CCG 1961

Phase III Randomized Study of Treatment Based on Response to Induction Chemotherapy in Patients With Higher Risk Childhood Acute Lymphocytic Leukemia: Standard Versus Augmented Berlin-Frankfurt-Munster Regimen With Standard Versus Prolonged Intensification For Rapid Early Responders and Doxorubicin Versus Idarubicin and Cyclophosphamide With Delayed Intensification For Slow Early Responders

Note: this outline was patched together from the NCI online protocol and input from parents of kids with ALL. It is summarized here for our convenience, so that we can quickly compare our protocols. We do not guarantee the accuracy of this outline - it is not an official document. You can contact your child's oncologist and ask for the complete protocol document if you are interested in the details of your child's protocol.

CCG 1961 on the cancer.gov site.

(For abbreviations, see the bottom of this page.)

Treatment for high risk ALL, defined as presenting features of at least one of the following:

age 1-9 with WBC greater than 50,000/microliter
age of 10 years old or more (but less than 21)

Note the following stipulations:

FAB L3 is not eligible
CNS or overt testicular leukemia at diagnosis is eligible (these children receive radiation as noted below)

Protocol initiated, # patients: 10/96 (?), 1520 patients over 4 years

Specific Aims:

The study will determine the effects on treatment outcome of more prolonged and/or more rigorous intensification for patients with a rapid early response (RER) of vincristine-prednisone-L-asparaginase-daunorubicin (VPLD) induction.

Also:

Sequential idarubicin/cyclophosphamide is used in intensification for patients with a slow early response (SER)
Immunotoxin (B43-PAP) is used during induction for CD19 positive patients with a SER.
To decrease the incidence of avascular necrosis, dexamethasone dosing is alternated in patients with 2 delints
Studies further the impact of day 7 marrow status on outcome.
Determines prognosis more precisely by studying immunophenotype, ploidy, cytogenetics and early marrow response with BAX/BCL-2 ratios, pattern of tyrosine kinase activation, end-induction and end-intensification leukemic burden, and development of high titer antibody to E. coli asparaginase.

4 arms of treatment:

A: standard duration and intensity
B: increased duration and standard intensity
C: standard duration and increased intensity
D: increased duration and increased intensity

Patients on regimen C and D will also receive a new form of the drug L-asparaginase know as PEG asparaginase which permits a simpler treatment schedule.

SERs in remission on day 28 are randomized to 2 intensive treatments, one of which uses idarubicin instead of doxorubicin.

NOTE: delint = delayed intensification

CCG1961A

This treatment is considered "standard BFM for high-risk ALL"

4 weeks induction
- vincristine IV (days 0, 7, 14, 21)
- daunomycin IV (days 0, 7, 14, 21)
- prednisone PO (days 0-27)
- L-asparaginase IM (3 x per week for 9 doses total in induction)
- ara C IT (day 0)
- methotrexate IT (day 7, also 14 and 21 if leukemia in spinal fluid)
5 weeks consolidation
- methotrexate IT (days 1, 8, 15, 22)
- cyclophosphamide IV (days 0, 14)
- ara C IV/SQ (days 1-4, 8-11, 15-18, 22-25)
- 6 MP PO daily
- prednisone PO (over 10 days weaning off)
- (plus radiation if CNS involvement)
8 weeks interim maintenance
- methotrexate IT (days 0, 28)
- 6MP PO (days 0-41)
- methotrexate PO (days 7, 14, 21, 35)
7 weeks delint
- vincristine IV (days 0, 7, 14)
- doxorubicin IV (days 0, 7, 14)
- L-asparaginase IM (3x per week for 6 doses)
- dexamethasone PO (days 0-20, then weaning off)
- cyclophosphamide IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, 35)
maintenance (84 day courses):
- vincristine IV (days 0, 28, 56)
- prednisone PO (days 0-4, 28-32, 56-60)
- methotrexate PO (weekly, days 7-77)
- 6MP PO (days 0-83)
- methotrexate IT (day 0, ±28)

CCG1961B

increased duration, standard intensity

4 weeks induction
- vincristine IV (days 0, 7, 14, 21)
- daunomycin IV (days 0, 7, 14, 21)
- prednisone PO (days 0-27)
- L-asparaginase IM (3 x per week for 9 doses total in induction)
- ara C IT (day 0)
- methotrexate IT (day 7, also 14 and 21 if leukemia inspinal fluid)
5 weeks consolidation
- methotrexate IT (days 1, 8, 15, 22)
- cyclophosphamide IV (days 0, 14)
- ara C IV/SQ (days 1-4, 8-11, 15-18, 22-25)
- 6 MP PO daily
- prednisone PO (over 10 days weaning off)
- (plus radiation if CNS involvement)
8 weeks interim maintenance with methotrexate, 6-MP, methotrexate
- methotrexate IT (days 0, 28)
- 6MP PO (days 0-41)
- methotrexate PO (days 7, 14, 21, 35)
7 weeks delint
- vincristine IV (days 0, 7, 14)
- doxorubicin IV (days 0, 7, 14)
- L-asparaginase IM (3x per week for 6 doses)
- dexamethasone PO (days 0-7, 15-21)
- cyclophosphamide IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, 35)
8 weeks interim maintenance with methotrexate, 6-MP, methotrexate
- methotrexate IT (days 0, 28)
- 6MP PO (days 0-41)
- methotrexate PO (days 7, 14, 21, 35)
7 weeks delint
- vincristine IV (days 0, 7, 14)
- doxorubicin IV (days 0, 7, 14)
- L-asparaginase IM (3x per week for 6 doses)
- dexamethasone PO (days 0-7, 15-21)
- cyclophosphamide IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, 35)
maintenance (84 day courses):
- vincristine IV (days 0, 28, 56)
- prednisone PO (days 0-4, 28-32, 56-60)
- methotrexate PO (weekly, days 7-77)
- 6MP PO (days 0-83)
- methotrexate IT (day 0, ±28)

CCG1961C

9 weeks induction-consolidation
- vincristine IV (days 0, 7, 14, 21, 42, 49)
- daunorubicin IV (days 0, 7)
- prednisone PO (days 0-7, then weaning off)
- L-asparaginase IM (days 3, 5, 7)
- PEG asparaginase IM (days 14, 42)
- ara C IT (day 0)
- ara C IV/SQ (days 1-4, 8-11, 29-32, 36-39)
- methotrexate IT (days 1, 8, ±15, 22)
- cytoxin IV (days 0, 28)
- (radiation if CNS involvement)
8 weeks interim maintenance
- vincristine IV (days 0, 10, 20, 30, 40)
- methotrexate IV (days 0, 10, 20, 30, 40)
- PEG asparaginase (days 1, 21)
- methotrexate IT (days 0, 30)
7 weeks delint
- vincristine IV (days 0, 7, 14, 42, 49)
- doxorubicin IV (days 0, 7, 14)
- PEG asparaginase IM (days 3, 42)
- dexamethasone PO (days 0-6, 14-20)
- cytoxin IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, ±35)
maintenance (84 day courses):
- vincristine IV (days 0, 28, 56)
- prednisone PO (days 0-4, 28-32, 56-60)
- methotrexate PO (weekly, days 7-77)
- 6MP PO (days 0-83)
- methotrexate IT (day 0, ±28)

CCG1961D (RER)

9 weeks induction-consolidation
- vincristine IV (days 0, 7, 14, 21, 42, 49)
- daunorubicin IV (days 0, 7)
- prednisone PO (days 0-7, then weaning off)
- L-asparaginase IM (days 3, 5, 7)
- PEG asparaginase IM (days 14, 42)
- ara C IT (day 0)
- ara C IV/SQ (days 1-4, 8-11, 29-32, 36-39)
- methotrexate IT (days 1, 8, ±15, 22)
- cytoxin IV (days 0, 28)
- (radiation if CNS involvement)
8 weeks interim maintenance
- vincristine IV (days 0, 10, 20, 30, 40)
- methotrexate IV (days 0, 10, 20, 30, 40)
- PEG asparaginase (days 1, 21)
- methotrexate IT (days 0, 30)
7 weeks delint
- vincristine IV (days 0, 7, 14, 42, 49)
- doxorubicin IV (days 0, 7, 14)
- PEG asparaginase IM (days 3, 42)
- dexamethasone PO (days 0-6, 14-20)
- cytoxin IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, ±35)
8 weeks interim maintenance
- vincristine IV (days 0, 10, 20, 30, 40)
- methotrexate IV (days 0, 10, 20, 30, 40)
- PEG asparaginase (days 1, 21)
- methotrexate IT (days 0, 30)
7 weeks delint
- vincristine IV (days 0, 7, 14, 42, 49)
- doxorubicin IV (days 0, 7, 14)
- PEG asparaginase IM (days 3, 42)
- dexamethasone PO (days 0-6, 14-20)
- cytoxin IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, ±35)
maintenance (84 day courses):
- vincristine IV (days 0, 28, 56)
- prednisone PO (days 0-4, 28-32, 56-60)
- methotrexate PO (weekly, days 7-77)
- 6MP PO (days 0-83)
- methotrexate IT (day 0, ±28)

CCG1961D (SER)

(note: another SER arm D substitutes idarubicin and uses it and cytoxin on a slightly different schedule)

(note: if PEG asp is not available, E asp can be substituted IM on a MWF schedule x 6 doses)

4 weeks induction
- vincristine IV (days 0, 7, 14, 21)
- daunorubicin IV (days 0, 7, 14, 21)
- prednisone PO (days 0-27, then tapered off)
- L-asparaginase IM (9 doses on MWFs)
- ara C IT (day 0)
- methotrexate IT (days 7, 28)
9 weeks consolidation (begin day 35 of induction or when counts allow)
- continue prednisone taper
- cytoxan (IV) days 0 and 28
- ara-c (IV or SC) days 1-4, 8-11, 29-32, and 36-39
- 6-mercaptopurine (oral) days 0-13 and 28-41
- vincristine (IV) days 14, 21, 42, and 49
- asparaginase (IM) days 14, 16, 18, 21, 23, 25, 42, 44, 46, 49, 51, and 53
- IT methotrexate days 0, 8, 15, and 22
- cranial radiation for 10 days during the first 2 weeks
8 weeks interim maintenance
- vincristine IV (days 0, 10, 20, 30, 40)
- methotrexate IV - escalating doses (days 0, 10, 20, 30, 40)
- PEG asparaginase (days 1, 21)
- methotrexate IT (day 0)
4 weeks reinduction
- vincristine IV weekly x 3 (days 0, 7, 14)
- doxorubicin IV (days 0, 7, 14)
- PEG asparaginase IM (days 3)
- dexamethasone PO (days 0-6, 14-20)
- methotrexate IT (day 0)
4 weeks reconsolidation
- cytoxin IV (day 28)
- 6-TG PO (days 28-41)
- ara-C IV (days 29-32 and 36-39)
- vincristine IV (days 42 adn 49)
- PEG Asp IM (day 42)
- IT methotrexate (day 28)
8 weeks interim maintenance
- vincristine IV (days 0, 10, 20, 30, 40)
- methotrexate IV (days 0, 10, 20, 30, 40)
- PEG asparaginase (days 1, 21)
- methotrexate IT (days 0, 30)
7 weeks delint
- vincristine IV (days 0, 7, 14, 42, 49)
- doxorubicin IV (days 0, 7, 14)
- PEG asparaginase IM (days 3, 42)
- dexamethasone PO (days 0-6, 14-20)
- cytoxin IV (day 28)
- ara C IV/SQ (days 29-32, 36-39)
- TG PO (days 28-41)
- methotrexate IT (days 0, 28, ±35)
maintenance (84 day courses):
- vincristine IV (days 0, 28, 56)
- prednisone PO (days 0-4, 28-32, 56-60)
- methotrexate PO (weekly, days 7-77)
- 6MP PO (days 0-83)
- methotrexate IT (day 0, ±28)

Notes:

Separates out RER from SER; SER have more intense regimen, similar to D but with 9 weeks consolidation and with radiation

C and D are more intense in that they use PEG asparaginase more often, methotrexate IV 5 times in interim maintenance instead of methotrexate PO, vincristine IV in interim maintenance

Skipping radiation for RERs who have no CNS involvement

Skipping mid week of dexamethasone to decrease aseptic bone necrosis noted on CCG 1882

No prior treatment for ALL is allowed on this trial.

Abbreviations:

WBC is white blood cell count. The WBC for a healthy child is 5,000-10,000/microliter

FAB is "French-American-British", a designation of the histology of the leukemic cell type. L1 and L2 are considered more favorable prognostically than L3.

CNS is central nervous system. The presence of leukemic cells in the central nervous system is monitored throughout the treatment.

RER Rapid early response. Day 7 marrow showing < 25% blasts (M1 or M2) defines rapid early responders (RER).

VPLD - vincristine-prednisone-L-asparaginase-daunorubicin treatment.

SER Slow early response, defined as > 25% marrow blasts (M3) at day 7.

delint Delayed intensification.

BFM (The Berlin-Frankfurt-Munster (BFM) 76/79 trial of acute lymphoblastic leukemia (ALL) in children produced impressive disease-free survival (DFS) rates with a protocol that began with 8 weeks of intensive therapy, followed by 8 weeks of maintenance therapy, and then another 6 weeks of intensive treatment)

M1, M2, M3 marrow:

M2 means the marrow has between 5% and 25% leukemic blasts.

M3 means there are more than 25% leukemic blasts.

M1 means less than 5% blasts and is the usual definition of a "remission"

marrow.

EFS Event free survival.

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

HC Hydrocortisone, NSC-10483

MP Mercaptopurine, NSC-755

MTX Methotrexate, NSC-740

PEG-ASP Pegaspargase, NSC-624239

PRED Prednisone, NSC-10023

TG Thioguanine, NSC-752

TIT Triple Intrathecal Therapy (IT MTX/IT ARA-C/IT HC)

VCR Vincristine, NSC-67574

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Last Updated 4/06

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