Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) decreases the incidence of interstitial pneumonia in B cell non- Hodgkin lymphoma patients receiving chemotherapy with rituximab

doi:10.21203/rs.2.16712/v1

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Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) decreases the incidence of interstitial pneumonia in B cell non- Hodgkin lymphoma patients receiving chemotherapy with rituximab

https://doi.org/10.21203/rs.2.16712/v1

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published 08 Aug, 2020

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Several studies have reported incidence of interstitial pneumonia (IP) among patients with non-hodgkin lymphoma (NHL) receiving chemotherapy with rituximab, however the best prophylaxis method remains unclear. This retrospective study was intended to identify the effect of prophylactic TMP-SMX once daily on IP and high risk factors effecting IP in patients with NHL. From March 2013 to April 2018, 498 patients (264 male, 53%) with B cell NHL receiving first-line CHOP-like chemotherapy with rituximab were enrolled in this study. The median age of the patients was 56 years old. Among these patients, 311 patients (62.4%) received prophylaxis of TMP-SMX. IP occurred in 65 patients, so the incidence rate of IP was 13.1%. The prophylactic use of TMP-SMX given one tablet daily could significantly decrease the rate of IP from 21.4% to 8.0% (p<0.001). For 311 patients with prophylactic TMP-SMX, 2 (1.2%) had rashes, 38 (12.2%) suffered nausea and vomiting, 52 (16.7%) exhibited neutropenia, and 18 (5.8%) suffered kidney dysfunction. Being male, having a history of diabetes and not receiving TMP-SMX prophylactic therapy were considered as statistically significant risk factors for IP in univariate and multivariate analysis. Disease progression was observed in 55/311 (17.7%) patients with prophylactic TMP-SMX and in 63/187 (33.7%) patients without prophylactic TMP-SMX treatment (p<0.001). The present study concluded that IP occurrence is not rare in B cell non-hodgkin lymphoma patients receiving chemotherapy with rituximab, while prophylaxis of oral TMP-SMX given one tablet daily significantly decreased incidence of IP.

Cancer Biology

Oncology

Non-Hodgkin Lymphoma

TMP-SMX

Rituximab

Chemotherapy

Pneumonia

Interstitial

CHOP chemotherapy combined with rituximab has been widely employed for treatment of CD20+ non-Hodgkin lymphoma (NHL)^1-3. Previous studies have reported that 1.3% to 14% patients undergoing chemotherapy regimens including rituximab develop interstitial pneumonia (IP)^4-7. IP is a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations⁸. IP can be caused by various factors and can lead to dyspnea, respiratory failure, and even death. Individuals suffering from IP are also more likely to suffer from delayed treatment of premature cessation of chemotherapeutic treatment, which will reduce the efficiency of chemotherapy and reduce survival⁹. Therefore, active treatment and effective prevention of IP is important for patients undergoing immunochemotherapy. Rituximab combined with chemotherapy could inhibit immune function of patients, and increase opportunistic infection. Several studies concluded elevated the incidence of IP possibly because of an increase in the risk of PCP^4-6^,¹⁰^,¹¹. However, the most effective prophylactic drugs and methods for preventing IP remain controversial. Trimethoprim-sulfamethoxazole (TMP-SMX), an oral broad-spectrum antibiotic, is a specific therapeutic and prophylactic agent used to treat pneumocystis carinii pneumonia (PCP) infection⁵^,⁶^,¹¹. Since 2013, hundreds of patients with lymphoma have taken prophylaxis of TMP-SMX in our hospital. Here, we present this retrospective study summarizing the effects of TMP-SMX prophylaxis as a means of reducing IP incidence among patients of B cell non-Hodgkin lymphoma via a combination of chemotherapy and rituximab.

Participants and data collection

We retrospectively reviewed treatment data from patients with CD20+ B cell non-Hodgkin lymphoma as diagnosed by a local pathologist according to WHO criteria.¹² All patients had received rituximab combined with CHOP-like chemotherapy for at least two cycles. Prophylactic granulocyte colony-stimulating factor (G-CSF) and antiemetic administration was allowed. Prophylactic TMP-SMX was taken once daily from treatment initiation to completion of chemotherapy. Each tablet contained 0.08 g TMP and 0.4 g SMX. TMP-SMX use was not permitted in patients with allergies to the drug, megaloblastic anemia, or severe liver or kidney damage. A group of patients that did not undergo prophylactic TMP-SMX treatment were analyzed as control group. Radiographic documents and data regarding patient clinical characteristics, histological diagnosis, chemotherapy regimens, and survival outcome were extracted from the original computer medical files. The trial was approved by the research ethics boards of Zhejiang cancer hospital, with all patients giving written informed consent.

IP Diagnosis and treatment

The observation period for IP extends from the first day of immunochemotherapy to 8 months after completion of immunochemotherapy. Routine imaging evaluations were performed every two cycles during chemotherapy and every 3 months after chemotherapy in observation period. Patients received thoracic CT scans when they exhibited symptoms of pulmonary infection. Diagnosis of IP can be done via multidisciplinary approach in which the clinical symptoms, laboratory tests, radiologic and pathologic findings. Typical imaging presentations of IP was diffuse pulmonary interstitial infiltrates with reticular or ground-glass opacity, alveolitis, and the presence of diffuse infiltrates on CT scans.¹¹^,¹³ When IP was suspected, laboratory tests measuring blood cell counts, C reactive protein (CRP), procalcitonin (PCT), 3-b-D glucan antigens, Gram-negative lipopolysaccharides, Galactomannan antigen detection (GM), and bacterial culture were conducted to facilitate appropriate diagnosis. Once diagnosed with IP, patients started empirical treatment with a combination of antibiotics, antifungal agents, and glucocorticoids. Ganciclovir was given when virus infection was suspected. TMP-SMX should be used at therapeutic dose if PCP was suspected. CT scans were conducted weekly until complete interstitial infiltrate absorbance was evident. After patients recovered from IP, retreatment with chemotherapy and/or rituximab was allowed. TMP-SMX was administered at prophylactic doses as described previously. Parameters relating to clinical presentation, diagnosis, causative pathogen, treatments, and outcomes were additionally summarized for all patients as appropriate.

Statistical analysis

For this study, overall survival (OS) and progression-free survival (PFS) were measured, with the former corresponding to the amount of time between starting chemotherapy and last follow-up or death of any cause, and the latter corresponding to the period of time from start of chemotherapy to last follow-up, cancer progression, or all-cause death. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.0 criteria were used for gradation of all adverse events (AEs). χ2 tests were used for comparing categorical variables between patient groups. A binary logistic regression was used to conduct univariate analyses with appropriate hazard ratios (HRs) with 95% confidence intervals (CIs). Each variable with a p<0.05 in the initial univariate analysis was incorporated into a multivariable model. P<0.05 was the threshold of significance. SPSS 23.0 was used for all statistical testing.

Patient characteristics

Between March 2013 and April 2018, a total of 498 patients were analyzed and the majority (264/498; 53%) of them were male. The clinical characteristics of these patients are compiled in Table 1. The median age was 56 years old (range: 18 - 82). 414 (83.1%) patients were diagnosed with diffuse large B cell lymphoma (DLBCL), 9 (1.8%) were diagnosed with mantle cell lymphoma (MCL), 36 (7.2%) were diagnosed with follicular lymphoma (FL), 7 (1.7%) were diagnosed with chronic lymphocytic leukemia/small B cell lymphoma (CLL/SLL), 25 (5%) were diagnosed with marginal zone lymphoma (MZL), and 7 (1.7%) were diagnosed with “highly aggressive B cell lymphoma”. The most common chemotherapy regimens were RCHOP (n=428, 85.9%), REPOCH (n=57, 11.4%), and RCOP (n=13, 2.6%). 311 patients (62.4%) received TMP-SMX prophylactically, while another 187 patients (37.6%) did not receive prophylaxis. With the exception of gender, baseline characteristics such as age, ECOG score, baseline LDH level, smoking history, disease stage, bone marrow involvement, or International Prognostic Index (IPI) did not differ significantly between groups.

Diagnosis and treatment of IP

IP occurred in 65 patients (13.1%), of whom 25 (38.5%) were in the TMP-SMX prophylaxis group. IP patients were a median of 60 years old (range: 18 - 78), with the following pathological diagnoses: 57 cases of DLBCL, 1 of FL, 1 of MCL, 1 of CLL/SLL, 3 of MZL, and 2 of “highly aggressive B cell lymphoma”. IP incidence was significantly greater among patients who did not receive TMP-SMX prophylaxis relative to those who did (21.4% vs 8.0%, p<0.001). The median time between the first day of immunochemotherapy and the date of IP diagnosis was 74 days, (range: 7 - 158 days). Prior to IP diagnosis, patients had been treated with a median of 3 rituximab-chemotherapy cycles (range: 1 - 8 cycles). The median cumulative dose of rituximab upon IP diagnosis was 2100 mg (range: 600 – 4800 mg). A review of these 65 cases is shown in Table 2.

A total of 15 (23.1%) patients showed no symptoms at upon IP diagnosis, with the infection having been detected by routine radiological examination. Common clinical presentations included cough (n=24), fever (n=31), chest distress (n=20), expectoration (n=17), and shortness of breath (n=11). All patients diagnosed with IP were assessed for measurements of inflammatory markers. Elevated CRP (> 10mg/L) was evident in 54 patients. Elevated PCT (>0.5ng/ml) was evident in 5 patients. A positive G test for 3-b-D glucan fungal antigens (> 60 pg/mL) was detected in 18 patients. Elevated levels of Gram-negative lipopolysaccharides (> 10pg/mL) were detected in 36 cases. Hypoxemia was detectable in 5 cases as determined based upon arterial blood gas measurements. Sputum cultures were performed in patients following expectoration, and positive pathogenic bacteria included Candida albicans (n=3), Staphylococcus aureus (n=1), Klebsiella aeruginosa (n=2), Klebsiella pneumonia (n=2), hemolytic Steptotoccus (n=1), and Staphylococcus haemolyticus (n=1). Blood culture was performed in pyrexic patients with temperatures higher than 38.5 °C, but the results were all negative for all 8 tested patients. 7 patients received bronchoalveolar lavage (BAL) but no Pneumocystis carinii was detected. Other common suspicious pathogens included haemophilus, stenotrophomonas, tropheryma, exophiala, human gammaherpesvirus 4.

Further chemotherapy and rituximab treatments were withheld immediately following IP diagnosis. The average time to IP remission was 12 days (range: 7 day to 58 days). No patients died as a consequence of their infection. After remission from IP, 21 patients completed further chemotherapy combined with rituximab, 35 patients received subsequent chemotherapy without rituximab, and 9 patients did not receive chemotherapy nor rituximab. No patients suffered a recurrence of IP following continued immunochemotherapy treatments.

Complications of prophylaxis

Of the 311 patients receiving prophylactic TMP-SMX, 2 (1.2%) had rashes, 38 (12.2%) suffered nausea and vomiting, 52 (16.7%) exhibited neutropenia, and 18 (5.8%) suffered kidney dysfunction. No patients discontinued TMP-SMX prophylaxis as a result of adverse reactions. Because of concomitant chemotherapy, it is difficult to determine whether these adverse reactions were specifically associated with TMP-SMX prophylaxis in most cases.

IP Risk factors

To assess IP risk factors in study participants, we examined different clinical parameters (Table 3). In a univariate analysis, being male, having a history of diabetes, and not receiving TMP-SMX prophylactic therapy were identified as IP risk factors. In a subsequent multivariate analysis, all three of these variables were found to independently predict a higher IP risk.

Impact of IP on survival

After a median 26 months follow-up period, median PFS and OS were 23.1 and 26.7 months, respectively, in all patients. Among the 311 patients receiving prophylactic TMP-SMX, 55 exhibited disease progression, while among the 187 patients that did not receive prophylactic TMP-SMX, 63 exhibited disease progression - a significantly larger proportion (17.7% vs 33.7%, p<0.001).

As rituximab combined with chemotherapy was widely employed to treat non-Hodgkin lymphoma, there are increasing reports regarding treatment-associated IP. However, there is substantial variability among previous studies with respect to IP incidence among lymphoma patients. In one retrospective study of 2212 consecutive Chinese lymphoma, overall IP incidence was determined to be 3.75%, with 3.9% (7/287) and 2.4% (76/925) in patients with hodgkin and non-Hodgkin lymphoma, respectively⁹. However, in other studies the incidence of IP among non-Hodgkin lymphoma following CHOP-based chemotherapy with or without rituximab has ranged from 1.3% in a study by Giselle Salmasi et al⁷. to 14.8% in a study by Wang qian et al¹⁴. Other groups have reported values within this range, including reports of 4.4% (5/114 patients) by Toshiro Kurokawa et al¹⁵, 6.2% (8/129 patients) by Katsuya Hiroo el al¹³, 7% (5/71 patients) by Lim KH et al¹⁶, and 4.9% (26/529 patients) by Huang et al¹⁷. These studies have also suggested that the addition of rituximab to therapeutic regimens may increase IP incidence. In the present study, we observed an IP incidence of 21.4% in patients not receiving preventive treatment, which is higher than in previous reports. There are several possible reasons for this difference. As an anti-CD20 antibody with an extended in vivo half life, rituximab can modulate many immune processes. It can induce the apoptotic death of B cells, alter complement activation and induce the release of particular cytokines, thereby potentially interfering with normal cytotoxic T cell responses and immune functioning, thereby facilitating the occurrence of various opportunistic infections¹⁸. In this study, all patients received rituximab and chemotherapeutic treatments simultaneously, which may also explain our results. It is also possible that the IP incidence rate was higher because patients were being actively monitored for this condition, leading to increased diagnostic rates and detection in asymptomatic patients. Other possible causes include differences in baseline characteristics of patient populations, chemotherapy regimens administered, chemotherapy dose intensity, diagnostic techniques, the small size of previous studies, or the fact that we employed a longer observation period. Therefore, our results suggest that it will be necessary to administer prophylactic IP treatment to patients undergoing therapy as in this study.

The pathological changes of IP refer to the inflammatory changes in the interstitial tissue, mainly the supporting tissues outside the alveolar and terminal epithelial cells, including blood vessels and lymphatics¹⁹. Actually, IP can be caused by a variety of factors including environmental, occupational, physical and chemical factors, or immune-related inflammation. For patients receiving immunochemotherapy treatment, opportunistic infections are the leading cause. Common pathogens included bacteria, fungi, viruses, atypical bacteria and other less common microbial entities. Among them, PCP might be the most important and lethal pathogen. The most appropriate prophylactic agents are those which are efficient, safe, convenient, and economical medicines while offering broad efficacy against a range of pathogens, especially PCP. TMP-SMX, a compound of sulfamethoxazole (SMZ) and trimethoprim (TMP), is a sulfa antibiotic with good antibacterial effect against a range of bacteria with a low frequency of adverse reactions²⁰. TMP-SMX is the first choice agent for PCP prophylaxis in HIV-infected individuals²¹^,²². Even among immunocompromised individuals not infected by HIV, the preventive use of TMP-SMX during chemotherapy may decrease the incidence of PCP¹⁵^,²³. Toshiro et have found after prophylactic treatment of TMP/SMX to patients with non-Hodgkin’s lymphoma treated with RCHOP-based regimens, no patients have developed PCP¹⁵. With adequate drug adherence and tolerance, TMP-SMX prophylaxis has been able to protect against 89% of PCP cases²⁴^,²⁵. Moreover, TMP-SMX is widely available and cost-effective, at a price of just 1 dollar per 100 tablets in China. As such, TMP-SMX was chosen as a prophylactic agent in this study.

To our knowledge, there are currently no studies regarding the use of prophylactic TMP-SMX to prevent IP infections in patients with lymphoma. Extant data regarding the efficiency of prophylactic TMP-SMX treatment is thus mainly from studies regarding PCP infection. Hughes et al. first demonstrated the successful use of TMP-SMX to treat pediatric oncology patients in 1977, with untreated patients suffering a 21% PCP incidence and treated patients suffering a 0% incidence rate both if TMP-SMX was administered daily or 3 days per week²⁶^,²⁷. More recently, many studies have also confirmed the efficiency of TMP-SMX prophylaxis as a means of decreasing the incidence of PCP in adult patients with lymphoma or in pediatric oncology patients¹⁵^,^28-31. A meta-analysis identified twelve randomized trials and found that TMP-SMX administration was linked to a 91% drop in the incidence of PCP, with a significant reduction in PCP-related mortality²³. Consistent with these findings, in the present study we found that prophylactic TMP-SMX treatment significantly decreased the incidence IP in B cell lymphoma patients undergoing R-CHOP-like chemotherapy from 21.4% to 8.0% (p<0.001).

The optimal administration schedule for prophylactic TMP-SMX is not well defined. Most previous studies have concluded that intermittent dosing with TMP-SMX is an effective alternative prophylactic regimen. TMP-SMX is thus often given twice daily two times a week³⁰, 2 consecutive days per week²⁸^,³²^,³³, twice weekly³¹, or three days a week²⁷. Intermittent TMP/SMZ is effective for preventing PCP, and intermittent dosing is linked to reduced costs and a lower rate of fungal infections. However, a study by Toshiro et al. instead gave one TMP-SMX tablet daily throughout chemotherapy¹⁵. A meta-analysis concluded that lower doses of TMP-SMX were an effective means of improving tolerance while not compromising primary prophylactic efficacy³⁴. No differences between once-daily and thrice-weekly administration schedules have been found²³. TMP-SMX was given as one tablet daily in the present study, and this approach was convenient and easy to implement.

Roughly 30% - 40% of patients stop TMP-SMX therapy as a result of poor drug tolerance when receiving intermittent prophylactic treatment, according to previous reports³⁵. The most common AEs linked with such discontinuation include skin rash, myelosuppression, nausea, fever, renal and liver toxicity, and hyperkalemia^36-39. The observed AEs associated with prophylactic TMP-SMX in the present study were consistent with these previous reports, however drug tolerance for this daily TMP-SMX regimen was high, with no discontinuations due to adverse reactions. Moreover, the incidence of leukopenia and nausea and vomiting was low, which may be explained by the fact that patients were allowed to receive prophylactic G-CSF injections after chemotherapy and antiemetic treatments in this study.

We found that a history of diabetes, being male, and not undergoing prophylactic TMP-SMX treatment were independent risk factors for IP. In diabetic patients, hyperglycemia can affect the chemotaxis, adhesion, phagocytosis and intracellular bactericidal efficacy of immune cells. In addition, the thickening of alveolar epithelium, vascular hyaline degeneration, and pulmonary microangiopathy in diabetic patients can affect lung function. These factors will damage immune function and increase rates of opportunistic infections among patients with diabetes, who experience 30% more pneumonia-related mortality than do non-diabetic patient populations⁴⁰. Males usually receive higher doses of rituximab, have a longer smoking history, and are more likely to have poorer basic lung function than are females. Other factors from previous studies included application of rituximab^13-15^,¹⁷^,⁴¹, pre-treatment absolute lymphocyte counts <1x10⁹/L ¹⁷, B symptoms (fever, weight loss, night sweat), a drug allergy history⁹^,¹⁴, and increased intensity of corticosteroid exposure⁵^,⁴²^,⁴³.

Owing to the following limitations, caution is warranted when interpreting the results of this study. For one, BAL, as an important auxiliary examination procedure, has not been widely used in this study. Only 7 patients received BAL and no PCP infection was found. We therefore lack sufficient evidence regarding the specific cause of IP. Secondly, there were still 8% patients developed IP after prophylactic treatment of TMP/SMX, which meant there may be other causes. Therefore, more prospective studies are needed to explore other prophylactic drugs and their optimal administration. In addition, the retrospective nature of this study implies a potential information bias, potentially explaining the observed discrepancies regarding rates of side effects associated with TMP-SMX.

It is clear that among B cell non-Hodgkin lymphoma patients undergoing chemotherapy with rituximab, IP is a relatively common occurrence. We conclude that prophylaxis with once daily oral TMP-SMX from the start of immunochemotherapy to the completion of chemotherapy significantly decreases the incidence of IP.

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Table 1 Baseline characteristics of all the patients (n=498)

Factor		All patients (%)	prophylaxis of TMP/SMX		p
Factor		All patients (%)	Yes	No	p
Age	> 60 years	182（36.5%）	112(61.5%)	70(38.5%)	0.774
Age	≤ 60 years	316（63.5%）	199(63%)	117(37%)
Gender	Female	234（47%）	158(67.5%)	76(32.5%)	0.033
Gender	Male	264（53%）	153(58%)	111(42%)
ECOG	PS >1	57（11.4%）	42（73.7%）	15（26.3%）	0.08
ECOG	PS ≤1	441（88.6%）	269（61%）	172（39%）
Elevated LDH	YES	231(46.4%)	145(62.8%)	86(37.2%)	0.926
Elevated LDH	NO	267（53.6%）	166(62.2%)	101(37.8%)
Smoking history	YES	131(26.3%)	77(58.8%)	54(41.2%)	0.344
Smoking history	NO	367(73.7%)	234(63.8%)	133(36.2%)
Ann Arbor stage	I	88(17.7%)	45（51.1%）	43（48.9%）	0.071
	II	162(32.5%)	103（63.6%）	59（36.4%）
	III	97(19.5%)	60（61.9%）	37（38.1%）
	IV	151(30.3%)	103（68.2%）	48（31.8%）
BM involvement	YES	27(5.4%)	19(70.4%)	8(29.6%)	0.422
BM involvement	NO	471(94.6%)	292(62%）	179（38%）
IPI risk (score)	Low (0–1)	236（47.4%）	140（59.3%）	96（40.7%）	0.378
	Low–intermediate-2	126（25.3%）	81（64.3%）	45（35.7%）
	High–intermediate-3	80（16.1%）	50（62.5%）	30（37.5%）
	High (4–5)	56(11.2%)	40（71.4%）	16（28.6%）

Table 2 Review of 65 cases with interstitial pneumonia
Factor		Number
Factor		Number
Age	> 60 years	30 (46.2%)
Age	≤60 years	35 (35.8%)
Sex	Female	23 (35.4%)
Sex	Male	42 (64.6%)
ECOG	>1	3 (4.6%)
ECOG	≤1	62 (95.4%)
Elevated LDH	YES	29 (44.6%)
Elevated LDH	NO	36 (55.4%)
Smoking history	YES	23 (35.4%)
Smoking history	NO	42 (64.6%)
Ann Arbor stage	I	12 (18.5%)
	II	24 (36.9%)
	III	15 (23.1%)
	IV	14 (21.5%)
IPI risk (score)	Low (0–1)	34 (52.3%)
	Low–high (2-3)	26 (40.0%)
	High (4–5)	5 (7.7%)
Diabetes history	YES	12 (18.5%)
Diabetes history	NO	53 (81.5%)

Table 3 Binary logistic regression analysis of risk factors for interstitial pneumonia
Factor	Univariate analysis				Multivariate analysis
	Odds ratio	P value	95%CI		Odds ratio	P value	95%CI
	Odds ratio	P value	Lower	Upper	Odds ratio	P value	Lower	Upper
Male vs female	1.736	0.046	1.009	2.985	1.779	0.048	1.006	3.145
Age>60 vs <=60	1.585	0.086	0.936	2.682
IPI score >2 vs <=2	1.587	0.159	0.835	3.018
ECOG PS>1 vs <=1	2.945	0.076	0.893	9.71
diabetes,yes or no	3.042	0.003	1.468	6.3	3.625	0.001	1.675	7.845
smoking history, yes or no	1.648	0.077	0.948	2.865
baseline lung disease, yes or no	3.405	0.162	0.611	18.973
prophylactic TMP/SMX, yes or no	0.321	<0.001	0.188	0.55	0.33	<0.001	0.19	0.57
Elevated LDH, yes vs no	0.921	0.759	0.545	1.556

This paper was a retrospective study, so ethics approval wasn't obtained. But all the participants have written informed consent to provide their pathological and clinical information. No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. All the authors listed have approved the manuscript that is enclosed. The study is supported by "Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2015KYB067)".

Competing interests: The authors declare that they have no competing interests.

Authors’ contributions: the individual contributions of authors to the manuscript are listed in the following： (I) Conception and design and administrative support: Yang Haiyan, Li Cong. (II): Provision of study materials or patients: Li Cong. (III) Confirmation of image data: Lu Fangxiao. (IV) Collection and assembly of data: Li Cong, Lei Tao, Yu Haifeng, Chen Xi, Peng Shuailing. (V) Data analysis and interpretation: Li Cong. (VI) Manuscript writing: Li Cong. (VII) Final approval of manuscript: Yang Haiyan.

Acknowledgements: Thank you for Dr. Zhang Yigong who provided professional supporting and statistical help.

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published 08 Aug, 2020

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Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) decreases the incidence of interstitial pneumonia in B cell non- Hodgkin lymphoma patients receiving chemotherapy with rituximab

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