International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

Leukemia Clinical Trial

Official title:

International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01117441
• Other study ID #: AIEOP-BFM ALL 2009
• Status: Completed
• Phase: Phase 3
• Start date: June 2010
• Est. completion date: December 31, 2021

Study information

• Verified date: May 2022
• Source: University Hospital Schleswig-Holstein
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rationale/Purpose: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating young patients with acute lymphoblastic leukemia (ALL).

This trial is studying several different combination chemotherapy regimens to compare how well they work in treating young patients with ALL.

Study objectives

Primary study questions:

• Non high-risk (non-HR) precursor-B ALL (pB-ALL) patients with TEL/AML1-negative ALL or unknown TEL/AML1 status and flow cytometry minimal residual disease (MRD) in bone marrow on day 15 <0.1% or with TEL/AML1-positive ALL (randomized study question R1): Can the daunorubicin dose in Protocol IA be safely reduced by 50 % with a non-inferior EFS and a reduction of toxicity (treatment-related mortality and AE/SAE in Protocol I)?

• Patients with pB-ALL and risk group medium risk (MR) (randomized study question R2): Can the clinical outcome be improved by protracted asparagine depletion achieved through application of intensified PEG-L-asparaginase during reintensification and early maintenance?

• High-risk (HR) patients (as identified by day 33 - randomized study question RHR): Can the clinical outcome be improved by protracted exposure to PEG-L-asparaginase during Protocol IB?

Secondary study questions:

• Standard risk (SR) patients identified by at least one sensitive marker: Is the clinical outcome comparable to that obtained in SR patients (identified with two sensitive markers) in AIEOP-BFM ALL 2000, or can the outcome even be improved with the use of PEG-L-asparaginase instead of native E. coli L-ASP?

• T-ALL non-HR patients: Can the high level of outcome which was obtained for these patients in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of PEG-L-ASP instead of native E. coli L-ASP?

• HR patients with persisting high MRD levels despite the use of the HR blocks in the intensified consolidation phase "MRD Non-Responders": Is it possible to improve the outcome and to achieve a further reduction of leukemic cell burden by administration of an innovative treatment schedule (DNX-FLA)?

• Patients participating in the randomized asparaginase studies (pB-ALL/MR, HR): Are asparaginase activity and asparaginase antibodies associated with development of allergic reactions, and do they have an effect on the outcome of the patients?

• What is the relative value of different methods of MRD monitoring in the definition of alternative stratification systems within a BFM-oriented protocol?

Description:

Risk Stratification

• T/non-HR: T-ALL in absence of any HR criteria (see below)

• pB/non-HR: pB-ALL in absence of any HR criteria (see below).

• SR (polymerase chain reaction(PCR)-MRD-SR (MRD-negative on day 33 and 78) or, if no PCR-MRD result available, FCM d15 < 0.1%)

• MR (no SR)

• HR: Prednisone poor-response (≥1000 blast cells/µl in peripheral blood on day 8), blast cells ≥10% in bone marrow on day 15 as measured by FCM, non-remission on day 33, positivity for MLL/AF4 or t(4;11), hypodiploidy (< 45 chromosomes), PCR-MRD-HR (MRD ≥10E-3 on day 78) or PCR-MRD-MR SER (only in pB-ALL, MRD ≥ 10-3 on day 33 and MRD positive at a level of < 10E-3 on day 78)

Chemotherapy

According to the risk group, patients receive the following chemotherapy elements:

T/non-HR: Protocol I, Protocol M, Protocol II and Maintenance pB/non-HR: Protocol I, Protocol M, Protocol II and Maintenance HR: Protocol I, HR-1', HR-2', HR-3', 3x Protocol III, Maintenance Patients of the HR group with PCR-MRD ≥10E-3 after element HR-3' are eligible for treatment with element DNX-FLA.

Protocol I Cytoreductive prephase: Prednisone (PDN) on days 1-7 and one dose of methotrexate (MTX) intrathecal (IT) on day 1 Protocol IA: Prednisone (PDN) on days 8 to 28 (21 days); vincristine (VCR) on days 8, 15, 22, 29 (4 doses); daunorubicin (DNR) on days 8, 15, 22 and 29 (4 doses); pegylated L-asparaginase (PEG-L-ASP) on days 12 and 26; MTX IT on days 12 and 33 and in case of blast cells in cerebrospinal fluid at diagnosis additional IT MTX is given on days 19 and 26.

Protocol IA': Only two doses of DNR on days 8 and 15 given to patients eligible for randomization R1 and randomized into the experimental arm Protocol IA-CPM: additional cyclophosphamide (CPM) on day 10 only in T-ALL patients with prednisone poor-response Protocol IA-Dexa (IAD): Dexamethasone (DXM) instead of PDN is given to all patients with T-ALL without any high-risk criteria as identified by day 8.

Protocol IB: CPM on days 36 and 64; cytarabine (ARA-C) on days 38-41, 45-48, 52-55 and 59-62; 6-mercaptopurine (6-MP) on days 36 to 63 (28 days); MTX IT on day 45 and 59 Protocol IB-ASP+: additional PEG-L-ASP on days 40, 47, 54, and 61 (4 doses) are given to the patients eligible for randomization RHR and randomized into the experimental arm.

Protocol M 6-MP on days 1- 56, high-dose MTX (HD-MTX) on days 8, 22, 36, 50 and MTX IT on days 8, 22, 36 and 50 Protocol II Protocol IIA: DXM on days 1 to 21 (21 days); VCR on days 8, 15, 22, 29 (4 doses); doxorubicine (DOX) on days 8, 15, 22 and 29 (4 doses); PEG-L-ASP on day 8 (1 dose); MTX IT on days 1 and 18 only in patients with initial CNS involvement.

Protocol IIA-ASP+: additional PEG-L-ASP on day 22 for patients eligible for randomization R2 and randomized into the experimental arm.

Protocol IIB: CPM on day 36; ARA-C on days 38-41 and 45-48; thioguanine (TG) on days 36 to 49 (14 days) and MTX IT on days 38 and 45.

Protocol IIB-ASP+: additional PEG-L-ASP on days 36 and 50 for eligible for randomization R2 and randomized into the experimental arm.

Protocol III DXM on days 1-15; VCR on days 1 and 8; DOX on days 1 and 8; PEG-L-ASP on day 1; CPM on day 15; ARA-C on days 17-20 and 24-27; TG on days 15 - 28 and MTX IT on days 17 and 24, also on day 1 in patients with initial CNS involvement HR-1' DXM on days 1-5; VCR on days 1 and 6; HD-MTX on day 1; CPM every 12 hours on days 2-4 (5 doses); HD-ARA-C every 12 hours on day 5 (2 doses); PEG-L-ASP on day 6, MTX IT on day 1 HR-2' DXM on days 1 to 5; VDS on days 1 and 6; HD-MTX on day 1; IFO every 12 hours on days 2-4 (5 doses); DNR on day 5; PEG-L-ASP on day 6; MTX IT on day 1 and 1 in patients with initial CNS involvement also day 5 HR-3' DXM on days 1-5; ARA-C 4 x on days 1-2 in 12 h intervals; etoposide (VP-16) every 12 hours on days 3-5 (5 doses); PEG-L-ASP on day 6; MTX IT on day 1 DNX-FLA Flucytosine (FLU) on days 1-5 (5 doses); HD-ARA-C on days 1 to 5 (5 doses); liposomal daunorubicin (DNX) on days 1, 3 and 5 (3 doses); MTX IT on day 1

Interim/Maintenance (until week 104):

6-MP p.o. daily; MTX p.o. once a week, doses adjusted to white blood cell count; PEG-L-ASP:

every second week (6 doses), only for patients eligible for randomization R2 and randomized into the experimental arm; MTX IT every 6 weeks up to a total of 6 doses for the following subgroups (all CNS-negative):

• T-ALL (HR or non-HR) with < 2 years of age at start of maintenance,

• T-ALL, non-HR and initial WBC < 100 000/μl

• pB-ALL with PPR and/or FCM-MRD day 15 ≥ 10 % and/or PCR-MRDMR SER as only HR criteria

Radiotherapy Patients without CNS involvement and

• T-ALL/non-HR, WBC ≥ 100 000/μl, and age ≥ 2 years at start of pCRT or

• with risk group HR and age ≥ 2 years at start of pCRT except pB-ALL with PPR and/or FCM-MRD day 15 ≥ 10 % and/or PCR-MRD-MR SER as only HR criteria receive preventive cranial radiotherapy with 12 Gy

Patients with CNS involvement receive therapeutic cranial radiotherapy with 18 Gy (age 1 to <2 years 12 Gy).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6136
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

Inclusion Criteria:

• newly diagnosed acute lymphoblastic leukemia

• age = 1 year (> 365 days) and < 18 years old (up to 17 years old and 365 days)

• no Ph+ (BCR/ABL or t(9;22)-positive) ALL

• no evidence of pregnancy or lactation period

• no participation in another clinical study

• patient enrolled in a participating center

• written informed consent

Exclusion Criteria:

• pre-treatment with cytostatic drugs

• pre-treatment with cytostatic drugs

• steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis

• treatment started according to another protocol

• underlying diseases that prohibit treatment according to the protocol

• ALL diagnosed as second malignancy steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• PEG-L-asparaginase
see detailed protocol description
• cyclophosphamide
see detailed protocol description
• cytarabine
see detailed protocol description
• daunorubicin hydrochloride
see detailed protocol description
• dexamethasone
see detailed protocol description
• doxorubicin hydrochloride
see detailed protocol description
• etoposide
see detailed protocol description
• ifosfamide
see detailed protocol description
• mercaptopurine
see detailed protocol description
• methotrexate
see detailed protocol description
• prednisone
see detailed protocol description
• thioguanine
see detailed protocol description
• vincristine sulfate
see detailed protocol description
• vindesine
see detailed protocol description
• daunoxome
see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment
• fludarabine
see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment

Radiation:
• Radiation Therapy
for eligibility for radiotherapy see detailed protocol description

Locations

Country	Name	City	State
Australia	The Sydney Children's Hospital, Centre for Children's Cancer and Blood Disorders	Randwick
Australia	The Children's Hospital at Westmead, Department of Oncology	Westmead
Austria	Krankenhaus Dornbirn, Abt. für Kinder- und Jugendheilkunde	Dornbirn
Austria	Univ.-Kinderklinik Graz, Abt. Pädiatrische Hämato-Onkologie	Graz
Austria	Department f. Kinder- u. Jugendheilkunde, Universitätsklinik f. Pädiatrie II	Innsbruck
Austria	A.oe. Landeskrankenhaus Klagenfurt, Abt. für Kinder- und Jugendheilkunde	Klagenfurt
Austria	A.oe. Landeskrankenhaus Leoben, Abt. für Kinder und Jugendliche	Leoben
Austria	Landes-Kinderklinik Linz, Haematologie/Onkologie	Linz
Austria	St. Johanns Spital / Landeskrankenhaus, Salzburg, Kinderspital Abt. Kinder u. Jugendheilkunde	Salzburg
Austria	St. Anna Kinderspital, Zentrum für Kinder- und Jugendheilkunde	Wien
Czechia	University Hospital Brno, Department of Pediatric Oncology	Brno
Czechia	Regional Hospital Ceské Budejovice, Department of Pediatrics	Ceské Budejovice
Czechia	University Hospital Hradec Králové, Department of Pediatrics	Hradec Králové
Czechia	University Hospital Olomouc, Department of Pediatrics	Olomouc
Czechia	Teaching Hospital Ostrava-Poruba, Department of Pediatrics	Ostrava-Poruba
Czechia	University Hospital Plzen, Department of Pediatrics	Plzen
Czechia	University Hospital Motol, Department of Pediatric Hematology and Oncology	Praha 5
Czechia	Masaryk´s Hospital Ústí nad Labem, Department of Pediatrics	Ústí nad Labem
Germany	Kinderklinik der med. Fakultät der RWTH, Bereich Hämatologie/Onkologie	Aachen
Germany	I. Klinik für Kinder u. Jugendliche, Klinikum Augsburg, Hämatologie/ Onkologie	Augsburg
Germany	Klinikum Bayreuth, Kinderklinik	Bayreuth
Germany	Kinderklinik der Charité, Campus Virchow Klinikum (CVK), Abt.: Kinderhämatologie	Berlin
Germany	Klinikum Berlin-Buch II. Kinderklinik, Bereich Onkologie/Allg. Pädiatrie	Berlin
Germany	Städtisches Krankenhaus, Kinderklinik	Braunschweig
Germany	Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie / Onkologie	Chemnitz
Germany	Carl-Thiem-Klinikum, Kinderklinik, Abt. Hämatologie/Onkologie	Cottbus
Germany	Vestische Kinder- u. Jugendklinik, Universitätsklinik Witten/Herdecke	Datteln
Germany	Klinikum Lippe-Detmold, Kinder- und Jugendmedizin	Detmold
Germany	Klinikum Dortmund, Klinik f. Kinder- und Jugendmedizin	Dortmund
Germany	Uni.Klinik Carl Gustav Carus, Klinik f. Kinderheilkunde	Dresden
Germany	Universitätskinderklinik	Düsseldorf
Germany	Helios Klinikum Erfurt GmbH, Klinik für Kinderheilkunde	Erfurt
Germany	Universitätsklinikum Erlangen, Kinder- und Jugendmedizin, Abt. für Onkologie/ Hämatologie/Immunologie	Erlangen
Germany	Universitätsklinikum Essen, Kinderklinik, Hämatologie/Onkologie	Essen
Germany	Universitäts-Kinderklinik, Klinik für Kinderheilkunde III, Pädiatrische Hämatologie/Onkologie	Frankfurt
Germany	Universitäts-Kinderklinik, Haematologie/ Onkologie	Freiburg
Germany	Klinikum der Justus-Liebig-Universität, Zentrum für Kinderheilkunde, Abt. Hämatologie/Onkologie	Gießen
Germany	Universitäts-Kinderklinik Päd. I, Hämatologie/Onkologie	Göttingen
Germany	Klinik und Poliklinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie mit Poliklinik/Pädiatrische Onkologie und Hämatologie	Greifswald
Germany	Uniklinikum d. Martin Luther Universität, Halle Wittenberg, Univ.-und Poliklinik für Kinder- und Jugendmedizin	Halle
Germany	Medizinische Hochschule Hannover, Zentrum Kinderheilkunde u. Jugendmedizin	Hannover
Germany	Universitäts-Kinderklinik, Päd. Onkologie, Hämatologie, und Immunologie	Heidelberg
Germany	Klinikum Heilbronn GmbH, Klinik für Kinderheilkunde und Jugendmedizin/Perinatalzentrum	Heilbronn
Germany	Gemeinschaftskrankenhaus Herdecke, Kinderabteilung	Herdecke
Germany	Universitätsklinik für, Kinder- und Jugendmedizin, Päd. Hämatologie/ Onkologie	Homburg / Saar
Germany	Klinikum, der Friedrich-Schiller-Universität, Klinik für Kinder- und Jugendmedizin	Jena
Germany	Städtisches Klinikum Karlsruhe, Kinderklinik	Karlsruhe
Germany	Klinikum Kassel, Kinderklinik	Kassel
Germany	Klinik für Allgemeine Paediatrie, Univ.-Klinikum Schleswig-Holstein, Campus Kiel	Kiel
Germany	Städtisches Krankenhaus Kemperhof, Kinderklinik	Koblenz
Germany	Kliniken der Stadt Köln GmbH, Kinderkrankenhaus Riehl	Köln
Germany	Med. Einrichtungen der Universität zu Köln, Klinik für Allg. Kinderheilkunde, Onkologisch-hämatologische Station	Köln
Germany	Department für Frauen- und Kindermedizin, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie	Leipzig
Germany	Universität zu Lübeck, Klinik für Kinder- u. Jugendmedizin, Abt. Hämatologie/ Onkologie/Immunologie	Lübeck
Germany	Universitätsklinikum Magdeburg, Klinik für Päd. Hämatologie/Onkologie	Magdeburg
Germany	Klinikum Mannheim gGmbH, Kinderklinik, Abt. Hämatologie/Onkologie	Mannheim
Germany	Johannes Wesling Klinikum Minden	Minden
Germany	Städt. Krankenhaus München GmbH, Krankenhaus München-Schwabingen, Kinderklinik d. TU	München
Germany	Universitäts-Kinderklinik, Päd. Hämatologie und Onkologie	Münster
Germany	Cnopf'sche Kinderklinik, Onkologie	Nürnberg
Germany	Klinikum Oldenburg gGmbH, Zentrum für Kinder- u. Jugendmedizin, (Elisabeth Kinderkrankenhaus)	Oldenburg
Germany	Universitäts-Kinderklinik	Rostock
Germany	Asklepios-Klinik, Sankt Augustin GmbH	Sankt Augustin
Germany	HELIOS Kliniken Schwerin, Klinik f. Kinder-u. Jugendmedizin	Schwerin
Germany	Olga-Hospital, Kinderklinik, Pädiatrisches Zentrum, Abt. Hämatologie/Onkologie	Stuttgart
Germany	Krankenanstalt Trier, Mutterhaus der Borromaeerinnen, Pädiatrische Abteilung	Trier
Germany	Universitäts-Kinderklinik, Abt. Kinderheilkunde II, Hämatologie/Onkologie	Tübingen
Germany	Universitäts-Kinderklinik	Ulm
Germany	Stadtkrankenhaus, Kinderklinik	Wolfsburg
Germany	Universitäts-Kinderklinik	Würzburg
Israel	HaEmek Medical Center	Afula
Israel	Soroka Medical Center	Beer-Sheva
Israel	Bnai-Zion Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Hadassah University Medical Center	Jerusalem
Israel	Schneider Children Medical Center of Israel	Petach Tikva
Israel	Dana children hospital	Tel-Aviv
Israel	Sheba Medical Center	Tel-Hashomer
Italy	Centro Regionale Oncoematologia Pediatrica Ospedale dei Bambini "G. Salesi" Clinica Pediatrica	Ancona
Italy	Dipartimento Biomedicina Età Evolutiva U.O Pediatrica I Policlinico	Bari
Italy	U.O.C. Pediatria e Patologia Neonatale Ospedale San Martino	Belluno
Italy	U.O. Pediatrica - OO.RR Bergamo	Bergamo
Italy	Istituto Ortopedico Rizzoli Sez. di chemioterapia dei tumori dell'apparato locomotore	Bologna
Italy	Oncologia ed Ematologia "Lalla Seràgnoli" Clinica Pediatrica Policlinico Sant'Orsola Malpighi	Bologna
Italy	Pediatria Ospedale Regionale	Bolzano
Italy	Clinica Pediatrica Oncoematologia pediatrica e TMO Ospedale dei Bambini	Brescia
Italy	Istituto di Clinica Pediatrica Ospedale Regionale per le Microcitemie	Cagliari
Italy	Divisione Ematologia - Oncologia Pediatrica Clinica Pediatrica	Catania
Italy	Unità Operativa di Ematologia ed Oncologia Pediatrica Az. Osp. "Pugliese-Ciaccio"	Catanzaro
Italy	Unità Operativa Pediatria Azienda Ospedaliera Annuziata	Cosenza
Italy	Dipartimento di Medicina Clinica e Sperimentale Sezione di Pediatria Università di Ferrara	Ferrara
Italy	Dipartimento A.I. Oncoematologia Pediatrica e Cure Domiciliari U.O. Oncoematologia Pediatrica Azienda Ospedaliero-Universitaria Meyer	Firenze
Italy	Dipartimento di Ematologia e Oncologia Pediatrica Instituto " G. Gaslini"	Genova
Italy	Ospedale "Vito Fazzi" U.O. di Pediatria	Lecce
Italy	Clinica Pediatrica II De Marchi	Milano
Italy	Divisione di Oncologia Pediatrica Ist. Nazionale Studio e Cura Tumori	Milano
Italy	Divisione Pediatria "Mariani" Ospedale "Niguarda Ca' Granda"	Milano
Italy	Unità di Ricerca Clinica Pediatrica HSR TIGET - Istituto Scientifico San Raffaele	Milano
Italy	U.O. di Ematologia, oncologia e trapianto Azienda Policlinico di Modena	Modena
Italy	Clinica Pediatrica dell'Università Milano - Bicocca A.O. San Gerardo - Fondazione MBBM	Monza
Italy	A.O. "A. Cardarelli", U.O.S. Talassemia pediatrica ed emoglobinopatie pediatriche	Napoli
Italy	Dipartimento di Oncologia A.O. Santobono - Pausilipon	Napoli
Italy	Servizio di Oncologia Pediatrica Dipartimento di Pediatria Seconda Università degli Studi di Napoli	Napoli
Italy	U.O.C. Pediatria - TIN, Ospedale "Umberto Primo" ASL SA - 1	Nocera Inferiore
Italy	S.C.D.U. Azienda Ospedaliera "Maggiore della carità"	Novara
Italy	Dipartimento di Pediatria Università di Padova Cattedra Di Oncoematologia Pediatrica	Padova
Italy	Oncoematologia Pediatrica Ospedale dei Bambini G. di Cristina	Palermo
Italy	U.O. di Pediatria e Oncoematologia Pediatrica Az. Osp. Di Parma Ospedali Riuniti	Parma
Italy	Oncoematologia Pediatrica IRCCS, Policlinico San Matteo	Pavia
Italy	S.C. di Oncoematologia Pediatrica con Trapianto di CSE, Ospedale "S.M. della Misericordia" A.O. Perugia	Perugia
Italy	Ematologia, Ospedale di Muraglia	Pesaro
Italy	U.O. Pediatrica Azienda Ospedaliera San Salvatore	Pesaro
Italy	Dipartimento di Ematologia Ospedale Civile	Pescara
Italy	Centro di Oncoematologia Pediatrica e Trapianto Midollo Osseo Azienda Ospedaliero Universitaria Pisana Ospedale S. Chiara	Pisa
Italy	Centro Integrato di Emato-oncologia e dell'adolescenza A.O. S. Maria degli Angeli - Pordenone e IRCCS Centro di Riferimento Oncologico - Aviano	Pordenone
Italy	Divisione Ematologia Ospedali Riuniti	Reggio Calabria
Italy	U.O Pediatria Ospedale Infermi Azienda USL Rimini	Rimini
Italy	Divisione di Ematologia Pediatrica Ospedale "Bambin Gesù"Istituto di Ricerca Scientifica	Roma
Italy	Divisione Oncologia Pediatrica Ospedale "Bambin Gesù"	Roma
Italy	Divisione Oncologia Pediatrica Università Cattolica di Roma	Roma
Italy	Oncoematologia pediatrica Università "La Sapienza" Roma	Roma
Italy	Ospedale Sant'Eugenio clinica pediatrica Univ. Tor Vergata	Roma
Italy	Sezione Ematologia Dipart. di biotecnologie Cellulari ed Ematologia Università "La Sapienza"	Roma
Italy	U.O. Oncoematologia Pediatrica Ospedale "Casa Sollievo della Sofferenza"	San Giovanni Rotondo
Italy	Clinica Pediatrica Università	Sassari
Italy	Dipartimento di Pediatria Ostetricia e Medicina della Riproduzione Università degli Studi di Siena	Siena
Italy	Ospedale Infantile Regina Margherita	Torino
Italy	Unità Operativa di Pediatria - U.T.I.N. Az.Osp. "Card. G. Panico"	Tricase
Italy	U.O. Emato-Oncologia Pediatrica Università degli studi di Trieste Ospedale Infantile Burlo Garofolo	Trieste
Italy	SOS Oncologia Pediatrica Policlinico Universitario	Udine
Italy	Clinica Pediatrica Università degli Studi dell'Insubria di Varese Ospedale "Filippo del Ponte"	Varese
Italy	U.O.C Oncoematologia Pediatrica Policlinico "G.B: Rossi"	Verona
Italy	Ospedale San Bortolo, U.O. di Pediatria e patologia Neonatale	Vicenza
Switzerland	Kinderklinik, Hämatologie/Onkologie	Aarau
Switzerland	Baseler Kinderspital, Hämatologische Poliklinik	Basel
Switzerland	Repartio di Pediatria	Bellinzona
Switzerland	Pädiatrische Klinik, Kinderspital Luzern, Kinderonkologie	Luzern
Switzerland	Hämatologie/Onkologie, Ostschweizer Kinderspital, FMH Pädiatrie, Hämatologie	St. Gallen
Switzerland	Kinderspital Zürich, Universitäts-Kinderklinik	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Schleswig-Holstein	Deutsche Krebshilfe e.V., Bonn (Germany)

Countries where clinical trial is conducted

Australia,  Austria,  Czechia,  Germany,  Israel,  Italy,  Switzerland, 

References & Publications (3)

Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke A, Aricò M, Zimmermann M, Mann G, De Rossi G, Stanulla M, Locatelli F, Basso G, Niggli F, Barisone E, Henze G, Ludwig WD, Haas OA, Cazzaniga G, Koehler R, Silvestri D, Bradtke J, Parasole R, Beier R, van Dongen JJ, Biondi A, Schrappe M. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010 Apr 22;115(16):3206-14. doi: 10.1182/blood-2009-10-248146. Epub 2010 Feb 12. — View Citation

Flohr T, Schrauder A, Cazzaniga G, Panzer-Grümayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schäfer BW, Sutton R, Koehler R, Zimmermann M, Valsecchi MG, Gadner H, Masera G, Schrappe M, van Dongen JJ, Biondi A, Bartram CR; International BFM Study Group (I-BFM-SG). Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008 Apr;22(4):771-82. doi: 10.1038/leu.2008.5. Epub 2008 Jan 31. — View Citation

Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010 Feb;24(2):265-84. doi: 10.1038/leu.2009.257. Epub 2009 Dec 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival	Randomization R1: Event-free survival from time of randomization; Historical comparison non-HR T-ALL: Event-free survival from diagnosis; Historical comparison "MRD Non-Responders": Event-free survival from start of DNX-FLA (morphological non-response after HR-3' is no event for this study question)	10 years from the start of recruitment
Primary	Disease-free survival	Randomization R2: Disease-free survival from time of randomization; Historical comparison SR: Disease-free survival from start of Protocol M	10 years from the start of recruitment
Primary	minimal residual disease (MRD)	Randomization RHR: rate of MRD highly positive patients (MRD = 10-3) at TP2 (week 12)	week 12 of treatment
Secondary	survival	All randomized and historical comparisons: Survival	10 years from the start of recruitment
Secondary	treatment-related mortality	All randomized and historical comparisons: treatment-related mortality in induction or CCR (overall and by chemotherapy/SCT)	up to 25 months from the diagnosis
Secondary	adverse events	All randomized and historical comparisons: incidence and frequency of adverse events of interest and serious adverse events	up to 25 months from the diagnosis
Secondary	event-free survival	Randomization R-HR: Event-free survival from time of randomization	10 years from the start of recruitment
Secondary	minimal residual disease	"MRD Non-Responders": MRD levels after DNX-FLA	after 24 weeks of treatment