LBL 2018

Children and adolescents unter 18 year of age with a newly diagnosed lymphoblastic lymphoma (LBL)

International inter-group multi-centre open-label randomized prospective clinical trial

Primary study questions

Randomization R1 (open for all patients of the core study cohort): Can the cumulative incidence of relapses with involvement of the CNS (CNS relapse, pCICR) be decreased by an induction therapy phase including two weeks of dexamethasone (10 mg/m²/d) instead of the standard glucocorticoid schema with 3 weeks of prednisone (60 mg/m²/d) and a 9-day tapering phase?
Randomization R2 (open for all high risk LBL patients of the core study cohort): Can the probability of event-free survival (pEFS) in these patients be improved by intensified (protocol Ib* and intensified protocol M) versus standard treatment arm (protocol Ib and protocol M)?

Secondary study questions

• the pEFS and cumulative incidence of relapse/CNS-relapse as compared to study EURO-LB 02
• overall survival (pOS) defined as time from diagnosis to death of any cause or to date of last contact for patients alive as compared to study EURO-LB 02
• treatment related mortality in the randomized arms and compared to study EURO-LB 02
• adverse event and severe adverse event profile in specific protocol elements or randomized arms and during follow-up and compared to study EURO-LB 02
• feasibility and results of risk group stratification
• Identification of prognostic molecular markers in T-LBL
• feasibility of MRD evaluation in children and adolescents with LBL

Risk group stratification

Patients will be stratified according to CNS status, immunophenotype, genetic markers and stage of disease at diagnosis.
The standard risk group I/II (SR I/II) includes patients who fulfill the following criteria:precursor-B-cell lymphoblastic lymphoma (pB-LBL) including mixed phenotype lymphoblastic lymphoma (MPAL) LBL (B/myeloid) stage I and II disease
The standard risk group (SR) includes patients who fulfill the following criteria: T-cell lymphoblastic lymphoma (T-LBL) including MPAL LBL (T/myeloid or T/B) stage I-IV CNS negative (type 1 or 2) with mutations in NOTCH1 and/or FBXW7 (N/Fmut) or in whom molecular analysis was not performed or inconclusive, all LBL with insufficient risk group stratification
The high risk group (HR) includes patients who fulfill the following criteria: LBL of any immunophenotype with CNS involvement (typ 3), T-LBL including MPAL LBL (T/myeloid or T/B) stage I-IV with NOTCH1 and FBXW7 wildtype (N/FWT), pB-LBL including MPAL LBL (B/myeloid) with stage III and IV disease

Treatment plan

Induction: all patients are enclosed in the first randomization, independend of the result of the risk group stratification.The patients are treated or with protocol 1a with Prednisone or with protocol Ia with Dexamethasone.
The further treatment takes place dependend of the risk group:
Standard risk group I/II: All Patients are treated with protocol Ib and protocol M. All patients start with maintenance therapy after the end of Protocol M.
Standard risk group: All Patients are treated with protocol Ib, protocol M and protocol II. All patients start with maintenance therapy after the end of Protocol II.
High risk group: All patients are randomized. The patients are treated with the standard therapy with protokol Ib, protocol M and protocol II or with intensified protocol Ib*, intensified protocol M and protocol II. All patients start with maintenance therapy after the end of protocol II.

• newly diagnosed lymphoblastic lymphoma
• age <18 years
• patient enrolled in a participating center
• written informed consent of patient (>14 years of age or according to local law and regulation) and parents to trial participation and transfer and processing of data
• willingness of patients and the investigator/pathologist to provide adequate slides/blocks for reference (molecular) pathology and international pathology panel and/or fresh or fresh frozen samples for genetic risk group stratification if these samples are available after standard diagnostic procedures.

• lymphoblastic lymphoma as secondary malignancy
• non-lymphoma related relevant medical, psychiatric or social conditions incompatible with trial treatment, including among others: prior organ transplant, severe immunodeficiency, demyelinating Charcot-Marie Tooth syndrome, serious acute or chronic infections, such as HIV, VZV and tuberculosis, urinary tract infection, cystitis, urinary outflow obstruction, severe renal impairment (creatinine clearance less than 20 ml/min), severe hepatic impairment (bilirubin >3 times ULN, transaminases >10 times ULN), myocardial insufficiency, severe arrhythmias, ulcers of the oral cavity and known active gastrointestinal ulcer disease, known hypersensitivity to any IMP and to any excipient (listed in section 6.1 of the respective SmPC), steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis, vaccination with live vaccines within 2 weeks before start of protocol treatment, treatment started according to another protocol or pre-treatment with cytostatic drugs
• participation in another clinical trial that interferes with the protocol, except NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment, which can run parallel to LBL 2018 without influencing the outcome of this trial (e.g. trials on antiemetics, antibiotics, strategies for psychosocial support)
• evidence of pregnancy or lactation period
• sexually active adolescents not willing to use highly effective contraceptive method (pearl index < 1) until 12 months after end of cytostatic therapy