Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Anti-Infective Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Dexamethasone

Etoposide

Cytarabine

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Methotrexate

Prednisone

Vincristine

Daunorubicin

Dexamethasone acetate

Pegaspargase

Etoposide phosphate

Mercaptopurine

Asparaginase

Imatinib Mesylate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antimetabolites

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Antiviral Agents

Tubulin Modulators

Antimitotic Agents

Folinic Acid

Folate

Vitamin B9

See Detailed Description sections for details on treatment interventions.

Prednisone, Dexamethasone, Vincristine, Daunorubicin

Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase

Methotrexate, Cyclophosphamide, Cytarabine, Etoposide

Mercaptopurine, Imatinib

chemotherapy, intrathecal chemotherapy

steroid therapy, hematopoietic stem cell transplantation

Ching-Hon Pui, M.D.

The primary objective is to estimate the overall event-free survival of children at least one year of age at diagnosis who are treated with risk-directed therapy and to monitor the molecular remission induction rate.

These are the following secondary objectives:

* To determine if CNS irradiation can be safely omitted in the context of the systemic therapy used in the protocol.
* To identify whether prolonged (24 hour) intravenous infusions of HDMTX produce greater methotrexate polyglutamate (MTXPG) accumulation than short (4 hour) infusions 42 hours after 1 gm/m2 of HDMTX, stratified for lineage (T- vs B-lineage) and ploidy (hyperdiploid vs non-hyperdiploid B-lineage).
* To determine whether prolonged (24 hour) intravenous infusions of HDMTX produce greater antileukemic effects than short (4 hour) infusions, based on the inhibition of de novo purine synthesis in bone marrow blasts and the decrease in circulating blasts during the 4 day "window" prior to initiation of conventional remission induction therapy.
* MRD
* Other exploratory objectives

Details of Treatment Plan

Treatment will consist of three main phases, Remission Induction, Consolidation, and Continuation. Treatment with an Upfront HDMTX Window for research purposes will be optional.

All patients will receive IT therapy on day 1, dose is age dependent.

Upfront High-Dose Methotrexate Window

HDMTX (1 g/m2) as a 4 hour infusion versus as a 24 hour infusion. Leucovorin rescue will be given.

Remission Induction

Prednisone 40 mg/m2/day PO Days 5 - 32 Vincristine 1.5 mg/m2/week IV Days 5, 12, 19, 26 Daunorubicin 25 mg/m2/week IV Days 5, 12 L-asparaginase 10,000 Unit/m2/dose IM Days 6, 8, 10, 12, 14, 16 (19, 21, 23) Cyclophosphamide 1000 mg/m2/dose IV Day 26 Cytarabine 75 mg/m2/dose IV Days 27-30, 34-37 6-Mercaptopurine 60 mg/m2/dose PO Days 26-39 Imatinib 40 mg/m2 bid for Ph positive patients starting Day 22 of induction. Intrathecal therapy will be administered on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive additional IT treatments on days 8 and 26.

Consolidation Treatment

High dose methotrexate targeted dose depending on risk status, days 1, 15, 29, and 43 and mercaptopurine 50 mg/m2/day, days 1-56.

Reintensification treatment for patients with high risk disease:

Patients with high risk disease will be offered the option of hematopoietic stem cell transplant (HSCT) and may receive an additional 1-2 cycles of reintensification treatment prior to maximize the anti-leukemic kill before transplant.

Dexamethasone 20 mg/m2 PO days 1-3 Cytarabine 2 g/m2 IV x 4 doses, days 3-5 Etoposide 100 mg/m2 IV x 5 doses, days 3-5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment Day 5

Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys)

Treatment will depend on risk classification: low versus standard versus high risk

Treatment weeks 1 to 20:

Week Standard/High Risk Low Risk

1. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
2. 6MP + ASP 6MP + MTX
3. 6MP + ASP 6MP + MTX
4. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
5. 6MP + ASP 6MP + MTX
6. 6MP + ASP 6MP + MTX
7. Reinduction I§ Reinduction I
8. Reinduction I Reinduction I
9. Reinduction I Reinduction I
10. 6MP + ASP 6MP + MTX
11. DOX + VCR + 6MP + ASP 6MP + MTX
12. 6MP + ASP 6MP + MTX
13. 6MP + ASP 6MP + MTX
14. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
15. 6MP + ASP 6MP + MTX
16. 6MP + ASP 6MP + MTX
17. Reinduction II Reinduction II
18. Reinduction II Reinduction II
19. Reinduction II Reinduction II
20. No chemotherapy 6MP + MTX

    Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days, Days 1-5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1 Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1-7 75 mg/m2 PO daily x 7 days (low risk), Days 1-7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40 mg/m2 IV or IM, Day 1

    Reinduction I and II

    This phase of treatment will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients.

    Reinduction I for Standard/High Risk ALL:

    Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15, 21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2 IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1.

    Reinduction II for Standard/High Risk ALL:

    Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17, Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12 Days 15, 16

    Reinduction I and II for Low Risk ALL Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000 Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1

    Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk
21. 6MP + MTX 6MP + MTX
22. 6MP + MTX 6MP + MTX
23. Cyclo + Ara-C 6MP + MTX
24. DEX + VCR 6MP + DEX + VCR
25. 6MP + MTX 6MP + MTX
26. 6MP + MTX 6MP + MTX
27. Cyclo + Ara-C 6MP + MTX
28. DEX + VCR 6MP + DEX + VCR

Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1-7 Methotrexate 40 mg/m2 IV or IM, Day 1 Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1-5 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1

The same treatment (weeks 21-28) will be repeated for a total of 6 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at high risk of CNS relapse after week 48 and will be discontinued after week 96. Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in boys

Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic stem cell transplantation. However, if the option is declined by the patients or guardians, or the procedure is deemed unsuitable by the attending physician and the principal investigator, the patient will remain on study and continue to receive chemotherapy

Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Prednisolone sensitivity was measured in primary leukemia cells from bone marrow collected at diagnosis. Expression of CASP1 was determined by HG-U133A microarray. Values given are gene expression values, and the unit is arbitrary units (AU) defined as scaled fluorescence measured on microarray.

Prednisolone sensitivity was measured in primary leukemia cells from bone marrow collected at diagnosis. Expression of NLRP3 was determined by HG-U133A microarray. Values given are gene expression values, and the unit is arbitrary units (AU) defined as scaled fluorescence measured on microarray.

EFS was measured from the start of on-study to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Failure to enter remission was considered an event at time zero. Measurement was determined by Kaplan-Meyer estimate.

CCR was measured from end of week 56 therapy to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Measurement was determined by Kaplan-Meyer estimate.

Detection of MRD at end of induction where positive MRD was defined as one or more leukemic cell per 10,000 mononuclear bone-marrow cells (\>=0.01%).

Children were randomly assigned to receive initial single-agent treatment with HDMTX (1g/m\^2) as either a 24-hour infusion or a 4-hour infusion and the outcome measure was the accumulation of MTXPG in leukemia cells.

White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count

Measurement: Percentage change of leukemia cells from baseline

National Cancer Institute (NCI)

St. Jude Children's Research Hospital

Total therapy applies to all eligible patients.

Total Therapy

Total therapy applies to all eligible patients and includes remission induction, consolidation, and continuation therapy.

4 hour High-Dose Methotrexate Infusion in upfront window treatment

4 hr

24 hour High-Dose Methotrexate Infusion in upfront window treatment

24 hr

Non Randomized

Total

1 to 9 years

>=10 years

Prior experience indicate different responses for children under the age of ten and those who are 10 and older.

Age, Customized

Sex: Female, Male

Ching-Hon Pui

498 enrolled patients were eligible for analysis to estimate the overall event-free survival of children at least one year of age at diagnosis who are treated with risk-directed therapy.

Overall Event-free Survival (EFS)

This is a subset of all patients enrolled. It is not a specific treatment arm.

Patients With High Risk of CNS Relapse

Patients meeting the following high risk CNS Relapse criteria: white cell blood cell count at diagnosis more than 100,000; Philadelphia Chromosome Positive; CNS 3 at diagnosis; T-Lineage with white blood cell count more than 50,000.

Continuous Complete Remission Since Week 56 Therapy.

Of the 498 eligible patients, 492 were successfully evaluated with day 46 MRD measurement.

Negative <0.01%

Positive >= 0.01%

Patients who completed induction and had successful MRD studies on day 46.

Minimal Residual Disease (MRD)

The 286 patients randomized to treatment with high-dose methotrexate (HDMTX) who had methotrexate polyglutamate (MTXPG) concentration measured in bone marrow ALL cells .

Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours).

Three hundred twenty (320) patients were evaluable to assess the influence of infusion duration on methotrexate's antileukemic effects.

Circulating Leukemia Cells in Peripheral Blood Change From Prior to the Methotrexate Infusion to Three Days After Between Two Arms (4 Hours vs. 24 Hours)

Prednisolone-sensitive cells

Prednisolone-resistant cells

One hundred forty-four (144) patients were evaluable to assess prednisolone sensitivity measured in bone marrow ALL cells and CASP1 expression in RNA by MTT assay.

Median Difference in CASP1 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs Glucocorticoid-sensitive Cells

One hundred forty-four (144) patients were evaluable to assess prednisolone sensitivity measured in bone marrow ALL cells and NLRP3 expression in RNA by MTT assay

Median Difference in NLRP3 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs. Glucocorticoid-sensitive Cells

Window Therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia	NCT00137111	Lymphoblastic L...	Prednisone, Dex... Doxorubicin, L-... Methotrexate, C... Mercaptopurine,... chemotherapy, i... steroid therapy...	12 Months - 18 Years	St. Jude Children's Research Hospital
Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia	NCT00137111	Lymphoblastic L...	Prednisone, Dex... Doxorubicin, L-... Methotrexate, C... Mercaptopurine,... chemotherapy, i... steroid therapy...	12 Months - 18 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for chemotherapy, intrathecal chemotherapy