Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia

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Basic Trial Information

PhaseTypeAgeTrial IDs
No phase specifiedTreatment365 days and underCDR0000570260
NCI-2014-00665, CCLG-LK-2006-10, DCOG-INTERFANT-06, EUDRACT-2005-004599-19, NCT00550992

Trial Description

Summary

RATIONALE: Giving chemotherapy before a donor stem cell transplant helps stop the growth of

cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem

cells. When the healthy stem cells from a donor are infused into the patient they may help

the patient's bone marrow make stem cells, red blood cells, white blood cells, and

platelets. Sometimes the transplanted cells from a donor can make an immune response against

the body's normal cells. Giving cyclosporine, methotrexate, leucovorin, and antithymocyte

globulin before and after transplant may stop this from happening. It is not yet known which

treatment regimen is most effective in treating acute leukemia.

PURPOSE: This randomized clinical trial is studying how well different therapies work in

treating infants with newly diagnosed acute leukemia.

Further Study Information

OBJECTIVES:

Primary

To compare an early intensification regimen comprising two "acute myeloid leukemia"

induction therapy blocks with a standard protocol IB regimen administered directly

after induction therapy in medium-risk (MR) and high-risk (HR) patients with newly

diagnosed acute lymphoblastic or biphenotypic leukemia.

Secondary

To compare through a randomized study the role of these regimens in treating these

patients.

To compare the overall outcome of the Interfant-06 study with outcomes in the

historical control series, especially in the Interfant-99 study.

To compare the outcomes of low-risk, MR, or HR patients in this study with those of

patients in the historical control series Interfant-99 study.

To study which factors have independent prognostic value in patients treated with these

regimens.

To assess the role of stem cell transplantation in HR patients.

OUTLINE: This is a multicenter study.

Induction therapy:

Prednisone phase: Patients receive prednisone orally or IV three times daily on

days 1-7 and methotrexate (MTX) and prednisolone (PRDL) intrathecally (IT) on day

1. Patients then proceed to remission induction therapy.

Remission induction phase: Patients receive dexamethasone (DEXA) IV or orally

three times daily on days 8-28 followed by a taper to 0 over 1 week; vincristine

(VCR) IV on days 8, 15, 22, and 29; cytarabine (ARA-C) IV over 30 minutes on days

8-21; daunorubicin hydrochloride (DNR) IV over 1 hour on days 8 and 9;

asparaginase (ASP) IV over 1 hour or intramuscularly (IM) on days 15, 18, 22, 25,

29, and 33; MTX IT on days 1 and 29*; and ARA-C IT on day 15. Patients also

receive PRDL or therapeutic hydrocortisone (HC) IT on days 1, 15, and 29.

NOTE: *Patients with CNS involvement at initial diagnosis also receive MTX IT on days 8 and

22. If CNS leukemia is still present at day 29, then patients receive weekly MTX IT until

the CNS is free of leukemia.

After completion of induction therapy, patients are stratified according to risk group

(low-risk [LR] vs medium-risk [MR] vs high-risk [HR]). Patients with low-risk disease are

assigned to treatment arm I. Patients with MR or HR disease that is in complete remission

(CR) on day 33 are randomized to 1 of 2 treatment arms. These patients are stratified

according to status (MR with rearranged MLL vs MR with unknown MLL vs HR).

Arm I (standard therapy):

Protocol IB therapy (beginning on day 36 of induction therapy): Patients receive

cyclophosphamide (CPM) IV over 1 hour on days 1 and 29 and oral mercaptopurine

(MP) on days 1-28; ARA-C IV on days 3-6, 10-13, 17-20, and 24-27; ARA-C IT on day

10; and MTX IT on day 24. Patients also receive PRDL or therapeutic HC IT on days

10 and 24.

MARMA therapy:

Part I: Patients receive oral MP once daily on days 1-14; high-dose (HD) MTX

IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV at 42, 48,

and 54 hours after each dose of MTX until MTX plasma levels are safe; and MTX

IT on days 2 and 9. Patients also receive PRDL or therapeutic HC IT on days 2

and 9.

Part II: Patients receive HD ARA-C IV over 3 hours twice daily with 12-hour

intervals on days 15, 16, 22, and 23; and pegaspargase (PEG-ASP) IV over 1

hour or IM on day 23.

OCTADA(D) reinduction therapy:

Part I: At least 2 weeks after the completion of MARMA chemotherapy, patients

receive oral dexamethasone (DEXA) three times daily on days 1-14, followed by

a taper to 0 at day 21; oral thioguanine (TG) once daily on days 1-28; VCR IV

on days 1, 8, 15, and 22; DNR IV over 1 hour on days 1, 8, 15, and 22;

PEG-ASP IV over 1 hour or IM on day 1; ARA-C IV on days 2-5, 9-12, 16-19, and

23-26; and ARA-C IT on days 1 and 15. Patients also receive PRDL or

therapeutic HC IT on days 1 and 15.

Part II: Patients receive oral TG once daily on days 36-49; ARA-C IV once

daily on days 37-40 and 45-48; and CPM IV over 1 hour on days 36 and 49.

Maintenance therapy: At least 2 weeks after completion of the last course of

OCTADA(D) chemotherapy, patients receive oral MP once daily; oral MTX once weekly;

MTX IT in weeks 1 and 15; and ARA-C IT in week 8. Patients also receive PRDL or

therapeutic HC IT in weeks 1, 8, and 15. Treatment continues for up to 104 weeks

after initial diagnosis in the absence of disease progression or unacceptable

toxicity.

Arm II (experimental therapy):

ADE therapy (beginning on day 36 of induction therapy: Patients receive ARA-C IV

every 12 hours on days 1-10; DNR IV over 1 hour on days 1, 3, and 5; etoposide

(VP-16) IV over 4 hours on days 1-5; and ARA-C IT on day 1. Patients also receive

PRDL or therapeutic HC IT on day 1.

MAE therapy: Patients receive ARA-C IV every 12 hours on days 1-10; mitoxantrone

hydrochloride IV over 1 hour on days 1, 3, and 5; VP-16 IV over 4 hours on days

1-5; and MTX IT on day 1. Patients also receive PRDL or therapeutic HC IT on day

1.

MARMA therapy:

Part I: Patients receive oral MP once daily on days 1-14; high-dose (HD) MTX

IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV at 42, 48,

and 54 hours after each dose of MTX until MTX plasma levels are safe; and MTX

IT on days 2 and 9. Patients also receive PRDL or therapeutic HC IT on days 2

and 9.

Part II: Patients receive HD ARA-C IV over 3 hours twice daily with 12-hour

intervals on days 15, 16, 22, and 23; and pegaspargase (PEG-ASP) IV over 1

hour or IM on day 23.

OCTADA reinduction therapy:

Part I: At least 2 weeks after the completion of MARMA chemotherapy, patients

receive oral DEXA three times daily on days 1-14, followed by a taper to 0 at

day 21; oral TG once daily on days 1-28; VCR IV on days 1, 8, 15, and 22;

PEG-ASP IV over 1 hour or IM on day 1; ARA-C IV on days 2-5, 9-12, 16-19, and

23-26; and ARA-C IT on days 1 and 15. Patients also receive PRDL or

therapeutic HC IT on days 1 and 15.

Part II: Beginning 1 week after completion of part I, patients receive oral

TG once daily on days 36-49; ARA-C IV once daily on days 37-40 and 45-48; and

CPM IV over 1 hour on days 36 and 49.

Maintenance therapy: At least 2 weeks after completion of the last course of

OCTADA chemotherapy, patients receive oral MP once daily; oral MTX once weekly;

MTX IT in weeks 1 and 15; and ARA-C IT in week 8. Patients also receive PRDL or

therapeutic HC IT in weeks 1, 8, and 15. Treatment continues for up to 104 weeks

after initial diagnosis in the absence of disease progression or unacceptable

toxicity.

All HR patients with a suitably matched donor are scheduled for allogeneic stem cell

transplantation (SCT) after MARMA or before or during OCTADA(D) chemotherapy, provided they

are in CR1 and no more than 8 months have elapsed since initial diagnosis.

Conditioning regimens for allogeneic SCT:

Matched sibling donor (MSD): Patients receive oral busulfan (BU) every 6 hours on

days -7 to -4; CPM IV over 1 hour on days -3 to -2; and melphalan (MEL) IV over 1

hour on day -1.

Matched donors (MD): Patients receive oral BU every 6 hours on days -7 to -4; CPM

IV over 1 hour on days -3 to -2; MEL IV over 1 hour on day -1; and anti-thymocyte

globulin (ATG) IV over 4 hours on days -3 to -1.

Graft-Versus-Host Disease (GVHD) prophylaxis and therapy:

MSD: Patients receive cyclosporine (CsA) IV or orally twice daily beginning on day

-1 and continuing to day 60 after SCT, followed by a taper in the absence of GVHD

symptoms.

MD: Patients receive CsA as in group MSD; MTX IV on days 1, 3, and 6; leucovorin

calcium IV on days 2, 4, and 7; and ATG IV on days -3 to -1.

Allogeneic SCT: Patients undergo infusion of bone marrow, peripheral blood, or cord

blood hematopoietic stem cells on day 0.

After completion of study therapy, patients are followed periodically for up to 2 years.

Eligibility Criteria

Inclusion Criteria:

MLL rearranged AND age < 6 months AND WBC < 300 x 10^9/L AND prednisone

good response

Diagnosis of acute lymphoblastic leukemia (ALL) or biphenotypic leukemia meeting the

following criteria:

Based on European Group for the Classification of Acute Leukemia (EGIL)

diagnostic criteria

Newly diagnosed disease

Verified by morphology and confirmed by cytochemistry and immunophenotyping

Trephine biopsy is recommended (unless diagnosis can be confirmed by

peripheral blood examination) in the event that bone marrow aspiration

results in a "dry tap"

Must have MLL gene rearrangements documented by split-signal fluorescence in situ

hybridization and meets 1 of the following risk criteria:

Low-risk disease, defined as all MLL germline cases

Medium-risk disease, defined by 1 of the following criteria:

MLL status unknown

MLL rearranged AND age > 6 months

High-risk disease, defined by MLL rearrangement AND meets the following

criteria:

Age at diagnosis < 6 months (i.e., < 183 days)

WBC ≥ 300 x 10^9/L AND/OR prednisone poor response

Minimum donor and stem cell requirements for high-risk patients undergoing stem cell

transplantation:

Donor meeting 1 of the following criteria:

HLA-identical sibling

Very well-matched related or unrelated donor

Must be HLA compatible in 10/10 or 9/10 alleles by 4 digit/allele

high-resolution molecular genotyping

Stem cell source

Bone marrow (preferred source) OR peripheral blood stem cells of filgrastim

[G-CSF]-stimulated donors OR cord blood

Highly-matched unrelated umbilical cord blood (UCB) (> 7/8 matches

identified by high-resolution typing) accepted if a sibling donor is

not able to donate bone marrow AND UCB with a sufficient number of

nucleated cells (NCs) (i.e., > 1.5 x 10^7/kg recipient body weight

[BW]) is cryopreserved

Must have ≥ 3 x 10^8 NCs/kg BW OR 3 x 10^6/kg BW CD34-positive cells available

for transplantation

CNS or testicular leukemia at diagnosis allowed

Exclusion Criteria:

Mature B-ALL, defined by the immunophenotypical presence of surface immunoglobulins

or t(8;14) and breakpoint as in B-ALL

Presence of the t(9;22) (q34;q11) or bcr-abl fusion in the leukemic cells (if data

are not known, patient still may be eligible)

Relapsed ALL

PATIENT CHARACTERISTICS:

See Disease Characteristics

PRIOR CONCURRENT THERAPY:

More than 4 weeks since prior systemic corticosteroids

Corticosteroids by aerosol are allowed

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Dutch Childhood Oncology Group

  • Coordinated Laboratory for Computational Genomics
  • BFM Austria
  • Associazione Italiana Ematologia Oncologia Pediatrica
  • BFM Germany
  • CORS Monza Italy
  • ANZCHOG Austria New Zealand
  • COALL Germany
  • CPH, Czech republic
  • DFCI consortium USA
  • FRALLE France
  • Hong Kong
  • M D Anderson Cancer Center
  • Nordic Society of Paediatric Hematology and Oncology NOPHO
  • PINDA, Chile
  • PPLLSG Poland
  • Seattle USA
  • St. Jude Children's Research Hospital
  • United Kingdom Children's Cancer Study Group

Trial Sites

U.S.A.

Massachusetts
Boston

Dana-Farber Cancer Institute

Lewis Barry Silverman
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00550992

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.