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

Alternate Title

Bone Marrow Transplantation Compared With Combination Chemotherapy in Treating Children With Relapsed Acute Lymphocytic Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Completed at least 1 + under 20 at diag. NCI CCG-1941 CCG-1941

Objectives

I.  Improve survival in children with acute lymphoblastic leukemia in early 
first bone marrow relapse.

II.  Compare survival in these children following prolonged intensive 
chemotherapy vs. bone marrow transplantation (BMT) using marrow from 
compatible sibling donors.

III.  Compare survival following BMT using marrow from compatible sibling 
donors vs. (in such a way as to minimize selection and waiting-time biases) 
alternative marrow sources, including matched unrelated donors, 
haplo-identical family donors, and purged autologous bone marrow, based on 
donor availability and investigator preference.

IV.  Compare survival following prolonged intensive chemotherapy vs. BMT using 
marrow from alternative sources.

V.  Assess the prognostic value of clonogenic and polymerase chain 
reaction-based in vitro assays of residual leukemia in predicting the duration 
of remission and disease-free survival of these patients, and use these assays 
to measure response to re-induction therapy.

VI.  Identify and study other prognostic factors and their interrelationships.

VII.  Evaluate the prognostic significance of immunophenotype, cytogenetics, 
transplantability in an SCID mouse system, ratios of molecular clonotypic 
markers bcr/abl and bax/bcl-2, tyrosine kinase expression, mdr-1 gene 
expression, plasma MTX levels, and post-Induction leukemic burden.

VIII.  Compare, 2 and 4 years after study entry, the effects of the various 
therapies on the health status of children who maintain the second remission.

IX.  Evaluate the prognostic significance of the presence of pretreatment 
asparaginase antibodies.

Entry Criteria

Disease Characteristics:

Acute lymphoblastic leukemia (ALL) in early first marrow relapse
  Relapse during or within 12 months of completing frontline therapy

  Diagnostic lumbar puncture and, if other exams equivocal, testicular biopsy
  required

No prior isolated extramedullary relapse
  Concurrent extramedullary relapse eligible

No Burkitt's ALL (greater than 25% L3 cells)

Prior/Concurrent Therapy:

Relapsed during or after frontline therapy

Patient Characteristics:

Age:
  Under 21 at diagnosis and at least 1 year at entry

Other:
  No Down syndrome

Expected Enrollment

232 patients will be randomized to Regimens A and C and an additional 64 
patients will be assigned to Regimen B over approximately 4 years.  If accrual 
after 2 years indicates that fewer than 120 patients will be randomized over 4 
years or if 15% or more of patients fail to complete their assigned therapy, 
the study will close.

Outline

Randomized study.  All patients receive identical Induction therapy, after 
which those with a compatible sibling donor are assigned to Regimen B for 
conventional BMT and those ineligible for BMT are assigned to prolonged 
Intensification/Maintenance chemotherapy on Regimen A (the latter group is not 
included in data analyses).  All other patients are randomized either to 
Regimen A or to alternative BMT (Regimen C) with marrow from a matched 
unrelated donor or other source.  All patients to be treated with BMT 
(Regimens B and C) receive at least 1 course of Intensification chemotherapy 
on Regimen A; if a donor for a Regimen C patient is not found within 3 months, 
BMT is carried out using marrow from a haplo-identical family member or purged 
allogeneic marrow (if for any reason it is not possible to carry out a donor 
search, BMT using haplo-identical or purged autologous marrow is initiated 
following 1 course of Intensification chemotherapy).

Management of Extramedullary Leukemia.

Therapeutic CNS Irradiation:  Transplant patients with CNS disease at entry 
for whom TBI is planned as part of myeloablative therapy receive WBI during 
the last planned Intensification course, while those for whom TBI is not 
planned receive CSI with the last planned course of Intensification; 
chemotherapy patients with CNS disease at entry receive CSI during the first 
month of Maintenance.

Prophylactic CNS Irradiation:  Transplant patients with no CNS disease at 
entry who will undergo TBI receive no further CNS irradiation, while those who 
will not undergo TBI receive WBI during the last planned Intensification 
course; chemotherapy patients without CNS disease at entry receive WBI during 
the first month of Maintenance.

Testicular Irradiation:  Therapeutic testicular irradiation is administered 
during the first course of Intensification to all transplant and chemotherapy 
patients with overt testicular disease at entry.  Transplant patients with or 
without overt testicular leukemia also receive testicular boost irradiation at 
the time of marrow ablation, while chemotherapy patients do not receive 
prophylactic testicular irradiation.

The following acronyms are used:
  ARA-C     Cytarabine, NSC-63878
  BMT       Bone Marrow Transplantation
  CF        Leucovorin calcium, NSC-3590
  CSI       Craniospinal Irradiation
  CYSP      Cyclosporine, NSC-290193
  DM        Dexamethasone, NSC-345211
  HC        Hydrocortisone, NSC-10483
  IDA       Idarubicin, NSC-256439
  IFF       Ifosfamide, NSC-109724
  Mesna     Mercaptoethane sulfonate, NSC-113891
  MTX       Methotrexate, NSC-740
  PEG-ASP   Pegaspargase, NSC-624239
  SAI       Spinal-Axis Irradiation
  TBI       Total-Body Irradiation
  TG        Thioguanine, NSC-752
  TIT       Triple Intrathecal Therapy:  MTX/HC/ARA-C
  TMP-SMX   Trimethoprim-sulfamethoxazole
  VCR       Vincristine, NSC-67574
  VP-16     Etoposide, NSC-141540
  WBI       Whole-Brain Irradiation

INDUCTION.

6-Drug Combination Systemic Chemotherapy plus 3-Drug Intrathecal Chemotherapy. 
 VP-16; IFF/Mesna; DM; VCR; PEG-ASP; MTX/CF; plus TIT.

INTENSIFICATION/MAINTENANCE CHEMOTHERAPY.

Regimen A:

Intensification:  9-Drug Combination Systemic Chemotherapy plus 3-Drug 
Intrathecal Chemotherapy.  DM; VCR; MTX/CF; TG; ARA-C; VP-16; PEG-ASP; 
IFF/Mesna; IDA; plus TIT.

Maintenance:  3-Drug Combination Systemic Chemotherapy plus 3-Drug Intrathecal 
Chemotherapy.  VCR; MTX; TG; plus TIT.

BONE MARROW TRANSPLANTATION (the marrow-ablative regimens outlined on Regimens 
B and C are recommended but not required; other regimens may be substituted).

Regimen B (Conventional Transplantation):  Marrow-Ablative Chemoradiotherapy 
followed by Hematopoietic Rescue.  TBI; VP-16; followed by allogeneic marrow 
from a compatible sibling.

Regimen C (Alternative Transplantation):  Marrow-Ablative Chemoradiotherapy 
followed by Hematopoietic Rescue.  TBI; VP-16; followed by allogeneic marrow 
(from unrelated donor or haplo-identical family member) or purged autologous 
marrow or peripheral blood stem cells.

MANAGEMENT OF EXTRAMEDULLARY LEUKEMIA.

Regimen D (CNS):  Radiotherapy.  WBI or CSI using 4-6 MV photons. 

Regimen E (Testicular):  Radiotherapy.  Bilateral testicular irradiation using 
4-6 MV photons or 6-12 MV electrons.

Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006.[PUBMED Abstract]

Jarrar M, Gaynon PS, Periclou AP, et al.: Asparagine depletion after pegylated E. coli asparaginase treatment and induction outcome in children with acute lymphoblastic leukemia in first bone marrow relapse: a Children's Oncology Group study (CCG-1941). Pediatr Blood Cancer 47 (2): 141-6, 2006.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Cancer Group

Paul Gaynon, MD, Protocol chair		Ph: 323-669-2163 Email: pgaynon@chla.usc.edu