Levofloxacin reduces febrile episodes, death early in therapy for newly diagnosed myeloma
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Levofloxacin prophylaxis during the first few months of active myeloma treatment significantly reduced febrile episodes and mortality compared with placebo among a cohort of U.K. patients with newly diagnosed myeloma, according to results of the randomized phase 3 TEAMM study published in The Lancet Oncology.
Researchers observed no increase in health care-associated infections associated with levofloxacin use.
“These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing antimyeloma therapy,” Mark T. Drayson, MBChB, PhD, FRCPath, professor in the department of clinical immunodiagnostics and director of clinical immunology service at University Hospital Birmingham and Heartlands Hospital in the U.K., and colleagues wrote.
“Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5,500 new cases of myeloma are diagnosed per year in the U.K., and one-quarter of patients will have a serious infection within 3 months of diagnosis,” they added.
For this reason, Drayson and colleagues sought to assess whether patients with newly diagnosed myeloma benefit from levofloxacin prophylaxis to prevent infection, as well as the effect on antibiotic-resistant organism carriage and health care-associated infections.
The prospective, multicenter, double-blind, placebo-controlled, TEAMM trial included 977 patients (median age, 67 years; range, 59-75) with newly diagnosed multiple myeloma who received treatment across 93 hospitals in the United Kingdom.
Researchers randomly assigned patients to either 500 mg once-daily oral levofloxacin (n = 489) or placebo (n = 488) for 12 weeks with dose reduction according to estimated glomerular filtration rate every 4 weeks.
Twenty-three percent of patients (n = 219) withdrew from the study. About half of the withdrawals occurred during the first 4 weeks, and researchers noted that the high number may reflect patients with newly diagnosed myeloma lacking commitment to a supportive care, placebo-controlled trial and instead focusing on disease control.
Researchers stratified treatment allocation by center, estimated glomerular filtration rate (> 50 mL/min, 20 mL/min to 50 mL/min, and < 20 mL/min) and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. Patients could not use other antibiotic prophylaxis, except for low-dose co-trimoxazole (n = 314) to prevent pneumocystis pneumonia. Patients underwent antimyeloma treatment according to local practice.
Researchers collected and assessed stool samples and nasal swabs every 4 weeks up to week 16 and again at 1 year for carriage of methicillin-resistant Staphylococcus aureas, Clostridium difficile and extended spectrum beta-lactamase gram-negative coliforms. Researchers additionally assessed myeloma activity and markers of immunocompetence in samples of blood and urine.
Time to first febrile episode or death due to all causes within the first 12 weeks of trial treatment served as the primary outcome. All patients were included in an intention-to-treat analysis of the primary endpoint.
Median follow-up was 12 months (interquartile range, 8-13).
Researchers observed first febrile episodes or deaths among 19% (n = 95) of patients assigned levofloxacin compared with 27% (n = 134) among those assigned placebo (HR = 0.66; 95% CI, 0.51-0.86).
Overall, 597 serious adverse events occurred up to 16 weeks after treatment initiation, including 308 (52%) in the levofloxacin group and 289 (48%) in the placebo group. Although the researchers observed similar adverse events between the two groups, five episodes (1%) of mostly reversible tendonitis occurred in the levofloxacin group.
Results of log-rank analyses showed 12-week OS of 98% (95% CI, 97-99) with levofloxacin compared with 95% (95% CI, 93-97) with placebo (P = .0081).
However, the OS benefit of levofloxacin did not persist at 1 year, according to the researchers. OS at 1 year was 90% (95% CI, 87-93) with levofloxacin vs. 91% (95% CI, 88-93) with placebo.
Researchers observed significant decreases in febrile episodes and death with use of prophylactic low-dose co-trimoxazole (HR = 0.59; 95% CI, 0.44-0.8).
Adjustment for co-trimoxazole made little difference to the levofloxacin benefit (HR = 0.66; 95% CI, 0.51-0.86; P = .0015), indicating that these two variables have independent effects, the researchers wrote.
“The reduction in deaths observed in the TEAMM study suggests that either the benefit of levofloxacin prophylaxis in newly diagnosed myeloma might be greater than in prolonged neutropenia, which could be shown in a future meta-analysis, or that our trial sample was just sufficient to show a benefit statistically and the real size benefit might be similar to that in prolonged neutropenia,” the researchers wrote. “Either way, to our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma.”
This study is timely in showing that fixed-duration levofloxacin prophylaxis reduces febrile infections and early deaths among patients with myeloma during induction chemotherapy, Karthik Ramasamy, MBBS, MRCP, FRCPath, PhD, consultant hematologist at Oxford University Hospitals NHS Foundation Trust, wrote in an accompanying editorial.
“However, further trials are required in this area,” Ramasamy wrote. “In particular, assessment of the therapeutic effects of a combination of cotrimoxazole and levofloxacin and investigation of various durations of antibiotic prophylaxis are crucial to optimize patient outcomes.” – by Jennifer Southall
Disclosures: The U.K. National Institute for Health Research funded the study. Drayson reports personal fees from Abingdon Health outside of the submitted work. Please see the study for all other authors’ relevant financial disclosures. Ramasamy reports research grants, advisory board funding and speaker fees from Amgen, Celgene, Janssen and Takeda; and speaker and advisory board fees from AbbVie, Oncopeptides and Sanofi outside of the submitted work.
Perspective
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Carlyn Tan, MD
The TEAMM trial demonstrated that fixed duration levofloxacin prophylaxis reduces febrile infections and early deaths among patients with newly diagnosed multiple myeloma during induction therapy. The rates of serious adverse events were similar in both arms, except for increased episodes of reversible tendonitis in the levofloxacin arm. Although this study did not show increased incidence of bacterial resistance, concerns remain. The benefits of levofloxacin prophylaxis appear to outweigh the risks for tendonitis and development of bacterial resistance. However, with median follow-up of 12 months, the reduced febrile episode rates did not translate into survival benefits; 12-month survival was 90% with levofloxacin and 91% with placebo. The study included a heterogeneous population. The subgroup analyses suggest that older and frail patients derived the most benefit from antibiotic prophylaxis. Based on this study, we can consider antibiotic prophylaxis for patients undergoing induction therapy, especially those at higher risk for infection. However, we need to keep in mind that treatment for multiple myeloma has changed significantly since the trial was conducted. Although the majority of patients received novel agents, less than half received lenalidomide (Revlimid, Celgene)-based and bortezomib (Velcade, Takeda)-based induction regimens, which typically are used in the U.S. and associated with higher response rates and better outcomes.
Future studies are needed in this field, specifically to establish the optimal antibiotic prophylaxis duration to optimize patient outcomes. It also would be interesting to evaluate the role of antibiotic prophylaxis in the relapsed/refractory myeloma setting, because these patients are significantly immunocompromised and at high risk for infection.
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