Acute Leukemias of Ambiguous Lineage, Bacterial Infection, Diarrhea, Fungal Infection, Musculoskeletal Complications, Neutropenia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
Conditions
Brief summary
This randomized phase III trial studies how well levofloxacin works in preventing infection in young patients with acute leukemia receiving chemotherapy or undergoing stem cell transplant. Giving antibiotics may be effective in preventing or controlling early infection in patients receiving chemotherapy or undergoing stem cell transplant for acute leukemia. It is not yet known whether levofloxacin is effective in preventing infection.
Detailed description
PRIMARY OBJECTIVES: I. To determine whether levofloxacin given prophylactically during periods of neutropenia to patients being treated with chemotherapy for acute leukemia (AL) or undergoing hematopoietic stem cell transplantation (HSCT) will decrease the incidence of bacteremia. SECONDARY OBJECTIVES: I. To determine the effect of prophylactic levofloxacin on resistance patterns of bacterial isolates from all sterile site cultures, and the evolution of antimicrobial resistance from peri-rectal swab isolates of Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus mitis. II. To determine the effect of levofloxacin prophylaxis on total number of days of antibiotic administration (prophylactic, empiric, and treatment) in children undergoing therapy for AL or HSCT. III. To determine whether levofloxacin prophylaxis reduces the incidence of fever with neutropenia, severe infection, and death from bacterial infection. IV. To assess the safety of levofloxacin prophylaxis, with specific attention to musculoskeletal disorders including tendinopathy and tendon rupture. V. To assess the impact of prophylactic levofloxacin on the incidence of Clostridium difficile-associated diarrhea (CDAD), and the incidence of microbiologically documented invasive fungal infections (IFI). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive levofloxacin orally (PO) or intravenously (IV) over 60-90 minutes once daily (QD) or twice daily (BID) beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover. ARM II: Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I. After completion of study therapy, patients are followed up for 1 year.
Interventions
DRUGlevofloxacin
Given PO or IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
SINGLE
Eligibility
Sex/Gender
ALL
Age
6 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
* Patient must fit 1 of the following 2 categories: * Chemotherapy patients * Planned to receive at least 2 consecutive cycles (not required to be the first 2 cycles) of intensive chemotherapy for either: * De novo, relapsed or secondary acute myeloid leukemia (AML), or acute leukemia of ambiguous lineage treated with standard AML therapy * Relapsed acute lymphoblastic leukemia (ALL) * For the purposes of this study, intensive chemotherapy is defined as regimens that are predicted by the local investigator to cause neutropenia for \> 7 days; examples include, but are not limited to, treatment with 4-drug induction (anthracycline, vincristine, asparaginase, and steroid), high dose cytarabine, anthracycline/cytarabine, ifosfamide/etoposide, and clofarabine-containing regimens * Stem cell transplantation patients * Planned to receive at least 1 myeloablative autologous or allogeneic HSCT * For the purposes of this study, myeloablative autologous and allogeneic HSCT are those in which the conditioning regimen is predicted by the local Investigator to cause neutropenia for \> 7 days * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \> 70 mL/min/1.73 m\^2 OR serum creatinine based on age/gender as follows: * 0.5 mg/dL (6 months to \< 1 year of age) * 0.6 mg/dL (1 to \< 2 years of age) * 0.8 mg/dL (2 to \< 6 years of age) * 1.0 mg/dL (6 to \< 10 years of age) * 1.2 mg/dL (10 to \< 13 years of age) * 1.5 mg/dL (male)/1.4 mg/dL (female) (13 to \< 16 years of age) * 1.7 mg/dL (male)/1.4 mg/dL (female) (\>= 16 years of age) * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion criteria
* Patients previously enrolled on the trial are not eligible; therefore, patients with AL who were on study during intensive chemotherapy are not eligible to be enrolled during the HSCT * Patients with an allergy to quinolones * Patients with chronic active arthritis * Patients with a known pathologic prolongation of the corrected QT (QTc) * Females who are pregnant or breast feeding * Patients being treated with antibacterial agents, other than any of the following: * Cotrimoxazole or other agents including dapsone, atovaquone, and pentamidine administered for Pneumocystitis jiroveci (PCP) prophylaxis * Topical antibiotics * Central venous catheter antibiotic lock therapy * Note: prophylactic antifungal therapy is NOT an exclusion criterion * Patients currently enrolled on the ACCL1034 study are not eligible until they have completed the 90 day observation period of that study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms | Up to 60 days after enrollment or receiving levofloxacin | A bacteremia incidence is defined as an occurrence of at least 1 episode of true (centrally reviewed) bacteremia among Acute Leukemia (AL) and Hematopoietic stem cell transplantation (HSCT) patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms | Up to 60 days after enrollment or receiving levofloxacin | Fever and febrile neutropenia defined as Absolute Neutrophil Count (ANC) \< 1000/mm3 with a single temperature of \>38.3 degrees C (101 degrees F) or a sustained temperature of \>= 38 degrees C (100.4 degrees F) for more than one hour. |
| Comparison of the Percentage of Patients Having Severe Infection Between Arms | Up to 60 days after enrollment or receiving levofloxacin | Severe infection defined as any grade 4 or 5 CTCAE catheter-related infection, enterocolitis, lung infection, sepsis, small intestine infection and other infections or infestations |
| Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Up to 60 days after enrollment or receiving levofloxacin | Exposure to antibiotics was considered during the infection observation period(s) was defined a priori as follows: Gram positive agents = vancomycin, linezolid, daptomycin or quinupristin/dalfopristin; Aminoglycosides = amikacin, gentamicin or tobramycin; Third or fourth generation cephalosporins = cefepime, ceftazidime, ceftriaxone or cefotaxime; Empiric antibiotics for fever and neutropenia = imipenem, meropenem, cefepime, ceftazidime or piperacillin/tazobactam |
| Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Enrollment, 2 months and 12 months post infection observation period | Musculoskeletal conditions included at least one occurrence of arthralgia, arthritis, gait abnormality or tendinopathy. |
| Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms | Up to 60 days after enrollment or receiving levofloxacin | Clostridium Difficile Associated Disease (CDAD) is defined as a positive C. difficile toxin assay result and diarrhea, CTCAE version 4, grade 2 and higher. |
| Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms | Up to 60 days after enrollment or receiving levofloxacin | — |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Levofloxacin) Patients receive levofloxacin PO or IV over 60-90 minutes once or twice daily beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover.
levofloxacin: Given PO or IV | 314 |
| Arm II (Standard of Care) Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I. | 310 |
| Total | 624 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 4 |
| Overall Study | Ineligible | 4 | 3 |
| Overall Study | Physician Decision | 46 | 7 |
| Overall Study | Withdrawal by Subject | 7 | 0 |
Baseline characteristics
| Characteristic | Arm I (Levofloxacin) | Arm II (Standard of Care) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 275 Participants | 284 Participants | 559 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 26 Participants | 65 Participants |
| Age, Continuous | 9.44 Years STANDARD_DEVIATION 6.18 | 9.18 Years STANDARD_DEVIATION 5.89 | 9.31 Years STANDARD_DEVIATION 6.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 89 Participants | 56 Participants | 145 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 208 Participants | 246 Participants | 454 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 8 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 22 Participants | 17 Participants | 39 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants | 45 Participants | 80 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 40 Participants | 32 Participants | 72 Participants |
| Race (NIH/OMB) White | 217 Participants | 216 Participants | 433 Participants |
| Region of Enrollment Canada | 26 Participants | 36 Participants | 62 Participants |
| Region of Enrollment India | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Ireland | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Mexico | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 287 Participants | 272 Participants | 559 Participants |
| Sex: Female, Male Female | 120 Participants | 127 Participants | 247 Participants |
| Sex: Female, Male Male | 194 Participants | 183 Participants | 377 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 69 / 306 | 67 / 307 |
| other Total, other adverse events | 36 / 306 | 37 / 307 |
| serious Total, serious adverse events | 4 / 306 | 3 / 307 |
Outcome results
Primary
Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms
A bacteremia incidence is defined as an occurrence of at least 1 episode of true (centrally reviewed) bacteremia among Acute Leukemia (AL) and Hematopoietic stem cell transplantation (HSCT) patients.
Time frame: Up to 60 days after enrollment or receiving levofloxacin
Population: All evaluable, and centrally reviewed AL and HSCT patients are reported. Ineligible patients and patients who withdrew of consent prior to treatment were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms | Evaluable AL patients | 21.9 Percentage of patients |
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms | Evaluable HSCT patients | 11 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms | Evaluable AL patients | 43.4 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms | Evaluable HSCT patients | 17.3 Percentage of patients |
Secondary
Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms
Exposure to antibiotics was considered during the infection observation period(s) was defined a priori as follows: Gram positive agents = vancomycin, linezolid, daptomycin or quinupristin/dalfopristin; Aminoglycosides = amikacin, gentamicin or tobramycin; Third or fourth generation cephalosporins = cefepime, ceftazidime, ceftriaxone or cefotaxime; Empiric antibiotics for fever and neutropenia = imipenem, meropenem, cefepime, ceftazidime or piperacillin/tazobactam
Time frame: Up to 60 days after enrollment or receiving levofloxacin
Population: All evaluable, and centrally reviewed AL and HSCT patients are reported. Ineligible patients and patients who withdrew of consent prior to treatment were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Gram positive agents | 58.8 Percentage of patients |
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Aminoglycosides | 22.9 Percentage of patients |
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Third or fourth generation cephalosporins | 46.1 Percentage of patients |
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Empiric antibiotics for fever and neutropenia | 68.6 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Empiric antibiotics for fever and neutropenia | 85.7 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Gram positive agents | 65.8 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Third or fourth generation cephalosporins | 59.9 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Aminoglycosides | 35.5 Percentage of patients |
Secondary
Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms
Clostridium Difficile Associated Disease (CDAD) is defined as a positive C. difficile toxin assay result and diarrhea, CTCAE version 4, grade 2 and higher.
Time frame: Up to 60 days after enrollment or receiving levofloxacin
Population: All evaluable, and centrally reviewed AL and HSCT patients are reported. Ineligible patients and patients who withdrew of consent prior to treatment were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms | 2.3 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms | 5.2 Percentage of patients |
Secondary
Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms
Fever and febrile neutropenia defined as Absolute Neutrophil Count (ANC) \< 1000/mm3 with a single temperature of \>38.3 degrees C (101 degrees F) or a sustained temperature of \>= 38 degrees C (100.4 degrees F) for more than one hour.
Time frame: Up to 60 days after enrollment or receiving levofloxacin
Population: All evaluable, and centrally reviewed AL and HSCT patients are reported. Ineligible patients and patients who withdrew of consent prior to treatment were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms | 71.2 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms | 82.1 Percentage of patients |
Secondary
Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms
Musculoskeletal conditions included at least one occurrence of arthralgia, arthritis, gait abnormality or tendinopathy.
Time frame: Enrollment, 2 months and 12 months post infection observation period
Population: Evaluable patients who submitted musculoskeletal Case Record Form (CRF) combined from both Acute Leukemia (AL) and Hematopoietic stem cell transplantation (HSCT) cohorts at enrollment. Ineligible and withdrew of Consent prior to treatment were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Evaluable AL and HSCT Patients at Baseline | 5.9 Percentage of patients |
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Evaluable AL and HSCT Patients at 2 Months | 11.4 Percentage of patients |
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Evaluable AL and HSCT Patients at 12 Months | 10.1 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Evaluable AL and HSCT Patients at Baseline | 10 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Evaluable AL and HSCT Patients at 2 Months | 16.3 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Evaluable AL and HSCT Patients at 12 Months | 14.4 Percentage of patients |
Secondary
Comparison of the Percentage of Patients Having Severe Infection Between Arms
Severe infection defined as any grade 4 or 5 CTCAE catheter-related infection, enterocolitis, lung infection, sepsis, small intestine infection and other infections or infestations
Time frame: Up to 60 days after enrollment or receiving levofloxacin
Population: All evaluable, and centrally reviewed AL and HSCT patients are reported. Ineligible patients and patients who withdrew of consent prior to treatment were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients Having Severe Infection Between Arms | 3.6 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients Having Severe Infection Between Arms | 5.9 Percentage of patients |
Secondary
Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms
Time frame: Up to 60 days after enrollment or receiving levofloxacin
Population: Evaluable patients combined from both AL and HSCT cohorts were reported. Ineligible and withdrew of Consent prior to Tx were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Levofloxacin) | Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms | 0 Percentage of patients |
| Arm II (Standard of Care) | Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms | 0 Percentage of patients |