Twice-Weekly Trimethoprim-Sulfamethoxazole for the Prevention of Pneumocystis Jiroveci Pneumonia in Non-Hodgkin Lymphoma Patients
Authors: Ono Keiko , Tsujimura Hideki , Sugawara Takeaki , Ise Mikiko , Satou Akiyasu , Wang Xiaofei , Kumagai Kyoya 
Published: November 2019

Abstract
BACKGROUND: Pneumocystis jiroveci pneumonia (PcP) is the representative opportunistic infection and the primary prophylaxis against PcP has become the standard of care in individuals who are immunosuppressed. The current recommendations for PcP prophylaxis are oral trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of one tablet (400 mg of sulfamethoxazole and 80 mg of trimethoprim) once a day, daily (7 tablets/week) or two tablets twice a day, twice-weekly (8 tablets/week). These regimens have been proven effective in HIV/AIDS patients and allogeneic stem cell transplant (allo-SCT) recipients; however, they sometimes cause unpleasant side effects such as rash, fever, leukopenia and renal dysfunction. To overcome this problem, low-dose TMP-SMX regimen was challenged for patients undergoing allo-SCT (Muto at al., Bone Mallow Transplant 2011). They decreased the dose of TMP-SMX to 4 tablets/week (one tablet twice a day, twice-weekly) and reported that none of their 156 patients developed PcP during the prophylaxis. Rituximab plus CHOP (R-CHOP) therapy has been widely accepted as the standard first-line treatment for B-cell lymphoma. Since rituximab and prednisolone are potentially immunosuppressive, primary prophylaxis of PcP has been considered indispensable during R-CHOP therapy. However, the standard schedule of TMP-SMX administration has not been established in this situation. For a number of years, we have employed the same low-dose method reported by Muto for our B-cell lymphoma patients receiving R-CHOP therapy. To evaluate the efficacy and tolerability of this regimen, we performed a retrospective analysis.
METHODS: We reviewed medical records of patients with newly diagnosed B-cell lymphoma who underwent 6 to 8 courses of R-CHOP therapy every 3 weeks from January 2009 to September 2014. TMP-SMX at a dose of one tablet twice a day, twice-weekly was started simultaneously with the induction of R-CHOP in all patients. To improve medication adherence, administration day was fixed on every Tuesday and Friday. The observation period is from the initial day of first R-CHOP to the last outpatient visit day or the day when recurrence was confirmed, which required salvage chemotherapy.
RESULTS: During the study period, data from 292 patients (154 males and 138 females) with a median age of 67 (21-89) years were collected. These patients included diffuse large B-cell lymphoma (n=213, 72.9%), follicular lymphoma (n=65, 22.3%), mantle cell lymphoma (n=6, 2.1%) and others (n=8, 2.7%). The median length of observation period was 29.4 (5.9-78.7) months. The median length of prophylaxis after the last day of R-CHOP was 5.7 (0.6-16.6) months. The median lymphocyte count before treatment was 1.1 (0.07-19.2) x 109/L, and the lowest lymphocyte count during R-CHOP therapy was 0.4 (0.03-1.4) x 109/L. Of 292 patients, 291 patients showed no evidence of clinical feature indicating PcP during the observation period. Although one patient developed PcP and required dose elevation of TMP-SMX to the therapeutic dose, the diagnosis of PcP was given on day 12 of the first course of R-CHOP. This means that the patient may have had potential PcP before the initiation of prophylaxis and could be excluded from this study. In the other 291 patients, TMP-SMX was well tolerated and there were no related adverse events which required discontinuation of the prophylaxis.
CONCLUSIONS: This study demonstrates that low-dose TMP-SMX perfectly prevented the　development of PcP with minimum toxicities even in elderly patients. In general, the purpose of R-CHOP is the cure from the disease and the completion of scheduled treatment is very important. On the other hand, elderly patients or patients with several complications who need R-CHOP are increasing. In this context, the identification of not only effective but also tolerable supportive care is required. Our data provides a valuable insight into the total treatment strategy of B-cell lymphoma.

Disclosures
No relevant conflicts of interest to declare.