INSPIRE: Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA

Sponsor

Onconova Therapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02562443

Collaborator

(none)

360

Enrollment

158

Locations

Arms

Anticipated Duration (Months)

2.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study's primary objective [in a population of patients with MDS after failure of treatment with azacitidine (AZA) or decitabine (DAC)], is to compare the overall survival (OS) of patients in the rigosertib group vs the Physician's Choice group, in all patients and in a subgroup of patients with IPSS-R very high risk.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome MDS Refractory Anemia With Excess Blasts RAEB	Drug: rigosertib Drug: Any approved or standard-of-care therapy Drug: best supportive care (BSC) Drug: best supportive care (BSC)	Phase 3

Detailed Description

This is a Phase III, open-label, randomized, controlled, international study. Approximately 360 patients < 82 years of age with MDS classified as RAEB-1, RAEB-2, or RAEB-t who received AZA or DAC for ≤ 9 months and/or ≤ 9 cycles over 12 months and had their last dose of AZA or

DAC within 6 months prior to screening will be stratified by:

Very high risk (VHR) vs non-VHR per IPSS-R, and
Geographic region (North America vs Europe vs Asia; because approved products and standard of care may vary by region), and randomly assigned in a 2:1 ratio to one of the following 2 treatment groups:
Rigosertib 1800 mg/24 hr administered as a 72 hr CIV infusion on Days 1, 2, and 3 of a 2 week cycle for the first 8 cycles, and on Days 1, 2, and 3 of a 4-week cycle thereafter (N = approximately 240 patients);
Physician's Choice of alternative treatment, which may include any approved or standard-of-care therapy that the patient has not shown to be hypersensitive to, based on frequently used treatment for MDS, as per institutional guidelines, after receipt of HMAs (N = approximately 120 patients). The drugs used in the Physician's Choice arm should be used according to the recommendations, if clinically appropriate, provided in the corresponding Summary of Product Characteristics (SmPC) and Prescribing Information of these drugs. Experimental therapies are not allowed on the PC arm.

Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias) or until an unacceptable toxicity or intolerance.

For all randomized patients who discontinue study treatment, subsequent therapies with their start and end dates, as well as survival time after treatment discontinuation, will be documented at least monthly until death.

Patients in the PC group who progress will not be allowed to cross over to rigosertib.

All patients in both treatment groups will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (granulocyte colony-stimulating factor (G-CSF), erythropoietin, and thrombopoietin).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

360 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III, International, Randomized, Controlled Study of Rigosertib Versus Physician's Choice of Treatment in Patients With Myelodysplastic Syndrome After Failure of a Hypomethylating Agent

Actual Study Start Date :

Dec 2, 2015

Actual Primary Completion Date :

Oct 17, 2020

Anticipated Study Completion Date :

Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rigosertib + best supportive care (BSC)	Drug: rigosertib Patients will receive intravenous rigosertib 1800 mg/24 hr for 3 days every 2 weeks for first 8 cycles, then every 4 weeks thereafter + best supportive care (BSC). Other Names: ON 01910.Na Drug: best supportive care (BSC) Patients will receive best supportive care (BSC).
Active Comparator: Physician's Choice (PC) + best supportive care (BSC)	Drug: Any approved or standard-of-care therapy Patients will receive Physician's Choice of Treatment or alternative treatment which may include any approved or standard-of-care therapy, based on frequently used treatment for MDS (no experimental therapy) + best supportive care. Drug: best supportive care (BSC) Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.

Arm

Intervention/Treatment

Experimental: rigosertib + best supportive care (BSC)

Drug: rigosertib

Patients will receive intravenous rigosertib 1800 mg/24 hr for 3 days every 2 weeks for first 8 cycles, then every 4 weeks thereafter + best supportive care (BSC).

Other Names:

ON 01910.Na

Drug: best supportive care (BSC)

Patients will receive best supportive care (BSC).

Active Comparator: Physician's Choice (PC) + best supportive care (BSC)

Drug: Any approved or standard-of-care therapy

Patients will receive Physician's Choice of Treatment or alternative treatment which may include any approved or standard-of-care therapy, based on frequently used treatment for MDS (no experimental therapy) + best supportive care.

Drug: best supportive care (BSC)

Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.

Outcome Measures

Primary Outcome Measures

Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk. [Up to 30 Months]
The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.

Secondary Outcome Measures

Overall survival of patients with monosomy 7 chromosomal aberrations. [Up to 30 Months]
Evaluate OS of patients with monosomy 7 chromosomal aberrations in the rigosertib vs PC group. Overall survival is the time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.
Overall survival of patients with trisomy 8 chromosomal aberrations. [Up to 30 Months]
Evaluate OS of patients with trisomy 8 chromosomal aberrations in the rigosertib vs PC group. Overall survival is the time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.
Percent of patients with response according to 2006 IWG criteria. [Up to 30 Months]
Responses of complete remission (CR), partial remission (PR), mCR, SD, failure, and PD will be determined by 2006 IWG criteria. The number and percent of patients with CR, PR, mCR, SD, Failure, or PD will be summarized by treatment group.
Scores of Quality of Life Questionnaire. [At Baseline, at Week 4, Every 4 Weeks thereafter, and at the End-of-treatment.]
Compare rigosertib vs PC in regard to the the scores of the EuroQol EQ-5D-5L Questionnaire. The EuroQol EQ-5D-5L Questionnaire includes five levels of severity in each of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and a visual analogue scale.
Percent of patients with bone marrow blast response rate according to 2006 IWG criteria. [Up to 30 Months]
Compare rigosertib vs PC in regard to the bone marrow blast responses of marrow complete response (mCR ≥ 50% decrease of BMBL vs pretreatment values to a value ≤ 5%), marrow partial response (mPR, ≥ 50% decrease of BMBL vs pretreatment values to a value > 5%), stable disease (SD, no mCR or mPR, but no progressive disease (PD), and PD (≥ 50% BMBL increase relative to baseline or nadir) will be assessed. The number and percent of patients with mCR, mPR, SD, or PD will be summarized by treatment group. Responses of complete remission (CR), partial remission (PR), mCR, SD, failure, and PD will be determined by 2006 International Working Group (IWG) criteria.
Percent of patients with hematologic improvement (HI) (erythroid, platelet and neutrophil responses) according to 2006 IWG criteria. [Up to 30 Months]
Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.

Other Outcome Measures

Exploratory Objective: Bone Marrow Genomic Mutational Status [At screening, every 8 week during study treatment, and at the end of study treatment]
Bone marrow genomic mutational status.
Exploratory Objective: Transition to Acute Myelogenous Leukemia (AML) [Through study completion, an average of 8 months]
Transformation time to AML (defined as a bone marrow or peripheral blood blast percentage >30%).
Safety Objective: Number of Patients with AEs. [Monthly, through study completion]
Treatment-emergent adverse events (TEAEs) will be graded according to NCI CTCAE version 4, grouped by MedDRA preferred term, and summarized by worst grade of severity per patient by treatment group.
Safety Objective: Rigosertib population pharmacokinetics (PK). [At Cycle 1 (Week 1) and Cycle 2 (Week 3), on Day 1 of the infusion, 1 hr after its start and on Day 2 of the infusion, 6 hr after its start]
Blood samples for population PK analysis will be taken in rigosertib patients

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 81 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

MDS classified as follows:
RAEB-1 per World Health Organization (WHO) MDS criteria (5% to <10% BM blasts)
RAEB-2 per WHO MDS criteria (10% to <20% BM blasts)
RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts)
At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin [Hgb] < 10 g/dL)
Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DAC treatment or Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC administered or Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
Duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy in ≤ 12 months
Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation
Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Willing to adhere to protocol prohibitions and restrictions
Patient must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate. Should patient be incapable of giving consent, the patient's legally authorized representative (as defined by local regulation) must give consent. However, should patient, in any manner, choose not to participate this takes precedence and will be respected.
Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide, where available and indicated

Exclusion Criteria:

Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening for other rigosertib studies may be screened for participation
Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside plus 2-3 days of an anthracycline, or high-dose cytarabine
Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell transplant or a suitable donor cannot be found
Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ that is unlikely to progress in two years
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
Active infection not adequately responding to appropriate therapy
Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert's disease
Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN)
Serum creatinine ≥2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) < 40 mL/min.
Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:
HIV or hepatitis C - presence of viral load
Hepatitis B - antigen positive
Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)
Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day non-treatment follow-up period. Examples of acceptable contraception methods include:
estrogen-gestagen based contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal),
gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable),
intra-uterine devices (IUDs),
intra-uterine hormone-releasing systems (IUSs),
bilateral tubal occlusion
vasectomized partner
sexual abstinence in accordance with an individual's lifestyle
Female patients of child-bearing potential (pre-menopausal and not surgically sterilized) who are breast-feeding or have a positive blood beta-human chorionic gonadotropin pregnancy test at Screening
Major surgery without full recovery or within 3 weeks before planned randomization;
Uncontrolled hypertension
New onset seizures (within 3 months before planned randomization) or poorly controlled seizures
Any other concurrent investigational agent or chemotherapy, radiotherapy, immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions)
Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization
Investigational therapy within 4 weeks of planned randomization
Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage of >30%).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
2	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	UCLA Medical Center	Los Angeles	California	United States	90095
4	Cancer Specialists of North Florida	Fleming Island	Florida	United States	32003
5	UF Health Shands Cancer Hospital	Gainesville	Florida	United States	32608
6	Mid Florida Hematology and Oncology Centers	Orange City	Florida	United States	32763
7	Advanced Research Institute, Inc	Saint Petersburg	Florida	United States	33710
8	Rush University Medical Center	Chicago	Illinois	United States	60612
9	University of Illinois Cancer Center	Chicago	Illinois	United States	60612
10	Loyola University Chicago at Loyola University Medical Center	Maywood	Illinois	United States	60153
11	Indiana University Health Hospital	Indianapolis	Indiana	United States	46202
12	The University of Kansas Cancer Center	Westwood	Kansas	United States	66205
13	Tulane Medical Center	New Orleans	Louisiana	United States	70112
14	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
15	Tufts Medical Center	Boston	Massachusetts	United States	02111
16	University of Minnesota Physicians Bone Marrow Transplant Clinic	Minneapolis	Minnesota	United States	55455
17	Mayo Clinic	Rochester	Minnesota	United States	55905
18	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
19	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
20	The Valley Hospital	Ridgewood	New Jersey	United States	07450
21	Mount Sinai School of Medicine	New York	New York	United States	10029
22	Columbia University Medical Center	New York	New York	United States	10032
23	New York Medical College	Valhalla	New York	United States	10595
24	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
25	Albert Einstein Medical Center, Cancer Center	Philadelphia	Pennsylvania	United States	19141
26	Greenville Health System (GHS) Cancer Institute	Greenville	South Carolina	United States	29605
27	UT Southwestern Medical Center	Dallas	Texas	United States	75390-9015
28	MD Anderson Cancer Center	Houston	Texas	United States	77030
29	Emily Couric Clinical Cancer Center	Charlottesville	Virginia	United States	22903
30	Seattle Cancer Care Alliance (SCCA)	Seattle	Washington	United States	98109
31	University of Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53792
32	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
33	Icon Cancer Care Icon South Brisbane	South Brisbane	Queensland	Australia	4101
34	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
35	Monash Health, Monash Medical Centre	Melbourne	Victoria	Australia	3168
36	Hospital of the Elisabethinen Linz GmbH	Linz		Austria	4020
37	Salzburg University Hospital	Salzburg		Austria	5020
38	Hanusch Hospital	Vienna		Austria	1140
39	Antwerp Hospital Network Stuivenberg	Antwerp		Belgium	2060
40	University Hospital Ghent	Ghent		Belgium	9000
41	University Hospital Leuven, Campus Gasthuisberg	Leuven		Belgium	3000
42	CHU UCL Namur - Site Godinne	Yvoir		Belgium	B-5530
43	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
44	Sunnybrook Research Institute	Toronto	Ontario	Canada	M4N 3M5
45	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
46	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
47	Klinički bolnički centar Osijek	Osijek		Croatia	31000
48	Clinical Hospital Merkur	Zagreb		Croatia	10000
49	Klinički bolnicki centar Sestre milosrdnice	Zagreb		Croatia	10000
50	Klinički bolnički centar Zagreb	Zagreb		Croatia	10000
51	University Hospital Brno	Brno		Czechia	625 00
52	University Hospital Hradec Kralove	Hradec Kralove		Czechia	500 05
53	University Hospital Ostrava, Department of Hematooncology	Ostrava Poruba		Czechia	708 52
54	General University Hospital	Prague 2		Czechia	128 00
55	Institute of Hematology and Blood Transfusion	Prague 2		Czechia	128 20
56	North Estonia Medical Centre	Tallinn		Estonia	13419
57	Tartu University Hospital	Tartu		Estonia	51014
58	CHD Vendée	La Roche Sur Yon Cedex 9		France	85925
59	Hôpital Claude Huriez, CHRU Lille	Lille Cedex		France	59037
60	Institut Paoli-Calmettes	Marseille		France	13009
61	Hôpital l'Archet 1	Nice Cedex 3		France	06202
62	Institut de Cancérologie du Gard	Nimes Cedex 9		France	30029
63	Hôpital Saint Louis	Paris Cedex 10		France	75475
64	Centre Hospitalier Lyon-Sud	Pierre-Bénite		France	69495
65	Hôpital civil, Strasbourg	Strasbourg Cedex		France	67091
66	CHRU Tours Hôspital Bretonneau	Tours		France	37044
67	Universitätsklinikum Carl Gustav Carus	Dresden		Germany	01307
68	Marien Hospital Düsseldorf	Düsseldorf		Germany	40479
69	Universitätsklinikum Frankfurt am Main	Frankfurt		Germany	60590
70	Semmelweis University Medical School	Budapest		Hungary	1083
71	Somogy County Kaposi Mór Teaching Hospital	Kaposvár		Hungary	7400
72	Jósa András Teaching Hospital	Nyíregyháza		Hungary	4400
73	University of Pécs 1st Department of Internal Medicine	Pécs		Hungary	7624
74	Hemato Oncology Clinic Pvt. Ltd	Ahmedabad	Gujarat	India	380009
75	St. John's Medical College Hospital	Bangalore	Karnataka	India	560034
76	Tata Memorial Hospital	Mumbai	Maharashtra	India	400012
77	Jaslok Hospital and Research Center	Mumbai	Maharashtra	India	400026
78	Sahyadri Clinical Research and Development Center	Pune	Maharashtra	India	411004
79	Christian Medical College	Vellore	Tamil Nadu	India	632004
80	Institute Of Hematology And Transfusion Medicine	Kolkata	West Bengal	India	700073
81	Cork University Hospital	Cork		Ireland
82	Adelaide and Meath Hospital, Incorporating the National Children's Hospital	Dublin		Ireland	Dublin 24
83	University Hospital Waterford	Waterford		Ireland
84	Ha'Emek Medical Center	'Afula		Israel	1834111
85	Soroka University Medical Center	Beer Sheva		Israel	84101
86	Rambam Medical Center	Haifa		Israel	31096
87	Hadassah Medical Center	Jerusalem		Israel	91120
88	Kaplan Medical Center	Rehovot		Israel	76100
89	Sourasky Medical Center	Tel Aviv		Israel	64239
90	The Chaim Sheba Medical Center	Tel Hashomer		Israel	52621
91	Polyclinic S. Orsola-Malpighi	Bologna		Italy	40138
92	Azienda Ospedaliera Spedali Civili	Brescia		Italy	25123
93	Azienda Ospedaliero Universitaria Careggi	Firenze		Italy	50134
94	Azienda Ospedaliero-Universitaria Maggiore della Carità	Novara		Italy	28100
95	A.O.U. Pisana, Divisione di Ematologia - University Hospital of Pisa	Pisa		Italy	56126
96	Policlinico Universitario Tor Vergata	Roma		Italy	00133
97	Ospedale S. Eugenio - S. Eugenio Hospital	Roma		Italy	00144
98	Azienda Ospedaliera Santa Maria di Terni	Terni		Italy	05100
99	Cittá della Salute e della Scienza di Torino	Torino		Italy	10126
100	Kokura Memorial Hospital	Kitakyushu	Fukuoka	Japan	802-8555
101	Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers	Fukuyama	Hiroshima	Japan	720-0001
102	Sapporo Medical University Hospital	Sapporo	Hokkaido	Japan	060-8556
103	Kanazawa University Hospital	Kanazawa	Ishikawa	Japan	920-8641
104	Yokohama City University Hospital	Yokohama-shi	Kanagawa	Japan	236-0004
105	Shimane University Hospital	Izumo	Shimane	Japan	693-8501
106	Japanese Red Cross Medical Center	Shibuya	Tokyo	Japan	150-8935
107	Akita University Hospital	Akita		Japan	010-8543
108	Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital	Bunkyo-ku		Japan	113-8677
109	National Hospital Organization Kyushu Cancer Center	Fukuoka-shi		Japan	811-1395
110	Kagoshima University Hospital	Kagoshima		Japan	890-8544
111	Tokai Central Hospital of the Mutual Aid Association of Public School Teachers	Kakamigahara		Japan	504-8601
112	Saitama Medical Center	Kawagoe		Japan	350-8550
113	Kobe City Hospital Organization Kobe City Medical Center General Hospital	Kobe		Japan	650-0047
114	National Hospital Organization Kumamoto Medical Center	Kumamoto		Japan	860-008,
115	Japanese Red Cross Kyoto Daini Hospital	Kyoto		Japan	602-8026
116	Nagasaki University Hospital	Nagasaki		Japan	852-8102
117	Japanese Red Cross Nagoya Daini Hospital	Nagoya-shi		Japan	466-8650
118	Niigata University Medical and Dental Hospital	Niigata		Japan	951-8510,
119	Oita Prefectural Hospital	Oita		Japan	870-8511
120	National Hospital Organization Okayama Medical Center	Okayama		Japan	701-1192
121	Kindai University Hospital	Osakasayama-shi		Japan	589-8511
122	Hokkaido University Hospital	Sapporo-shi		Japan	060-8648
123	Tohoku University Hospital	Sendai-shi		Japan	980-8574
124	NTT Medical Center Tokyo	Shinagawa-ku		Japan	141-8625
125	Tokyo Medical University Hospital	Shinjuku-ku		Japan	160-0023
126	Dokkyo Medical University Hospital	Tochigi		Japan	321-0293
127	Tokushima University Hospital	Tokushima		Japan	770-8503
128	Yamagata University Hospital	Yamagata		Japan	990-9585
129	Saiseikai Yokohamashi Nanbu Hospital	Yokohama-shi		Japan	234-8503
130	University of Fukui Hospital	Yoshida		Japan	910-1193
131	Independent Public Healthcare Facility University Hospital in Cracow, Clinical Department of Hematology	Kraków		Poland	31-501
132	Independent Public Health Care Facility of the Ministry of Internal Affairs with Warmia and Mazury Oncology Centre in Olsztyn	Olsztyn		Poland	10-228
133	Ludwik Rydygier Provinicial Hospital in Suwalki, Department of Clinical Oncology and Hematology	Suwalki		Poland	16-400
134	MTZ Clinical Research Sp. z o.o.	Warsaw		Poland	02-106
135	Independent Public University Hospital No. 1 in Wroclaw, Department of Hematology, Blood Cancers and Bone Marrow	Wroclaw		Poland	50-367
136	State Autonomous Healthcare Institution of Kemerovo region "Kemerovo Regional Clinical Hospital n.a. S.V. Belyaev",	Kemerovo		Russian Federation	650066
137	State Budgetary Healthcare Institution of Moscow City	Moscow		Russian Federation	129301
138	FSBI "Russian Scientific Research Hematology and Tranfusiology Institute of the Federal Biomedical Agency"	Saint Petersburg		Russian Federation	191024
139	Hospital Son Llàtzer	Palma de Mallorca	Balearic Islands	Spain	07198
140	Hospital Duran i Reynals - Instituto Catalán de Oncología	Hospitalet de Llobregat	Barcelona	Spain	08908
141	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
142	Hospital Universitari Germans Trias i Pujol	Barcelona		Spain	08916
143	Hospital Universitario Gregorio Marañón	Madrid		Spain	28007
144	Fundación Jiménez Díaz	Madrid		Spain	28040
145	Hospital Universitario Virgen de la Victoria	Málaga		Spain	29010
146	Hospital Universitario Salamanca	Salamanca		Spain	37007
147	Hospital Universitari i Politècnic La Fe	Valencia		Spain	46026
148	Karolinska University Hospital	Stockholm	Huddinge	Sweden	141 57
149	Skåne University Hospital, Department of Hematology	Lund		Sweden	222 82
150	Uppsala University Hospital	Uppsala		Sweden	751 81
151	Linköping University Hospital	Linköping	Östergötland	Sweden	581 85
152	University Hospital and University of Bern; Inselspital Bern	Bern		Switzerland	3010
153	University Hospital Zurich	Zurich		Switzerland	8091
154	Royal Bournemouth Hospital	Bournemouth	Dorset	United Kingdom	BH7 7DW
155	Aberdeen Royal Infirmary	Aberdeen	Scotland	United Kingdom	AB25 2ZN
156	The Royal Liverpool University Hospital	Liverpool		United Kingdom	L7 8XP
157	St Bartholomew's Hospital, Barts Health NHS Trust	London		United Kingdom	EC1A 7BE
158	King's College Hospital NHS Foundation Trust	London		United Kingdom	SE5 9RS