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Phase III Randomized Study of Intensive Schedule vs Standard Schedule Induction Chemotherapy with DNR/ARA-C/VP-16/TG/DM and of Autologous BMT vs Combination Chemotherapy for Intensification in Children with ANLL or Myelodysplastic Syndrome

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 Down Syndrome and Acute Nonlymphoblastic Leukemia or Myelodysplastic Syndrome

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedunder 21NCICCG-2891

Objectives

I.  Assess, in children with acute nonlymphoblastic leukemia (ANLL) and Down 
syndrome, Induction chemotherapy with DCTER (daunorubicin, cytarabine, 
etoposide, thioguanine, dexamethasone) followed by sequential Intensification 
chemotherapy with the Capizzi II regimen (cytarabine and asparaginase), 
CCG-241A Maintenance therapy (thioguanine, vincristine, cytarabine, and 
cyclophosphamide), and the Denver Maintenance regimen (etoposide, 
daunorubicin, cytarabine, thioguanine, and dexamethasone).

II.  Evaluate the prognostic significance of several disease/patient 
characteristics with regard to long-term outcome:  age, initial WBC, presence 
of CNS leukemia, antecedent leukemia (preleukemia), cytogenetic abnormalities, 
FAB classification, various other cellular characteristics (e.g., surface 
antigens), status of the day 7 bone marrow, and alterations in cell cycle 
kinetics and cell cycle-regulated genes and oncogenes after 1 day of therapy.

Entry Criteria

Disease Characteristics:


Previously untreated hematologic malignancies of the following types:
  ANLL of any cell subtype except promyelocytic leukemia (APO, FAB M3)
  Myelodysplastic syndromes, i.e.:
     Refractory anemia
     Refractory anemia with ringed sideroblasts
     Refractory anemia with excess blasts
     Refractory anemia with excess blasts in transformation)
  Juvenile CML (based on response to aggressive therapy)
  Chronic myelomonocytic leukemia
  Granulocytic sarcoma (chloroma) with or without bone marrow involvement

Following diseases are specifically excluded:
  Acute undifferentiated leukemia
  Biphenotypic (mixed lineage) leukemia that histologically resembles acute
     lymphocytic leukemia
  Fanconi anemia
  CML in chronic or accelerated phase

Histologic myeloid leukemia is eligible regardless of "lineage infidelity" by
cell markers

Diagnostic bone marrow requirements:
  Cytogenetic and cell marker studies
  Wright or Giemsa stain
  Chloracetate esterase (or nonspecific esterase) with and without fluoride
     inhibition
  PAS stain
  Peroxidase stain
  Sudan black
  FAB classification must be recorded

Myelodysplastic syndrome patients with an MLC-compatible sibling or parent
donor should be considered for bone marrow transplant while in the
myelodysplastic phase


Prior/Concurrent Therapy:


No prior therapy for current diagnosis
Chemotherapy or radiotherapy for prior malignancies allowed


Patient Characteristics:


Age:
  Less than 21

Performance status:
  Not specified


Expected Enrollment

Approximately 340, 400, and 160 patients will be accrued to Arms I, II, and 
III, respectively.  As of 4/15/95, only Down syndrome and AML patients are 
eligible for entry.

Outline

Randomized study.  As of 4/15/95, only Down syndrome patients are eligible and 
are nonrandomly treated on Arms II and IV; other patients were nonrandomly 
assigned to Arm III after closure of Arm I as of 2/16/93.  Patients with CNS 
leukemia at presentation receive concomitant treatment for their CNS disease 
on Regimen A.  Patients with granulocytic sarcomas, regardless of whether they 
are symptomatic, receive local radiotherapy on Regimen B concomitantly with 
Induction therapy.  Patients (other than those with Down syndrome) with no 
HLA-identical MLC-nonreactive donors had bone marrow harvested and stored, 
after which they were randomized to Arm IV for conventional intensive 
chemotherapy.  Arm V was closed in 10/97.  Regimen C was also closed in 10/97.

The following acronyms are used:
  AlBMT  Allogeneic Bone Marrow Transplant
  AuBMT  Autologous Bone Marrow Transplant
  ARA-C  Cytarabine, NSC-63878
  ASP    Asparaginase, NSC-109229
  BU     Busulfan, NSC-750
  CTX    Cyclophosphamide, NSC-26271
  DM     Dexamethasone, NSC-34521
  DNR    Daunorubicin, NSC-82151
  G-CSF  Granulocyte Colony Stimulating Factor (supplier not specified)
  GVHD   Graft-vs.-Host Disease
  HC     Hydrocortisone, NSC-10483
  4-HC   4-hydroperoxycyclophosphamide
  MTX    Methotrexate, NSC-740
  TG     Thioguanine, NSC-752
  TIT    Triple Intrathecal Chemotherapy (ARA-C/HC/MTX)
  VCR    Vincristine, NSC-67574
  VP-16  Etoposide, NSC-141540

Induction.

Arm I (closed as of 2/16/93):  5-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.  DCTER:  DM/DNR/ARA-C/TG/VP-16; plus IT 
ARA-C.  Intensive schedule.

Arm II (for Down syndrome patients):  5-Drug Combination Systemic Chemotherapy 
plus Single-Agent Intrathecal Chemotherapy.  DCTER; plus IT ARA-C.  Standard 
schedule.

Arm III (closed as of 4/15/95):  5-Drug Combination Systemic Chemotherapy with 
Hematologic Toxicity Attenuation plus Single-Agent Intrathecal Chemotherapy.  
DCTER; with G-CSF; plus IT ARA-C.  Intensive schedule with G-CSF.

Regimen A:  CNS Therapy.  Single-Agent Intrathecal Chemotherapy followed (as 
indicated) by 3-Drug Combination Intrathecal Chemotherapy followed (as 
indicated) by Radiotherapy.  IT ARA-C; followed (if single-agent IT 
chemotherapy fails) by TIT; followed (only in patients with persistent blasts 
in the CSF after TIT) by craniospinal irradiation using megavoltage equipment 
with energies ranging from Co60 to 6 MV x-rays.

Regimen B:  Radiotherapy.  Irradiation of granulocytic sarcoma nodules using 
megavoltage equipment as in Regimen A (electron beams may be used for 
subcutaneous nodules).

Intensification.

Arm IV:  2-Drug Combination Systemic Chemotherapy followed by 4-Drug 
Combination Systemic Chemotherapy plus Single-Agent Intrathecal Chemotherapy 
followed by 5-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  Capizzi II:  High-dose ARA-C; ASP; followed by 
CCG-241A Maintenance:  TG; VCR; ARA-C; CTX; plus IT ARA-C; followed by Denver 
Maintenance:  VP-16; DNR; ARA-C; TG; DM; plus IT ARA-C.

Arm V (Closed as of 10/97): 2-Drug Combination Marrow-Ablative Chemotherapy 
followed by Hematopoietic Rescue.  BU; CTX; followed by AuBMT purged with 4-HC.

Regimen C (Closed as of 10/97):  2-Drug Combination Marrow-Ablative 
Chemotherapy followed by Hematopoietic Rescue followed by GVHD Prophylaxis.  
BU; CTX; followed by AlBMT; followed by MTX.

Published Results

Sung L, Buxton A, Gamis A, et al.: Life-threatening and fatal infections in children with acute myeloid leukemia: a report from the Children's Oncology Group. J Pediatr Hematol Oncol 34 (1): e30-5, 2012.[PUBMED Abstract]

Sung L, Gamis A, Alonzo TA, et al.: Infections and association with different intensity of chemotherapy in children with acute myeloid leukemia. Cancer 115 (5): 1100-8, 2009.[PUBMED Abstract]

Barnard DR, Alonzo TA, Gerbing RB, et al.: Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children's Oncology Group. Pediatr Blood Cancer 49 (1): 17-22, 2007.[PUBMED Abstract]

Neudorf S, Sanders J, Kobrinsky N, et al.: Autologous bone marrow transplantation for children with AML in first remission. Bone Marrow Transplant 40 (4): 313-8, 2007.[PUBMED Abstract]

Neudorf S, Sanders J, Kobrinsky N, et al.: Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood 103 (10): 3655-61, 2004.[PUBMED Abstract]

Tse W, Meshinchi S, Alonzo TA, et al.: Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia. Blood 104 (10): 3058-63, 2004.[PUBMED Abstract]

Woods WG: Intensified induction therapy for children with AML. Ann Hematol 83 (Suppl 1): S119-20, 2004.[PUBMED Abstract]

Casillas JN, Woods WG, Hunger SP, et al.: Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (8): 594-600, 2003.[PUBMED Abstract]

Gamis AS, Woods WG, Alonzo TA, et al.: Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol 21 (18): 3415-22, 2003.[PUBMED Abstract]

Alonzo TA, Kobrinsky NL, Aledo A, et al.: Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 24 (8): 627-35, 2002.[PUBMED Abstract]

Barnard DR, Lange B, Alonzo TA, et al.: Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 100 (2): 427-34, 2002.[PUBMED Abstract]

Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001.[PUBMED Abstract]

Gamis AS, Howells WB, DeSwarte-Wallace J, et al.: Alpha hemolytic streptococcal infection during intensive treatment for acute myeloid leukemia: a report from the Children's cancer group study CCG-2891. J Clin Oncol 18 (9): 1845-55, 2000.[PUBMED Abstract]

Casillas J, Woods WG, Arthur DC, et al.: Poor prognosis in pediatric acute myelogenous leukemia (AML) with T (10;11) (p11. 2--P13; q21--q23). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A2183, 1999.

Garnis AS, De Swarte J, Howell WB, et al.: Alpha strep sepsis (ASS) in children with AML: results of Childrens Cancer Group (CCG) protocol 2891. [Abstract] Proceedings of the American Society of Clinical Oncology 17: S2029, 528a, 1998.

Woods WG, Kobrinsky N, Buckley JD, et al.: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 87 (12): 4979-89, 1996.[PUBMED Abstract]

Woods WG, Neudorf S, Gold S, et al.: Aggressive post-remission (REM) chemotherapy is better than autologous bone marrow transplantation (BMT) and allogeneic BMT is superior to both in children with acute myeloid leukemia (AML). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-1091, 368, 1996.

Woods WG, Kobrinsky N, Buckley J, et al.: Timing intensive induction therapy improves post-remission outcome in acute myeloid leukemia (AML) irrespective of the use of bone marrow transplantation (BTM). [Abstract] Blood 84 (Suppl 11): 232A, 1994.

Related Publications

Johnston DL, Alonzo TA, Gerbing RB, et al.: Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 58 (4): 519-24, 2012.[PUBMED Abstract]

Kutny MA, Moser BK, Laumann K, et al.: FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (4): 662-7, 2012.[PUBMED Abstract]

Johnston DL, Alonzo TA, Gerbing RB, et al.: The presence of central nervous system disease at diagnosis in pediatric acute myeloid leukemia does not affect survival: a Children's Oncology Group study. Pediatr Blood Cancer 55 (3): 414-20, 2010.[PUBMED Abstract]

Pollard JA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood 115 (12): 2372-9, 2010.[PUBMED Abstract]

Schultz KA, Chen L, Chen Z, et al.: Health and risk behaviors in survivors of childhood acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 55 (1): 157-64, 2010.[PUBMED Abstract]

Castellino SM, Alonzo TA, Buxton A, et al.: Outcomes in childhood AML in the absence of transplantation in first remission--Children's Cancer Group (CCG) studies 2891 and CCG 213. Pediatr Blood Cancer 50 (1): 9-16, 2008.[PUBMED Abstract]

Horan JT, Alonzo TA, Lyman GH, et al.: Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol 26 (35): 5797-801, 2008.[PUBMED Abstract]

Sung L, Alonzo TA, Gerbing RB, et al.: Respiratory syncytial virus infections in children with acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 784-6, 2008.[PUBMED Abstract]

Barbaric D, Alonzo TA, Gerbing RB, et al.: Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961. Blood 109 (6): 2314-21, 2007.[PUBMED Abstract]

Pollard J, Alonzo T, Gerbing R, et al.: Prevalence and prognostic significance of c-KIT mutations in pediatric CBF AML patients enrolled on serial CCG/COG protocols. [Abstract] Blood 110 (11): A-1442, 2007.

Aplenc R, Alonzo TA, Gerbing RB, et al.: Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group. Blood 108 (1): 74-80, 2006.[PUBMED Abstract]

Smith FO, Alonzo TA, Gerbing RB, et al.: Long-term results of children with acute myeloid leukemia: a report of three consecutive Phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891. Leukemia 19 (12): 2054-62, 2005.[PUBMED Abstract]

Loew TW, Gamis A, Smith FO, et al.: Down syndrome patients with relapsed acute myelogenous leukemia. [Abstract] Blood 104 (11): A-4526, 2004.

Loew TW, Gamis A, Smith FO, et al.: Induction therapy failures in Down Syndrome patients with acute myelogenous leukemia. [Abstract] Blood 104 (11): A-4527, 2004.

Trial Contact Information

Trial Lead Organizations

Children's Cancer Group

William Woods, MD, Protocol chair
Ph: 404-785-6170

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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