Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias

Phase 2

Completed

Conditions: Chronic Myeloid Leukemia

Interventions: Drug: Bosutinib

Registration Number: NCT00261846

Lead Sponsor: Pfizer

Brief Summary: This is an open-label, continuous daily dosing, two-part safety and efficacy study of SKI-606 (bosutinib) in Philadelphia chromosome positive leukemias (Ph+). Part 1 is a dose-escalation study in chronic phase Chronic Myelogenous Leukemia (CML) subjects to establish the maximum tolerated dose (MTD) in this subject population. Part 2 has begun after the completion of Part 1 and after a dose has been established for the compound in chronic phase subjects. Part 2 is a study of the the efficacy of 500mg daily oral SKI-606 (bosutinib) in patients with all phases of Ph+ CML and Ph+ Acute Lymphocytic Leukemia (ALL). The protocol will test the hypotheses that oral daily dosing of bosutinib at 500 mg will attain (1) Major Cytogenetic Response (MCyR) in chronic phase CML patients and (2) Overall Hematological Response (OHR) in advanced leukemia patients. Each phase of the disease will be evaluated as a separate cohort.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 571

Inclusion Criteria

Ph+ CML or Ph+ ALL who are primarily refractory to full-dose imatinib (600 mg), have disease progression/relapse while on full-dose imatinib, or are intolerant of any dose of imatinib.
At least 3 months post stem cell transplantation
Able to take daily oral capsules/tablets reliably

Exclusion Criteria

Subjects with Philadelphia chromosome, and bcr-abl negative CML
Overt leptomeningeal leukemia
Subjects without evidence of leukemia in bone marrow (extramedullary disease only)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
SKI-606	Bosutinib	-

Primary Outcome Measures

Name	Time	Method
Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15	Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.
Number of Participants With Dose Limiting Toxicity (DLT)	Part 1 Baseline up to Day 28	DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).
Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Plasma Decay Half-Life (t1/2) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. NA = not estimable.
Area Under the Concentration-Time Curve (AUC) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1	AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. NA = not estimable.
Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life over 24 hours at steady state (ss), on Day 15 was calculated.
Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15	AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC over 24 hours at steady state (ss), on Day 15 was calculated.
Maximum Tolerated Dose (MTD)	Part 1 Baseline up to Day 28	MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1). NA = not estimable.
Maximum Observed Plasma Concentration (Cmax) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1	AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).
Apparent Oral Clearance (CL/F) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. NA = not estimable.
Apparent Volume of Distribution (Vz/F) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15	Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.
Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral clearence over 24 hours at steady state (ss), on Day 15 was calculated.
Accumulation Ratio (R)	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15	R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)
Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2	Week 24	CyR is based on the prevalence of Ph+ cells. Major cytogenetic response was categorized as either CCyR or partial CyR (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or less than (\<) 1% positive cells from at least 200 cells analyzed from fluorescent in situ hybridization (FISH). PCyR was achieved when 1 to 35% Ph+ cells were present.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1	6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15	CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the CD3+ (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using FACS flow cytometry. NA = not estimable.
Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1	Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52)	Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.
Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1	Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52)	bcr-Abl is a protein resulting from the transcription of the Philadelphia chromosome following 9:22 chromosomal translocation, and phosphorylation inhibition of which correlates with inhibition of tumor cell growth.
Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1	0 (pre-dose) on Day 1 (Baseline)	CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the cluster of differentiation 3 (CD3+) (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using fluorescent activated cell sorter (FACS) flow cytometry.
Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2	Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L) or Year 5 (CP2L)	CyR is based on the prevalence of Ph+ cells. MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.
Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2	From first MCyR to loss of MCyR or censoring, assessed every 12 weeks up to 2 years and then every 24 weeks thereafter up to Year 5	MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. The Kaplan-Meier probability of retaining an attained/maintained MCyR at Year 5 is reported. Median durations were not reached as of the minimum follow-up. Duration of response in weeks =(date of confirmed loss of first attained response or last valid cytogenetic assessment for those censored - date of first attained response)/7.
Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2	Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5	MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or \<1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. Time to MCyR was the interval from the date of first dose of study medication until the first date of achieving a given response. Time to response in weeks equals (=) (event date minus (-) first dose date plus (+) 1)divided (/)7, where the event date is the non-missing date of the first attained response for responders only.
Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2	From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)	Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes \<5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10\^9 per liter (/L) , platelets ≥100×10\^9/L \& \<450×10\^9/L, \<20% basophils in blood \& no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (ADV only \& applicable to CP if BM aspirate was performed). The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. The Kaplan-Meier estimate of maintaining CHR at the end of minimum follow-up is presented (CP2L: Year 5; CP3L \& ADV: Year 4). NA = not estimable. NA = not estimable.
Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2	Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)	The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response for responders only.
Duration of Complete Hematologic Response (CHR) - Part 2	From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)	Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes less than (\<)5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10\^9 per liter (/L) , platelets \<450×10\^9/L, platelets ≥100×10\^9/L, \<20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed). The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. NA = not estimable.
Cumulative Incidence of Progression/Death - Part 2	Years 1, 2, 3, 4, and 5 (CP2L only)	The cumulative incidence of on-treatment progression or death adjusting for the competing risk of treatment discontinuation without the event. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4. 95% confidence intervals were calculated using Gray's method. NA = not estimable. One year = 12 months.
Progression Free Survival (PFS) - Part 2	Years 1, 2, 3, 4, and 5 (CP2L only)	PFS was based on Kaplan-Meier method. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4. NA = not estimable. One year = 12 months
Overall Survival (OS) - Part 2	Years 1, 2, 3, 4, and 5 (CP2L only)	OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death or date of last contact for those censored. NA = not estimable. One year = 12 months.
Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	Baseline up to follow up visit (30 days after last dose of study treatment)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)	Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter	ECOG-PS measured on-therapy (time between first dose and last dose date with a 30-day lag) assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work;2=ambulatory (\>50% of waking hrs), capable of all self care, unable to carry out any work activities;3=capable of only limited self care, confined to bed/chair \>50% of waking hrs;4=completely disabled, cannot carry on any self care, totally confined to bed/chair;5=dead.
Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values	Post-therapy	Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of \<40 beats per min and value \>150 beats per min, SBP of \<80 or \>210 mmHg, DBP of \<40 or \>130 mmHg, temperature \<32 or \>40 degree centigrade, Resp of \<10 or \>50 breaths/min and criteria for PCI change in physical examination: \>=10% increase or decrease of body weight in kg. No Ph+ ALL participants were analyzed post-therapy (N=0). Part 1 safety data were originally presented in 2011 and are included as cumulative data in the Part 2 final safety results.
Kaplan-Meier Estimate of Overall Survival (OS) - Part 2	Years 1, 2, 3, 4, and 5 (CP2L only)	OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death or date of last contact for those censored. NA = not estimable. One year = 12 months.
Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2	Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)	Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells ≤ institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes \<5% in blood, absolute neutrophil count ≥ 1.0×10\^9/L , platelets \<450×10\^9/L, platelets ≥100×10\^9/L, \<20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed).
Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2	Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 1 year	OHR included CHR, no evidence of leukemia (≤5% bone marrow blasts, no peripheral blood blasts or promyelocytes, \<5% myelocytes + metamyelocytes in blood, white blood cells ≤ institutional upper limit of normal, 450x10\^9/L \> platelets \> 20x10\^9/L, absolute neutrophil count ≥0.5x10\^9/L, \<20% basophils in blood, no extramedullary involvement \[including liver or spleen\]), minor hematologic response (acute lymphoblastic leukemia \[ALL\] patients only, defined as \<15% blasts in marrow \& blood, \<30% blasts + promyelocytes in marrow \& blood, \<20% basophils in peripheral blood \& no extramedullary disease other than spleen \& liver) or return to chronic phase (AP/BP participants, defined as \<15% blasts in both peripheral blood \&bone marrow, \<30% blasts + promyelocytes in both peripheral blood \& bone marrow, \<20% basophils in both peripheral blood \& bone marrow, no extramedullary Involvement other than liver or spleen). Participants had to meet at least 1 criterion.
Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)	Baseline up to follow-up visit (30 days after last dose of study treatment)	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. The event did not necessarily have a causal relationship with the treatment. PCI AEs included anemia, alanine aminotranferase (ALT), aspartate aminotransferase (AST), cardiac, diarrhea, edema, effusion, gastrointestinal, hemorrhage, hypersensitivity, hypertension, infection, liver, myelosuppression, nausea, neutropenia, rash, renal, thrombocytopenia, vomiting, and vascular events. Duration of AE was calculated as (stop date minus start date) plus 1 for non-missing and non-partial dates. NA = not estimable.
Percentage of Participants With Change From Baseline in Laboratory Tests Results	Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter	Laboratory assessments included urinalysis, complete blood count (CBC), prothrombin time/partial prothromboplastin time (PT/PPT), international normalized ratio (INR), blood chemistry and serum pregnancy test (β-HCG). Parameters of special interest included liver function tests and those related to myelosuppression. Potentially clinically important (PCI) laboratory values were defined as National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher. Maximum CTCAE grade, and only participants who shifted to Grade 3/4 on-treatment, are reported.
Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings	Baseline, 0 (pre-dose), 2, 4, 6 hours on Day 1, 0 (pre-dose), 2, 4, 6, 20-23 hours on Day 21, and end of treatment visit	Criteria for PCI changes in ECG (12-lead) were defined as: no sinus rhythm; PR interval \>=220 msec and increase of \>=20 msec; QRS interval \>=120 msec; QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett formula (QTcB) \>500 msec or increase of \>60 msec; heart rate \<=45 beats per minute (bpm) or \>=120 bpm or decrease/increase of \>=15 bpm.
Number of Participants With Change From Baseline in Findings of Chest X-ray	Baseline, Week 8, and end of treatment	Number of participants whose chest X-ray results changed (worsened or improved) from the Baseline.
Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)	Baseline and Weeks 1, 2, 3, 4, 8, 12, then every 12 weeks thereafter until end of treatment, for a mean duration of 28 months	Number of participants taking any non-study medications which were administered from Study Day 1 to 30 days after last dose of study treatment as a management of an AE are reported.
Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs	Screening, Baseline, and end of treatment	Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of \<40 beats per min and value \>150 beats per min, systolic blood pressure (SBP) of \<80 or \>210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of \<40 or \>130 mmHg, temperature \<32 or \>40 degree centigrade, respiratory rate (Resp) of \<10 or \>50 breaths/min and criteria for PCI change in physical examination: \>=10% increase or decrease of body weight in kilogram (kg).

Trial Locations

Locations (110): The University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University Health Network Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Penn State Milton S Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States
University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
Christian Medical College
🇮🇳
Vellore, Tamil Nadu, India
University of Rochester
🇺🇸
Rochester, New York, United States
Rocky Mountain Cancer Centers
🇺🇸
Denver, Colorado, United States
University Of Maryland
🇺🇸
Baltimore, Maryland, United States
Westchester Medical Center
🇺🇸
Valhalla, New York, United States
Indiana Blood and Marrow Transplantation
🇺🇸
Indianapolis, Indiana, United States
Westchester Oncology Hematology Group, P.C.
🇺🇸
Hawthorne, New York, United States
Hospital universitario austral
🇦🇷
Pcia de Buenos Aires, Argentina
HealthONE Presbyterian
🇺🇸
Denver, Colorado, United States
The University of Texas
🇺🇸
Houston, Texas, United States
Peking Union Medical College Hospital of Chinese Academy of Medical Sciences
🇨🇳
Beijing, P.r. China, China
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Westchester Oncology Hematology, Group, P.C.
🇺🇸
Hawthorne, New York, United States
Institute of Medical and Veterinary Science
🇦🇺
Adelaide, Australia
Department of Clinical Haematology and Bone Marrow Transplantation
🇦🇺
Melbourne, Australia
Emory Clinic
🇺🇸
Atlanta, Georgia, United States
Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
University of Rochester Medical Center Strong Memorial Hospital - James P. Wilmot Cancer Center
🇺🇸
Rochester, New York, United States
New York Presbyterian Hospital
🇺🇸
New York, New York, United States
Emory University Hospital
🇺🇸
Atlanta, Georgia, United States
University Of Maryland Medical Center
🇺🇸
Baltimore, Maryland, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Klinikum Kreuzschwestern Wels
🇦🇹
Wels, Austria
Cross Cancer Institute
🇨🇦
Edmonton, Alberta, Canada
Royal Brisbane and Women's Hospital
🇦🇺
Queensland, Australia
Hospital Britanico
🇦🇷
Buenos Aires, Argentina
Centro Medico S.A.
🇦🇷
Corrientes, Argentina
Hospital Jose Ramon Vidal
🇦🇷
Corrientes, Argentina
The Department of Hematology, Ruijin Hospital Affiliated to School of Medicine of Shanghai Jiaotong
🇨🇳
Shanghai, China
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Royal Adelaide Hospital
🇦🇺
Adelaide, South Australia, Australia
Biomedicum Helsinki
🇫🇮
Helsinki, Finland
The First Hospital affiliated to the Medical School of Zhejiang University
🇨🇳
Zhejiang, P.r China, China
The Department of Hematology, The Chinese PLA General Hospital
🇨🇳
Beijing, P.r. China, China
The Hematology Hospital of Chinese Academy of Medical Sciences
🇨🇳
Tianjin, P.r. China, China
Hospital Pablo Tobon Uribe
🇨🇴
Medellin, Antioquia, Colombia
Universitaet Mainz Iii. Medizinische Klinik Abteilung Fuer Haematologie
🇩🇪
Mainz, Germany
Fundacion Santa Fe de Bogota
🇨🇴
Bogota, Cundinamarca, Colombia
III Medizinische Klinik und Poliklinik
🇩🇪
Mainz, Germany
Klinikum der Johann Gutenberg Universitaet Mainz
🇩🇪
Mainz, Germany
Azienda Ospedaliero - Universitaria San Luigi Gonzaga
🇮🇹
Orbassano, Torino, Italy
Azienda Ospedaliera San Gerardo
🇮🇹
Monza, Italy
University Medical Center Groningen
🇳🇱
Groningen, Netherlands
Fovarosi Onkormanyzat Egyesitett Szent Istvan es Szent Laszlo
🇭🇺
Budapest, Hungary
University of Bologna
🇮🇹
Bologna, Province of Bologna, Italy
AOU-S.Orsola-Malpighi - Universita degli Studi di Bologna
🇮🇹
Bologna, Italy
Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
🇲🇽
Nuevo Leon, Mexico
Akademiska University Hospital
🇸🇪
Uppsala, Sweden
School of Clinical and Laboratory Sciences
🇬🇧
University upon Tyne, North East England, United Kingdom
Johannesburg Hospital
🇿🇦
Parktown, South Africa
Hospital Nacional Edgardo Rebagliati Martins
🇵🇪
Lima, Peru
Hospital Clinico Universitario de Valencia (CHUV)
🇪🇸
Valencia, Spain
University of Cape Town
🇿🇦
Cape Town, South Africa
Hospital Clinic de Barcelona (Hospital Clinic i Provincial)
🇪🇸
Barcelona, Catalonia, Spain
Hospital Universitari Clinic de Barcelona
🇪🇸
Barcelona, Catalonia, Spain
Singapore General Hospital
🇸🇬
Singapore, Singapore
Hammersmith Hospital
🇬🇧
London, United Kingdom
Clinical Research Facility
🇬🇧
Newcastle Upon Tyne, North East England, United Kingdom
University of the Free State
🇿🇦
Bloemfontein, South Africa
Hospital Universitario La Princesa
🇪🇸
Madrid, Spain
Clinical Haematology Unit
🇿🇦
Soweto, South Africa
Northern Centre for Cancer Care - The Newcastle Upon Tyne Hospitals - NHS Foundation Trust
🇬🇧
Newcastle Upon Tyne, North East England, United Kingdom
Hematological Research Centre of RAMS
🇷🇺
Moscow, Russian Federation
Oncology Specialists, S.C.
🇺🇸
Niles, Illinois, United States
Hudson Valley Hematology and Oncology Associates
🇺🇸
Hawthorne, New York, United States
Clinica del Sol
🇦🇷
Ciudad Autonoma de Buenos Aires, Argentina
Haematology and Oncology Clinics of Australia
🇦🇺
Queensland, Australia
University of Rochester-James P. Wilmot Cancer Center
🇺🇸
Rochester, New York, United States
Instituto Medico Especializado Alexander Fleming
🇦🇷
Buenos Aires, Argentina
Hospital Brigadeiro da Secretaria de Estado da Saude de Sao Paulo
🇧🇷
Jardim Paulista, Sao Paulo/sp - Brazil, Brazil
Sir Mortimer B. Davis, Jewish General Hospital
🇨🇦
Montreal, Quebec, Canada
Universitaetsklinikum Magdeburg A. oe. R.
🇩🇪
Magdeburg, Germany
Universitaetsklinikum Hamburg-Eppendorf
🇩🇪
Hamburg, Germany
State Healthcare Institution, Sverdlovsk Regional Clinical Hospital
🇷🇺
Ekaterinburg, Russian Federation
Universitair Medisch Centrum Groningen
🇳🇱
Groningen, Netherlands
The Catholic University of Korea, Seoul St. Mary Hospital
🇰🇷
Seoul, Korea, Republic of
Kirov Research Institute of Hematology and Blood transfusion of Roszdrav Hematology clinic
🇷🇺
Kirov, Russian Federation
VUMC
🇳🇱
The Netherlands, Netherlands
Instituto Clinico Oncologico del Sur
🇨🇱
Temuco, Chile
Universitaet Mainz
🇩🇪
Mainz, RP, Germany
Dept. of Hematology
🇰🇷
Seoul, Korea, Republic of
University Hospital Carl Gustav Carus
🇩🇪
Dresden, Germany
Universitaetsklinikum Hamburg - Eppendorf
🇩🇪
Hamburg, Germany
Georgetown University Hospital
🇺🇸
Washington, D.C., District of Columbia, United States
Universitaetsklinikum Mainz
🇩🇪
Mainz, Germany
Avd. for blodsykdommer
🇳🇴
Trondheim, Norge, Norway
Moscow regional Clinical Research Institute named after M.F Vladimirsky
🇷🇺
Moscow, Russian Federation
III. Medizinische Klinik
🇩🇪
Mannheim, Germany
Rostov State Medical University of Roszdrav
🇷🇺
Rostov-on Don, Russian Federation
Academia Nacional de Medicina-Instituto de Investigaciones Hematologicas
🇦🇷
Buenos Aires, Argentina
Centro Oncologico Estatal ISSEMYM
🇲🇽
Toluca Estado de Mexico, Mexico
VU University Medical Center
🇳🇱
Amsterdam, Netherlands
LSU Health Sciences Center
🇺🇸
Shreveport, Louisiana, United States
Centro de Estudos da Disciplina dr Hematologia da Faculdade de Medicine do ABC
🇧🇷
Santo Andre, Sp - Brazil, Brazil
Hospital de Clinicas - Universidade Federal do Parana
🇧🇷
Curitiba, PR, Brazil
UMCG - Pharmacy
🇳🇱
Groningen, Netherlands
Saint Petersburg State Medical University Hematology Department
🇷🇺
Saint Petersburg, Russian Federation
National Taiwan University Hospital - Section of Hematology-Oncology
🇨🇳
Taipei 100, Taiwan
Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
🇧🇷
Sao Paulo, Sp Brazil, Brazil
BC Cancer Agency - Cancer Centre for the Southern Interior
🇨🇦
Kelowna, British Columbia, Canada
Hospital Italiano de la Plata
🇦🇷
La Plata, Provincia de Buenos Aires, Argentina
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
University of Rochester Cancer Center Pharmacy
🇺🇸
Rochester, New York, United States
Queen Mary Hospital
🇭🇰
Hong Kong, Hong Kong
Pamela Youde Nethersole Eastern Hosp.
🇭🇰
Chai Wan, Hong Kong