Phase III Randomized Study of Different Combination Chemotherapy Regimens in Pediatric Patients With Newly Diagnosed Standard Risk B-Precursor Acute Lymphoblastic Leukemia./p>

Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

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.

This trial on the cancer.gov site.

Classification of newly diagnosed leukemia

All newly diagnosed ALL patients are enrolled in COG AALL03B1, Classification of Acute Lymphoblastic Leukemia.

At diagnosis of ALL, the oncologists at the local hospital determine an initial risk classification as follows:

• standard risk ALL, or SR ALL: B-precursor and WBC less than 50,000/microliter and age 1-9 years
• higher risk ALL, or HR ALL: B-precursor and WBC greater than or equal to 50,000/microliter or age greater or equal to 10 years (note that they go all the way up to 30 years of age)
• infant ALL: less than 1 year is classified separately
• T-cell

(This method of risk classification is known as "NCI/Rome criteria".)

At diagnosis samples of blood/bone marrow aspirate/CFS are taken and studied for cytogenetic/immunophenotype characteristics (see later in the protocol how the results of these tests might effect the treatment.)

SR ALL is treated on AALL0331, as outlined below. HR ALL is treated on AALL0232. The protocols for infant, T-cell, and very high risk will be added to this site when they are available.

AALL0331

Patients are assigned to one of three groups of SR (Standard Risk) level, called SR-low, SR-average, and SR-high. (Historically, the POG 9904 and 9905 trials also defined different levels of average/low risk - activated early 2000s and still active 2005 - while CCG 1991 lumped these lower-risk groups together.) Remember: this trial is for 0-9 year olds, WBC less than 50K at diagnosis, and pre-B ALL. MRD levels direct the treatment to some extent (details below).

SR-low:

• RER: blasts in bone marrow less than 5% by day 15 and MRD negative by day 29
• CNS1 (no blasts in spinal fluid, meaning no CNS disease)
• no testicular disease
• must have either trisomies of 4, 10 and 17 or the TEL-AML1 translocation (these are favorable)
• cannot have MLL rearrangements, the BCR-ABL fusion transcript, t(9;22)(q34;q11), or less than 44 chromosomes (hypodyploid)

SR-average

• RER: blasts in bone marrow less than 5% by day 15 and MRD negative by day 29
• CNS1 or CNS2
• no testicular disease
• cannot have MLL rearrangements, the BCR-ABL fusion transcript, t(9;22)(q34;q11), or less than 44 chromosomes (hypodyploid)

SR-high (this is not a randomized arm)

• SER
• CNS3 or testicular disease is present at diagnosis
• shows M2 marrow (over 5% blasts but less than 25% blasts) and an MRD of greater than or equal to 1% at day 29 - but and M1 marrow (less than 5% blasts) and less than 1% MRD at day 43
• can have if MLL rearrangements if is a RER
• cannot have the BCR-ABL fusion transcript, t(9;22)(q34;q11), or less than 44 chromosomes (hypodyploid) - these patients go on the very high risk protocol, not on 331

A patient must go to a higher risk protocol if they have:

• greater than 1% MRD or M2 or M3 after the extended induction therapy.
• MLL rearrangement and and is a SER
• the BCR-ABL fusion transcript, t(9;22)(q34;q11), or less than 44 chromosomes (hypodyploid)

Induction, 4 weeks

(Same induction for low-, average-, and high-risk arms.)

All patients receive:

• cytarabine intrathecally (IT) on day 1
• vincristine IV on days 1, 8, 15, and 22
• dexamethasone IV or orally twice daily on days 1-28
• pegaspargase intramuscularly (IM) on day 4, 5 or 6
• methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease)

Day 29: Patients are assessed for response to treatment on by doing a traditional bone marrow assessment (giving the M1, M2, M3 value) and by testing for MRD (minimal residual disease, a more sensitive leukemia test).

• Patients with M1 bone marrow and minimal residual disease (MRD) less than 0.1% or MRD greater than or equal to 0.1% and less than 1% proceed to consolidation therapy as per their low- or average-risk assessment.
• Patients with M2 bone marrow or M1 bone marrow and MRD greater than or equal to 1% proceed to extended induction therapy.
• Patients with M3 bone marrow are removed from the study.

Extended induction therapy:

dexamethasone IV or orally twice daily on days 1-14

vincristine IV on days 1 and 8

pegaspargase IM on day 4, 5, or 6

daunorubicin IV

SR-low regimens for consolidation, interim maintenance, and delayed intensification

Patients are randomized to one of two treatment arms. One is the standard arm (LRS Arm), and one has increased asparaginase (4 additional doses) LRAsp Arm).

Standard consolidation therapy

• vincristine IV on day 1
• oral 6MP on days 1-28
• methotrexate IT on days 1, 8, and 15

Standard interim maintenance therapy

• vincristine IV on days 1 and 29
• dexamethasone IV or orally twice daily on days 1-5 and 29-33
• oral 6MP on days 1-50
• oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50
• methotrexate IT on day 29

Standard delayed intensification therapy

• vincristine IV on days 1, 8, and 15
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV over 15 minutes to 2 hours on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6
• cyclophosphamide IV over 30 minutes on day 29
• cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1 and 29

Experimental consolidation therapy (additional pegaspargase)

• vincristine IV on day 1
• oral 6MP on days 1-28
• methotrexate IT on days 1, 8, and 15
• pegaspargase IM on days 1 and 22

Experimental interim maintenance therapy (additional pegaspargase)

• vincristine IV on days 1 and 29
• dexamethasone IV or orally twice daily on days 1-5 and 29-33
• oral 6MP on days 1-50
• oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50
• methotrexate IT on day 29
• pegaspargase IM on days 15 and 36

Experimental delayed intensification therapy

Patients receive the same - standard - therapy as in the non-increased-asparaginase arm:

• vincristine IV on days 1, 8, and 15
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV over 15 minutes to 2 hours on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6
• cyclophosphamide IV over 30 minutes on day 29
• cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1 and 29

SR-average regimens for consolidation, interim maintenance, and delayed intensification

Patients are randomized to 1 of 4 treatment arms:

• Arm I (SS Arm): Standard consolidation therapy, standard interim maintenance therapy, and standard DI therapy as in the low-risk group, standard arm
• Arm II (SA Arm): Standard consolidation therapy, augmented interim maintenance therapy, and augmented DI therapy
• Arm III (IS Arm): Intensified consolidation therapy, standard interim maintenance therapy, standard DI therapy
• Arm IV (IA Arm): Intensified consolidation therapy, augmented interim maintenance therapy, and augmented DI therapy

Arm I: SR-average

Standard consolidation therapy

• vincristine IV on day 1
• oral 6MP on days 1-28
• methotrexate IT on days 1, 8, and 15

Standard interim maintenance therapy

• vincristine IV on days 1 and 29
• dexamethasone IV or orally twice daily on days 1-5 and 29-33
• oral 6MP on days 1-50
• oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50
• methotrexate IT on day 29

Standard delayed intensification therapy

• vincristine IV on days 1, 8, and 15
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV over 15 minutes to 2 hours on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6
• cyclophosphamide IV over 30 minutes on day 29
• cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1 and 29

Arm II: SR-average

Standard consolidation therapy

• vincristine IV on day 1
• oral 6MP on days 1-28
• methotrexate IT on days 1, 8, and 15

Augmented interim maintenance therapy

• vincristine IV on days 1, 11, 21, 31, and 41
• methotrexate IV on days 1, 11, 21, 31, and 41
• pegaspargase IM on days 2 and 22
• methotrexate IT on days 1 and 31

Augmented delayed intensification therapy

• vincristine IV on days 1, 8, 15, 43, and 50
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6 AND day 43
• cyclophosphamide IV on day 29
• cytarabine IV or SC on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1, 29, and 36

Arm III: SR-average

Augmented consolidation therapy

• cyclophosphamide IV on days 1 and 29
• cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39
• oral mercaptopurine on days 1-14 and 29-42
• vincristine IV on days 15, 22, 43, and 50
• pegaspargase IM on days 15 and 43
• methotrexate IT on days 1, 8, 15, and 22

Standard interim maintenance therapy

• vincristine IV on days 1 and 29
• dexamethasone IV or orally twice daily on days 1-5 and 29-33
• oral 6MP on days 1-50
• oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50
• methotrexate IT on day 29

Standard delayed intensification therapy

• vincristine IV on days 1, 8, and 15
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV over 15 minutes to 2 hours on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6
• cyclophosphamide IV over 30 minutes on day 29
• cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1 and 29

Arm IV SR-average

Augmented consolidation therapy

• cyclophosphamide IV on days 1 and 29
• cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39
• oral mercaptopurine on days 1-14 and 29-42
• vincristine IV on days 15, 22, 43, and 50
• pegaspargase IM on days 15 and 43
• methotrexate IT on days 1, 8, 15, and 22

Augmented interim maintenance therapy

• vincristine IV on days 1, 11, 21, 31, and 41
• methotrexate IV on days 1, 11, 21, 31, and 41
• pegaspargase IM on days 2 and 22
• methotrexate IT on days 1 and 31

Augmented delayed intensification therapy

• vincristine IV on days 1, 8, 15, 43, and 50
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6 AND day 43
• cyclophosphamide IV on day 29
• cytarabine IV or SC on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1, 29, and 36

SR-high

There is no randomization for the high risk group.

Augmented consolidation therapy

• cyclophosphamide IV on days 1 and 29
• cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39
• oral mercaptopurine on days 1-14 and 29-42
• vincristine IV on days 15, 22, 43, and 50
• pegaspargase IM on days 15 and 43
• methotrexate IT on days 1, 8, 15, and 22

Patients with testicular disease at diagnosis also undergo bilateral testicular radiotherapy once daily, 5 days a week, for approximately 2.5 weeks.

Double delayed intensification. The following interim maintenance and delayed intensification is repeated once:

Augmented interim maintenance therapy

• vincristine IV on days 1, 11, 21, 31, and 41
• methotrexate IV on days 1, 11, 21, 31, and 41
• pegaspargase IM on days 2 and 22
• methotrexate IT on days 1 and 31

Augmented delayed intensification therapy

• vincristine IV on days 1, 8, 15, 43, and 50
• dexamethasone IV or orally twice daily on days 1-21
• doxorubicin IV on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6 AND day 43
• cyclophosphamide IV on day 29
• cytarabine IV or SC on days 29-32 and 36-39
• oral thioguanine on days 29-42
• methotrexate IT on days 1, 29, and 36

Patients with CNS3 disease at diagnosis also undergo cranial radiotherapy on days 29-33 and 36-40 during course 2 only.

Maintenance therapy, all arms, all risk levels

Maintenance:

Each course of maintenance proceeds as outlined below. Courses repeat every 84 days for a total of 2 years from the start of interim maintenance therapy for female patients and 3 years from the start of interim maintenance therapy for male patients.

• vincristine IV on days 1, 29, and 57
• oral dexamethasone twice daily on days 1-5, 29-33, and 57-61
• oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78
• oral mercaptopurine on days 1-84
• methotrexate IT on day 1