Español
Questions About Cancer? 1-800-4-CANCER
  • Print
  • Email
  • Facebook
  • Twitter
  • Google+
  • Pinterest

Clinical Trials (PDQ®)

Phase III Randomized Evaluation of High-Dose ARA-C During Interval Therapy and of Intravenous Maintenance Therapy in Previously Untreated Children with Non-B-Cell ALL or Non-B-Cell NHL

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

Alternate Title

Combination Chemotherapy in Treating Children With Previously Untreated Acute Lymphoblastic Leukemia or Non-Hodgkin's Lymphoma

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedunder 18NCIEORTC-58881
NCI-T90-0065A

Objectives

I.  Determine, in a randomized Phase III trial, whether addition of high-dose 
cytarabine to interval chemotherapy improves the disease-free survival and the 
CNS-free interval among children with increased-risk non-B-cell ALL and in 
children with Stage III/IV non-B-cell NHL.

II.  Determine whether alternation of intravenous and oral administration vs. 
exclusively oral administration of mercaptopurine during maintenance therapy 
improves the disease-free survival and the CNS-free interval in all but very 
high-risk children with non-B-cell ALL and non-B-cell NHL.

Entry Criteria

Disease Characteristics:


Non-B-cell ALL or any stage of non-B-cell NHL previously
untreated (except for up to 7 days of corticosteroids)

  B-cell ALL defined as:

     L3 morphology and the presence of immunoglobulins on the
     membranes or in the cytoplasm of at least 20% of the
     leukemic blasts

     Presence of translocations specific for B-cell neoplasia,
     i.e., t(2;8), t(8;14), or t(8;22)

     Less mature immunophenotypes within the B-cell lineage,
     including cytoplasmic mu chains and L1 or L2 morphology
     (pre-B-cell ALL) also eligible

  Diagnosis of B-cell NHL established on cytologic and
  histologic criteria according to the Kiel classification
  allowed if immunophenotype not available

Increased-risk ALL (risk factor of 0.8 or greater, excluding
very high-risk patients, and all T-cell ALL) and Stage III/IV
NHL eligible for the randomized trial for interval therapy if
the following conditions are met:

  CR achieved by end of Induction
  Remain in CR at the end of Consolidation
  No overt CNS involvement initially

All ALL (except very high-risk patients) and all lymphomas
regardless of stage eligible for the randomized trial for
maintenance therapy if the following conditions are met:

  CR achieved by end of Induction
  Remain in CR after Reconsolidation
  No overt CNS involvement initially

Non-B-cell ALL and non-B-cell NHL eligible for the pilot
protocol for very high-risk patients if any of the following
high-risk characteristics are present:

  Poor response to prednisolone (or prednisone) Preinduction
  therapy (i.e., a leukemic blast count of more than 1,000
  after 7 days of Preinduction)

  Absence of CR after completion of Induction (failure to
  achieve CR must be documented by bone marrow exam at day 42)

  Undifferentiated phenotype, i.e., negativity for the
  following:

     B-cell markers (including CD19, CD20, and CD24)
     T-cell markers
     CALLA (CD10)
     Myeloid markers (acute undifferentiated leukemia)

  Presence of cytogenetic abnormalities e.g., t(9;22) or
  t(4;11) translocation or near-haploidy

Registration within 10 days of diagnosis required


Prior/Concurrent Therapy:


No prior therapy other than up to 7 days of corticosteroids


Patient Characteristics:


Age:
  Under 18

Performance status:
  Not specified

Hematopoietic:
  Not specified

Hepatic:
  Not specified

Renal:
  Not specified


Expected Enrollment

A total of 270 increased-risk patients and 135 low-risk patients will be 
required for randomization.  At an anticipated accrual rate of 150-200/year, 
the study will be open to patient entry for about 3 years.  Final analysis 
will be carried out when a total of 81 relapses or deaths in CR has been 
reported in the randomized groups.

Outline

All patients receive identical Preinduction and Induction therapy, after which 
patients with high-risk characteristics proceed to Consolidation therapy and 
all subsequent treatment on the Very High-Risk Pilot Study and patients whose 
disease is low-risk (risk factor less than 0.8 and non T-cell ALL) or 
increased-risk (risk factor 0.8 and above but without high-risk 
characteristics or T-cell ALL with any risk factor) continue treatment on the 
Randomized Study.  After completing Consolidation, increased-risk patients who 
remain in CR are randomized on Arms I and II for Interval Therapy with vs. 
without the addition of high-dose cytarabine, while low-risk patients are 
assigned nonrandomly to Arm I (without high-dose cytarabine).  Following 
completion of Interval Therapy, all low- and increased-risk patients receive 
identical Reinduction/Reconsolidation, after which those who remain in CR are 
randomized on Arms III and IV for conventional Maintenance therapy vs. 
alternating oral/intravenous Maintenance therapy.

Preinduction:  Single-agent Chemotherapy.  Prednisolone, PRDL, NSC-9900; or 
Prednisone, PRED, NSC-10023.

Induction:  4-Drug Combination Systemic Chemotherapy plus Single-agent 
Intrathecal Chemotherapy.  PRDL or PRED; Vincristine, VCR, NSC-67574; 
Daunorubicin, DNR, NSC-82151; Asparaginase, ASP, NSC-109229; plus Intrathecal 
Methotrexate, IT MTX, NSC-740.

RANDOMIZED STUDY.

Consolidation:  3-Drug Combination Systemic Chemotherapy with Urothelial 
Protection plus Single-agent Intrathecal Chemotherapy.  Cyclophosphamide, CTX, 
NSC-26271; Mercaptopurine, MP, NSC-755; Cytarabine, ARA-C, NSC-63878; with 
Mercaptoethane sulfonate, Mesna, NSC-113891; plus IT MTX.

Interval Therapy.

Arm I:  2-Drug Combination Systemic Chemotherapy with Leucovorin Rescue plus 
Single-agent Intrathecal Chemotherapy.  MP; High-dose MTX; with Leucovorin 
calcium, CF, NSC-3590; plus IT MTX.

Arm II:  3-Drug Combination Systemic Chemotherapy with Leucovorin Rescue plus 
Single-agent Intrathecal Chemotherapy.  MP; High-dose MTX; High-dose ARA-C; 
with CF; plus IT MTX.

Reinduction/Reconsolidation:  Reinduction:  4-Drug Combination Systemic 
Chemotherapy followed by Reconsolidation:  3-Drug Combination Systemic 
Chemotherapy plus Single-agent Intrathecal Chemotherapy.  Dexamethasone, DM, 
NSC-34521; VCR; Doxorubicin, DOX, NSC-123127; ASP; followed by CTX; 
Thioguanine, TG, NSC-752; ARA-C; plus IT MTX.

Maintenance.

Arm III:  2-Drug Combination Chemotherapy.  MP; MTX.  Oral administration of 
MP and MTX.

Arm IV:  2-Drug Combination Chemotherapy.  MP; MTX.  Alternating oral and 
intravenous administration of MP.

VERY HIGH-RISK PILOT STUDY.

Consolidation:  5-Drug Combination Systemic Chemotherapy with Leucovorin 
Rescue and Urothelial Protection plus Single-agent Intrathecal Chemotherapy.  
CTX; High-dose MTX; High-dose ARA-C; ASP; MP; with CF and Mesna; plus IT MTX.

Reinduction:  4-Drug Combination Chemotherapy.  DM; VCR; DOX; ASP.

Interval Therapy:  3-Drug Combination Systemic Chemotherapy with Leucovorin 
Rescue plus Single-agent Intrathecal Chemotherapy.  MP; High-dose MTX; 
High-dose ARA-C; with CF; plus IT MTX.

Continuation Therapy:  7-Drug Combination Systemic Chemotherapy with 
Leucovorin Rescue plus Single-agent Intrathecal Chemotherapy; alternating with 
6-Drug Combination Systemic Chemotherapy with Leucovorin Rescue and Urothelial 
Protection plus Single-agent Intrathecal Chemotherapy.  R1:  PRDL; MP; VCR; 
Intermediate-dose MTX; ARA-C; Teniposide, VM-26, NSC-122819; ASP; with CF; 
plus IT MTX; alternating with R2:  DM; TG; Vindesine, DAVA, NSC-245467; 
Intermediate-dose MTX; Ifosfamide, IFF, NSC-109724; DNR; with CF and Mesna; 
plus IT MTX.

Published Results

Renard M, Suciu S, Bertrand Y, et al.: Second neoplasm in children treated in EORTC 58881 trial for acute lymphoblastic malignancies: low incidence of CNS tumours. Pediatr Blood Cancer 57 (1): 119-25, 2011.[PUBMED Abstract]

Sirvent N, Suciu S, Rialland X, et al.: Prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. Eur J Cancer 47 (2): 239-47, 2011.[PUBMED Abstract]

Uyttebroeck A, Suciu S, Laureys G, et al.: Treatment of childhood T-cell lymphoblastic lymphoma according to the strategy for acute lymphoblastic leukaemia, without radiotherapy: long term results of the EORTC CLG 58881 trial. Eur J Cancer 44 (6): 840-6, 2008.[PUBMED Abstract]

Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007.[PUBMED Abstract]

Sirvent N, Suciu S, Rialland X, et al.: Prognostic significance of blasts with/without pleiocytosis in the cerebro-spinal fluid (CSF) of children with acute lymphoblastic leukemia (ALL) treated without cranial Irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. [Abstract] Blood 108 (11): A-149, 2006.

van der Werff Ten Bosch J, Suciu S, Thyss A, et al.: Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia 19 (5): 721-6, 2005.[PUBMED Abstract]

Duval M, Suciu S, Ferster A, et al.: Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood 99 (8): 2734-9, 2002.[PUBMED Abstract]

Cave H, Suciu S, Dastugue N, et al.: Outcome of acute lymphoblastic leukemia (ALL) patients with t(12;21) or hyperdiploidy (51-66 chromosomes) according to treatment received: results of a prospective study performed within the EORTC trail 58881. [Abstract] Blood 94 (suppl 1): A-2792, 628a, 1999.

Dastugue N, Suciu S, Pages MP, et al.: Frequency, clinical features and outcome of monosomy 7 in childhood acute lymphoblastic leukemia (ALL): results of the EORTC-CLCG study 58881. [Abstract] Blood 94 (Suppl 1): A-4095, 202b, 1999.

Millot F, Suciu S, Philippe N, et al.: Value of high-dose ara-c during the interval-therapy of a BFM-like protocol in increased risk ALL and NHL stage III and IV patients: results of the EORTC 58881 trial. [Abstract] Blood 94 (suppl 1): A-1700, 382a, 1999.

Van Der Werfften Bosch J, Suciu S, Philippe F, et al.: The value of 6-MP i.v. during maintenance treatment in childhood acute lymphoblastic leukemia (ALL) and non-hodgkin lymphoma (NHL): results of the randomized phase III trial 58881 of EORTC Childhood Leukemia Cooperative Group (CLCG). [Abstract] Blood 94 (suppl 1): A-2791, 628a, 1999.

Otten J, Suciu S, Lutz P, et al.: The importance of L-Asparaginase in the treatment of acute lymphoblastic leukemia in children: results of the EORTC 58881 randomized phase III trial showing greater efficiency of echerichia coli as compared to Erwina A'ASE. [Abstract] Blood 88 (10 suppl 1): A-2633, 669a, 1996.

Related Publications

Ducassou S, Ferlay C, Bergeron C, et al.: Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951. Br J Haematol 152 (4): 441-51, 2011.[PUBMED Abstract]

Clappier E, Collette S, Grardel N, et al.: NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia 24 (12): 2023-31, 2010.[PUBMED Abstract]

Clappier E, Collette S, Grardel N, et al.: Prognostic significance of NOTCH1 and FBXW7 mutations in childhood T-cell acute lymphoblastic leukemia (T-ALL): results from the EORTC Children Leukemia Group. [Abstract] Blood 114 (22): A-909, 2009.

Renneville A, Kaltenbach S, Clappier E, et al.: Wilms' tumor 1 (WT1) gene mutations in pediatric T-acute lymphoblastic leukemia. [Abstract] Blood 114 (22): A-3075, 2009.

Mirebeau D, Acquaviva C, Suciu S, et al.: The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Haematologica 91 (7): 881-5, 2006.[PUBMED Abstract]

Cavé H, Suciu S, Preudhomme C, et al.: Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood 103 (2): 442-50, 2004.[PUBMED Abstract]

Mirebeau D, Acquaviva C, Suciu S, et al.: Is CDKN2A +/- CDKN2B and MTAP inactivation of prognostic significance in B-precursor childhood acute lymphoblastic leukemia? Results of EORTC studies 58881 and 58951. [Abstract] Blood 104 (11): A-1076, 2004.

Cavé H, Suciu S, Preudhomme C, et al.: HOX11L2 expression linked to t(5;14)(q35;q32) is not associated with poor prognosis in childhood T-ALL treated in EORTC trials 58 881 and 58 951. [Abstract] Blood 100(11 pt 1): A-576, 153a, 2002.

Trial Contact Information

Trial Lead Organizations

European Organization for Research and Treatment of Cancer

Jacques Otten, MD, Protocol chair
Ph: 32-2-477-5775
Email: jacques.otten@az.vub.ac.be

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

Back to TopBack to Top