Levofloxacin in Preventing Infection in Young Patients Receiving Chemotherapy For Acute Leukemia or Undergoing Stem Cell Transplantation

• Susceptibility of E. coli, K. pneumoniae, and P. aeruginosa to cefepime, imipenem, and levofloxacin and the susceptibility of S. mitis to cefepime, levofloxacin, and penicillin at the start and end of each treatment period [ Designated as safety issue: No ]
• Incidence of febrile neutropenia, severe infection, and death from bacterial infection [ Designated as safety issue: No ]
• Safety of levofloxacin with special attention to musculoskeletal disorders, particularly tendinopathy and tendon rupture, as assessed by CTCAE v. 4.0 every 6 months for 2 years and annually thereafter [ Designated as safety issue: Yes ]
• Duration of parenteral antibiotic administration during 2 courses of chemotherapy or 1 transplantation procedure [ Designated as safety issue: No ]

RATIONALE: 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.

PURPOSE: This randomized phase III trial studies how well levofloxacin works in preventing infection in young patients receiving chemotherapy for acute leukemia or undergoing stem cell transplant.

OBJECTIVES:

Primary

• 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

• 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 Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus mitis.
• 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.
• To determine whether levofloxacin prophylaxis reduces the incidence of fever with neutropenia, severe infection, and death from bacterial infection.
• To assess the safety of levofloxacin prophylaxis, with specific attention to musculoskeletal disorders including tendinopathy and tendon rupture.
• 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: This is a multicenter study. Patients are stratified according to diagnosis (de novo acute myeloid leukemia [AML] vs secondary AML vs relapsed AML vs relapsed acute lymphoblastic leukemia [ALL]), and therapy (undergoing autologous HSCT vs undergoing allogeneic HSCT). Patients are randomized to 1 of 2 treatment groups.

• Arm I: Patients receive levofloxacin orally (PO) or IV over 60-90 minutes once or twice daily beginning on day 1 during 2 consecutive courses of chemotherapy or beginning on day -2 during hematopoietic stem cell transplantation (HSCT) and continuing until blood counts recover.
• Arm II: Patients receive established standard of care and receive chemotherapy or HSCT as patients in arm 1.

Musculoskeletal assessment is conducted at baseline and at 2 and 12 months.

Patients may undergo perirectal or stool swab collection for ancillary studies.

After completion of study therapy, patients are followed up for 1 year.

• Bacterial Infection
• Leukemia
• Musculoskeletal Complications
• Neutropenia

• Drug: levofloxacin
  Given PO or IV
• Procedure: standard follow-up care
  Established standard of care

• Experimental: Arm I
  Patients receive levofloxacin orally (PO) or IV over 60-90 minutes once or twice daily beginning on day 1 during 2 consecutive courses of chemotherapy or beginning on day -2 during hematopoietic stem cell transplantation (HSCT) and continuing until blood counts recover.
  Intervention: Drug: levofloxacin
• No Intervention: Arm II
  Patients receive established standard of care and receive chemotherapy or HSCT as patients in arm 1.
  Intervention: Procedure: standard follow-up care

DISEASE CHARACTERISTICS:

• Patients must fit 1 of the following categories:

  • Chemotherapy patients

    • Scheduled to receive at least 2 consecutive courses (not required to be the first 2 courses) of intensive chemotherapy for de novo, relapsed, or secondary acute myeloid leukemia (AML), or 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 including, but not limited to:

      • Treatment with "4-drug induction" (anthracycline, vincristine, asparaginase, and steroid)
      • High-dose cytarabine, anthracycline/cytarabine, or ifosfamide/etoposide
      • Clofarabine-containing regimens

  • Stem cell transplantation patients*

    • Scheduled to receive at least 1 myeloablative autologous or allogeneic hematopoietic stem cell transplantation (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 NOTE: *Patients with AML or ALL who were enrolled on this study during intensive chemotherapy are not eligible to be enrolled during HSCT.

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Creatinine clearance or radioisotope GFR > 70 mL/min OR serum creatinine based on age and/or 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) or 1.4 mg/dL (female) (13 to < 16 years of age)
  • 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
• No patients with an allergy to quinolones
• No patients with chronic active arthritis
• No patients with a known pathologic prolongation of the QTc
• No females who are pregnant or breast feeding

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No patients scheduled to receive non-intensive or palliative chemotherapy
• No patients undergoing non-myeloablative hematopoietic stem cell transplantation (HSCT)
• No patients being treated with antibacterial agents, other than cotrimoxazole for Pneumocystitis jiroveci (PCP) prophylaxis