Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents (B-NHL 2013)

B-NHL 2013 - Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents

The trial B-NHL 2013 is a collaborative prospective, multi-national, multi-center, randomized trial with participating centers of the NHL-BFM group (Austria, Switzerland, Czech Republic, Germany) and the Scandinavian NOPHO group (Denmark, Finland, Norway, Sweden). The aim of the trial is to evaluate the role of rituximab in the treatment of mature aggressive B-cell Non-Hodgkin lymphoma and leukemia (B-NHL and B-AL) in children and adolescents.

The following primary study questions are going to be analyzed:

• the effectiveness (event-free survival) in pediatric patients with very limited mature B-NHL (R1 and R2 stage I and II) of substituting anthracyclines by the rituximab window without compromising survival rates.
• the effectiveness (event-free survival) in pediatric patients with limited mature B-NHL (R2 stage III) randomly assigned to receive the rituximab window plus standard chemotherapy or standard chemotherapy without the rituximab window.
• the effectiveness (event-free survival) and the immune reconstitution (recovery of CD19+ B-cells, IR) in pediatric patients with advanced mature B-NHL/B-AL (R3 and R4 incl. R4 CNS+) treated with BFM-type chemotherapy and randomly assigned schedules of one versus seven doses rituximab.

Secondary study questions will address

• additional parameters for immune reconstitution, lymphocyte subpopulations, immunoglobulin levels, vaccination titers and infection rates
• kinetics of immune reconstitution after treatment
• adverse event and severe adverse event profile
• inter-individual variability of rituximab response
• role of different mechanisms of action of rituximab in advanced B-NHL/B-AL

Study Overview

• Status: Active, not recruiting
• Conditions: Mature B-cell Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: Rituximab window; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Dexamethasone; Drug: Etoposide; Drug: Ifosfamide; Drug: Methotrexate; Drug: Prednisolone; Drug: Vincristine; Drug: Doxorubicin hydrochloride; Drug: Additional doses of Rituximab; Drug: Vindesine Sulfate

Detailed Description

Risk group stratification:

R1/R2 stage I+II:

• R1: resection status: complete
• R2: resection status: incomplete, stage I and II

R2 III:

- R 2: resection status: incomplete, stage III and LDH < 2 x ULN (according to local reference value for adults)

R3/R4:

• R3: resection status: incomplete, stage III and LDH ≥ 2 x ULN but < 4 x ULN or stage IV/B-AL and LDH < 4 x ULN and CNS negative
• R4: resection status: incomplete, Stage III and LDH ≥ 4 x ULN or stage IV/B-AL and LDH ≥ 4 x ULN and CNS negative
• R4 CNS +: stage IV/B-AL and CNS positive

For patients with very limited disease (R1/R2 stage I/II), the addition of rituximab might allow the omission of anthracyclines without jeopardizing survival rates but reducing acute and long term toxicities. In this treatment arm, it is tested whether the event-free survival is similar to that of the historical control when all patients receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy as a substitute for anthracyclines.

For patients with limited disease (R2 stage III) it is tested whether the event-free survival can be improved by adding rituximab to the standard chemotherapy. Two different treatment regimens will be evaluated in a randomized design: Patients in the standard arm will receive the standard chemotherapy. Patients of the rituximab plus arm will receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy.

For patients with advanced disease (R3/R4) it is tested whether the event-free survival can be improved by adding rituximab to the standard chemotherapy. Two different rituximab regimens will be evaluated in a randomized design: Patients in the standard arm will receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy. Patients of the rituximab plus arm will receive the rituximab window and additional six doses of rituximab added to the first four courses of chemotherapy. In addition the immune reconstitution will be analyzed comparing the effect of the two regimens of rituximab added to standard chemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 650
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato-Onkologie
  • Innsbruck, Austria, 6020
    • Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie I
  • Klagenfurt, Austria, 9020
    • Klinikum Klagenfurt am Wörthersee, Abteilung für Kinder- und Jugendheilkunde
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum, Med Campus IV / Onkologie
  • Salzburg, Austria, 5020
    • LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie
  • Vienna, Austria, 1090
    • St. Anna Kinderspital
• Czechia
  • Prague, Czechia, 150 06
    • Department of Pediatric Hematology and Oncology, University Hospital Motol
• Denmark
  • Aalborg, Denmark, 9000
    • Børneonkologisk afsnit 303B, Børneafdelingen, Aalborg Universitetshospital Nord
  • Aarhus, Denmark, 8200 N
    • Børn og Unge afsnit 4, Børneafdelingen, Aarhus Universitetshospital Skejby
  • Copenhagen, Denmark, 2100 Ø
    • Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, Rigshospitalet
  • Odense, Denmark, 5000 C
    • Børneonkologisk afsnit H2, H. C. Andersen Børnehospital, Odense Universitetshospital
• Finland
  • Helsinki, Finland, 00029 HUS
    • Helsinki University Hospital, Children´s Hospital, Dept of Pediatric Hematology and Oncology
  • Kuopio, Finland, 70029 KYS
    • Kuopio University Hospital, Paediatric Haematology and Oncology
  • Oulu, Finland, 90029 OYS
    • University Hospital of Oulu, Paediatric Haematology and Oncology
  • Tampere, Finland, 33521
    • Tampere University Hospital, Paediatric Haematology and Oncology
  • Turku, Finland, 20521
    • Turku University Hospital, Paediatric and Adolescent Haematology and Oncology
• Germany
  • Aachen, Germany, 52057
    • Universitätsklinikum Aachen, Klinik für Kinder - und Jugendmedizin, Hämatologie / Onkologie
  • Augsburg, Germany, 86156
    • Klinikum Augsburg, Schwäbisches Kinderkrebszentrum, I. Klinik für Kinder und Jugendliche, Hämatologie / Onkologie
  • Berg, Germany, 13353
    • Charité Campus Virchow-Klinikum, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie
  • Berlin, Germany, 13125
    • HELIOS Klinikum Berlin-Buch, Kinderklinik, Pädiatrische Hämatologie und Onkologie
  • Bielefeld, Germany, 33617
    • Evangelisches Krankenhaus Bielefeld GmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie
  • Bonn, Germany, 53113
    • Zentrum für Kinderheilkunde der Universität Bonn, Abt. Päd. Hämatologie / Onkologie
  • Braunschweig, Germany, 38118
    • Städtisches Klinikum Braunschweig gGmbH, Klinik für Kinder- und Jugendmedizin, Station K5 / Päd. Hämato- und Onkologie
  • Bremen, Germany, 28177
    • Klinikum Bremen-Mitte gGmbH, Prof.-Hess-Kinderklinik,Pädiatrische Onkologie und Hämatologie
  • Cologne, Germany, 50924
    • Klinikum der Universität zu Köln, Klinik für Kinder- und Jugendmedizin, Abt. Kinderonkologie und -hämatologie
  • Cottbus, Germany, 03048
    • Carl-Thieme-Klinikum Cottbus gGmbH, Klinik für Kinder- und Jugendmedizin
  • Datteln, Germany, 45711
    • Vestische Kinderklinik, Universität Witten / Herdecke
  • Dortmund, Germany, 44137
    • Klinikum Dortmund gGmbH, Klinik für Kinder- und Jugendmedizin, Station K1, Abt. Päd. Onkologie / Hämatologie
  • Dresden, Germany, 01307
    • Universitätsklinik Carl Gustav Carus der TU Dresden, Klinik für Kinder- und Jugendmedizin
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf, Zentrum für Kinder- und Jugendmedizin, Klinik für Päd. Hämatologie und Onkologie
  • Erfurt, Germany, 99089
    • HELIOS Klinikum Erfurt GmbH, Klinik für Kinder- und Jugendmedizin, Päd. Onkologie / Hämatologie
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen, Klinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie / Hämatologie
  • Essen, Germany, 45122
    • Universitätsklinikum Essen, Zentrum für Kinder- und Jugendmedizin, Hämatologie / Onkologie
  • Frankfurt am Main, Germany, 60590
    • Universitätsklinikum Frankfurt, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie
  • Freiburg im Breisgau, Germany, 79106
    • Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV: Päd. Hämatologie und Onkologie
  • Giessen, Germany, 35385
    • Universitätsklinikum Gießen und Marburg, Standort Gießen, Zentrum für Kinderhämatologie und -onkologie
  • Greifswald, Germany, 17475
    • Universitätsklinikum Greifswald KdöR, Klinik und Poliklinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Onkologie und Hämatologie
  • Göttingen, Germany, 37075
    • Georg-August-Universität Universitäts-Kinderklinik, Pädiatrie I
  • Halle, Germany, 06120
    • Universitätsklinikum Halle (Saale), Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg Eppendorf, Zentrum für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie
  • Hanover, Germany, 30625
    • Medizinische Hochschule Hannover, Kinderheilkunde, Päd. Hämatologie / Onkologie
  • Heidelberg, Germany, 69120
    • Universitäts-Kinderklinik Heidelberg, Abt. Hämatologie / Onkologie
  • Herdecke, Germany, 58313
    • Gemeinschaftskrankenhaus Herdecke, Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie
  • Homburg, Germany, 66421
    • Universitätskliniken für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie, Geb. 9
  • Jena, Germany, 07745
    • Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin
  • Karlsruhe, Germany, 76133
    • Städtisches Klinikum Karlsruhe gGmbH, Kinderklinik, Station S 24
  • Kassel, Germany, 34125
    • Klinikum Kassel Gesundheit Nordhessen Holding AG, Klinik für pädiatrische Hämatologie und Onkologie
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig Holstein Campus Kiel, Klinik für Allgemeine Pädiatrie, Päd. Onkologie / Hämatologie
  • Koblenz, Germany, 56073
    • Gemeinschaftsklinikum Mittelrhein Kemperhof, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie
  • Krefeld, Germany, 47805
    • HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Päd. Hämatologie/Onkologie
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig, Klinik für Kinder und Jugendliche, Abt. Päd. Hämatologie / Onkologie
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig Holstein Campus Lübeck, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie
  • Magdeburg, Germany, 39120
    • Universitätsklinikum Magdeburg A. ö. R., Kinderklinik, Päd. Hämatologie / Onkologie
  • Mainz, Germany, 55101
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie
  • Mannheim, Germany, 68167
    • Klinikum Mannheim gGmbH, Universitäts-Kinderklinik, Päd. Onkologie /Hämatologie
  • Minden, Germany, 32429
    • Johannes Wesling Klinikum Minden, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie, Station E 22
  • München, Germany, 80337
    • Klinikum der LMU, Dr. von Haunersches Kinderspital, Pädiatrische Hämatologie / Onkologie
  • München, Germany, 80804
    • Klinikum Schwabing, Kinderklinik der TU Päd. Hämatologie / Onkologie, Station 24d
  • Münster, Germany, 48149
    • Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie
  • Nuremberg, Germany, 90419
    • Diakonie Neuendettelsau, Kliniken Hallerwiese / Cnopf'sche Kinderklinik, Pädiatrische Hämatologie /Onkologie
  • Oldenburg, Germany, 26133
    • Klinikum Oldenburg AöR, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg, Klinik für Kinder- und Jugendmedizin, Abt. Päd. Hämatologie, Onkologie, SZT
  • Rostock, Germany, 18057
    • Universitätsklinikum Rostock, Kinder- und Jugendklinik, Päd. Hämatologie und Onkologie
  • Sankt Augustin, Germany, 53757
    • Asklepios Klinik St. Augustin GmbH, Kinder- und Jugendmedizin, Kinder-Hämatologie und Onkologie
  • Schwerin, Germany, 19049
    • HELIOS Kliniken Schwerin GmbH, Klinik für Kinder- und Jugendmedizin, Station A1
  • Stuttgart, Germany, 70174
    • Klinikum Stuttgart, Olgahospital Zentrum für Kinder- und Jugendmedizin Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)
  • Tübingen, Germany, 72076
    • Universitätsklinik Tübingen Klinik für Kinderheilkunde und Jugendmedizin, Päd. Hämatologie / Onkologie
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie
  • Würzburg, Germany, 97080
    • Universitätskinderklinik Würzburg, Päd. Onkologie und Hämatologie
• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital, National Study Center Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital, Rikshospitalet
  • Tromsø, Norway, 9038
    • University Hospital Northern Norway
  • Trondheim, Norway, 7006
    • St Olavs hospital
• Sweden
  • Gothenburg, Sweden, 416 85
    • Sahlgrenska Universitetssjukhuset, Drottning Silvias Barn och Ungdomssjukhus, Barncancercentrum
  • Linköping, Sweden, 581 85
    • Universitetssjukhuset i Linköping, Barn och Ungdomsmedicinska kliniken, Barnonkologiska enheten
  • Lund, Sweden, 221 85
    • Skåne Universitetssjukhus, Barnonkologi
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset, Astrid Lindgrens Barnsjukhus, Barnonkologen
  • Umeå, Sweden, 901 85
    • Universitetssjukhus Umeå, Barnonkologiska avdelningen, Barn 3 Norrlands
  • Uppsala, Sweden, 752 39
    • Akademiska sjukhuset, Barnavdelningen för blod- och tumörsjukdomar
• Switzerland
  • Aarau, Switzerland, 5001
    • Kantonsspital Aarau, Kinderklinik
  • Basel, Switzerland, 4031
    • Universitäts - Kinderspital beider Basel
  • Bellinzona, Switzerland, 6500
    • Ospedale San Giovanni, Reparto die Pediatria
  • Bern, Switzerland, 3010
    • Universitätsklinik für Kinderheilkunde, Pädiatrische Hämatologie/ Onkologie, Inselspital
  • Geneva, Switzerland, 1211
    • Hôpital des Enfants, Unité d'Oncologie Hématologie
  • Lausanne, Switzerland, 1011
    • Centre hospitalier universitaire vaudois, Unité d'hémato-oncologie pédiatrique
  • Lucerne, Switzerland, 6000
    • Kinderspital Pädiatrische Hämatologie/ Onkologie
  • Sankt Gallen, Switzerland, 9006
    • Ostschweizer Kinderspital, Hämatologie/ Onkologie
  • Zurich, Switzerland, 8032
    • Universitäts-Kinderspital, Pädiatrische Onkologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newly diagnosed, histological or cytological and immunological proven aggressive mature B-cell Non-Hodgkin lymphoma including Burkitt lymphoma (BL), Burkitt leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), or mature B-cell NHL not further classified according to current WHO classification124. For rare subtypes (e.g. primary mediastinal large B-NHL, PMLBL, double hit lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements), consultation of the study center is recommended.
• availability of slides/blocks for reference pathology and international pathology panel (except in cases with immunological and cytomorphological assurance of diagnosis)
• age at diagnosis < 18 years
• diagnostics and treatment in one of the participating centers of the trial
• no previous chemotherapy, no previous lymphoma-directed treatment. No application of steroids for more than two days during the last month
• adequate hepatic, renal and cardiac function, except if alteration is due to lymphoma infiltration. Please contact the study center in case of unclear cases.
• signed informed consent of patient and/or parents/guardians for treatment according to the protocol, participation and transfer of data
• follow-up of at least two years after initial diagnosis is expected

• Certificate of vaccination against hepatitis B or negative serology, defined as

  • evidence of immunization with HBs-antigen negative, anti-HBs positive and anti-HBc negative or
  • negative hepatitis B serology with HBs-antigen negative, anti-HBs and anti- HBc negative

Exclusion Criteria:

• patients with insufficient work up not allowing a correct stratification into the risk groups
• B-cell neoplasia as second malignancy
• any other medical, psychiatric or social condition prohibiting treatment according to the protocol (e.g. previous malignancy, prior organ transplant, HIV infection or AIDS or severe immunodeficiency, etc.)
• participation within a different trial for treatment of B-cell malignancies and/or concurrent treatment within any other clinical trial. Exceptions to this are the NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment which can run parallel to B-NHL 2013 without influencing the outcome of this trial e.g. trials on antiemetics, antibiotics, strategies for psychosocial support etc.
• overt hepatitis B or history of hepatitis B
• hypersensitivity to rituximab or to murine proteins or to any of the other excipients of the Investigational Medicinal Product rituximab (MabThera®) or to ingredients of other IMPs.
• lack of CD20 expression of the lymphoma cells
• pregnancy and lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: R1/R2 stage I+II; Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)	Drug: Rituximab window; Rituximab window (375 mg/m²); Drug: Cyclophosphamide; see detailed protocol description; Drug: Cytarabine; see detailed protocol description; Drug: Dexamethasone; see detailed protocol description; Drug: Etoposide; see detailed protocol description; Drug: Ifosfamide; see detailed protocol description; Drug: Methotrexate; see detailed protocol description; Drug: Prednisolone; see detailed protocol description; Drug: Vincristine; see detailed protocol description
Experimental: R2 stage III experimental arm; Rituximab window + Standard chemotherapy	Drug: Rituximab window; Rituximab window (375 mg/m²); Drug: Cyclophosphamide; see detailed protocol description; Drug: Cytarabine; see detailed protocol description; Drug: Dexamethasone; see detailed protocol description; Drug: Etoposide; see detailed protocol description; Drug: Ifosfamide; see detailed protocol description; Drug: Methotrexate; see detailed protocol description; Drug: Prednisolone; see detailed protocol description; Drug: Vincristine; see detailed protocol description; Drug: Doxorubicin hydrochloride; see detailed protocol description
Other: R2 stage III standard arm; Standard chemotherapy	Drug: Cyclophosphamide; see detailed protocol description; Drug: Cytarabine; see detailed protocol description; Drug: Dexamethasone; see detailed protocol description; Drug: Etoposide; see detailed protocol description; Drug: Ifosfamide; see detailed protocol description; Drug: Methotrexate; see detailed protocol description; Drug: Prednisolone; see detailed protocol description; Drug: Vincristine; see detailed protocol description; Drug: Doxorubicin hydrochloride; see detailed protocol description
Experimental: R3/R4 rituximab plus arm; Rituximab window + standard chemotherapy plus six additional doses of rituximab	Drug: Rituximab window; Rituximab window (375 mg/m²); Drug: Cyclophosphamide; see detailed protocol description; Drug: Cytarabine; see detailed protocol description; Drug: Dexamethasone; see detailed protocol description; Drug: Etoposide; see detailed protocol description; Drug: Ifosfamide; see detailed protocol description; Drug: Methotrexate; see detailed protocol description; Drug: Prednisolone; see detailed protocol description; Drug: Vincristine; see detailed protocol description; Drug: Doxorubicin hydrochloride; see detailed protocol description; Drug: Additional doses of Rituximab; 2 doses of Rituximab (375 mg/m²) before the start of the first chemotherapy cycle, 2 doses of Rituximab before the start of the second chemotherapy cycle, 1 dose of rituximab before the start of the third chemotherapy cycle, 1 dose of Rituximab before the start of the forth chemotherapy cycle; Drug: Vindesine Sulfate; see detailed protocol description
Experimental: R3/R4 standard arm; Rituximab window + standard chemotherapy	Drug: Rituximab window; Rituximab window (375 mg/m²); Drug: Cyclophosphamide; see detailed protocol description; Drug: Cytarabine; see detailed protocol description; Drug: Dexamethasone; see detailed protocol description; Drug: Etoposide; see detailed protocol description; Drug: Ifosfamide; see detailed protocol description; Drug: Methotrexate; see detailed protocol description; Drug: Prednisolone; see detailed protocol description; Drug: Vincristine; see detailed protocol description; Drug: Doxorubicin hydrochloride; see detailed protocol description; Drug: Vindesine Sulfate; see detailed protocol description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	EFS is defined as time from start of treatment/randomization up to event or to date of last contact for patients without event. The following occurrences are defined as an event: non-response, progressive disease or relapse, treatment related death, death of any other cause or diagnosis of secondary malignancies.	through study completion, maximal seven years
Immune reconstitution rate (only in R3/R4 patients)	Immune reconstitution rate is defined as percentage of patients achieving age adjusted normal B-cell counts (CD19 positive subpopulations) 12 months after start of treatment.	12 months after start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS is defined as time from start of treatment/randomization up to death of any cause or to date of last contact for patients alive.	through study completion, maximal seven years
Relapse-free survival (RFS)	RFS is defined as time from start of treatment/randomization up to event or to date of last contact for patients without event. The following occurrences are defined as an event: non-response, progressive disease, or relapse.	through study completion, maximal seven years
Response rate (RR)	Complete response, partial remission, objective effect, stable disease or progressive disease	after rituximab window on day 5, after prephase (patients with rituximab window on day 10, patients without rituximab window on day 6) and after second course (on an average 5 to 6 weeks after start of treatment)
Adverse event rate	Rate of patients with acute toxicity defined as grade III/IV/V AE	from the first day of protocol defined treatment until two years after start of protocol defined treatment
Rate of patients achieving normal immunoglobulin level 12 months after start of treatment		12 months after start of treatment
Time interval to normal immunoglobulin level		through study completion, maximal seven years
Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood.		through study completion, maximal seven years
Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment		12 months after start of treatment
Interval to normal lymphocyte subpopulations in the peripheral blood.		through study completion, maximal seven years
Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until 24 months after start of treatment		24 months after start of treatment
Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until immune reconstitution (achievement of age adjusted normal B-cell counts)		through study completion, maximal seven years
Rate of patients with sufficient titers after vaccination one year after start of treatment		1 year after start of treatment
Immune reconstitution rate (only in R1/R2 patients)	Immune reconstitution rate is defined as percentage of patients achieving age adjusted normal B-cell counts (CD19 positive subpopulations) 12 months after start of treatment.	12 months after start of treatment

Collaborators and Investigators

• Sponsor: University Hospital Muenster
• Collaborators: Deutsche Krebshilfe e.V., Bonn (Germany)
• Investigators: Principal Investigator: Birgit Burkhardt, Prof. Dr. Dr., University Hospital Muenster, Klinik für Kinder- und Jugendmedizin - Pädiatrische Hämatologie und Onkologie

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2017
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: June 27, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Indoles; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Pterins; Pteridines; Pregnadienetriols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Anthracyclines; Naphthacenes; Aminoglycosides; Daunorubicin; Oxazines; Dexamethasone; Methotrexate; Prednisolone; Cyclophosphamide; Cytarabine; Etoposide; Doxorubicin; Vincristine; Ifosfamide; Vindesine
• Other Study ID Numbers: UKM12_0020; 2013-003253-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No