Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	up to 18		GER-GPOH-NHL-BFM-90 EU-92004

Objectives

I.  Determine whether the response and relapse rates in patients with Stage 
III B-cell NHL presenting with high abdominal tumor burden (LDH greater than 
500) can be improved by an intensified chemotherapy approach compared to 
historical controls.

II.  Determine whether CNS remission can be achieved by fractionated 
intraventricular chemotherapy in patients with B-cell NHL and B-cell ALL with 
initial CNS involvement.

III.  Determine whether survival of incomplete responders after 2 treatment 
cycles can be improved by escalating intensified chemotherapy, including 
ablative therapy with autologous bone marrow rescue, in patients with B-cell 
NHL and B-cell ALL.

IV.  Determine whether therapy intensity can be reduced from 3 to 2 cycles 
without an increased failure rate compared to historical controls in patients 
with B-cell NHL with complete initial resection.

V.  Determine whether patients with mediastinal T-cell lymphoma who have 
residual tumor after induction therapy can be cured without mediastinal 
irradiation.

VI.  Evaluate prospectively the dynamics of regression of lymphomatous tumors 
as prognostic indicators of outcome.

VII.  Evaluate prospectively the prognostic value of dose intensity during the 
first 3 cycles of therapy.

Entry Criteria

Disease Characteristics:

Newly diagnosed non-Hodgkin's lymphoma of any type and B-cell
acute lymphoblastic leukemia

Previously misdiagnosed and inadequately treated NHL not
eligible

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy (other than a maximum of 2 doses of
  vincristine/daunorubicin within 4 weeks prior to entry)

Endocrine therapy:
  No more than 4 weeks of prior corticosteroids

Radiotherapy:
  No prior radiotherapy

Surgery:
  Not specified

Patient Characteristics:

Age:
  Up to 18

Performance status:
  Any status

Hematopoietic:
  Not specified

Hepatic:
  Not specified

Renal:
  Not specified

Other:
  No significant morbidity from nonmalignant disease
  No history of a second malignancy

Expected Enrollment

Approximately 350 patients will be entered over a period of 2 years and 9 
months.

Outline

The St. Jude staging system is used throughout.  Non-B-cell NHL patients with 
Stage I/II disease are treated on Regimen SRG, while those with Stage III/IV 
disease are treated on Regimen RG.  B-cell NHL and B-cell ALL patients who 
achieve initial complete resection are treated on Regimen R1; those with 
incomplete or no resection and those with no abdominal tumor or with abdominal 
tumor and LDH less than 500 are treated on Regimen R2, while those with 
abdominal tumor and LDH of 500 or above and/or bone marrow/CNS involvement 
and/or multiple bone lesions are treated on Regimen R3.  Patients who fail 
therapy on Regimens R2 and R3 receive further therapy on Regimen BMT.  Large 
cell anaplastic lymphoma patients with Stage I or completely resected Stage II 
disease are treated on Regimen K1, while those with incompletely resected 
Stage II or Stage III disease are treated on Regimen K2 and those with Stage 
IV disease are treated on Regimen K3.  Patients failing therapy on Regimens 
K1, K2, and K3 receive further therapy on Regimen BMT.

Regimen SRG:

Induction:  7-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  Prednisone, PRED, NSC-10023; Vincristine, VCR, 
NSC-67574; Daunorubicin, DNR, NSC-82151; Asparaginase, ASP; Cyclophosphamide, 
CTX, NSC-26271; Cytarabine, ARA-C, NSC-63878; Mercaptopurine, MP, NSC-755; 
plus Intrathecal Methotrexate, IT MTX, NSC-740.

Intensification:  2-Drug Combination Systemic Chemotherapy/Leucovorin plus 
Single-Agent Intrathecal Chemotherapy.  MP; MTX; Leucovorin calcium, CF, 
NSC-3590; plus IT MTX.

Maintenance:  2-Drug Combination Systemic Chemotherapy.  MP; MTX.

Regimen RG:

Induction:  7-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  PRED; VCR; DNR; ASP; CTX; ARA-C; MP; plus IT MTX.

Intensification:  2-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  MP; MTX; plus IT MTX.

Re-induction:  7-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  Dexamethasone, DM, NSC-34521; VCR; Doxorubicin, 
DOX, NSC-123127; ASP; CTX; ARA-C; Thioguanine, TG, NSC-752; plus IT MTX.

Cranial irradiation:  Prophylactic/therapeutic cranial irradiation (equipment 
unspecified).

Maintenance:  2-Drug Combination Systemic Chemotherapy.  MP; MTX.

Regimen R1:  2-Drug Combination Systemic Chemotherapy plus Triple Intrathecal 
Therapy (TIT) followed by 5-Drug Combination Systemic Chemotherapy/Leucovorin 
plus TIT followed by 4-Drug Combination Systemic Chemotherapy/Leucovorin plus 
TIT.  Prephase V:  DM; CTX; plus TIT (IT MTX, IT ARA-C, IT PRED); followed by 
Block A:  DM; Ifosfamide, IFF, NSC-109724; MTX; Etoposide, VP-16, NSC-141540; 
ARA-C; CF; plus TIT; followed by Block B:  CTX; DOX; DM; MTX; CF; plus TIT.

Regimen R2:  2-Drug Combination Systemic Chemotherapy plus TIT followed by 
alternating courses of 6-Drug Combination Systemic Chemotherapy/Leucovorin 
plus TIT and 5-Drug Combination Systemic Chemotherapy/Leucovorin plus TIT.  
Prephase V; followed by alternating courses of Block AA:  DM; IFF; VCR; MTX; 
VP-16; ARA-C; CF; plus TIT; and Block BB:  CTX; DOX; DM; VCR; MTX; CF; plus 
TIT.  2 cycles (4 courses) of alternating therapy (AA-BB-AA-BB).

Regimen R3:  2-Drug Combination Systemic Chemotherapy plus TIT followed by 
alternating courses of 6-Drug Combination Systemic Chemotherapy/Leucovorin 
plus TIT and 5-Drug Combination Systemic Chemotherapy/Leucovorin plus TIT.  
Prephase V; followed by alternating courses of Block AA and Block BB (with 
intraventricular or intrathecal TIT) for 3 cycles (6 courses) of alternating 
therapy (AA-BB-AA-BB-AA-BB).

Regimen BMT:  3-Drug Combination Marrow-Ablative Systemic Chemotherapy 
followed by Bone Marrow Rescue.  Busulfan, BU, NSC-750; VP-16; CTX (in 
patients without CNS disease) or Thiotepa, TSPA, NSC-6396 (in patients with 
CNS disease); followed by Autologous Bone Marrow Rescue, ABM.

Regimen K1:  2-Drug Combination Systemic Chemotherapy plus TIT followed by 
5-Drug Combination Systemic Chemotherapy/Leucovorin plus TIT followed by 
4-Drug Combination Systemic Chemotherapy/Leucovorin plus TIT followed by 
5-Drug Combination Systemic Chemotherapy/Leucovorin plus TIT.  Prephase V; 
followed by Block A; followed by Block B; followed by Block A.

Regimen K2:  2-Drug Combination Systemic Chemotherapy plus TIT followed by 
alternating courses of 5-Drug Combination Systemic Chemotherapy/Leucovorin 
plus TIT and 4-Drug Combination Systemic Chemotherapy/Leucovorin plus TIT.  
Prephase V; followed by alternating courses of Block A and Block B for 3 
cycles (6 courses) of alternating therapy (A-B-A-B-A-B).

Regimen K3:  2-Drug Combination Systemic Chemotherapy plus TIT followed by 
alternating sequential courses of 6-Drug Combination Systemic 
Chemotherapy/Leucovorin plus TIT, 5-Drug Combination Systemic 
Chemotherapy/Leucovorin plus TIT, and 4-Drug Combination Systemic Chemotherapy 
plus TIT.  Prephase V; followed by alternating sequential courses of Block AA, 
Block BB, and Block CC:  DM; Vindesine, DAVA, NSC-245467; ARA-C; VP-16; plus 
TIT.  2 cycles (6 courses) of alternating therapy (AA-BB-CC-AA-BB-CC).

Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.[PUBMED Abstract]

Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.[PUBMED Abstract]

Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.[PUBMED Abstract]

Wössmann W, Schrappe M, Meyer U, et al.: Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase. Ann Hematol 82 (3): 160-5, 2003.[PUBMED Abstract]

Attarbaschi A, Mann G, Dworzak M, et al.: Malignant non-Hodgkin's lymphoma of childhood and adolescence in Austria--therapy results between 1986 and 2000. Wien Klin Wochenschr 114 (23-24): 978-86, 2002.[PUBMED Abstract]

Möricke A, Zimmermann M, Reiter A, et al.: Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 217 (6): 310-20, 2005 Nov-Dec.[PUBMED Abstract]

Reiter A, Schrappe M, Tiemann M, et al.: Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies. J Clin Oncol 12 (5): 899-908, 1994.[PUBMED Abstract]

Attarbaschi A, Mann G, Panzer-Grümayer R, et al.: Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol 26 (18): 3046-50, 2008.[PUBMED Abstract]

Müller J, Csóka M, Jakab Z, et al.: Treatment of pediatric non-Hodgkin lymphoma in Hungary: 15 years experience with NHL-BFM 90 and 95 protocols. Pediatr Blood Cancer 50 (3): 633-5, 2008.[PUBMED Abstract]

Mann G, Attarbaschi A, Burkhardt B, et al.: Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma. Br J Haematol 139 (3): 443-9, 2007.[PUBMED Abstract]

Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Medizinische Hochschule Hannover

Alfred Reiter, MD, Protocol chair(Contact information may not be current)		Ph: 49-511-532-9123