A Phase III Randomized Trial Investigating Bortezomib (NSC# 681239) on a Modified Augmented BFM (ABFM) Backbone in Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LLy)
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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.
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.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| Arm A (combination chemotherapy) | Active comparator | Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Daunorubicin Hydrochloride; Drug: Dexamethasone; Drug: Doxorubicin; Drug: Doxorubicin Hydrochloride; Drug: Etoposide; Drug: Hydrocortisone Sodium Succinate; Drug: Ifosfamide; Drug: Leucovorin Calcium; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Radiation: Radiation Therapy; Drug: Thioguanine; Drug: Vincristine; Drug: Vincristine Sulfate | Patients receive combination chemotherapy without bortezomib. See Detailed Description. |
| Arm B (combination chemotherapy, bortezomib) | Experimental | Drug: Bortezomib; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Daunorubicin Hydrochloride; Drug: Dexamethasone; Drug: Doxorubicin; Drug: Doxorubicin Hydrochloride; Drug: Etoposide; Drug: Hydrocortisone Sodium Succinate; Drug: Ifosfamide; Drug: Leucovorin Calcium; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Radiation: Radiation Therapy; Drug: Thioguanine; Drug: Vincristine; Drug: Vincristine Sulfate | Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description. |
Sex: All, ages: 1 Year to 30 Years
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| Milestone | 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 |
|---|---|---|---|---|
| Started | 312 | 315 | 111 | 109 |
| Completed | 108 | 123 | 52 | 62 |
| Not completed | 204 | 192 | 59 | 47 |
Time frame: 3 years from start of therapy by patient
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|---|---|---|
| Arm A (Combination Chemotherapy): T-ALL | 38/308 (12.3%) | 56/308 (18.2%) | 231/308 (75.0%) |
| Arm B (Combination Chemotherapy, Bortezomib): T-ALL | 38/307 (12.4%) | 153/307 (49.8%) | 217/307 (70.7%) |
| Arm A (Combination Chemotherapy): T-LLy | 23/108 (21.3%) | 25/108 (23.1%) | 86/108 (79.6%) |
| Arm B (Combination Chemotherapy, Bortezomib): T-LLy | 9/101 (8.9%) | 60/101 (59.4%) | 74/101 (73.3%) |
| Term | Organ system | 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 |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | 0/308 | 2/307 | 0/108 | 1/101 |
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Bone marrow hypocellular | Blood and lymphatic system disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Disseminated intravascular coagulation | Blood and lymphatic system disorders | 0/308 | 3/307 | 0/108 | 1/101 |
| Febrile neutropenia | Blood and lymphatic system disorders | 10/308 | 38/307 | 2/108 | 15/101 |
| Hemolysis | Blood and lymphatic system disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Cardiac arrest | Cardiac disorders | 1/308 | 2/307 | 3/108 | 0/101 |
| Heart failure | Cardiac disorders | 2/308 | 0/307 | 0/108 | 2/101 |
| Left ventricular systolic dysfunction | Cardiac disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Myocardial infarction | Cardiac disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Sinus bradycardia | Cardiac disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Sinus tachycardia | Cardiac disorders | 0/308 | 1/307 | 0/108 | 1/101 |
| Ventricular arrhythmia | Cardiac disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Ventricular tachycardia | Cardiac disorders | 0/308 | 1/307 | 1/108 | 0/101 |
| Endocrine disorders - Other, specify | Endocrine disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Eye disorders - Other, specify | Eye disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Abdominal distension | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Abdominal pain | Gastrointestinal disorders | 0/308 | 0/307 | 1/108 | 3/101 |
| Anal ulcer | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Ascites | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Colitis | Gastrointestinal disorders | 0/308 | 2/307 | 0/108 | 1/101 |
| Colonic perforation | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Constipation | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 2/101 |
| Diarrhea | Gastrointestinal disorders | 0/308 | 3/307 | 0/108 | 0/101 |
| Duodenal perforation | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Duodenal ulcer | Gastrointestinal disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Dysphagia | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 1/101 |
| Enterocolitis | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 1/101 |
| Esophageal hemorrhage | Gastrointestinal disorders | 0/308 | 0/307 | 0/108 | 1/101 |
| Esophagitis | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Gastric hemorrhage | Gastrointestinal disorders | 1/308 | 3/307 | 0/108 | 1/101 |
| Gastritis | Gastrointestinal disorders | 2/308 | 1/307 | 1/108 | 0/101 |
| Gastrointestinal disorders - Other, specify | Gastrointestinal disorders | 0/308 | 3/307 | 0/108 | 0/101 |
| Ileus | Gastrointestinal disorders | 0/308 | 3/307 | 0/108 | 2/101 |
| Lower gastrointestinal hemorrhage | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 2/101 |
| Mucositis oral | Gastrointestinal disorders | 3/308 | 10/307 | 1/108 | 3/101 |
| Nausea | Gastrointestinal disorders | 0/308 | 0/307 | 1/108 | 3/101 |
| Oral pain | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Pancreatic hemorrhage | Gastrointestinal disorders | 0/308 | 2/307 | 0/108 | 0/101 |
| Pancreatitis | Gastrointestinal disorders | 2/308 | 14/307 | 5/108 | 7/101 |
| Rectal mucositis | Gastrointestinal disorders | 0/308 | 0/307 | 0/108 | 1/101 |
| Rectal pain | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 2/101 |
| Rectal ulcer | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Small intestinal mucositis | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Small intestinal obstruction | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Typhlitis | Gastrointestinal disorders | 0/308 | 6/307 | 0/108 | 4/101 |
| Upper gastrointestinal hemorrhage | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Vomiting | Gastrointestinal disorders | 0/308 | 6/307 | 1/108 | 3/101 |
| Death NOS | General disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Edema face | General disorders | 0/308 | 1/307 | 1/108 | 0/101 |
| Edema limbs | General disorders | 0/308 | 0/307 | 0/108 | 1/101 |
| Fatigue | General disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Fever | General disorders | 1/308 | 5/307 | 0/108 | 2/101 |
| General disorders and administration site conditions - Other, specify | General disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Hypothermia | General disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Infusion related reaction | General disorders | 0/308 | 1/307 | 0/108 | 2/101 |
| Multi-organ failure | General disorders | 1/308 | 2/307 | 0/108 | 2/101 |
| Non-cardiac chest pain | General disorders | 0/308 | 1/307 | 1/108 | 1/101 |
| Hepatic failure | Hepatobiliary disorders | 1/308 | 4/307 | 0/108 | 0/101 |
| Hepatobiliary disorders - Other, specify | Hepatobiliary disorders | 3/308 | 4/307 | 0/108 | 1/101 |
143 more terms not shown.
| Term | Organ system | 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 |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | 3/308 | 3/307 | 1/108 | 1/101 |
| Blood and lymphatic system disorders - Other, specify | Blood and lymphatic system disorders | 2/308 | 0/307 | 0/108 | 0/101 |
| Bone marrow hypocellular | Blood and lymphatic system disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Disseminated intravascular coagulation | Blood and lymphatic system disorders | 1/308 | 0/307 | 1/108 | 1/101 |
| Febrile neutropenia | Blood and lymphatic system disorders | 16/308 | 25/307 | 6/108 | 7/101 |
| Cardiac arrest | Cardiac disorders | 1/308 | 1/307 | 0/108 | 0/101 |
| Left ventricular systolic dysfunction | Cardiac disorders | 0/308 | 1/307 | 1/108 | 0/101 |
| Pericardial effusion | Cardiac disorders | 2/308 | 0/307 | 1/108 | 0/101 |
| Pericardial tamponade | Cardiac disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Sinus bradycardia | Cardiac disorders | 0/308 | 1/307 | 1/108 | 0/101 |
| Sinus tachycardia | Cardiac disorders | 0/308 | 2/307 | 0/108 | 0/101 |
| Supraventricular tachycardia | Cardiac disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Ventricular arrhythmia | Cardiac disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Ventricular tachycardia | Cardiac disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Blurred vision | Eye disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Optic nerve disorder | Eye disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Photophobia | Eye disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Abdominal distension | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Abdominal pain | Gastrointestinal disorders | 0/308 | 3/307 | 0/108 | 0/101 |
| Anal mucositis | Gastrointestinal disorders | 1/308 | 1/307 | 0/108 | 0/101 |
| Anal pain | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Ascites | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Colitis | Gastrointestinal disorders | 2/308 | 0/307 | 1/108 | 1/101 |
| Colonic perforation | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Constipation | Gastrointestinal disorders | 0/308 | 4/307 | 0/108 | 0/101 |
| Diarrhea | Gastrointestinal disorders | 1/308 | 3/307 | 0/108 | 0/101 |
| Dysphagia | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 1/101 |
| Enterocolitis | Gastrointestinal disorders | 2/308 | 1/307 | 0/108 | 0/101 |
| Esophagitis | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Gastric hemorrhage | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Gastrointestinal disorders - Other, specify | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Ileus | Gastrointestinal disorders | 4/308 | 5/307 | 1/108 | 1/101 |
| Lower gastrointestinal hemorrhage | Gastrointestinal disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Mucositis oral | Gastrointestinal disorders | 60/308 | 56/307 | 23/108 | 24/101 |
| Nausea | Gastrointestinal disorders | 0/308 | 2/307 | 0/108 | 0/101 |
| Pancreatitis | Gastrointestinal disorders | 23/308 | 29/307 | 15/108 | 11/101 |
| Proctitis | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Rectal mucositis | Gastrointestinal disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Rectal pain | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Retroperitoneal hemorrhage | Gastrointestinal disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Small intestinal mucositis | Gastrointestinal disorders | 0/308 | 1/307 | 1/108 | 0/101 |
| Small intestinal obstruction | Gastrointestinal disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Typhlitis | Gastrointestinal disorders | 7/308 | 2/307 | 0/108 | 1/101 |
| Vomiting | Gastrointestinal disorders | 1/308 | 2/307 | 0/108 | 1/101 |
| Death NOS | General disorders | 16/308 | 15/307 | 10/108 | 1/101 |
| Edema face | General disorders | 0/308 | 0/307 | 0/108 | 1/101 |
| Edema limbs | General disorders | 1/308 | 0/307 | 0/108 | 2/101 |
| Facial pain | General disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Fever | General disorders | 1/308 | 1/307 | 0/108 | 0/101 |
| Flu like symptoms | General disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| General disorders and administration site conditions - Other, specify | General disorders | 0/308 | 1/307 | 1/108 | 0/101 |
| Hypothermia | General disorders | 0/308 | 0/307 | 1/108 | 0/101 |
| Infusion related reaction | General disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Multi-organ failure | General disorders | 2/308 | 1/307 | 1/108 | 0/101 |
| Pain | General disorders | 0/308 | 2/307 | 1/108 | 0/101 |
| Sudden death NOS | General disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Cholecystitis | Hepatobiliary disorders | 1/308 | 1/307 | 0/108 | 0/101 |
| Gallbladder pain | Hepatobiliary disorders | 1/308 | 0/307 | 0/108 | 0/101 |
| Hepatic failure | Hepatobiliary disorders | 0/308 | 1/307 | 0/108 | 0/101 |
| Portal vein thrombosis | Hepatobiliary disorders | 0/308 | 0/307 | 0/108 | 1/101 |
114 more terms not shown.
| Facility | City | Country | Status |
|---|---|---|---|
| Children's Hospital of Alabama | Birmingham, Alabama | United States | |
| USA Health Strada Patient Care Center | Mobile, Alabama | United States | |
| Providence Alaska Medical Center | Anchorage, Alaska | United States | |
| Banner Children's at Desert | Mesa, Arizona | United States | |
| Phoenix Childrens Hospital | Phoenix, Arizona | United States | |
| Banner University Medical Center - Tucson | Tucson, Arizona | United States | |
| Arkansas Children's Hospital | Little Rock, Arkansas | United States | |
| Kaiser Permanente Downey Medical Center | Downey, California | United States | |
| City of Hope Comprehensive Cancer Center | Duarte, California | United States | |
| Loma Linda University Medical Center | Loma Linda, California | United States | |
| Miller Children's and Women's Hospital Long Beach | Long Beach, California | United States | |
| Children's Hospital Los Angeles | Los Angeles, California | United States | |
| Cedars-Sinai Medical Center | Los Angeles, California | United States | |
| Valley Children's Hospital | Madera, California | United States | |
| UCSF Benioff Children's Hospital Oakland | Oakland, California | United States | |
| Kaiser Permanente-Oakland | Oakland, California | United States | |
| Children's Hospital of Orange County | Orange, California | United States | |
| Lucile Packard Children's Hospital Stanford University | Palo Alto, California | United States | |
| Sutter Medical Center Sacramento | Sacramento, California | United States | |
| University of California Davis Comprehensive Cancer Center | Sacramento, California | United States | |
| Rady Children's Hospital - San Diego | San Diego, California | United States | |
| Naval Medical Center -San Diego | San Diego, California | United States | |
| UCSF Medical Center-Mission Bay | San Francisco, California | United States | |
| Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center | Torrance, California | United States | |
| Children's Hospital Colorado | Aurora, Colorado | United States | |
| Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center | Denver, Colorado | United States | |
| Connecticut Children's Medical Center | Hartford, Connecticut | United States | |
| Yale University | New Haven, Connecticut | United States | |
| Alfred I duPont Hospital for Children | Wilmington, Delaware | United States | |
| MedStar Georgetown University Hospital | Washington D.C., District of Columbia | United States | |
| Children's National Medical Center | Washington D.C., District of Columbia | United States | |
| Broward Health Medical Center | Fort Lauderdale, Florida | United States | |
| Golisano Children's Hospital of Southwest Florida | Fort Myers, Florida | United States | |
| UF Health Cancer Institute - Gainesville | Gainesville, Florida | United States | |
| Memorial Regional Hospital/Joe DiMaggio Children's Hospital | Hollywood, Florida | United States | |
| Nemours Children's Clinic-Jacksonville | Jacksonville, Florida | United States | |
| University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami, Florida | United States | |
| Nicklaus Children's Hospital | Miami, Florida | United States | |
| Miami Cancer Institute | Miami, Florida | United States | |
| AdventHealth Orlando | Orlando, Florida | United States | |
| Arnold Palmer Hospital for Children | Orlando, Florida | United States | |
| Nemours Children's Hospital | Orlando, Florida | United States | |
| Nemours Children's Clinic - Pensacola | Pensacola, Florida | United States | |
| Johns Hopkins All Children's Hospital | St. Petersburg, Florida | United States | |
| Tampa General Hospital | Tampa, Florida | United States | |
| Saint Joseph's Hospital/Children's Hospital-Tampa | Tampa, Florida | United States | |
| Saint Mary's Medical Center | West Palm Beach, Florida | United States | |
| Children's Healthcare of Atlanta - Arthur M Blank Hospital | Atlanta, Georgia | United States | |
| Augusta University Medical Center | Augusta, Georgia | United States | |
| Memorial Health University Medical Center | Savannah, Georgia | United States | |
| Kapiolani Medical Center for Women and Children | Honolulu, Hawaii | United States | |
| Saint Luke's Cancer Institute - Boise | Boise, Idaho | United States | |
| Lurie Children's Hospital-Chicago | Chicago, Illinois | United States | |
| University of Illinois | Chicago, Illinois | United States | |
| University of Chicago Comprehensive Cancer Center | Chicago, Illinois | United States | |
| Loyola University Medical Center | Maywood, Illinois | United States | |
| Advocate Children's Hospital-Oak Lawn | Oak Lawn, Illinois | United States | |
| Advocate Children's Hospital-Park Ridge | Park Ridge, Illinois | United States | |
| OSF Children's Hospital of Illinois | Peoria, Illinois | United States | |
| Southern Illinois University School of Medicine | Springfield, Illinois | United States | |
| Riley Hospital for Children | Indianapolis, Indiana | United States | |
| Ascension Saint Vincent Indianapolis Hospital | Indianapolis, Indiana | United States | |
| Blank Children's Hospital | Des Moines, Iowa | United States | |
| University of Iowa/Holden Comprehensive Cancer Center | Iowa City, Iowa | United States | |
| University of Kentucky/Markey Cancer Center | Lexington, Kentucky | United States | |
| Norton Children's Hospital | Louisville, Kentucky | United States | |
| Children's Hospital New Orleans | New Orleans, Louisiana | United States | |
| Ochsner Medical Center Jefferson | New Orleans, Louisiana | United States | |
| Eastern Maine Medical Center | Bangor, Maine | United States | |
| Maine Children's Cancer Program | Scarborough, Maine | United States | |
| University of Maryland/Greenebaum Cancer Center | Baltimore, Maryland | United States | |
| Sinai Hospital of Baltimore | Baltimore, Maryland | United States | |
| Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore, Maryland | United States | |
| Walter Reed National Military Medical Center | Bethesda, Maryland | United States | |
| Tufts Children's Hospital | Boston, Massachusetts | United States | |
| Massachusetts General Hospital Cancer Center | Boston, Massachusetts | United States | |
| Baystate Medical Center | Springfield, Massachusetts | United States | |
| UMass Memorial Medical Center - University Campus | Worcester, Massachusetts | United States | |
| C S Mott Children's Hospital | Ann Arbor, Michigan | United States | |
| Wayne State University/Karmanos Cancer Institute | Detroit, Michigan | United States | |
| Henry Ford Health Saint John Hospital | Detroit, Michigan | United States | |
| Michigan State University | East Lansing, Michigan | United States | |
| Hurley Medical Center | Flint, Michigan | United States | |
| Corewell Health Grand Rapids Hospitals - Butterworth Hospital | Grand Rapids, Michigan | United States | |
| Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital | Grand Rapids, Michigan | United States | |
| Bronson Methodist Hospital | Kalamazoo, Michigan | United States | |
| West Michigan Cancer Center | Kalamazoo, Michigan | United States | |
| Corewell Health Children's | Royal Oak, Michigan | United States | |
| Children's Hospitals and Clinics of Minnesota - Minneapolis | Minneapolis, Minnesota | United States | |
| University of Minnesota/Masonic Cancer Center | Minneapolis, Minnesota | United States | |
| Mayo Clinic in Rochester | Rochester, Minnesota | United States | |
| University of Mississippi Medical Center | Jackson, Mississippi | United States | |
| University of Missouri Children's Hospital | Columbia, Missouri | United States | |
| Children's Mercy Hospitals and Clinics | Kansas City, Missouri | United States | |
| Cardinal Glennon Children's Medical Center | St Louis, Missouri | United States | |
| Washington University School of Medicine | St Louis, Missouri | United States | |
| Mercy Hospital Saint Louis | St Louis, Missouri | United States | |
| Children's Hospital and Medical Center of Omaha | Omaha, Nebraska | United States | |
| University of Nebraska Medical Center | Omaha, Nebraska | United States | |
| University Medical Center of Southern Nevada | Las Vegas, Nevada | United States |
112 more sites not listed.
NIH grants: U10CA098543, U10CA180886