Treatment of Patients with Newly Diagnosed Standard Risk B-Precursor Acute Lymphoblastic Leukemia (ALL)

Full Title: Phase III Partially Randomized Study of Risk-Adapted Chemotherapy in Pediatric Patients With Newly Diagnosed Standard-Risk B-Precursor 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. (Excellent summary.)

This trial is designed to determine if maintenance therapy for AR patients is best at an oral dosing of methotrexate is best at 40 mg/m2/week or 20 mg/m2/week, and if vincristine/dexamethasone pulses can be dropped from once a month to once every 3 months.

LR patients are treated with either a P9904-based regimen of 6 courses of intermediate dose IV methotrexate (no cyclophosphamide or anthracyclines) OR an out-patient regimen similar to that of the AR patients with reduced vincristine sulfate/dexamethasone pulses at 12-week intervals during maintenance.

Provides a separate treatment arm for standard risk Down syndrome patients. This is not outlined below, please see the cancer.gov site.

This trial is for treatment of newly diagnosed standard risk ALL patients. "Standard risk" is by NCI definitions, meaning as below. Since any child who is 10 years or older is NCI-HR (high risk), this trial is only for patients under the age of 10. Since at the trial's activation date the new trial for high risk patients is not yet open, patients who begin on this plan but are determined to be high risk at the end of induction will have to consult their oncologist. (4/2011 note: this will change when the new trial opens in mid-2011.)

NCI definitions of standard risk (NCI-SR) or high risk (NCI-HR):

• NCI-SR ALL: B-precursor and WBC less than 50,000/microliter and age 1-9 years (and CNS 1)
• NCI-HR ALL: B-precursor and WBC greater than or equal to 50,000/microliter or age greater or equal to 10 years

Classification of newly diagnosed leukemia

Definitive risk assignment comes after day 29:

• LR (low risk): NCI-SR; Favorable genetics (double trisomy 4 and 10 OR ETV6-RUNX1 fusion - TEL/AML1); day 8 peripheral blood MRD less than 0.01%; day 29 bone marrow MRD less than 0.01%)
• AR (average risk):
  • NCI-SR; Favorable genetics and day 8 peripheral blood MRD greater than 0.01% and day 29 bone marrow MRD less than 0.01%
  • NCI-SR; Not having favorable genetics and day 8 peripheral blood MRD less than 1% and day 29 bone marrow MRD less than 0.01%
• HR (high risk)
  • NCI-SR; favorable genetics, day 8 PB MRD any, day 29 BM MRD greater than 0.01%
  • NCI-SR; not having favorable genetics; day 8 PB MRD greater than 1% and day 29 BM MRD less than 0.01%
  • NCI-HR; any genetics, day 8 PB MRD any, day 29 BM MRD less than 0.01%
• VHR (very high risk)
  • NCI-SR, no favorable genetics, any day 8 PB MRD, day 29 BM MRD greater than 0.01%
  • NCI-HR; any genetics, any day 8 PB MRD, day 29 BM MRD greater than 0.01%
  • any NCI; induction failure, any day 8 or day 29 MRD values; infavorable genetics - includes hypodiploidy (< 44 chromosomes and/or DNA index < 0.81), and MLL rearrangement (not MLL deletion). BCR-ABL1 positive patients go to a separate, dedicated Ph+ ALL study.

T-cell and infant ALL are treated on separate trials. Downs Syndrome patients go to a specific arm. (I am not including this DS arm here.)

CNS 2 patients are in average risk subset. CNS 3 goes to HR protocol.

• CNS 1: no blasts on cytospin
• CNS 2: less than 5 WBC per microliter and cytospin positive for blasts
• CNS 3: over 5 WBC per microliter anc cytospin positive for blasts

The description of this trial on the NCI (cancer.gov) website is excellent, better than the summary below. I strongly recommend you visit that site via this link: cancer.gov site.

Induction, 35 days

This induction therapy is essentially the same as that of CCG 1991. (Same induction for low-, average-, and high-risk arms. DS patients are treated separately.)

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 IV on day 4
• methotrexate IT on days 8 and 29

Day 8: peripheral blood sample taken for MRD sample taken (PB-MRD)

Day 29: bone marrow sample taken for MRD sample taken (BM-MRD)

AR (average risk) patients and LR patients randomized to arm LR-C

Consolidation (28 days), begins Day 36

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

Interim Maintenance (56 das)

• vincristine IV days 1, 11, 21, 31, 41
• methotrexate IV days 1, 11, 21, 31, 41
• methotrexate IT day 31

Delayed Intensification (56 days)

• dexamethasone PO days 1-7 and 15-21
• vincristine days 1, 8, 15
• doxorubicin days 1, 8, 15
• pegaspargase IV day 4
• cyclophosphamide IV day 29
• thioguanine PO days 29-42
• cytarabine IV days 29-32 and 36-39
• methotrexate IT days 1 and 29

Interim maintenance II (56 days)

• vincristine IV days 1, 11, 21, 31, 41
• methotrexate IV days 1, 11, 21, 31, 41
• methotrexate IT days 1 and 31

Maintenance has 4 arms: A, B, C, D

arm A:

• vincristine and dexamethasone pulses at 4 week intervals
• methotrexate IT every 12 weeks
• methotrexate PO at 20 mg/m2/week
• oral 6MP daily

arm B:

• vincristine and dexamethasone pulses at 4 week intervals
• methotrexate IT every 12 weeks
• methotrexate PO at 40 mg/m2/week
• oral 6MP daily

arm C:

• vincristine and dexamethasone pulses at 12 week intervals
• methotrexate IT every 12 weeks
• methotrexate PO at 20 mg/m2/week
• oral 6MP daily

arm D:

• vincristine and dexamethasone pulses at 12 week intervals
• methotrexate IT every 12 weeks
• methotrexate PO at 40 mg/m2/week
• oral 6MP daily

LR patients randomized to arm LR-M

Arm I

Consolidation (19 weeks), begins Day 36

• vincristine IV on days 15, 22, 78, 85
• methotrexate IV days 8, 29, 50, 71, 92, 113
• leucovorin PO days 9-10, 30-31, 51-52, 72-73, 93-94, 114-115
• methotrexate IT days 8, 29, 50, 71, 92, 113
• dexamethasone PO days 15-21 and 78-84
• 6 MP days 1-133

Maintenance (16 week cycles for 2 1/2 years from date of dx for both boys and girls)

• vincristine IV days 1 and 8
• dexamethasone days 1-7
• methotrexate PO days 8, 15, and so on every 7 days to day 106
• 6 MP days 1-112
• varies as per cycle methotrexate IT days 1 and 85 or 57

Arm II (this is the same as for AR patients, up to maintenance)

Consolidation (4 weeks), begins Day 36

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

Interim maintenance

• vincristine IV and methotrexate IV days 1, 11, 21, 31, 41
• methotrexate IT day 31

delayed intensifictaion

• dexamethasone days 1-7 and 15-21
• vincristine and doxorubicin IV days 1, 8, 15
• pegaspargase IV day 4
• cyclophosphamide IV day 29
• thioguanine days 29-42
• cytarabie IV days 29-32 and 36-39
• IT methotrexate days 1 and 29

interim maintenance

• vincristine and methotrexate IV days 1, 11, 21, 31, 41
• IT methotrxate days 1 and 31

maintenance

• vincristine IV day 1
• oral dexamethasone days 1-5
• methotrexate PO days 8, 15, and weekly until day 78
• 6 MP days 1-84
• IT methotrexate day 1 - 20 mg/m2/week
• courses repeat every 12 weeks for 2 years girls, 3 years boys timed from the start of maintenance I therapy