Modified BFM (Berlin-Frankfurt-Munster)Backbone Therapy for Chinese Children or Adolescents With Newly Diagnosed Lymphoblastic Lymphoma
Phase: PHASE3
Conditions: Lymphoblastic Lymphoma
Sponsor: Children's Cancer Group, China

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A Phase 3 multi-institutional study for treatment of children with newly 
diagnosed Lymphoblastic Lymphoma using a modified BFM (Berlin-
Frankfurt-Munster) Backbone strategy  
CCCG-LBL-2016 
 
(A 5-year study program of CCCG lymphoma group)  
 
 

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Site 
Investigator 
Shanghai Children's Medical Center (SCMC) 
Yi-Jin Gao 
Tongji Hospital (TJ) 
Ai-Guo Liu 
West China Second University Hospital (HX) 
Yi-Ping Zhu 
Qilu Hospital (QL) 
Xiu-Li Ju 
Tianjin Medical University Cancer Institute and 
Hospital (TJZ) 
Jie Yan 
Children's Hospital of Sochow University, China (SZ) 
Jun Lu 
Nanjing Children's Hospital (NJ) 
Yong-Jun Fang 
Xiangya Hospital of Central South University (XY) 
Min Xie 
 
 
 

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Table of Contents 
Section 
Experimental Design Schema 
1.0        Objectives (Scientific Aims) and Background 
2.0        Patient Eligibility 
3.0        Treatment Plan 
4.0        Evaluation, End of Therapy and Follow up 
5.0        Therapy Delivery Map 
 
 
 
 

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Experimental design schema: CCCG-LBL-2016 
 
 
 
 

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1.0 Objectives (Scientific Aims) and Background 
Primary aims:  
⚫ 
To determine the 3-year EFS (event free survival) in all evaluable patients with 
newly diagnosed lymphoblastic lymphoma enrolled in the study compared with the 
historical study 
⚫ 
To describe the 3-year EFS in high-risk group  
 
Secondary aims:  
⚫ 
To describe the 3-year OS (overall survival) in all evaluable patients with newly 
diagnosed lymphoblastic lymphoma enrolled in the study 
 
Background 
Lymphoblastic lymphoma (LBL) represents about 25%~30% of all non-Hodgkin lymphoma 
(NHL) cases in children worldwide. In developed countries, LBL therapy is based on acute 
lymphoblastic leukemia (ALL) protocols that achieve survival rates of >90% for low-stage 
disease and >80% for advanced-stage disease. The Chinese Children’s Cancer Group (CCCG) 
was set up in 1997 to improve the quality of children with cancer in China. Two prior 
retrospective multicenter studies for LBL organized by CCCG yielded a 63% 5-year event 
free survival (EFS) and a 77% 2-year EFS, respectively. These survival rates are 10~20% 
lower than the rates reported by most medical-developed countries. We are aware of 3 issues 
through the previous studies: 1) Both 2 previous studies are retrospective studies; 2) 
Compared with the BFM backbone protocols, many treatment protocols for pediatric LBL 
used in China have more intensification treatment; 3) Patients who had not achieved complete 
remission on day 33 of induction (high risk group) had much worse EFS (Less than 30%).  
The CCCG-LBL-2016 trial is a planned 5-year study. A total of 8 tertiary referral centers for 
childhood cancers in CCCG will participate. The BFM backbone was chosen for the 
following reasons: 1) The favorable results for BFM trials were achieved; 2) BFM trials for 
pediatric LBL are well-known in China; 3) A 55% 5-year EFS was achieved in the high-risk 
group in the intercontinental trial ALL IC-BFM 2002.  
Besides the scientific aims, we are also willing to test the feasibility of developing 
prospective multicenter studies for childhood LBL in China.        
 
 

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2.0 
Patient eligibility 
2.1 General 
Each center was responsible for its own data collection. A predefined set of data was 
collected for each patient using protocol-specific forms (EXCEL table) and sent to a 
coordinating center where the findings were reviewed for consistency and completeness. 
The data were transferred every 12 months. All 12-month reports were reviewed by each 
local investigator. The protocol was approved by the primary institutional ethnics 
committee located in Shanghai Children’s Medical Center (SCMC), and written informed 
consent was obtained for all patients or their legal guardian in the treating hospital. All 
cases were reviewed by two individual pathologists based on morphological features and 
immunophenotypic studies. Any discordant diagnoses were reviewed by the third 
pathologists from the National Pathology Experts Group to reach a final consensus 
diagnosis. 
 
2.2 Patient Eligibility Criteria 
⚫ 
Patient must be >1 year and ≤ 18 years of age with newly diagnosed biopsy-proven 
lymphoblastic lymphoma (LBL).  
⚫ 
Patients shall have had no prior cytotoxic chemotherapy with the exception of 1-
week steroids (<420mg/m2) 
⚫ 
Exclusion Criteria: Patients with congenital disease or primary/secondary immune 
compromised disease.  
 
Risk stratification for LBL patients 
 
Low risk group 
(R1) 
Stage* I or II 
Intermediate 
risk group 
(R2) 
Stage III or IV or receiving steroids within one week prior to the 
diagnosis (<420mg/m2) 
High-risk group 
(R3) 
Failure to qualify a PR, or >5% BM blasts, or with CNS disease on d33 of 
induction 
*International Pediatric Non-Hodgkin Lymphoma Staging System 
 
 
 

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3.0 
Treatment plan 
3.1 CCCG-LBL-2016 Treatment protocols 
Drug 
Dose 
Days of administration 
Induction I 
Prednisone (orally) 
60 mg/m2 per day 
1-28, then taper over 9 days 
Vincristine (iv) 
1.5 mg/m2 per day (max 2 mg) 
1，8, 15, 22 
Daunorubincin (iv over 1h) 
25 mg/m2 per dose 
1，8, 15, 22 
PEG-LASP (im)  
2000 IU/m2 per dose 
4,29,57 
Cyclophosphamide (iv over 1 h) 
1000 mg/m2 per dose 
36, 57 
Cytarabine (iv over 30min 或皮
下) 
75 mg/m2 /d 
36-42, 57-63 
6-Mercaptopurine (orally) 
60 mg/m2 per day 
36-42, 57-63 
Triple it a 
 
8,15,22,29,36,57 (43b,50b) 
Protocol M   
 
 
6-Mercaptopurine (orally) 
25 mg/m2 per day 
1-56 
Methotrexatec 
5 g/m2 per dose 
1, 15, 29, 43 
Triple ita 
 
1, 15, 29, 43 
Reinduction II  
Dexamethasone (orally) 
10 mg/m2 per day 
1-7, 15-21  
Vincristine (iv) 
1.5 mg/m2 per day (max 2 mg) 
8, 15, 22, 29 
Doxorubincin (iv over 1 h) 
25 mg/m2 per dose 
8, 15, 22 
PEG-LASP (im) 
2,000 IU/m2 per dose 
4, 25 
Cyclophosphamide (iv over 1 h) 
1000 mg/m2 per dose 
36 
Cytarabine (iv) 
75 mg/m2 /d 
36-42, 
6-Mercaptopurine (orally) 
60 mg/m2 per day 
36-42 
Triple ita 
 
1, 36 
HR 1’ 
Dexamethasone(orally or iv) 
20mg/m2/d, in 3 fractions 
1-5 
Vincristine (iv) 
1.5 mg/m2 per day (max 2 mg) 
1, 6 
Methotrexatec 
5000mg/m2, 24hr 
1 
Cyclophosphamide (iv over 1 h)d 
200mg/m2/per dose, q12h×5, 
MESNA  70mg/m2，IV，×3，
0h，+4h，+8h 
2-4 
Cytarabine (iv over 3 hr) 
2000mg/m2/per dose，q12h×2 
5 
PEG-Lasp (im) 
2,000 IU/m2 per dose 
6 
Triple ita 
 
1 
HR 2’ 
Dexamethasone (orally or iv) 
20mg/m2/d, PO/IV, in 3 fractions 
1-5 
Vindesine (iv) 
3mg/m2（MAX 5mg） 
1, 6 
Methotrexatec 
5000mg/m2, 24hr 
1 

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Ifosfamide (iv over 1 hr) d 
800mg/m2/per dose, q12h×5 
2-4 
Daunorubicin (iv over 1 hr) 
30mg/m2/day 
5 
PEG-Lasp (im) 
2,000 IU/m2 per dose 
6 
Triple ita 
 
1, 5b 
HR 3’ 
Dexamethasone (orally or iv) 
20mg/m2/d, PO/IV, in 3 fractions 
1-5 
Cytarabine (iv over 3 hr) 
2000mg/m2/per dose，q12h× 4 
1, 2 
Etoposide (iv over 2 hr) 
100mg/m2/per dose，q12h×5 
3-5 
PEG-Lasp 
2,000 IU/m2 per dose 
6 
Triple ita 
 
5 
iv, intravenously; im, intramuscularly; it, intrathecally; max, maximum. 
a Doses were adjusted for children younger than 3 years. 
b Patients with CNS disease received additional IT. 
c A loading dose of 10% was infused over 30 minutes, the remaining 90% over 23.5 hours.  Leucovorin 
rescue was given 15 mg/m2 at hour 42, 48 and 54. If the MTX level at hour 42（44） was >1.0 μmol/L, 
rescue was continued at 6-hour intervals until MTX levels were ≤0.3μmol/L.   
dFrom Day 2 night 
3.2 Dose of CCCG-LBL-2016 
 
Total 
(maintenance)  
wks 
Systemic chemotherapy 
IT N.O. 
*  
HDMTX 
(g/ m2) 
HDAra-C 
(g/ m2) 
DOX+DNR 
(mg/ m2) 
PEG-LSP 
(U/ m2) 
ETO 
(mg/ m2) 
CPM 
(g/ m2) 
IFOS 
(g/ m2) 
R1 
96 (76) 
20  
-- 
90  
2000 *3 
-- 
2 
-- 
20 
R2 
104 (75)  
20  
-- 
180  
2000 *5 
-- 
3 
-- 
22 
+(3#) 
R3 
104 (74)  
20  
24  
230  
2000 *11 
1000 
5 
8 
22  
+ (5#) 
i.t., intrathecally; CPM, cyclophosphamide; IFOS, ifosfamide; DOX, doxorubincin; DNR, Daunorubicin; MTX, 
methotrexate; Ara-C, cytarabine; ETO, etoposide; PEG-LSP, Pegaspargase; * Doses were adjusted for children by 
age.; # For patients with central nervous system disease;  
 
 
 
 

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4.0 
Evaluation, End of therapy and Follow-up 
4.1 Disease Evaluation at diagnosis or during therapy (See 5.0) 
⚫ 
CBC with differentiation 
⚫ 
Liver/Kidney function 
⚫ 
Bone marrow Cytomorphology  
⚫ 
C.S.F cell count and cytospin: with each intrathecal therapy  
⚫ 
Primary or Metastatic tumor site imaging: Either CT or MRI can be performed; 
Contrast CT is preferred; Ultrasound may be performed at diagnosis or each 
imaging time point as part of the work-up, however, it can not be tumor 
response assessment. 
4.2 Response Criteria 
4.1.1 Complete Remission (CR): Disappearance of all evidence of disease from all 
sites for at least 4 weeks. This will be determined by physical exam and appropriate 
imaging studies. Bone marrow aspirate/biopsy must be morphologically normal and 
any macroscopic nodules in any organs detectable on CT should no longer be present. 
OR A residual lymph node mass > 1.5 cm in greatest transverse diameter that has 
regressed by > 75% in sum of the products of the greatest perpendicular diameters 
(SPD), or any residual lesions in organs that have decreased by > 75%. 
4.1.2 Partial Remission (PR): > 50% decrease in the SPD of the lesions for at least 4 
weeks. No new lesions. 
4.1.3 No Response (NR): Failure to qualify for a PR. No new lesions. 
4.1.4 Progressive Disease: Greater than 25% increase in the size of any lesions or 
appearance of new lesion(s). 
4.3 End of Therapy & Follow-up 
End of Therapy 
Year 1  
(Month 
2,4,6,8,10,12) 
Year 2  
(Month 
3,6,9,12) 
Year 3 
 (Month 
4, 8,12) 
Year 4 
 (Month 
6, 12) 
Year 5 
(yearly) 
Physical Exam 
 
 
 
 
 
CBC with differential 
 
 
 
 
 
Liver/Renal function 
 
 
 
 
 
Primary Tumor Evaluation* 
 
 
 
 
 
*Mainly based on x-ray or Ultrasound. CT/MRI: Optional. 
 
4.4 Criteria for removal from protocol therapy 

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⚫ 
Progressive disease or relapse 
⚫ 
Found to be Ph+ LBL 
⚫ 
Unacceptable toxicity 
⚫ 
Refusal of further protocol therapy by patient/parent/guardian 
⚫ 
Completion of all protocol-specified chemotherapy. 
⚫ 
Physician determines it is in patient’s best interest. 
⚫ 
Development of a second malignancy 
⚫ 
D64, CT/MRI regression <50% or BM/CSF positive (Morphology) 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for 
Off Study (see below). Follow-up data will be required unless patient is taken off study 
  
4.5 Off study criteria 
⚫ 
Death 
⚫ 
Lost to follow-up 
⚫ 
Patient enrollment onto another therapeutic study (e.g., at recurrence). 
⚫ 
Withdrawal of consent for any further data submission 
 
 

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5.0 Therapy Delivery Map 
Date 
Risk group 
Regimen 
i.t. (N.O.) 
Note 
Induction 
At diagnosis evaluation (D-7~D0)  
 
R1,R2,R3 
PVDL 
2 (if CNS+,4) 
D33 evaluation 
 
R1,R2 
CAM 
1 
 
 
R1,R2 
CAM 
1 
D64 evaluation 
Consolidation 
 
R1,R2 
HDMTX＋6-MP/CF 
1 
 
 
R1,R2 
HDMTX＋6-MP/CF  
1 
 
 
R1,R2 
HDMTX＋6-MP/CF 
1 
 
 
R1,R2 
HDMTX＋6-MP/CF 
1 
 
 
R3 
HR1’ 
1 
 
 
R3 
HR2’ 
1 (if CNS+,2) 
 
 
R3 
HR3’ 
1 
D64 evaluation 
 
R3 
HR1’ 
1 
 
 
R3 
HR2’ 
1 (if CNS+,2) 
 
 
R3 
HR3’ 
1 
 
Re-induction 
 
R2,R3 
VDLD 
1 (if CNS+,2) 
Evaluation，if indicated 
 
R2,R3 
CAM  
1 
 
Maintenance 
W1 
 
（6-MP+MTX）ⅹ4 wks 
1 
Radiation，if indicated 
 
 
 
Evaluation，if indicated 
W5 
 
（6-MP+MTX）ⅹ4 wks 
1 
W9 
 
（6-MP+MTX）ⅹ4 wks 
1 
W13 
 
（6-MP+MTX）ⅹ4 wks 
1 
W17 
 
（6-MP+MTX）ⅹ4 wks 
1 
W21 
 
（6-MP+MTX）ⅹ4 wks 
1 
W25 
 
（6-MP+MTX）ⅹ4 wks 
1 
W29 
 
（6-MP+MTX）ⅹ4 wks 
1 
W33 
 
（6-MP+MTX）ⅹ4 wks 
1 
W37 
 
（6-MP+MTX）ⅹ4 wks 
1 
W41 
 
（6-MP+MTX）ⅹ4 wks 
1 
W45 
 
（6-MP+MTX）ⅹ4 wks 
1 
W49 
 
（6-MP+MTX）ⅹ4 wks 
   
W53 
 
（6-MP+MTX）ⅹ4 wks 
 
 
 
Evaluation，if indicated 
W57 
 
（6-MP+MTX）ⅹ4 wks 
 
W61 
 
（6-MP+MTX）ⅹ4 wks 
 
W65 
 
（6-MP+MTX）ⅹ4 wks 
 
W69 
 
（6-MP+MTX）ⅹ4 wks 
 
W73 
 
6-MP+MTX 
 
W74 
 
  6-MP+MTX 
R3, 104 wks (END) 
End of therapy 
evaluation 
W75 
 
6-MP+MTX 
R2, 104 wks (END) 
W76 
 
6-MP+MTX 
R1, 96 wks (END) 

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