Adult T Acute Lymphoblastic Leukemia, Ann Arbor Stage II Adult Lymphoblastic Lymphoma, Ann Arbor Stage II Childhood Lymphoblastic Lymphoma, Ann Arbor Stage III Adult Lymphoblastic Lymphoma, Ann Arbor Stage III Childhood Lymphoblastic Lymphoma, Ann Arbor Stage IV Adult Lymphoblastic Lymphoma, Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma, Childhood T Acute Lymphoblastic Leukemia
Conditions
Brief summary
This randomized phase III trial compares how well combination chemotherapy works when given with or without bortezomib in treating patients with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. Bortezomib may help reduce the number of leukemia or lymphoma cells by blocking some of the enzymes needed for cell growth. It may also help chemotherapy work better by making cancer cells more sensitive to the drugs. It is not yet known if giving standard chemotherapy with or without bortezomib is more effective in treating newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
Detailed description
PRIMARY OBJECTIVES: I. To compare event-free survival (EFS) in patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LLy) who are randomized to a modified augmented Berlin-Frankfurt-Munster (ABFM) backbone versus bortezomib plus the modified ABFM backbone. SECONDARY OBJECTIVES: I. To determine the safety and feasibility of modifying standard therapy for T-ALL and T-LLy based on the results of UKALL 2003, which includes a dexamethasone-based induction, additional doses of pegaspargase (PEG-ASP) during induction and delayed intensification (DI), and dexamethasone pulses during maintenance therapy. II. To determine if prophylactic (presymptomatic) cranial radiation therapy (CRT) can be safely and effectively eliminated in the 85-90% of T-ALL patients classified as standard or intermediate risk. III. To determine the proportion of end of consolidation (EOC) minimal residual disease (MRD) \>= 0.1% T-ALL patients who become MRD negative (undetectable by flow cytometry) after intensification of chemotherapy, using three high risk (HR) BFM blocks, and to compare EFS between the patients who become MRD negative after the three HR BFM blocks and continue on chemotherapy with those who continue to have detectable MRD and are eligible for other treatment strategies, including hematopoietic stem cell transplant (HSCT). IV. To compare the EFS between very high risk (induction failure) T-LLy patients treated with HR BFM intensification blocks who have partial or complete response (PR or CR) with those who do not respond (NR). CORRELATIVE OBJECTIVES: I. To investigate the prognostic significance of day 29 bone marrow (BM) MRD in T-LLy patients. II. To determine if protein expression patterns can predict bortezomib response and drug resistance in T-ALL. III. To analyze and target relevant signaling pathways in T-ALL blasts, focusing on early T cell precursor (ETP) acute lymphoblastic leukemia (ALL). OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients are risk assigned based on data from end of induction and/or consolidation therapy; this then modifies the subsequent therapy received. T-ALL Risk Group Definitions: Standard Risk (SR): CNS1\*, lumbar puncture prior to steroid therapy (not steroid pretreated), Day 29 (end of induction) bone marrow M1, Day 29 bone marrow minimal residual disease (MRD) \<=0.01%, no testicular leukemia at diagnosis. Intermediate Risk (IR): Not SR or VHR. Very High Risk (VHR): M3 marrow at Day 29 and/or end of consolidation (EOC) MRD \>=0.1%. \*CNS2 and CNS3 cannot be SR and are assigned to IR or VHR based on marrow response. T-LL Risk Group Definitions: Standard Risk (SR): CNS1\*, MRD at diagnosis \<1% in bone marrow, lumbar puncture prior to steroid therapy (not steroid pretreated), Day 29 (end of induction) complete response (CR) or partial response (PR). Intermediate Risk (IR): Not SR or VHR. Very High Risk (VHR): Stable Disease (SD)/No response (NR) at Day 29 (End of Induction). \*CNS2 and CNS3 cannot be SR and are assigned to IR or VHR based on radiographic response. ARM A INDUCTION: Patients receive cytarabine intrathecally (IT) at time of diagnostic lumbar puncture (if within 72 hours from start of protocol therapy) OR day 1; vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; dexamethasone orally (PO) twice daily (BID) on days 1-28 (no taper); daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 4 and 18; and methotrexate IT on days 8 and 29 (and on days 15 and 22 for central nervous system 3 involvement \[CNS3\] T-ALL patients). ARM A CONSOLIDATION: Beginning on day 36 from Induction, patients receive methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 T-ALL or CNS3 T-LLy patients); cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42; pegaspargase IV over 1-2 hours on days 15 and 43; and vincristine sulfate IV on days 15, 22, 43, and 50. Patients with persistent testicular disease undergo radiation therapy. Patients are then assigned to subsequent therapy according to risk assignment. Patients with standard risk (SR) disease receive Interim Maintenance with Capizzi methotrexate (CMTX); patients with intermediate risk (IR) disease receive Interim Maintenance with high-dose methotrexate (HDMTX), Delayed Intensification, and then Interim Maintenance with CMTX; and patients with very high risk (VHR) disease receive 3 HR Intensification Blocks, Delayed Intensification, and then Interim Maintenance with CMTX. ARM A CMTX INTERIM MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 11, 21, 31, and 41; methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. The next course (based on risk assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM A DELAYED INTENSIFICATION: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin hydrochloride IV over 15 minutes on days, 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4, 18, and 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. The next course (based on risk assignment) begins on day 64 or when blood counts recover (whichever occurs later). ARM A HDMTX INTERIM MAINTENANCE: Patients receive high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium IV or PO on days 3-4, 17-18, 31-32, and 45-46; vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. The next course (based on randomization assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM A INTENSIFICATION BLOCK I: Patients receive dexamethasone IV or PO BID on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium IV or PO on days 3-4; vincristine sulfate IV on days 1 and 6; cyclophosphamide IV over 1-6 hours on days 2-4; high-dose cytarabine IV over 3 hours every 12 hours on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. The next course (Intensification Block II) begins on day 22 or when blood counts recover (whichever occurs later). ARM A INTENSIFICATION BLOCK II: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium PO or IV on days 3-4; vincristine sulfate IV on days 1 and 6; ifosfamide IV over 1 hour every 12 hours on days 2-4; daunorubicin hydrochloride IV over 30 minutes on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 1 as in Intensification Block I. The next course (Intensification Block III) begins on day 22 or when blood counts recover (whichever occurs later). ARM A INTENSIFICATION BLOCK III: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose cytarabine IV over 3 hours every 12 hours on days 1-2; etoposide IV over 1-2 hours every 12 hours on days 3-5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 5 as in Intensification Block I. The next course (based on randomization) begins on day 22 or when blood counts recover (whichever occurs later). ARM A MAINTENANCE THERAPY: All patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 29 for SR patients during the first 4 cycles); methotrexate IT on day 1 (and day 29 during the first 4 cycles for SR patients and during the first 2 cycles for IR patients). Patients with CNS1-3VHR and CNS2 VHR, and CNS3 IR disease also undergo cranial radiation therapy during the first 4 weeks (cycle 1). Treatment in female patients with T-ALL and patients with T-LLY repeats every 12 weeks for up to 2 years from the start of Interim Maintenance (week 119). Treatment in male patients with T-ALL repeats every 12 weeks for up to 3 years from the start of Interim Maintenance (week 171). ARM B INDUCTION: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11(1.3 mg/m\^2 per dose); and cytarabine, vincristine sulfate, dexamethasone, daunorubicin hydrochloride, pegaspargase, and methotrexate as in Induction Arm A. ARM B CONSOLIDATION: Beginning on day 36 from Induction, patients receive methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 T-ALL or CNS3 T-LLy patients); cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42; pegaspargase IV over 1-2 hours on days 15 and 43; and vincristine sulfate IV on days 15, 22, 43, and 50. Patients with persistent testicular disease undergo radiation therapy. Patients are then assigned to subsequent therapy according to risk assignment. Patients with standard risk (SR) disease receive Interim Maintenance with Capizzi methotrexate (CMTX); patients with intermediate risk (IR) disease receive Interim Maintenance with high-dose methotrexate (HDMTX), Delayed Intensification, and then Interim Maintenance with CMTX; and patients with very high risk (VHR) disease receive 3 HR Intensification Blocks, Delayed Intensification, and then Interim Maintenance with CMTX. ARM B CMTX INTERIM MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 11, 21, 31, and 41; methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. The next course (based on risk assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM B DELAYED INTENSIFICATION: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 15, and 18 (1.3 mg/m\^2 per dose); and vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate, cyclophosphamide, cytarabine, and thioguanine as in Delayed Intensification Arm A. The next course (based on risk assignment) begins on day 64 or when blood counts recover (whichever occurs later). ARM B HDMTX INTERIM MAINTENANCE: Patients receive high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium IV or PO on days 3-4, 17-18, 31-32, and 45-46; vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. The next course (based on randomization assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM B INTENSIFICATION BLOCK I: Patients receive dexamethasone IV or PO BID on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium IV or PO on days 3-4; vincristine sulfate IV on days 1 and 6; cyclophosphamide IV over 1-6 hours on days 2-4; high-dose cytarabine IV over 3 hours every 12 hours on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. The next course (Intensification Block II) begins on day 22 or when blood counts recover (whichever occurs later). ARM B INTENSIFICATION BLOCK II: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium PO or IV on days 3-4; vincristine sulfate IV on days 1 and 6; ifosfamide IV over 1 hour every 12 hours on days 2-4; daunorubicin hydrochloride IV over 30 minutes on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 1 as in Intensification Block I. The next course (Intensification Block III) begins on day 22 or when blood counts recover (whichever occurs later). ARM B INTENSIFICATION BLOCK III: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose cytarabine IV over 3 hours every 12 hours on days 1-2; etoposide IV over 1-2 hours every 12 hours on days 3-5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 5 as in Intensification Block I. The next course (based on randomization) begins on day 22 or when blood counts recover (whichever occurs later). ARM B MAINTENANCE THERAPY: All patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 29 for SR patients during the first 4 cycles); methotrexate IT on day 1 (and day 29 during the first 4 cycles for SR patients and during the first 2 cycles for IR patients). Patients with CNS1-3VHR and CNS2 VHR, and CNS3 IR disease also undergo cranial radiation therapy during the first 4 weeks (cycle 1). Treatment in female patients with T-ALL and patients with T-LLY repeats every 12 weeks for up to 2 years from the start of Interim Maintenance (week 119). Treatment in male patients with T-ALL repeats every 12 weeks for up to 3 years from the start of Interim Maintenance (week 171). All treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 10 years.
Interventions
DRUGDexamethasone
Given PO or IV
DRUGDoxorubicin
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
Given IT
DRUGIfosfamide
Given IV
DRUGLeucovorin Calcium
Given PO or IV
DRUGMercaptopurine
Give PO
DRUGMethotrexate
Given IT, IV, or PO
DRUGPegaspargase
Given IV
RADIATIONRadiation Therapy
Undergo radiation therapy
DRUGThioguanine
Given PO
DRUGVincristine
Given IV
DRUGVincristine Sulfate
Given IV
DRUGBortezomib
Given IV
DRUGCyclophosphamide
Given IV
DRUGCytarabine
Given IT, IV, or SC
DRUGDaunorubicin
Given IV
DRUGDaunorubicin Hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* T-ALL: T-ALL patients must be enrolled on AALL08B1 or Project:EveryChild (APEC14B1, if open for the classification of ALL patients) prior to treatment and enrollment on AALL1231 * All patients must be \> 1 and \< 31 years of age * Patients must have newly diagnosed T-lymphoblastic leukemia (T-ALL) or T-lymphoblastic lymphoma (T-LLy) stages II-IV * Note: a diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (cluster of differentiation \[CD\]19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a, and are present either in peripheral blood or \> 25% in the bone marrow; if surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including terminal deoxynucleotidyl transferase (TdT), CD34 or CD99 will be assessed for expression; cases with uncertain expression will receive additional review within the appropriate Children's Oncology Group (COG) reference laboratory * For T-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to T-ALL; for tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-LLy defined by the submitting institution will be accepted * All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion criteria
* Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of T-ALL, T-L-Ly or for any cancer diagnosis prior to the initiation of protocol therapy on AALL1231, with the exception of: * Steroid pretreatment: prednisone or methylprednisolone for =\< 120 hours (5 days) in the 7 days prior to initiating induction chemotherapy or for =\< 336 hours (14 days) in the 28 days prior to initiating induction chemotherapy; prior exposure to ANY steroids that occurred \> 28 days before the initiation of protocol therapy does not affect eligibility; the dose of prednisone or methylprednisolone does not affect eligibility * Intrathecal cytarabine (the CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment) system chemotherapy must begin with 72 hours of this IT therapy; or * Pretreatment with hydroxyurea; or * 600 cGy of chest irradiation, if medically necessary * Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone use during sedation to prevent or treat airway edema; inhalation steroids and topical steroids are not considered pretreatment * Pre-existing \>= grade 2 sensory or motor peripheral neurotoxicity * Uncontrolled seizure disorder * Diagnosis of Down syndrome (Trisomy 21) * Patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential * Lactating females who plan to breastfeed * Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation * Patient has hypersensitivity to bortezomib, boron, or mannitol * Serious medical or psychiatric illness likely to interfere with participation in this clinical study * Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and within 30 days of any dose of bortezomib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients | 3 years | EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact. Three-year EFS rates will be calculated for both groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Rates Associated With Modified Standard Therapy, Including Dexamethasone and Additional Pegaspargase | 3 years from start of therapy by patient | Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 |
| EFS for Standard (SR) and Intermediate Risk (IR) T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no Cranial Radiation Therapy [CRT]) and Similar Patients on AALL0434 (Received CRT) | 3 years | EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact. |
| Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | 3 years | Cumulative incidence of isolated CNS relapse adjusting for competing risks using the method of: Gray R, A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1141:1154, 1988 |
| EFS for Very High Risk (VHR) T-ALL Patients Treated With High Risk (HR) Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Become Minimal Residual Disease (MRD) Negative and Those Who Remain MRD Positive at the End of HR Block 3 | 3 years | EFS will be calculated as time from the end of the three high-risk blocks of therapy to first event (relapse, second malignancy, remission death) or date of last contact. |
| EFS for Very High Risk (VHR) T-LLy Patients Treated With HR Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Have Complete or Partial Remission and Those Who do Not Respond | 3 years | EFS for very high risk (VHR) T-LLy patients treated with HR Berlin-Frankfurt-Munster (BFM) intensification blocks who have complete or partial remission and those who do not respond |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Combination Chemotherapy): T-ALL Patients receive combination chemotherapy without bortezomib. | 312 |
| Arm B (Combination Chemotherapy, Bortezomib): T-ALL Patients received combination therapy with bortezomib (4 doses at 1.3mg/m2 during Induction and 4 doses at 1.3mg/m2 during Delayed Intensification) | 315 |
| Arm A (Combination Chemotherapy): T-LLy Patients receive combination chemotherapy without bortezomib. | 111 |
| Arm B (Combination Chemotherapy, Bortezomib): T-LLy Patients received combination therapy with bortezomib (4 doses at 1.3mg/m2 during Induction and 4 doses at 1.3mg/m2 during Delayed Intensification) | 109 |
| Total | 847 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 9 | 3 | 2 |
| Overall Study | Death | 9 | 9 | 3 | 4 |
| Overall Study | Development of SMN | 1 | 0 | 0 | 1 |
| Overall Study | Identified to have Ph+ T-ALL | 0 | 1 | 0 | 0 |
| Overall Study | Identified to have Ph+ T-Lly | 0 | 0 | 1 | 0 |
| Overall Study | Ineligible | 4 | 8 | 3 | 8 |
| Overall Study | Inevaluable | 6 | 4 | 5 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 94 | 72 | 24 | 15 |
| Overall Study | Refusal of further protocol therapy | 19 | 16 | 1 | 7 |
| Overall Study | Relapse/Progression | 10 | 18 | 15 | 2 |
| Overall Study | Still on Therapy | 44 | 47 | 3 | 2 |
| Overall Study | VHR T-ALL who have an M2/M3 marrow and/or detectable MRD by end of the 3 HR Intensification Blocks | 5 | 5 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm A (Combination Chemotherapy): T-ALL | Arm B (Combination Chemotherapy, Bortezomib): T-ALL | Arm A (Combination Chemotherapy): T-LLy | Arm B (Combination Chemotherapy, Bortezomib): T-LLy | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 285 Participants | 296 Participants | 102 Participants | 97 Participants | 780 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 19 Participants | 9 Participants | 12 Participants | 67 Participants |
| Age, Continuous | 10.2 years STANDARD_DEVIATION 5.7 | 10.1 years STANDARD_DEVIATION 5.6 | 12.0 years STANDARD_DEVIATION 5.3 | 12.3 years STANDARD_DEVIATION 5.2 | 10.7 years STANDARD_DEVIATION 5.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 62 Participants | 17 Participants | 15 Participants | 146 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 236 Participants | 228 Participants | 86 Participants | 89 Participants | 639 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants | 25 Participants | 8 Participants | 5 Participants | 62 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 11 Participants | 5 Participants | 1 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants | 37 Participants | 21 Participants | 17 Participants | 110 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 6 Participants | 1 Participants | 0 Participants | 13 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 34 Participants | 33 Participants | 13 Participants | 17 Participants | 97 Participants |
| Race (NIH/OMB) White | 217 Participants | 225 Participants | 71 Participants | 74 Participants | 587 Participants |
| Region of Enrollment Australia | 6 participants | 7 participants | 3 participants | 2 participants | 18 participants |
| Region of Enrollment Canada | 12 participants | 6 participants | 3 participants | 5 participants | 26 participants |
| Region of Enrollment New Zealand | 0 participants | 7 participants | 0 participants | 0 participants | 7 participants |
| Region of Enrollment United States | 294 participants | 295 participants | 105 participants | 102 participants | 796 participants |
| Sex: Female, Male Female | 64 Participants | 96 Participants | 28 Participants | 25 Participants | 213 Participants |
| Sex: Female, Male Male | 248 Participants | 219 Participants | 83 Participants | 84 Participants | 634 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 38 / 308 | 38 / 307 | 23 / 108 | 9 / 101 |
| other Total, other adverse events | 231 / 308 | 217 / 307 | 86 / 108 | 74 / 101 |
| serious Total, serious adverse events | 56 / 308 | 153 / 307 | 25 / 108 | 60 / 101 |
Outcome results
Primary
Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients
EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact. Three-year EFS rates will be calculated for both groups.
Time frame: 3 years
Population: As pre-specified in the protocol, this analysis includes all eligible patients (T-ALL+T-LLy) enrolled on the study. Arms were combined for this analysis as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Combination Chemotherapy) | Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients | 81.7 Percentage of participants |
| Arm B (Combination Chemotherapy, Bortezomib) | Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients | 85.1 Percentage of participants |
Comparison: To compare the EFS of the randomized patients (T-ALL+T-LLy) on Arm A vs Arm B. Study was designed to accrue 1200 eligible, evaluable randomized patients (to provide 90.5% power to detect an improvement in 4-year EFS from 85% to 90% with an alpha of 0.05 (one-sided log-rank test) (Hazard Ratio (HR)=0.6483). Study was closed to accrual early due to results from AALL0434 for nelarabine.p-value: 0.07495% CI: [0.561, 1.091]Log Rank
Secondary
Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT)
Cumulative incidence of isolated CNS relapse adjusting for competing risks using the method of: Gray R, A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1141:1154, 1988
Time frame: 3 years
Population: T-ALL patients on AALL1231 who did not receive CRT or bortezomib: IR (exclude CNS3) and SR T-ALL (exclude those who met AALL0434 \[NCT00408005\] Low Risk definition). T-ALL on AALL0434 \[NCT00408005\](who received CRT, no nelarabine) excluding Low Risk, CNS3, M3 Day 29, and EOC MRD \>0.1%
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Combination Chemotherapy) | Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | Isolated CNS Relapse | 3.6 Percentage of participants |
| Arm A (Combination Chemotherapy) | Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | Isolated Bone Marrow Relapse | 1.4 Percentage of participants |
| Arm A (Combination Chemotherapy) | Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | Combined Bone Marrow Relapse | 1.3 Percentage of participants |
| Arm B (Combination Chemotherapy, Bortezomib) | Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | Isolated CNS Relapse | 2.2 Percentage of participants |
| Arm B (Combination Chemotherapy, Bortezomib) | Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | Isolated Bone Marrow Relapse | 3.0 Percentage of participants |
| Arm B (Combination Chemotherapy, Bortezomib) | Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT) | Combined Bone Marrow Relapse | 1.8 Percentage of participants |
Secondary
EFS for Standard (SR) and Intermediate Risk (IR) T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no Cranial Radiation Therapy [CRT]) and Similar Patients on AALL0434 (Received CRT)
EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact.
Time frame: 3 years
Population: T-ALL patients on AALL1231 who did not receive CRT or bortezomib: IR (exclude CNS3) and SR T-ALL (exclude those who met AALL0434 \[NCT00408005\] Low Risk definition). T-ALL on AALL0434 \[NCT00408005\] (who received CRT, no nelarabine) excluding Low Risk, CNS3, M3 Day 29, and EOC MRD \>0.1%
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Combination Chemotherapy) | EFS for Standard (SR) and Intermediate Risk (IR) T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no Cranial Radiation Therapy [CRT]) and Similar Patients on AALL0434 (Received CRT) | 88.3 Percentage of participants |
| Arm B (Combination Chemotherapy, Bortezomib) | EFS for Standard (SR) and Intermediate Risk (IR) T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no Cranial Radiation Therapy [CRT]) and Similar Patients on AALL0434 (Received CRT) | 88.8 Percentage of participants |
Secondary
EFS for Very High Risk (VHR) T-ALL Patients Treated With High Risk (HR) Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Become Minimal Residual Disease (MRD) Negative and Those Who Remain MRD Positive at the End of HR Block 3
EFS will be calculated as time from the end of the three high-risk blocks of therapy to first event (relapse, second malignancy, remission death) or date of last contact.
Time frame: 3 years
Population: VHR T-ALL patients who had EOC MRD \>= 0.1%, completed the three high-risk blocks of therapy, and had MRD assessment done after the three high-risk blocks. MRD was not performed in T-LLy patients at end of the VHR blocks. MRD is not used in T-LLy to measure disease response. This outcome measure was pre-specified to only be assessed in the T-ALL patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Combination Chemotherapy) | EFS for Very High Risk (VHR) T-ALL Patients Treated With High Risk (HR) Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Become Minimal Residual Disease (MRD) Negative and Those Who Remain MRD Positive at the End of HR Block 3 | 25.0 Percentage of participants |
| Arm B (Combination Chemotherapy, Bortezomib) | EFS for Very High Risk (VHR) T-ALL Patients Treated With High Risk (HR) Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Become Minimal Residual Disease (MRD) Negative and Those Who Remain MRD Positive at the End of HR Block 3 | 88.9 Percentage of participants |
Secondary
EFS for Very High Risk (VHR) T-LLy Patients Treated With HR Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Have Complete or Partial Remission and Those Who do Not Respond
EFS for very high risk (VHR) T-LLy patients treated with HR Berlin-Frankfurt-Munster (BFM) intensification blocks who have complete or partial remission and those who do not respond
Time frame: 3 years
Population: VHR T-LL patients who completed the three high-risk blocks of therapy. The T-LLy VHR patients are included in the table, but there were not enough patients to do any formal analysis, eg there was only one patient (n=1) on the study with T-LLy who had radiographic disease assessment after the intensification blocks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Combination Chemotherapy) | EFS for Very High Risk (VHR) T-LLy Patients Treated With HR Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Have Complete or Partial Remission and Those Who do Not Respond | 0 Percentage of participants |
Secondary
Toxicity Rates Associated With Modified Standard Therapy, Including Dexamethasone and Additional Pegaspargase
Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Time frame: 3 years from start of therapy by patient
Population: As pre-specified in the protocol, this analysis includes all eligible patients (T-ALL+T-LLy) enrolled on the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Combination Chemotherapy) | Toxicity Rates Associated With Modified Standard Therapy, Including Dexamethasone and Additional Pegaspargase | 78.0 Percentage of participants |