to maximum plasma concentration of luspatercept.
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48 From Week 1 through Week 48 of study treatment RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.
Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period Week 1 through Week 24 or Week 1 Through Week 48 of study treatment Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase \> 0.5 X 10\^9/L.
Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period Week 1 through Week 24 or Week 1 Through Week 48 of study treatment Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI - P reponse was defined as:
* Absolute increase of ≥ 30 X 10\^9/L in platelets for participants starting with \> 20 X 10\^9/L platelets
* Increase in platelets from \< 20 X 10\^9/L to \> 20 X 10\^9/L and by at least 100%Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24 From first dose to Week 24 of study treatment Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 24
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48 From first dose to Week 48 of study treatment Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 48
Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions Week 1 though Week 24 and Week 1 through 48 A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48 From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) From date of first dose up to 42 days after the last dose (up to approximately 83 weeks) The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs).
TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP.
The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F) Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax) Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter. Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.
Trial Locations
- Locations (74)
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
H Lee Moffitt Cancer Center and Research Institute
🇺🇸Tampa, Florida, United States
Universitatsklinikum Bonn
🇩🇪Bonn, Germany
AZ Sint-Jan AV Brugge
🇧🇪Brugge, Belgium
Cukurova University Medical Faculty Balcali Hospital
🇹🇷Adana, Turkey
Tom Baker Cancer Center
🇨🇦Calgary, Alberta, Canada
Hopital Haut Leveque
🇫🇷Pessac Cedex, France
Ankara University Medical Faculty Cebeci Hospital
🇹🇷Ankara, Turkey
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Azienda Ospedaliera Bianchi Melacrino Morelli
🇮🇹Reggio, Calabria, Italy
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Gabrail Cancer Center
🇺🇸Canton, Ohio, United States
Cleveland Clinic Taussig Cancer Institute
🇺🇸Cleveland, Ohio, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Stanford Cancer Center
🇺🇸Stanford, California, United States
Ochsner Medical Institutions
🇺🇸New Orleans, Louisiana, United States
Columbia-Presbyterian Medical Center
🇺🇸New York, New York, United States
Montefiore Medical Center Albert Einstein Cancer Center
🇺🇸Bronx, New York, United States
Algemeen Ziekenhuis Klina
🇧🇪Brasschaat, Belgium
UZ Brussels
🇧🇪Brussel, Belgium
Grand Hopital de Charleroi
🇧🇪Charleroi, Belgium
UZ Gent
🇧🇪Gent, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
Juravinski Cancer Centre
🇨🇦Hamilton, Ontario, Canada
Cliniques Universitaires UCL de Mont-Godine
🇧🇪Yvoir, Belgium
CHU de Nice Archet I
🇫🇷Nice, France
CHU d'Angers
🇫🇷Angers, France
CHU Hotel
🇫🇷Grenoble Cedex 09, France
CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang
🇫🇷Lille, France
Institut Paoli Calmettes
🇫🇷Marseille cedex, France
Hopital Saint Louis
🇫🇷Paris, France
Centre hospitalier Lyon Sud Hematologie
🇫🇷Pierre-Bénite cedex, France
Hopital civil
🇫🇷Strasbourg, France
Institut Universitaire du Cancer de Toulouse - Oncopole
🇫🇷Toulouse Cedex 9, France
Hopital Bretonneau
🇫🇷Tours, France
Marien Hospital
🇩🇪Dusseldorf, Germany
Universitatsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪Dresden, Germany
Universitätsklinikum Düsseldorf
🇩🇪Düsseldorf, Germany
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Klinikum rechts der Isar der Technischen Universität München
🇩🇪München, Germany
Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo
🇮🇹Allessandria, Italy
Azienda Ospedaliero Universitaria Di Bologna Policlinico Sorsola Malpighi
🇮🇹Bologna, Italy
Azienda Sanitaria Locale Lecce
🇮🇹Lecce, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Fondazione Policlinico Universitario A Gemelli
🇮🇹Roma, Italy
VU Medisch Centrum
🇳🇱Amsterdam, Netherlands
Fondazione PTV Policlinico Tor Vergata
🇮🇹Roma, Italy
Spaarne Ziekenhuis
🇳🇱Hoofddorp, Netherlands
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
Hospital Universitario Cruces
🇪🇸Barakaldo, Spain
Instituto Catalan de Oncologia-Hospital Duran i Reynals
🇪🇸Barcelona, Spain
Hospital Universitario Vall D hebron
🇪🇸Barcelona, Spain
Hospital Universitario Central de Asturias
🇪🇸Oviedo, Spain
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hospital Universitario La Fe
🇪🇸Valencia, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Seville, Spain
Skanes Universitetssjukhus Lund
🇸🇪Lund, Sweden
Sahlgrenska Universitetssjukhus
🇸🇪Göteborg, Sweden
Karolinska University Hospital
🇸🇪Stockholm, Sweden
Akademiska Sjukhuset
🇸🇪Uppsala, Sweden
Istanbul University Cerrahpasa Medical Faculty Hospital
🇹🇷Istanbul, Turkey
Ege Universitesi Tip Fakultesi Hastanesi
🇹🇷Izmir, Turkey
St James University Hospital
🇬🇧Leeds, United Kingdom
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
John Radcliffe Hospital
🇬🇧Headington, United Kingdom
Kings Mill Hospital
🇬🇧Sutton in Ashfield, United Kingdom
Guys Hospital
🇬🇧London, United Kingdom
Kings College Hospital
🇬🇧London, United Kingdom
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States