IN PATIENTS undergoing treatment of multiple myeloma, the prophylactic use of levofloxacin significantly reduced febrile episodes and deaths, without increasing healthcare-associated infections or carriage of key nosocomial pathogens, in a large multicenter study from the United Kingdom.1 The findings were reported at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition by Mark T. Drayson, MD, PhD, of the Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
Mark T. Drayson, MD, PhD
“Infection in the first 12 weeks is the biggest cause of the high early death rate in myeloma,” Dr. Drayson said. “Myeloma profoundly suppresses the immune system, and then we give antimyeloma therapy that deepens that suppression further, so infection continues to be a serious problem.”
Many patients die before they have had time to respond to antimyeloma therapy. In an analysis of 3,107 patients in the United Kingdom’s Myeloma Research Council (MRC) trials, 10% died within 60 days of diagnosis and 45% of those deaths were attributed to infections.2 Infections were also the primary cause of death in more than 20% of patients in the MRC IX trial, for which Dr. Drayson was a co-investigator.3
Levofloxacin is effective against the common bacterial infections in myeloma; taken once daily, the drug has proven efficacy as prophylaxis during treatment of other cancers. Concerns have been increasing, however, about the development of antibiotic resistance and the risk of health-care–associated infections with antibiotic prophylaxis, he said.
Phase III TEAMM Details
TO EVALUATE the benefit of levofloxacin in reducing febrile episodes and death and to investigate any associated risks of health-care–acquired infections, Dr. Drayson and his colleagues randomized newly diagnosed patients with multiple myeloma to receive levofloxacin or placebo for 12 weeks within 14 days of starting antimyeloma therapy. The patients were regularly screened for carriage of resistant organisms. The study aimed to answer, he said, “whether patients should be denied life-saving prophylactic antibiotics because of concerns about health-care–associated infections.”
“Infection in the first 12 weeks is the biggest cause of the high early death rate in myeloma.”— Mark T. Drayson, MD, PhD
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The randomized, double-blind, placebo-controlled phase III TEAMM trial enrolled 977 newly diagnosed patients with myeloma (median age, 67 years; Eastern Cooperative Oncology Group [ECOG] performance status mostly 0–1) from 93 hospitals in the United Kingdom between 2012 and 2016. Patients received 500 mg of levofloxacin or placebo once daily for 12 weeks, dose-adjusted for renal function. Patients were permitted to continue routine nonbacterial antimicrobial prophylaxis, including three-times-weekly sulfamethoxazole-trimethoprim for pneumocystis. Fecal and throat samples were taken every 4 weeks to detect carriage of Clostridium difficile, methicillin-resistant Staphylococcus aureus and gram-negative bacteria that were positive for extended-spectrum beta-lactamase.
The primary endpoint was the number of febrile episodes (defined as an oral temperature of ≥ 38°C treated with anti-infectives) and or death by any cause suffered in the first 12 weeks. The occurrence of febrile episodes was captured at clinic visits every 4 weeks up to 12 weeks.
Significant Benefit With Levofloxacin
IN THIS STUDY, levofloxacin reduced febrile episodes and deaths by 34%. Although 134 of 488 patients (27%) on the placebo arm experienced events, including 112 febrile episodes, 15 deaths, and 7 febrile episodes and death, the same was true for 95 of 489 levofloxacin recipients (19%), who had 87 febrile episodes, 4 deaths, and 4 febrile episodes and deaths—a highly significant 34% reduction (P = .002), Dr. Drayson reported. “You put that into a Kaplan-Meier curve and see a very significant benefit of taking levofloxacin to prevent febrile episodes and deaths,” he noted.
The benefit of levofloxacin was seen in both febrile and nonfebrile episodes (Table 1). The sites of infection were lower respiratory tract (49%), upper respiratory tract (12%), bloodstream (7%), urinary tract (7%), skin and soft tissue (8%), and gastrointestinal (3%).
Deaths within 12 weeks numbered 8 in the levofloxacin arm and 22 in the placebo arm, attributed to infection in 3 and 8 cases, respectively (P = .02).
“In the regression analysis, adjusting for baseline prognostic indicators, the benefit of levofloxacin held up, with a hazard ratio of 0.66 (P = .002),” he added. The effect of sulfamethoxazole-trimethoprim, which 315 patients received, was additive to the effects of levofloxacin; the hazard ratio for this combination was 0.59 (P = .0009). After adjustment for sulfamethoxazole-trimethoprim use, levofloxacin alone still showed benefit in this group of patients (P = .002).
Specific Organisms
LEVOFLOXACIN REDUCED the number of microbiologically proven infections: of the total 291 organisms detected, 99 were identified in the levofloxacin arm and 192, in the placebo arm. The reduction was predominantly in gram-negative organisms, with 137 gram-negative organisms, including 25 (18%) with levofloxacin and 112 (82%) with placebo; 101 gram-positive organisms, including 52 (51%) with levofloxacin and 49 (49%) with placebo; and 53 fungal and viral organisms, including 22 (42%) with levofloxacin and 31 (58%) with placebo.
“There was not much difference in the gram-positives, and, surprisingly, we saw no Streptococcus pneumoniae in the levofloxacin and only 4 in the placebo arms,” Dr. Drayson commented.
The prophylactic use of levofloxacin did not increase the risk of carriage of resistant bacteria. Of 2,595 stool samples and 2,933 nasal samples, C difficile carriage was found at baseline in 6 cases. New acquisitions for carriage in the levofloxacin and placebo arms included C difficile in 11 and 8 patients, respectively; gram-positive extended-spectrum beta-lactamase in 37 and 51; and methicillin-resistant S aureus in 4 and 7. The only significant difference between the arms was in the reduction of acquired extended-spectrum beta-lactamase in the levofloxacin arm.
At 1 year, there was no difference in overall survival between the arms. “We were concerned that maybe levofloxacin was merely delaying an inevitable early death, so we looked carefully and objectively, and this did not seem to be the case. It’s a good argument, though, for extending prophylaxis out to 12 months,” Dr. Drayson said.
He also maintained that prophylaxis should not be limited to the patient’s initial treatment, but should be reinstituted at the time of relapse as well. The researchers are now analyzing the findings further to look for correlations with antimyeloma treatment and steroid use. ■
DISCLOSURE: Dr. Drayson reported equity ownership or membership on Abingdon Health’s Board of Directors or advisory committee.
REFERENCES
1. Drayson MT, Bowcock S, Planche T, et al: Tackling early morbidity and mortality in myeloma (TEAMM): Assessing the benefit of antibiotic prophylaxis and its effect on healthcare associated infections in 977 patients. 2017 ASH Annual Meeting. Abstract 903. Presented December 11, 2017.
2. Augustson BM, Begum G, Dunn JA, et al: Early mortality after diagnosis of multiple myeloma: Analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 23:9219-9226, 2005.
3. Richardson PG, Laubach JP, Schlossman RL, et al: The Medical Research Council Myeloma IX trial: The impact on treatment paradigms. Eur J Haematol 88:1-7, 2012.
