Combination Chemotherapy Followed By Stem Cell Transplant in Treating Young Patients With Progressive or Relapsed Anaplastic Large Cell Lymphoma

Sponsor

European Inter-group Cooperation on Childhood and Adolescent Non Hodgkin Lymphoma (Other)

Overall Status

Unknown status

CT.gov ID

NCT00317408

Collaborator

(none)

Enrollment

Locations

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Giving combination chemotherapy and total-body irradiation before a peripheral stem cell transplant that uses the patient's or a donor's stem cells, helps stop both the growth of cancer cells and the patient's immune system from rejecting the stem cells. When the stem cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving combination chemotherapy and total-body irradiation followed by a stem cell transplant may be an effective treatment for anaplastic large cell lymphoma.

PURPOSE: This clinical trial is studying how well combination chemotherapy followed by stem cell transplant works in treating young patients with progressive or relapsed anaplastic large cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: anti-thymocyte globulin Drug: busulfan Drug: carboplatin Drug: carmustine Drug: cyclosporine Drug: cytarabine Drug: dexamethasone Drug: etoposide phosphate Drug: idarubicin Drug: ifosfamide Drug: leucovorin calcium Drug: lomustine Drug: melphalan Drug: methotrexate Drug: mitoxantrone hydrochloride Drug: prednisolone Drug: thiotepa Drug: vinblastine sulfate Drug: vindesine Procedure: allogeneic hematopoietic stem cell transplantation Procedure: autologous hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Radiation: total-body irradiation	N/A

Detailed Description

OBJECTIVES:

Primary

Improve the probability of event-free survival in children and adolescents with early progression of anaplastic large cell lymphoma (ALCL) and/or relapse of ALCL with CD3-positive immunophenotype treated with reinduction combination chemotherapy followed by allogeneic or autologous stem cell transplantation.
Determine whether a conditioning regimen comprising carmustine, etoposide phosphate, cytarabine, and melphalan (BEAM) (without total body irradiation) for autologous stem cell transplantation is an effective treatment for patients with relapsed CD3-negative ALCL occurring after the intensive phase of treatment.
Determine the impact of vinblastine in patients with late relapse of CD3-negative ALCL who have not received vinblastine during frontline therapy.

Secondary

Determine overall survival and treatment-related mortality in patients treated with these regimens.
Determine acute and long-term toxicity in patients treated with these regimens.
Determine the rate of acute and chronic graft-vs-host disease in patients treated with allogeneic stem cell transplantation.

OUTLINE: This is a multicenter, prospective, nonrandomized study. Patients are stratified according to time from initial diagnosis to progression/relapse, immunophenotype of lymphoma cells (CD3-positive + vs CD3-negative), stem cell donor availability (matched sibling donor vs 9/10 or 10/10 matched unrelated donor), and vinblastine during frontline therapy (yes vs no).

Group 1 (early progression): Patients receive 1 course of ICM chemotherapy followed by 1 course of ICI chemotherapy.
ICM chemotherapy: Patients receive methotrexate, cytarabine, and prednisolone intrathecally (IT) on day 1, mitoxantrone hydrochloride IV over 5 hours on days 1 and 2, carboplatin IV continuously on days 2-5 and ifosfamide IV continuously on days 2-6.
ICI chemotherapy: Patients receive methotrexate, cytarabine, and prednisolone intrathecally on day 1, idarubicin IV over 4 hours on days 1 and 2, carboplatin IV continuously on days 2-5, and ifosfamide IV continuously on days 2-6.

Patients then proceed to allogeneic stem cell transplantation.

Group 2 (relapsed disease and CD3-positive lymphoma cells): Patients are stratified according to stem cell donor availability (yes vs no).
Available donor: Patients receive 2 courses of CC chemotherapy and then proceed to allogeneic stem cell transplantation.
Unavailable donor : Patients receive 2 courses of CC chemotherapy comprising dexamethasone orally or IV on days 1-5, vindesine IV on day 1, cytarabine IV over 3 hours on days 1 and 2, etoposide phosphate IV over 2 hours on days 3-5, and methotrexate, cytarabine, and prednisolone IT on day 5. Patients then receive 1 course of CVA chemotherapy comprising oral lomustine on day 1, vinblastine IV on days 1, 8, 15, and 22, and cytarabine IV over 1 hour on days 1-5. Patients undergo leukapheresis for collection of autologous peripheral blood stem cells after the first and/or second course of CC chemotherapy. Patients then proceed to autologous stem cell transplantation.
Group 3 (relapsed disease, CD3-negative immunophenotype, and received vinblastine during frontline therapy): Patients receive 2 courses of CC chemotherapy and 1 course of CVA chemotherapy as described above. Patients undergo leukapheresis for collection of autologous peripheral blood stem cells (PBSC) after the first and/or second course of CC chemotherapy. Patients then proceed to autologous stem cell transplantation.
Group 4 (late relapse, CD3-negative immunophenotype, and did not receive vinblastine during frontline therapy): Patients receive vinblastine IV once weekly for 24 months. Patients with disease progression during or relapsed disease after vinblastine therapy undergo treatment as in group 3.
Autologous stem cell transplantation (SCT): Patients receive a conditioning regimen comprising carmustine IV over 1 hour on day -7, etoposide phosphate IV over 1 hour and cytarabine IV over 30 minutes on days -6 to -3, and melphalan IV over 15 minutes on day -2. Patients undergo autologous SCT on day 0.
Allogeneic SCT: Beginning 4-6 weeks after the start of the last chemotherapy course, patients receive 1 of the following conditioning regimens based on age:
Patients > 2 years of age undergo total body irradiation on days -7 to -5 and receive thiotepa IV over 1 hour on day -4 and etoposide IV over 4 hours on day -3. Patients undergo allogeneic SCT on day 0.
Patients ≤ 2 years of age receive oral busulfan 4 times daily on days -8 to -5, thiotepa IV over 1 hour twice on day -4, and etoposide phosphate IV over 4 hours on day -3. Patients undergo allogeneic SCT on day 0.

Patients undergoing SCT from an unrelated donor also receive antithymocyte globulin IV over 4 hours on days -3 to -1.

All patients receive graft-versus-host (GVHD) prophylaxis as described below.

GVHD prophylaxis: GVHD prophylaxis is administered as per donor status.
Matched sibling donor: Patients receive cyclosporine IV over 2 hours or orally on day -1 to 60 followed by a taper.
10/10 or 9/10 matched unrelated donor: Patients receive cyclosporine IV over 2 hours or orally on days -1 to 100 followed by a taper, methotrexate IV on days 1, 3, and 6, and leucovorin calcium IV on days 2, 4, and 7.
Mismatched donor: Patients do not receive GVHD prophylaxis, however, CD3-positive lymphocytes are extracted from donor stem cells.

After completion of study treatment, patients are followed periodically for 10 years.

PROJECTED ACCRUAL: A total of 96 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

96 participants

Allocation:

Non-Randomized

Primary Purpose:

Treatment

Official Title:

Treatment Protocol for Relapsed Anaplastic Large Cell Lymphoma of Childhood and Adolescence

Study Start Date :

Apr 1, 2004

Actual Primary Completion Date :

Feb 1, 2014

Outcome Measures

Primary Outcome Measures

Event-free survival as measured by the Kaplan-Meier method []

Secondary Outcome Measures

Proportion of patients who are treated on protocol among all patients who meet the inclusion criteria []
Overall survival []
Acute and long term toxicity []
Rate of acute and chronic graft-vs-host disease in patients with allogeneic stem cell transplantation []
Treatment related mortality []

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed anaplastic large cell lymphoma (ALCL)
Progressive disease OR first relapse
No second or subsequent relapse of ALCL
Slides available for national central pathology review
Availability of 1 of the following (for allogeneic stem cell transplantation only):
HLA-identical matched sibling donor
10/10 HLA-matched nonsibling donor (related or unrelated)
9/10 HLA-matched nonsibling donor (1-antigen-mismatched related or unrelated donor)
< 9/10 HLA-mismatched donor (related or unrelated)
Stem cells may be obtained from unmanipulated bone marrow or peripheral blood stem cells after filgrastim (G-CSF) stimulation

PATIENT CHARACTERISTICS:

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Adequate hepatic, renal, and cardiac function
No HIV infection or AIDS
No severe immunodeficiency
No other prior malignancy
No pre-existing disease or condition prohibiting study treatment

PRIOR CONCURRENT THERAPY:

At least 2 months since prior chemotherapy or radiotherapy
No significant pretreatment for first relapse
No prior organ transplantation
No concurrent participation in another clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Anna Children's Hospital	Vienna		Austria	A-1090
2	U.Z. Gasthuisberg	Leuven		Belgium	B-3000
3	University Hospital Brno	Brno		Czech Republic	CZ-662 63
4	Charles University Hospital	Prague 5		Czech Republic	CZ-150 06
5	Centre Leon Berard	Lyon		France	69373
6	Kinderklinik - Universitaetsklinikum Aachen	Aachen		Germany	D-52074
7	Klinikum Augsburg	Augsburg		Germany	D-86156
8	Helios Klinikum Berlin	Berlin		Germany	13125
9	Charite University Hospital - Campus Virchow Klinikum	Berlin		Germany	D-13353
10	Evangelisches Krankenhauus Bielfeld	Biefeld		Germany	33617
11	Kinderklinik der Universitaet Bonn	Bonn		Germany	D-53113
12	Staedtisches Klinikum - Howedestrase	Braunschweig		Germany	38118
13	Klinikum Bremen-Mitte	Bremen		Germany	D-28205
14	Klinikum Chemnitz gGmbH	Chemnitz		Germany	D-09116
15	Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl	Cologne		Germany	D-50735
16	Children's Hospital	Cologne		Germany	D-50924
17	Carl - Thiem - Klinkum Cottbus	Cottbus		Germany	D-03048
18	Vestische Kinderklinik	Datteln		Germany	45704
19	Klinikum Dortmund	Dortmund		Germany	D-44137
20	Universitatsklinikum Carl Gustav Carus	Dresden		Germany	D-01307
21	Universitaetsklinikum Duesseldorf	Duesseldorf		Germany	D-40225
22	Helios Klinikum Erfurt	Erfurt		Germany	99089
23	Universitaets - Kinderklinik	Erlangen		Germany	D-91054
24	Universitaetsklinikum Essen	Essen		Germany	D-45147
25	Klinikum der J.W. Goethe Universitaet	Frankfurt		Germany	D-60590
26	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg		Germany	D-79106
27	Kinderklinik	Giessen		Germany	D-35385
28	Universitaetsklinikum Goettingen	Goettingen		Germany	D-37075
29	Klinik und Poliklinik Fuer Kinder-und Jugendmedizin - Universitaetsklinikum Greifswald	Greifswald		Germany	17475
30	University Medical Center Hamburg - Eppendorf	Hamburg		Germany	D-20246
31	Medizinische Hochschule Hannover	Hannover		Germany	D-30625
32	Universitaets-Kinderklinik Heidelberg	Heidelberg		Germany	D-69120
33	Gemeinschaftskrankenhaus	Herdecke		Germany	58313
34	Universitaetsklinikum des Saarlandes	Homburg		Germany	66421
35	Universitaets - Kinderklinik	Jena		Germany	D-07745
36	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe		Germany	76133
37	Klinikum Kassel	Kassel		Germany	D-34125
38	University Hospital Schleswig-Holstein - Kiel Campus	Kiel		Germany	D-24105
39	Klinikum Kemperhof Koblenz	Koblenz		Germany	D-56065
40	Klinikum Krefeld GmbH	Krefeld		Germany	D-47805
41	Universitaets - Kinderklinik	Leipzig		Germany	D-04317
42	St. Annastift Krankenhaus	Ludwigshafen		Germany	67065
43	Universitaets - Kinderklinik - Luebeck	Luebeck		Germany	D-23538
44	Universitatsklinikum der MA	Magdeburg		Germany	39120
45	Johannes Gutenberg University	Mainz		Germany	D-55101
46	Staedtisches Klinik - Kinderklinik	Mannheim		Germany	D-68167
47	Universitaets - Kinderklinik	Marburg		Germany	35033
48	Klinikum Minden	Minden		Germany	D-32423
49	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster	Muenster		Germany	D-48149
50	Krankenhaus Muenchen Schwabing	Munich		Germany	80804
51	Dr. von Haunersches Kinderspital der Universitaet Muenchen	Munich		Germany	D-80337
52	Kinderklinik Kohlhof	Neunkirchen		Germany	D-66539
53	Cnopf'sche Kinderklinik	Nuremberg		Germany	90419
54	Klinikum Oldenburg	Oldenburg		Germany	26133
55	Klinik St. Hedwig-Kinderklinik	Regensburg		Germany	93049
56	Kinderklinik - Universitaetsklinikum Rostock	Rostock		Germany	D-18057
57	Saarbrucker Winterbergkliniken	Saarbrucken		Germany	66119
58	Klinikum Schwerin	Schwerin		Germany	D-19049
59	Kinderklink Siegen Deutsches Rotes Kreuz	Siegen		Germany	D-57072
60	Johanniter-Kinderklinik	St. Augustin		Germany	53757
61	Olgahospital	Stuttgart		Germany	D-70176
62	Krankenanstalt Mutterhaus der Borromaerinnen	Trier		Germany	D-54290
63	Universitaetsklinikum Tuebingen	Tuebingen		Germany	D-72076
64	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm		Germany	D-89075
65	Dr. Horst-Schmidt-Kliniken	Wiesbaden		Germany	D-65199
66	Universitaets - Kinderklinik Wuerzburg	Wuerzburg		Germany	D-97080
67	Helios Kliniken Wuppertal University Hospital	Wuppertal		Germany	D-42283
68	Our Lady's Hospital for Sick Children Crumlin	Dublin		Ireland	12
69	Azienda Ospedaliera di Padova	Padova		Italy	35128
70	Erasmus MC - Sophia Children's Hospital	Rotterdam		Netherlands	3015 GJ
71	Akademia Medyczna im. Piastow Slaskich	Wroclaw		Poland	50-367
72	Goeteborg University	Goeteborg		Sweden	S-141685
73	Kantonspital Aarau	Aarau		Switzerland	CH-5001
74	Universitaets-Kinderspital beider Basel	Basel		Switzerland	CH-4005
75	Ospedale "la Carita", Locarno	Locarno		Switzerland	6600
76	Kinderspital Luzern	Lucerne 16		Switzerland	CH-6000
77	Ostschweizer Kinderspital	St. Gallen		Switzerland	CH-9006
78	University Children's Hospital	Zurich		Switzerland	CH-8032
79	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
80	Institute of Child Health at University of Bristol	Bristol	England	United Kingdom	BS2 8AE
81	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
82	Leeds Cancer Centre at St. James's University Hospital	Leeds	England	United Kingdom	LS9 7TF
83	Leicester Royal Infirmary	Leicester	England	United Kingdom	LE1 5WW
84	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England	United Kingdom	L12 2AP
85	Middlesex Hospital	London	England	United Kingdom	W1T 3AA
86	Great Ormond Street Hospital for Children	London	England	United Kingdom	WC1N 3JH
87	Royal Manchester Children's Hospital	Manchester	England	United Kingdom	M27 4HA
88	Sir James Spence Institute of Child Health at Royal Victoria Infirmary	Newcastle-Upon-Tyne	England	United Kingdom	NE1 4LP
89	Queen's Medical Centre	Nottingham	England	United Kingdom	NG7 2UH
90	Oxford Radcliffe Hospital	Oxford	England	United Kingdom	0X3 9DU
91	Children's Hospital - Sheffield	Sheffield	England	United Kingdom	S10 2TH
92	Southampton General Hospital	Southampton	England	United Kingdom	SO16 6YD
93	Royal Marsden - Surrey	Sutton	England	United Kingdom	SM2 5PT
94	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland	United Kingdom	BT12 6BE
95	Royal Aberdeen Children's Hospital	Aberdeen	Scotland	United Kingdom	AB25 2ZG
96	Royal Hospital for Sick Children	Edinburgh	Scotland	United Kingdom	EH9 1LF
97	Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G3 8SJ
98	Childrens Hospital for Wales	Cardiff	Wales	United Kingdom	CF14 4XW