A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone Versus High-Dose Dexamethasone in Subjects With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study
- Registration Number
- NCT01311687
- Lead Sponsor
- Celgene
- Brief Summary
The purpose of this study is to compare efficacy and safety of pomalidomide in combination with low-dose dexamethasone versus high-dose dexamethasone in subjects with refractory or relapsed and refractory multiple myeloma.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 455
- Must be ≥ 18 years of age
- Subjects must have documented diagnosis of multiple myeloma and have measurable disease
- Subjects must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy
- Subjects must have either refractory or relapsed and refractory disease defined as documented disease progression during or within 60 days of completing their last myeloma therapy
- All subjects must have received at least 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib
- All subjects must have failed treatment with both lenalidomide and bortezomib in one of the following ways: 1) Documented progressive disease on or within 60 days of completing treatment with lenalidomide and/or bortezomib, or 2) In case of prior response [≥ partial response (PR)] to lenalidomide or bortezomib, subjects must have relapsed within 6 months after stopping treatment with lenalidomide and/or bortezomib-containing regimens, or 3) Subjects who have not had a ≥ minimal response (MR) and have developed intolerance/toxicity after a minimum of two cycles of lenalidomide- and/or bortezomib-containing regimen
- Patients must have received adequate prior alkylator therapy
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
- Females of childbearing potential (FCBP) must not become pregnant for 28 days prior to initiation of study drug, during the study, and for 28 days after discontinuation
- Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation
- Males must agree to use a latex condom during any sexual during the study and for 28 days following discontinuation from this study
- Males must also agree to refrain from donating semen or sperm while on pomalidomide and for 28 days after discontinuation from this study
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Any of the following laboratory abnormalities:
- Absolute neutrophil count (ANC) < 1,000/μL
- Platelet count < 75,000/ μL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells
- Creatinine clearance < 45 mL/min
- Corrected serum calcium > 14 mg/dL
- Hemoglobin ≤ 8 g/dL
- Serum glutamic oxaloacetic transaminase (SGOT)/ aspartate aminotransferase (AST) or transaminase, serum glutamic pyruvic (SGPT)/ alanine aminotransferase (ALT) > 3.0 x upper limit of normal (ULN)
- Serum total bilirubin > 2.0 mg/dL
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Previous therapy with pomalidomide
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Hypersensitivity to thalidomide, lenalidomide, or dexamethasone
-
Resistance to high-dose dexamethasone used in the last line of therapy
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Peripheral neuropathy ≥ Grade 2
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Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant
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Subjects who are planning for or who are eligible for stem cell transplant
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Subjects with any one of the following: 1) Congestive heart failure, 2) Myocardial infarction within 12 months prior to starting study treatment, 3) Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
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Subjects who received any of the following within the last 14 days of initiation of study treatment: 1) Plasmapheresis, 2) Major surgery, 3) Radiation therapy, 4) Use of any anti-myeloma drug therapy
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Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of treatment
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Subjects with conditions requiring chronic steroid or immunosuppressive treatment
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Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
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Incidence of gastrointestinal disease that may significantly alter the absorption of pomalidomide
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Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
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Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subjects from signing the informed consent form
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Pregnant or breastfeeding females
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Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis A, B, or C
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description High-Dose Dexamethasone Dexamethasone Participants received 40 mg dexamethasone (or 20 mg for participants \> 75 years of age) administered by mouth once per day on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day treatment cycle until disease progression. Pomalidomide + Low-Dose Dexamethasone pomalidomide Participants received 4 mg pomalidomide administered by mouth on Days 1 to 21 of each 28-day treatment cycle and 40 mg dexamethasone (or 20 mg for participants \> 75 years of age) administered by mouth once per day on Days 1, 8, 15, and 22 of each 28-day cycle until disease progression. Pomalidomide + Low-Dose Dexamethasone Dexamethasone Participants received 4 mg pomalidomide administered by mouth on Days 1 to 21 of each 28-day treatment cycle and 40 mg dexamethasone (or 20 mg for participants \> 75 years of age) administered by mouth once per day on Days 1, 8, 15, and 22 of each 28-day cycle until disease progression.
- Primary Outcome Measures
Name Time Method Progression-free Survival (PFS) - Primary Analysis From randomization until the data cut-off date of 07 September 2012. Maximum duration of follow-up for PFS assessments was 57 weeks. Progression-free survival was calculated as the time from randomization to disease progression as determined by the Independent Response Adjudication Committee based on the International Myeloma Working Group Uniform Response criteria (IMWG), or death on study, whichever occurred earlier. Progressive disease required 1 of the following: • Increase of ≥ 25% from nadir in: o Serum M-component (absolute increase ≥ 0.5 g/dl); o Urine M-component (absolute increase ≥ 200 mg/24 hours); o Bone marrow plasma cell percentage (absolute % ≥ 10%); • Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; • Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease.
Progression-free Survival (PFS) With a Later Cut-off Date From randomization until the data cut-off date of 01 March 2013. Maximum duration of follow-up for PFS assessments was 74 weeks. Progression-free survival was calculated as the time from randomization to disease progression as determined by the Independent Response Adjudication Committee based on the International Myeloma Working Group Uniform Response criteria (IMWG), or death on study, whichever occurred earlier. Progressive disease requires 1 of the following: • Increase of ≥ 25% from nadir in: o Serum M-component (absolute increase ≥ 0.5 g/dl); o Urine M-component (absolute increase ≥ 200 mg/24 hours); o Bone marrow plasma cell percentage (absolute % ≥ 10%); • Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; • Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease.
- Secondary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AEs) From first dose of study drug through to 30 days after the last dose as of the end of the study (29 August 2017); maximum time on treatment was 297, 269, and 239 weeks in the Pomalidomide + LD-Dex, HD-Dex, and cross-over groups respectively. An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0): Grade 1 = Mild (no limitation in activity or intervention required); Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); Grade 4 = Life-threatening; Grade 5 = Death.
Overall Survival - Primary Analysis From randomization until the data cut-off date of 07 September 2012. Maximum time on follow-up for survival was 70 weeks. Overall survival is calculated as the time from randomization to death from 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 participants who were lost to follow-up before death was documented.
Percentage of Participants With an Objective Response According to International Myeloma Working Group (IMWG) Uniform Response Criteria From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Objective response is defined as a best overall response of stringent complete response (SCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the Independent Response Adjudication Committee: SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level \< 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to \< 200 mg/24 hours. In addition to the above, if present at baseline a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required.
Overall Survival With a Later Cut-off Date From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up for survival was 93 weeks. Overall survival is calculated as the time from randomization to death from 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 participants who were lost to follow-up before death was documented.
Overall Survival Based on the Final Dataset From randomization until the data cut-off date of 29 August 2017. Maximum time on follow-up for survival was 324 weeks. Overall survival is calculated as the time from randomization to death from 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 participants who were lost to follow-up before death was documented.
Percentage of Participants With Objective Response According to European Group for Blood and Marrow Transplantation (EBMT) Criteria From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Objective response defined as a best overall response of complete response (CR) or partial response (PR) based on the Independent Response Adjudication Committee: CR requires all of the following: - Absence of original monoclonal paraprotein in serum and urine by immunofixation maintained at least 42 days. - \<5% plasma cell in bone marrow aspirate and on bone marrow biopsy, if performed. - No increase in size or number of lytic bone lesions. - Disappearance of soft tissue plasmacytomas. PR requires all of the following: - ≥ 50% reduction in level of serum monoclonal paraprotein, maintained at least 42 days. - Reduction in 24-hour urinary light chain extraction by ≥ 90% or to \< 200 mg, maintained at least 42 days. - For patients with non-secretory myeloma, ≥ 50% reduction in plasma cells in bone marrow aspirate and on biopsy, if performed, for at least 42 days. - ≥ 50% reduction in the size of soft tissue plasmacytomas. - No increase in size or number of lytic bone lesions.
Time to Progression From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Time to progression (TTP) is calculated as the time from randomization to the first documented progression confirmed by a blinded, independent Response Adjudication Committee and based on the International Myeloma Working Group Uniform Response criteria (IMWG). Progressive disease requires 1 of the following: • Increase of ≥ 25% from nadir in: o Serum M-component (absolute increase ≥ 0.5 g/dl); o Urine M-component (absolute increase ≥ 200 mg/24 hours); o Bone marrow plasma cell percentage (absolute % ≥ 10%); • Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; • Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease.
Time to Response From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Time to response is calculated as the time from randomization to the initial documented response (partial response or better) based on IMWG criteria. SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level \< 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to \< 200 mg/24 hours. If present at baseline a ≥ 50% reduction in size of soft tissue plasmacytomas is also required.
Duration of Response From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Duration of response (calculated for responders only) is defined as time from the initial documented response (partial response or better) to confirmed disease progression, based on IMWG criteria assessed by the Independent Response Adjudication Committee.
Time to the First Hemoglobin Improvement From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Time to increased hemoglobin, defined as the time from randomization to at least one category improvement from Baseline in common terminology criteria for adverse events (CTCAE) grade for hemoglobin level. Hemoglobin categories are: 1) Normal; 2) CTCAE Grade 1: \< lower limit of normal (LLN) to 10.0 g/dL; 3) CTCAE Grade 2: \< 10.0 to \<8.0 g/dL. Participants with CTCAE Grade 3 anemia or worse at Baseline were excluded from the study.
Time to Improvement in Bone Pain From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Time to improvement in bone pain is defined as the time from randomization to at least one category improvement from Baseline in bone pain category. Bone pain was categorized (from best to worst) according to answers to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for patients with Multiple Myeloma Module (QLQ-MY20), Question 1, "Have you had bone aches or pain?": 1) Not at all, 2) A little, 3) Quite a bit, or 4) Very much.
Time to Improvement in Renal Function From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Time to improvement in renal function is defined as the time from randomization to at least one category improvement from Baseline in renal function. Renal Function was categorized as (from best to worst): - Normal: creatinine clearance ≥80 mL/min; - Grade 1: creatinine clearance ≥60 to \<80 mL/min; - Grade 2 : creatinine clearance ≥45 to \< 60 mL/min. Participants with creatinine clearance \< 45 mL/min at baseline were excluded from the study.
Time to Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks. Time to improvement in ECOG performance status defined as the time from randomization until at least a one category improvement from Baseline in ECOG performance status score. The categories of the ECOG Performance Status Scale are as follows: -0: Fully active, able to carry on all pre-disease performance without restriction; -1: Restricted in physically strenuous activity but ambulatory and able to carry our work of a light or sedentary nature, e.g., light housework, office work; -2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Patients with a score of 3, 4 or 5 were excluded from participating in the study.
Change From Baseline in the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement.
Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Change From Baseline in the EORTC QLQ-C30 Fatigue Domain Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom).
Change From Baseline in the EORTC QLQ-C30 Pain Domain Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Pain Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reductions in pain (i.e. improvement in symptom) and positive values indicate increases in pain (i.e. worsening of symptom).
Change From Baseline in the European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients with Multiple Myeloma (EORTC QLQ-MY20) is a 20-question tool used in clinical research to assess health-related quality of life in multiple myeloma patients. The QLQ-MY20 includes four domains (Disease Symptoms, Side-Effects of Treatment, Body Image and Future Perspective). The EORTC QLQ-MY20 Disease Symptoms Scale is scored between 0 and 100, with a high score reflecting a higher level of symptoms. Negative change from Baseline values indicate reduction (i.e. improvement) in symptoms and positive values indicate increase (i.e. worsening) of symptoms.
Change From Baseline in the EORTC QLQ-MY20 Side Effects Domain Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 The European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients with Multiple Myeloma (EORTC QLQ-MY20) is a 20-question tool used in clinical research to assess health-related quality of life in multiple myeloma patients. The QLQ-MY20 includes four domains (Disease Symptoms, Side-Effects of Treatment, Body Image and Future Perspective). The EORTC QLQ-MY20 Side Effects Scale is scored between 0 and 100, with a high score reflecting a higher level of symptoms. Negative change from Baseline values indicate reduction in side effects (i.e.improvement in symptom) and positive values indicate increase in side effects (i.e. worsening of symptom).
Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Utility Index Score Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6 EQ-5D is a self-administered questionnaire that assesses health-related quality of life (QOL). The EQ-5D descriptive health profile comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 levels of response: No problem (1), some problems (2), and extreme problems (3). A unique EQ-5D health state is defined by combining one level from each of the five dimensions into a single utility index score. EQ-5D index values range from -0.59 to 1.00 where an EQ-5D score of 1.00 equals "perfect health", a score of 0 equals "death" and a score of -0.59 equals worst imaginable health state. A positive change from Baseline score indicates improvement in health status. A negative change from Baseline score indicates worsening in health status. Negative scores represent the possible though unlikely situation that a patient's QOL is worse than death, i.e. they would rather be dead than living with that QOL
Time to First Worsening of Quality of Life (QOL) Domains Assessed on Day 1 of the first 6 treatment cycles. Time to worsening in quality of life domains was calculated as the time from Baseline to the first worsened minimally important difference (MID), defined as the smallest change in a QOL score considered important to patients that would lead the patient or clinician to consider a change in therapy. MID thresholds were calculated in Standard Error of Measurement (SEM) units using the Baseline QOL data. Based on the MID, participants were classified as worsened according to the following: For the EORTC QLQ-C30 global health status and functional scales and the EQ-5D health utility score, participants were classified as worsened if their change from Baseline score was less than -1 SEM. For the EORTC QLQ-C30 symptom scores (fatigue and pain) and EORTC QLQ-MY20 disease symptoms and side effects scales, participants were classified as worsened if their change from Baseline score was greater than 1 SEM. See previous outcome measures for definitions of each scale.
Trial Locations
- Locations (94)
CHU UCL Mont-Godinne-Dinant asbl
🇧🇪Yvoir, Belgium
St. Petersburg Research Institute of Hematology and Blood Transfusion
🇷🇺St. Petersburg, Russian Federation
State Institution Moscow Regional Research Clinical Institute
🇷🇺Moscow, Russian Federation
Tom Baker Cancer Center
🇨🇦Calgary, Alberta, Canada
Royal Prince Alfred Hospital
🇦🇺Camperdown, Australia
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Charles University General Hospital
🇨🇿Praha 2, Czechia
Aarhus University Hospital
🇩🇰Arhus C, Denmark
CHU d'Angers
🇫🇷Angers Cedex 01, France
James Cancer Hospital
🇨🇦Halifax, Nova Scotia, Canada
Universitatsklinikum Essen
🇩🇪Essen, Germany
Border Medical Oncology
🇦🇺Wodonga, Australia
Wollongong Hospital
🇦🇺Wollongong, Australia
Juravinski Cancer Centre
🇨🇦Hamilton, Ontario, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Maisonneuve Rosemont
🇨🇦Montreal, Quebec, Canada
Alfred hospital
🇦🇺Melbourne, Australia
University of Tubingen
🇩🇪Tübingen, Germany
Centre Hospitalier de la cote basque
🇫🇷Bayonne, France
UZ Leuven
🇧🇪Leuven, Belgium
VU University Medical Center
🇳🇱Amsterdam, Netherlands
Hæmatologisk afd. B Aalborg Sygehus Syd
🇩🇰Aalborg, Denmark
University Hospital in Lund
🇸🇪Lund, Sweden
Centre Hospitalier Lyon Sud
🇫🇷Pierre Bénite, France
Odense Universitetshospital
🇩🇰Odense C, Denmark
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
Medizinische Universitatsklinik
🇨🇭Berne, Switzerland
Universitatsklinikum Wurzburg
🇩🇪Wuerzburg, Germany
Hospital Donostia
🇪🇸San Sebastián (Guipuzcoa), Spain
Hospital Clinic
🇮🇹Placenza, Italy
Department of Hematology Hematology Centre
🇸🇪Göteborg, Sweden
CHU Nancy
🇫🇷Vandoeuvre, France
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona (Barcelona), Spain
State Educational Institution, Saint Petersburg State Medical University
🇷🇺Saint Petersburg, Russian Federation
Universitatsklinikum Leipzig
🇩🇪Leipzig, Germany
Oncoematologia, Istituto Nazionale Tumori Fondazione G. Pascale
🇮🇹Napoli, Italy
St James's University Hospital
🇬🇧Leeds, United Kingdom
Hospital Clinic Provincial de Barcelona
🇪🇸Barcelona, Spain
Hospital de la Fe
🇪🇸Valencia, Spain
Hospital 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Marques de Valdecilla
🇪🇸Santander, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
King's College Hospital
🇬🇧London, United Kingdom
AOU San Luigi Gonzaga
🇮🇹Orbassano, Italy
Universita degli Studi di Padova
🇮🇹Padova, Italy
Univerita La Sapienza Dipartimento di Biotecnologie Cellulari ed Ematologia
🇮🇹Rome, Italy
Karolinska University Hospital
🇸🇪Stockholm, Sweden
St.Bartholomew's Hospital
🇬🇧London, United Kingdom
Hospital de La Princesa
🇪🇸Madrid, Spain
Nottingham City Hospital
🇬🇧Nottingham, United Kingdom
The Royal Wolverhampton Hospital NHS Trust
🇬🇧Wolverhampton, United Kingdom
Erasmus Medical Center
🇳🇱Rotterdam, Netherlands
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
University Health Network
🇨🇦Toronto, Ontario, Canada
Servizio di Ematologia, A.O. - Arcispedale S.Maria Nuova
🇮🇹Reggio Emilia, Italy
Azienda Ospedaliera San Giovanni Battista
🇮🇹Torino, Italy
Institut Paoli-Calmettes
🇫🇷Marseille Cedex 9, France
Hopital Saint-Louis
🇫🇷Paris, Cedex 10, France
CHRU - Hopital du Haut Leveque
🇫🇷Pessac, France
Hopital Bretonneau
🇫🇷Tours, France
Hopital Purpan
🇫🇷Tulouse Cedex 9, France
CHRU Nantes
🇫🇷Nantes Cedex 1, France
Peter MacCallum Cancer Institute
🇦🇺East Melbourne, Victoria, Australia
Frankston Hospital
🇦🇺Frankston, Victoria, Australia
Calvary Mater Hospital
🇦🇺Waratah, Australia
Princess Alexandra Hospital
🇦🇺Brisbane, Australia
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Australia
UZ Gent
🇧🇪Gent, Belgium
British Columbia Cancer Agency
🇨🇦Vancouver, British Columbia, Canada
Royal Victoria Hospital McGill Department of Oncology(RVH)
🇨🇦Montreal, Quebec, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Sir Mortimer B. Davis - Jewish Genl
🇨🇦Montreal, Quebec, Canada
CHRU de Lille FR
🇫🇷Lille, France
Vejle Hospital
🇩🇰Vejle, Denmark
Centre Hospitalier Departemental
🇫🇷La Roche sur Yon, France
CHU Hôpital St-Antoine
🇫🇷Paris, France
Universitatsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
Askepios Klinik St. Georg
🇩🇪Hamburg, Germany
Universitatsklinikum Jena
🇩🇪Jena, Germany
Universitatsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Alexandra General Hospital of Athens
🇬🇷Athens, Greece
Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
🇮🇹Bologna, Italy
Clinica Ematologica- A.O.U. San Martino
🇮🇹Genova, Italy
Overlakare Medocomcentrum, hematologi
🇸🇪Uppsala, Sweden
State Institution Hematological Research, Centre of Russian Academy of Medical Science
🇷🇺Moscow, Russian Federation
Karolinska University Hospital Huddinge
🇸🇪Stockholm, Sweden
UniversitatSspital Zurich
🇨🇭Zürich, Switzerland
Royal Bournemouth Hospital
🇬🇧Bournemouth, United Kingdom
Hopitaux Universitaires de Geneve-HUG
🇨🇭Geneva, Switzerland
Freeman Hospital
🇬🇧Newcastle Upon Tyne, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Royal Hallamshire HospitalSheffield Teaching Hospitals NHS Trust
🇬🇧Sheffield, United Kingdom
The Royal Marsden Hospital
🇬🇧Sutton-Surrey, United Kingdom
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands