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Phase III Treatment of Poor-Prognosis Childhood ALL (Excluding Infants and Patients with Lymphoma-Leukemia and FAB L3 Blasts), Including a Randomized Comparison of Standard vs Augmented BFM in Late Responders

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed1-20 years inclusiveNCICCG-1882

Objectives

I.  Compare, in a phase III setting, event-free survival in children with 
high-risk acute lymphocytic leukemia (ALL) who have an M1/M2 marrow response 
on day 7 of BFM Induction therapy randomly assigned to Consolidation regimens 
that employ intensive intrathecal methotrexate (IT MTX) vs. cranial 
irradiation.

II.  Attempt to improve the event-free survival of children with high-risk ALL 
who have an M3 marrow on day 7 of BFM Induction and subsequently have an M1/M2 
marrow on day 28 by intensifying standard BFM as follows:  addition of 
nonmyelosuppressive chemotherapy with vincristine and asparaginase to 
Consolidation and Reconsolidation courses; addition of a second 
Re-induction/Reconsolidation course; replacement of Interim Maintenance (oral 
mercaptopurine/methotrexate) with Capizzi I (vincristine, escalating 
parenteral methotrexate, asparaginase); addition of a second Capizzi I 
Intensification course following first Re-induction/Reconsolidation; and 
escalation of mercaptopurine and methotrexate dosage during Maintenance to 
maintain an absolute neutrophil count between 750 and 1,500.

III.  Study further the impact of the day 7 marrow status on outcome in 
children with high-risk ALL.

IV.  Gather information concerning cytogenetic abnormalities in children with 
high-risk ALL by correlating karyotype with morphology, immunologic phenotype, 
and clinical features at diagnosis and by using multivariate analysis to 
determine whether karyotype has independent prognostic significance in an 
optimal treatment setting.

V.  Collect information regarding immunophenotype distribution in children 
with high-risk ALL.

VI.  Study the interaction of traditional prognostic factors, day 7 marrow 
response, cytogenetics, and immunophenotype on outcome of treatment.

Entry Criteria

Disease Characteristics:


Acute lymphoblastic leukemia or undifferentiated leukemia
  Marrow L1/L2 lymphoblasts greater than 25%
  No L3 morphology (Burkitt's leukemia)
  No lymphoma-leukemia by at least 1 clinical and 1 laboratory feature:
     Clinical features:
        Massive lymphadenopathy
           Single node greater than 3 cm
           Nodal mass greater than 5 cm
           Grossly visible node
        Massive splenomegaly
           Palpable below umbilicus in supine position
        Large mediastinal mass
           Greater than 1/3 width of thorax at T5

     Laboratory features:
        WBC 50,000 or greater
        Hemoglobin 10 g/dL or greater
        Greater than 25% E-rosetting blasts (or greater than 20% positivity
           for antibodies 9.6, 35.1, or OKT11)


Prior/Concurrent Therapy:


No prior therapy for leukemia except emergency therapy for blast cell crisis,
superior vena cava syndrome, or renal failure resulting from leukemic
infiltration of the kidneys:
  Leukapheresis or exchange transfusion recommended for reduction of leukemic
  cell burden in cases of hyperleukocytosis

  Cranial irradiation for blast cell crisis and prednisone for WBC reduction
  strongly discouraged


Patient Characteristics:


Age:
  1 to 20

Performance status:
  Not specified

Hematopoietic:
  See Disease Characteristics

Hepatic:
  Not specified

Renal:
  Not specified


Expected Enrollment

As of 12/90, the accrual rate was about 260 patients/year; accrual may 
continue for 4 years.

Outline

Study randomized only for patients who respond slowly to remission induction.  
All patients receive identical BFM Induction therapy.  Only patients with 
M1/M2 status on day 28 continue protocol therapy:  those who had M1/M2 marrow 
status on day 7 and good risk factors at diagnosis (under 10 years old, WBC 
less than 100,000, and no CNS disease) are assigned to Regimen B for 
post-induction therapy, while all others with M1/M2 status on day 7 receive 
post-induction therapy on Regimen A; patients who have an M3 marrow on day 3 
and who achieve M1/M2 status by day 28 are randomized on Regimens A and C for 
subsequent treatment.  Patients with unknown day 7 marrow status are removed 
from protocol.

Patients currently receiving treatment on Regimen B as a result of 
randomization according to the original protocol are managed as follows:  
those more than 6 months since starting treatment and those under 10 at 
diagnosis with an initial WBC less than 100,000 continue treatment on Regimen 
B; all others are recalled for cranial irradiation as in Regimen A, after 
which treatment is resumed according to Regimen A, beginning with the next 
treatment phase.

The following acronyms are used:
  ARA-C     Cytarabine, NSC-63878
  ASP       Asparaginase (E. coli), NSC-109229
  CTX       Cyclophosphamide, NSC-26271
  DM        Dexamethasone,NSC-34521
  DNR       Daunorubicin, NSC-82151
  DOX       Doxorubicin, NSC-123127
  IT        Intrathecal
  MP        Mercaptopurine, NSC-755
  MTX       Methotrexate, NSC-740
  PRED      Prednisone, NSC-10023
  TG        Thioguanine, NSC-752
  VCR       Vincristine, NSC-67574

INDUCTION:

4-Drug Combination Systemic Chemotherapy plus 2-Drug Combination Intrathecal 
Chemotherapy.  PRED; VCR; DNR; ASP; plus IT ARA-C; IT MTX.

REGIMEN A:  STANDARD BFM.

Consolidation:  3-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy plus Radiotherapy.  CTX; MP; ARA-C; plus IT MTX; plus 
cranial irradiation (patients without CNS disease at diagnosis) or 
craniospinal irradiation (patients with CNS disease at diagnosis), using 
megavoltage equipment with energies ranging from Co60 to 6 MV x-rays; plus (in 
patients with testicular leukemia) bilateral testicular irradiation using 
megavoltage equipment as above or orthovoltage equipment or appropriate 
electron beams.

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

Delayed Intensification (Re-induction/Reconsolidation):  Re-induction:  4-Drug 
Combination Systemic Chemotherapy.  DM; VCR; DOX; ASP.  Reconsolidation:  
3-Drug Combination Chemotherapy plus Single-Agent Intrathecal Chemotherapy.  
CTX; TG; ARA-C; plus IT MTX.

Maintenance:  4-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  VCR; PRED; MP; MTX; plus IT MTX.

REGIMEN B:  BFM WITHOUT CRANIAL IRRADIATION (INTENSIVE IT MTX).

Consolidation:  3-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy plus (as indicated) Radiotherapy.  CTX; MP; ARA-C; 
plus IT MTX; plus (for patients with testiculomegaly) bilateral testicular 
irradiation using equipment as in Regimen A.

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

Delayed Intensification (Re-induction/Reconsolidation):  Re-induction:  4-Drug 
Combination Systemic Chemotherapy plus Single-Agent Intrathecal Chemotherapy.  
DM; VCR; DOX; ASP; plus IT MTX.  Reconsolidation:  3-Drug Combination Systemic 
Chemotherapy plus Single-Agent Intrathecal Chemotherapy.  CTX; TG; ARA-C; plus 
IT MTX.

Maintenance:  4-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  VCR; PRED; MP; MTX; plus IT MTX.

REGIMEN C:  AUGMENTED BFM.

Consolidation:  5-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy plus Radiotherapy.  CTX; MP; ARA-C; VCR; ASP; plus IT 
MTX; plus cranial or craniospinal irradiation and (as indicated) bilateral 
testicular irradiation as in Regimen A Consolidation.

Interim Maintenance I, Capizzi MTX:  3-Drug Combination Systemic Chemotherapy. 
 VCR; escalating MTX; ASP.

Delayed Intensification I (Re-induction/Reconsolidation):  Re-induction I:  
4-Drug Combination Systemic Chemotherapy.  DM; VCR; DOX; ASP.  Reconsolidation 
I:  5-Drug Combination Systemic Chemotherapy plus Single-Agent Intrathecal 
Chemotherapy.  CTX; TG; ARA-C; VCR; ASP; plus IT MTX.

Interim Maintenance II, Capizzi MTX:  3-Drug Combination Systemic Chemotherapy 
plus Single-Agent Intrathecal Chemotherapy.  VCR; escalating MTX; ASP; plus IT 
MTX.

Delayed Intensification II (Re-induction/Reconsolidation):  Re-induction II:  
4-Drug Combination Systemic Chemotherapy.  DM; VCR; DOX; ASP.  Reconsolidation 
II:  5-Drug Combination Systemic Chemotherapy plus Single-Agent Intrathecal 
Chemotherapy.  CTX; TG; ARA-C; VCR; ASP; plus IT MTX.

Maintenance:  4-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  VCR; PRED; MP; MTX; plus IT MTX.

Published Results

French D, Hamilton LH, Mattano LA Jr, et al.: A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 111 (9): 4496-9, 2008.[PUBMED Abstract]

Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.[PUBMED Abstract]

Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338 (23): 1663-71, 1998.[PUBMED Abstract]

Nachman J, Sather HN, Gaynon PS, et al.: Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group. J Clin Oncol 15 (6): 2222-30, 1997.[PUBMED Abstract]

Related Publications

Nguyen K, Devidas M, Cheng SC, et al.: Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22 (12): 2142-50, 2008.[PUBMED Abstract]

Butturini AM, Dorey FJ, Lange BJ, et al.: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25 (15): 2063-9, 2007.[PUBMED Abstract]

Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35, 2007.[PUBMED Abstract]

Butturini A, Dorey F, Gaynon P, et al.: Obesity and body weight independently predict relapse and survival in preadolescents and teenagers with acute lymphoblastic leukemia (ALL). A retrospective analysis of five Children Cancer Group (CCG) studies. [Abstract] Blood 104 (11): A-992, 2004.

Uckun FM, Nachman JB, Sather HN, et al.: Poor treatment outcome of Philadelphia chromosome-positive pediatric acute lymphoblastic leukemia despite intensive chemotherapy. Leuk Lymphoma 33 (1-2): 101-6, 1999.[PUBMED Abstract]

Heerema NA, Sather HN, Sensel MG, et al.: Frequency and clinical significance of cytogenetic abnormalities in pediatric T-lineage acute lymphoblastic leukemia: a report from the Children's Cancer Group. J Clin Oncol 16 (4): 1270-8, 1998.[PUBMED Abstract]

Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group. J Clin Oncol 16 (2): 527-35, 1998.[PUBMED Abstract]

Uckun FM, Gaynon PS, Sensel MG, et al.: Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study. J Clin Oncol 15 (6): 2214-21, 1997.[PUBMED Abstract]

Uckun FM, Yang Z, Sather H, et al.: Cellular expression of antiapoptotic BCL-2 oncoprotein in newly diagnosed childhood acute lymphoblastic leukemia: a Children's Cancer Group Study. Blood 89 (10): 3769-77, 1997.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Cancer Group

James Nachman, MD, Protocol chair
Ph: 773-702-6808; 800-289-6333

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.

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