Lymphoblastic Leukemia, Acute
Conditions
Keywords
Leukemia
Brief summary
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.
Detailed description
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
Interventions
DRUGPrednisone, Dexamethasone, Vincristine, Daunorubicin
See Detailed Description sections for details on treatment interventions.
DRUGDoxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase
See Detailed Description sections for details on treatment interventions.
DRUGMethotrexate, Cyclophosphamide, Cytarabine, Etoposide
See Detailed Description sections for details on treatment interventions.
DRUGMercaptopurine, Imatinib
See Detailed Description sections for details on treatment interventions.
PROCEDUREchemotherapy, intrathecal chemotherapy
See Detailed Description sections for details on treatment interventions.
PROCEDUREsteroid therapy, hematopoietic stem cell transplantation
See Detailed Description sections for details on treatment interventions.
Sponsors
National Cancer Institute (NCI)
St. Jude Children's Research Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of non-B-cell ALL by immunophenotyping, as determined by the reactivity pattern to a panel of monoclonal antibodies with flow cytometry as well as morphology and cytochemical staining. * Age range: 1 to 18 years (inclusive).
Exclusion criteria
• Previously treated with chemotherapy for one week or longer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Event-free Survival (EFS) | Median follow-up time (range) 5.6 (1.3 to 8.9) years | 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. |
| Continuous Complete Remission Since Week 56 Therapy. | Median follow up time (range) 4.5 (1 to 7.8) years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Immediately before the methotrexate infusion and three days after subsequent infusion | White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count Measurement: Percentage change of leukemia cells from baseline |
| Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours). | 42 hours after start of high dose methotrexate infusion (HDMTX) | 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. |
| Minimal Residual Disease (MRD) | End of Induction (Day 46 MRD measurement) | 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%). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Median Difference in CASP1 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs Glucocorticoid-sensitive Cells | Pre-treatment | 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. |
| Median Difference in NLRP3 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs. Glucocorticoid-sensitive Cells | Pre-treatment | 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. |
Countries
United States
Participant flow
Recruitment details
501 patients were recruited between June 2000 and October 2007.
Pre-assignment details
501 patients were enrolled on the study. 3 patients were determined to be ineligible shortly after enrollment (wrong diagnosis - AML or CML in blast crisis).498 patients started the study.
Participants by arm
| Arm | Count |
|---|---|
| Total Therapy Total therapy applies to all eligible patients and includes remission induction, consolidation, and continuation therapy. | 498 |
| 4 hr 4 hour High-Dose Methotrexate Infusion in upfront window treatment | 0 |
| 24 hr 24 hour High-Dose Methotrexate Infusion in upfront window treatment | 0 |
| Non Randomized Patients not randomized for window study | 0 |
| Total | 498 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Total Therapy | Death | 35 | 0 | 0 | 0 |
| Total Therapy | Non Compliance | 5 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total Therapy | Total |
|---|---|---|
| Age, Customized >=10 years | 126 participants | 126 participants |
| Age, Customized 1 to 9 years | 372 participants | 372 participants |
| Sex: Female, Male Female | 219 Participants | 219 Participants |
| Sex: Female, Male Male | 279 Participants | 279 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 468 / 498 |
| serious Total, serious adverse events | 74 / 498 |
Outcome results
Primary
Continuous Complete Remission Since Week 56 Therapy.
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.
Time frame: Median follow up time (range) 4.5 (1 to 7.8) years
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Total Therapy | Continuous Complete Remission Since Week 56 Therapy. | 92.2 Percentage of participants |
Primary
Overall Event-free Survival (EFS)
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.
Time frame: Median follow-up time (range) 5.6 (1.3 to 8.9) years
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Total Therapy | Overall Event-free Survival (EFS) | 87.3 Percentage of Participants |
Secondary
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)
White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count Measurement: Percentage change of leukemia cells from baseline
Time frame: Immediately before the methotrexate infusion and three days after subsequent infusion
Population: Three hundred twenty (320) patients were evaluable to assess the influence of infusion duration on methotrexate's antileukemic effects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Total Therapy | 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) | -44 Percent change | Standard Deviation 42.2 |
| 24 hr | 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) | -50 Percent change | Standard Deviation 35.5 |
Comparison: t-test adjusting for lineage and ploidyp-value: 0.15t-test, 2 sided
Secondary
Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours).
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.
Time frame: 42 hours after start of high dose methotrexate infusion (HDMTX)
Population: The 286 patients randomized to treatment with high-dose methotrexate (HDMTX) who had methotrexate polyglutamate (MTXPG) concentration measured in bone marrow ALL cells .
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Total Therapy | Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours). | 1688 pmol/1,000,000,000 cells | Standard Deviation 2015 |
| 24 hr | Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours). | 2521 pmol/1,000,000,000 cells | Standard Deviation 2950 |
Comparison: t-test stratified for lineage and ploidyp-value: 0.0062t-test, 2 sided
Secondary
Minimal Residual Disease (MRD)
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%).
Time frame: End of Induction (Day 46 MRD measurement)
Population: Patients who completed induction and had successful MRD studies on day 46.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total Therapy | Minimal Residual Disease (MRD) | Negative <0.01% | 390 participants |
| Total Therapy | Minimal Residual Disease (MRD) | Positive >= 0.01% | 102 participants |
Comparison: Of the 498 eligible patients, 492 were successfully evaluated with day 46 MRD measurement.95% CI: [75.69, 82.85]Binomial proportion
Other Pre-specified
Median Difference in CASP1 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs Glucocorticoid-sensitive Cells
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.
Time frame: Pre-treatment
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Total Therapy | Median Difference in CASP1 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs Glucocorticoid-sensitive Cells | Prednisolone-sensitive cells | 341.3 arbitrary units |
| Total Therapy | Median Difference in CASP1 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs Glucocorticoid-sensitive Cells | Prednisolone-resistant cells | 447.9 arbitrary units |
p-value: 9.5e-7Wilcoxon (Mann-Whitney)
Other Pre-specified
Median Difference in NLRP3 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs. Glucocorticoid-sensitive Cells
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.
Time frame: Pre-treatment
Population: 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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Total Therapy | Median Difference in NLRP3 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs. Glucocorticoid-sensitive Cells | Prednisolone-sensitive cells | 41.2 arbitrary units |
| Total Therapy | Median Difference in NLRP3 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs. Glucocorticoid-sensitive Cells | Prednisolone-resistant cells | 110.7 arbitrary units |
p-value: 7e-7Wilcoxon (Mann-Whitney)