Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome

Sponsor

Children's Oncology Group (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02521493

Collaborator

National Cancer Institute (NCI) (NIH)

312

Enrollment

191

Locations

Arms

103.2

Anticipated Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase III trial studies response-based chemotherapy in treating newly diagnosed acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Response-based chemotherapy separates patients into different risk groups and treats them according to how they respond to the first course of treatment (Induction I). Response-based treatment may be effective in treating acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome while reducing the side effects.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Down Syndrome Myelodysplastic Syndrome Myeloid Leukemia Associated With Down Syndrome Myeloproliferative Neoplasm	Drug: Asparaginase Drug: Asparaginase Erwinia chrysanthemi Drug: Cytarabine Drug: Daunorubicin Hydrochloride Drug: Etoposide Other: Laboratory Biomarker Analysis Drug: Mitoxantrone Hydrochloride Drug: Thioguanine	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

To determine the 2-year event-free-survival (EFS) for children with standard risk Down syndrome (DS) acute myeloid leukemia (AML) (minimal residual disease [MRD]-negative after one cycle of induction therapy) after elimination of high dose (HD) Ara-C (cytarabine) from the treatment regimen.
To determine the 2-year EFS for children with high risk DS AML (MRD-positive after one cycle of induction therapy) after intensification of treatment equivalent to that used for high risk AML in children without DS.

EXPLORATORY OBJECTIVES:

To compare the feasibility and analytical characteristics of flow cytometry, polymerase chain reaction (PCR) and targeted error-corrected sequencing of GATA binding protein 1 (globin transcription factor 1) (GATA1) mutations as methods to detect MRD in DS AML.
To establish a DS AML cell bank of viably frozen bone marrow samples collected at the end of induction and corresponding non-tumor deoxyribonucleic acid (DNA) samples collected at end of Induction 1.

OUTLINE:

INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and intravenously (IV) continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine orally (PO) twice daily (BID) on days 1-4. Induction I continues for a minimum of 28 days.

Patients are assigned to 1 of 2 treatment arms based on their MRD status after completion of Induction I.

ARM A (STANDARD RISK) (Closed to accrual and treatment with amendment #4A 01/07/2019):

INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days.

INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days.

INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days.

ARM B (HIGH RISK):

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours every 12 (Q12) hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days.

INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days.

INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi (E. carotovora) intramuscularly (IM) or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.

After completion of study treatment, patients are followed up at 1 month, monthly for 12 months, every 3 months for 12 months, every 6 months for 3 years, annually for 10 years, and in case of relapse.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

312 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome

Actual Study Start Date :

Nov 23, 2015

Anticipated Primary Completion Date :

Jun 30, 2024

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (standard risk) INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days. INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days. INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days. (This arm is closed to accrual and treatment with amendment #4A 01/07/2019)	Drug: Cytarabine Given IT and IV Drug: Daunorubicin Hydrochloride Given IV Drug: Etoposide Given IV Other: Laboratory Biomarker Analysis Correlative studies Drug: Thioguanine Given PO
Experimental: Arm B (high risk) INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days. INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi IM or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.	Drug: Asparaginase Given IM or IV Drug: Asparaginase Erwinia chrysanthemi Given IM or IV Drug: Cytarabine Given IT and IV Other: Laboratory Biomarker Analysis Correlative studies Drug: Mitoxantrone Hydrochloride Given IV

Arm

Intervention/Treatment

Experimental: Arm A (standard risk)

INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days. INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days. INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days. (This arm is closed to accrual and treatment with amendment #4A 01/07/2019)

Drug: Cytarabine

Given IT and IV

Drug: Daunorubicin Hydrochloride

Given IV

Drug: Etoposide

Given IV

Other: Laboratory Biomarker Analysis

Correlative studies

Drug: Thioguanine

Given PO

Experimental: Arm B (high risk)

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days. INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi IM or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.

Drug: Asparaginase

Given IM or IV

Drug: Asparaginase Erwinia chrysanthemi

Given IM or IV

Drug: Cytarabine

Given IT and IV

Other: Laboratory Biomarker Analysis

Correlative studies

Drug: Mitoxantrone Hydrochloride

Given IV

Outcome Measures

Primary Outcome Measures

Event-free survival probability at 2 years [At 2 years]
The Kaplan-Meier method will be used to estimate 2-year event-free survival (EFS) from the end of Induction I along with 95% log-minus-log transformed confidence limits. EFS is defined as the time from the end of Induction I to failure to achieve remission at the end of Induction II, relapse, occurrence of a second malignancy, or death.

Other Outcome Measures

Mean length on protocol therapy [6 months]
The mean number of days patients spent on protocol therapy.
Proportion of patients with an early death [1 month]
The proportion of patients experiencing an early death in the first month.
Overall survival probability at 2 years. [2 years]
The Kaplan-Meier method will be used to estimate 2-year Overall Survival (OS) from the end of Induction I along with 95% log-minus-log transformed confidence limits. OS is defined as the time from the end of Induction I to death.
Proportion with treatment related mortality [6 months]
The proportion of patients experiencing a treatment related death will be reported along with a corresponding confidence interval.
Proportion of patients experiencing a relapse risk [2 years]
The proportion of patients experiencing a relapse after achieving remission will be reported along with a corresponding confidence interval.
Percentage of patients experiencing grade 3 or adverse events [6 months]
The percentage of patients experiencing grade 3 or higher toxicity will be reported, where adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Mean time to absolute neutrophil count (ANC) recovery [6 months]
The mean time to recovery of ANC to at least 1000/uL will be reported.
Mean duration of hospitalization [6 months]
Mean number of days patients are hospitalized.
Proportion of patients with at least 1 infection [6 months]
The proportion of patients having at least one infection will be reported.

Eligibility Criteria

Criteria

Ages Eligible for Study:

91 Days to 3 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have constitutional trisomy 21 (Down syndrome) or trisomy 21 mosaicism (by karyotype or fluorescence in situ hybridization [FISH])
Patient has one of the following:
Patient has previously untreated de novo AML and meets the criteria for AML with

= 20% bone marrow blasts as set out in the World Health Organization (WHO) Myeloid Neoplasm classification

Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive; in cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis
Patient has cytopenias and/or bone marrow blasts but does not meet the criteria for the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20% marrow blasts and meets the criteria for a diagnosis of myelodysplastic syndrome (MDS)
For patients who do not meet criteria for AML or MDS as outlined above; patient has a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention and:
Is > 8 weeks since resolution of transient myeloproliferative disease (TMD) with >= 5% blasts, OR
Has an increasing blast count (>= 5%) in serial bone marrow aspirates performed at least 4 weeks apart
Children who have previously received chemotherapy, radiation therapy or any anti-leukemic therapy are not eligible for this protocol, with the exception of cytarabine for the treatment of TMD
There are no minimal organ function requirements for enrollment on this study
Note: Previous cardiac repair with sufficient cardiac function is not an exclusion criteria
Each patient's parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human subjects research must be met

Exclusion Criteria:

Patients with promyelocytic leukemia (French-American-British [FAB] M3)
Prior therapy
Patients =< 30 days from the last dose of cytarabine used for treatment of TMD

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
3	Banner Children's at Desert	Mesa	Arizona	United States	85202
4	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
5	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
6	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
7	Loma Linda University Medical Center	Loma Linda	California	United States	92354
8	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
9	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
10	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
11	Valley Children's Hospital	Madera	California	United States	93636
12	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
13	Kaiser Permanente-Oakland	Oakland	California	United States	94611
14	Children's Hospital of Orange County	Orange	California	United States	92868
15	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
16	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
17	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
18	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
19	Naval Medical Center -San Diego	San Diego	California	United States	92134
20	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
21	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California	United States	90502
22	Children's Hospital Colorado	Aurora	Colorado	United States	80045
23	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
24	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
25	Yale University	New Haven	Connecticut	United States	06520
26	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
27	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
28	Children's National Medical Center	Washington	District of Columbia	United States	20010
29	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
30	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
31	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
32	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
33	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
34	Palms West Radiation Therapy	Loxahatchee Groves	Florida	United States	33470
35	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
36	Nicklaus Children's Hospital	Miami	Florida	United States	33155
37	AdventHealth Orlando	Orlando	Florida	United States	32803
38	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
39	Nemours Children's Hospital	Orlando	Florida	United States	32827
40	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
41	Sacred Heart Hospital	Pensacola	Florida	United States	32504
42	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
43	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
44	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
45	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
46	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
47	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
48	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
49	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
50	University of Illinois	Chicago	Illinois	United States	60612
51	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
52	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
53	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois	United States	60068
54	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
55	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
56	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
57	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
58	Blank Children's Hospital	Des Moines	Iowa	United States	50309
59	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
60	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
61	Norton Children's Hospital	Louisville	Kentucky	United States	40202
62	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
63	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
64	Eastern Maine Medical Center	Bangor	Maine	United States	04401
65	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
66	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
67	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
68	Tufts Children's Hospital	Boston	Massachusetts	United States	02111
69	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
70	Baystate Medical Center	Springfield	Massachusetts	United States	01199
71	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts	United States	01655
72	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
73	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
74	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
75	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
76	Hurley Medical Center	Flint	Michigan	United States	48503
77	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
78	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
79	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
80	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
81	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
82	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
83	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
84	Columbia Regional	Columbia	Missouri	United States	65201
85	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
86	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
87	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
88	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
89	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
90	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
91	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
92	Renown Regional Medical Center	Reno	Nevada	United States	89502
93	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
94	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
95	Morristown Medical Center	Morristown	New Jersey	United States	07960
96	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
97	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
98	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
99	Presbyterian Hospital	Albuquerque	New Mexico	United States	87106
100	Albany Medical Center	Albany	New York	United States	12208
101	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
102	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
103	NYU Winthrop Hospital	Mineola	New York	United States	11501
104	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
105	Mount Sinai Hospital	New York	New York	United States	10029
106	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
107	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
108	University of Rochester	Rochester	New York	United States	14642
109	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
110	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
111	New York Medical College	Valhalla	New York	United States	10595
112	Mission Hospital	Asheville	North Carolina	United States	28801
113	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
114	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
115	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
116	Duke University Medical Center	Durham	North Carolina	United States	27710
117	East Carolina University	Greenville	North Carolina	United States	27834
118	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
119	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
120	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
121	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
122	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
123	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
124	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
125	Dayton Children's Hospital	Dayton	Ohio	United States	45404
126	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
127	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
128	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
129	Oregon Health and Science University	Portland	Oregon	United States	97239
130	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
131	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
132	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
133	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
134	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
135	Rhode Island Hospital	Providence	Rhode Island	United States	02903
136	Medical University of South Carolina	Charleston	South Carolina	United States	29425
137	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
138	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
139	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
140	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
141	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
142	The Children's Hospital at TriStar Centennial	Nashville	Tennessee	United States	37203
143	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
144	Texas Tech University Health Sciences Center-Amarillo	Amarillo	Texas	United States	79106
145	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
146	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
147	Medical City Dallas Hospital	Dallas	Texas	United States	75230
148	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
149	El Paso Children's Hospital	El Paso	Texas	United States	79905
150	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
151	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
152	Covenant Children's Hospital	Lubbock	Texas	United States	79410
153	UMC Cancer Center / UMC Health System	Lubbock	Texas	United States	79415
154	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
155	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
156	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
157	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
158	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
159	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
160	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
161	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
162	Seattle Children's Hospital	Seattle	Washington	United States	98105
163	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
164	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
165	Madigan Army Medical Center	Tacoma	Washington	United States	98431
166	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
167	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
168	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
169	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
170	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales	Australia	2310
171	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
172	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
173	Royal Children's Hospital	Parkville	Victoria	Australia	3052
174	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
175	Perth Children's Hospital	Perth	Western Australia	Australia	6009
176	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
177	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
178	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
179	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
180	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
181	Children's Hospital	London	Ontario	Canada	N6A 5W9
182	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
183	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
184	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
185	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
186	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
187	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
188	Christchurch Hospital	Christchurch		New Zealand	8011
189	San Jorge Children's Hospital	San Juan		Puerto Rico	00912
190	University Pediatric Hospital	San Juan		Puerto Rico	00926
191	King Faisal Specialist Hospital and Research Centre	Riyadh		Saudi Arabia	11211