Table 3.
Grade 3 and 4 adverse events deemed to be treatment-related
| Grade 3 | Grade 4 | |||||||
|---|---|---|---|---|---|---|---|---|
| LR (n=23) |
IR (n=32) |
HR (n=26) |
All (n=81) |
LR (n=23) |
IR (n=32) |
HR (n=26) |
All (n=81) |
|
| Hematologic | ||||||||
|
| ||||||||
| Febrile neutropenia | 15 (65%) | 15 (47%) | 18 (69%) | 48 (59%) | – | – | – | – |
| Neutropenia | 11 (47%) | 8 (25%) | 2 (8%) | 21 (26%) | 2 (9%) | 1 (3%) | 2 (8%) | 5 (6%) |
| Leukopenia (total WBC) | 7 (30%) | 6 (19%) | 2 (8%) | 15 (19%) | – | – | – | – |
| Anemia | 3 (13%) | – | 1 (4%) | 4 (5%) | 1 (4%) | – | – | 1 (1%) |
| Thrombocytopenia | – | 1 (3%) | 2 (8%) | 3 (4%) | 1 (4%) | – | 1 (4%) | 2 (3%) |
| Hemorrhage/Bleeding | 2 (9%) | 1 (3%) | – | 3 (4%) | – | – | – | – |
| Hematoma | 1 (4%) | – | – | 1 (1%) | – | – | – | – |
| Lymphopenia | – | 1 (3%) | – | 1 (1%) | – | – | – | – |
|
| ||||||||
| Infectious | ||||||||
|
| ||||||||
| Documented infection with Grade 3 or 4 neutropenia (blood, catheter-related, pneumonia, colitis, mucositis, otitis, cellulitis, cystitis) | 9 (39%) | 4 (13%) | 7 (26%) | 20 (25%) | – | – | 1 (4%) | 1 (1%) |
| Infection without Grade 3 or 4 neutropenia | 7 (30%) | 4 (13%) | 4 (15%) | 15 (19%) | – | 1 (3%) | – | 1 (1%) |
| Mucositis/stomatitis | 2 (9%) | 3 (9%) | 2 (8%) | 7 (9%) | – | – | 1 (4%) | 1 (1%) |
| Colitis, infectious | 2 (9%) | 1 (3%) | 3 (12%) | 6 (7%) | – | – | – | – |
| Infection - Other | 2 (9%) | 2 (6%) | 1 (4%) | 5 (6%) | – | – | – | – |
| Infection with unknown ANC | 1 (4%) | – | 1 (4%) | 2 (3%) | – | – | – | – |
| Cystitis | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
| Hypotension/Sepsis | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
|
| ||||||||
| Gastrointestinal | ||||||||
|
| ||||||||
| Vomiting | 5 (21%) | 3 (9%) | 7 (26%) | 15 (19%) | - | – | – | – |
| Anorexia | 3 (13%) | 4 (13%) | 6 (23%) | 13 (16%) | – | – | – | – |
| Diarrhea | 2 (9%) | 1 (3%) | 5 (19%) | 8 (10%) | – | – | – | – |
| Nausea | – | 3 (9%) | – | 3 (4%) | – | – | – | – |
| ALT elevation | – | – | 1 (4%) | 1 (1%) | – | 1 (3%) | – | 1 (1%) |
| AST elevation | – | – | – | – | – | 1 (3%) | – | 1 (1%) |
|
| ||||||||
| Constitutional | ||||||||
|
| ||||||||
| Dehydration | 1 (4%) | 2 (6%) | 1 (4%) | 4 (5%) | – | – | – | – |
| Ataxia (incoordination) | 1 (4%) | – | – | 1 (1%) | – | – | – | – |
| Irritability (children <3 years of age) | 1 (4%) | – | – | 1 (1%) | – | – | – | – |
| Fever (in the absence of neutropenia) | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
| Constitutional Symptoms - Other | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
| Fatigue (asthenia, lethargy, malaise) | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
| Weight loss | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
|
| ||||||||
| Nervous system | ||||||||
|
| ||||||||
| Hearing loss | 2 (9%) | – | – | 2 (3%) | – | – | – | – |
| Neuropathy: motor | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
| Seizure | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
| Urinary retention (neurogenic bladder) | – | – | 1 (4%) | 1 (1%) | – | – | – | – |
|
| ||||||||
| Metabolic | ||||||||
|
| ||||||||
| Potassium, serum-low (hypokalemia) | – | 1 (3%) | – | 1 (1%) | – | - | 2 (8%) | 2 (3%) |
| Calcium, serum-low (hypocalcemia) | – | – | – | – | – | – | 1 (4%) | 1 (1%) |
| Glucose, serum-low (hypoglycemia) | – | – | – | – | 1 (4%) | – | – | 1 (1%) |
|
| ||||||||
| Cutaneous | ||||||||
|
| ||||||||
| Rash/desquamation | 2 (9%) | 1 (3%) | 1 (4%) | 4 (5%) | – | – | – | – |
| Rash: dermatitis associated with radiation | – | 1 (3%) | – | 1 (1%) | – | – | – | – |
|
| ||||||||
| Pulmonary | ||||||||
|
| ||||||||
| Aspiration | – | 1 (3%) | 0.0% | 1 (1%) | – | – | – | – |
| Hypoxia | – | 1 (3%) | 0.0% | 1 (1%) | – | – | – | – |
| Pulmonary/Upper Respiratory - Other | – | – | 3.8% | 1 (1%) | – | – | – | – |
|
| ||||||||
| Musculoskeletal | ||||||||
|
| ||||||||
| Pain, Extremity-limb | 1 (4%) | 1 (3%) | – | 2 (3%) | – | – | – | – |
| Pain, Abdomen NOS | – | 1 (3%) | – | 1 (1%) | – | – | – | – |
Data are number of patients (%). Grade 1 and 2 events were not recorded as specified in the protocol. Also not recorded were: Grade 3 elevation in ALT or AST which occurred within 7 days after methotrexate infusion; grade 3 and 4 hematologic toxicities that occurred from the beginning of induction therapy through the end of consolidation therapy for low and high risk patients; grade 3 and 4 hematologic toxicities that occurred from the beginning of induction therapy through the end of induction for the intermediate risk patients; grade 3 or 4 electrolyte abnormalities that occurred from the beginning of induction chemotherapy to the end of maintenance therapy were not recorded unless these resulted in hospitalization. Events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Attribution to therapy was based on investigators’ judgment. No deaths (grade 5) events occurred during the study. LR = Low risk. IR = Intermediate risk. HR= High risk. WBC = white blood cell. NOS = not otherwise specified. AST = aspartateaminotransferase. ALT = alanineaminotransferase.