|Year : 2022 | Volume
| Issue : 1 | Page : 7-12
Febrile neutropenia risk factors in actively treated diffuse large B-cell lymphoma patients
Mehmet Bakirtas, Tuğçe Nur Yiğenoğlu, Semih Başci, Bahar Uncu Ulu, Samet Yaman, Merih Kizil Çakar, Mehmet Sinan Dal, Fevzi Altuntaş
Department of Hematology and Bone Marrow Transplantation Center, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey
|Date of Submission||10-Oct-2021|
|Date of Acceptance||27-Nov-2021|
|Date of Web Publication||09-Jun-2022|
Dr. Mehmet Bakirtas
Department of Hematology and Bone Marrow Transplantation Center, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, University of Health Sciences, Yenimahalle 06200, Ankara
Source of Support: None, Conflict of Interest: None
BACKGROUND: Febrile neutropenia (FN) is a serious problem, especially in hematologic malignancies, and can cause high mortality rates and it occurs in 10%–20% of patients with lymphoma. The aim of this research is to assess the risk factors for FN, and the impact of FN on overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL).
MATERIALS AND METHODS: The study included 263 patients who were diagnosed with DLBCL and treated with mostly R-CHOP-based chemotherapy. Data including gender, age, Ann Arbor stage, International Prognostic Index (IPI) score, immunohistologic subtype, treatment regimens, response to treatment, and any FN episode were recorded. The factors predicting FN were analyzed.
RESULTS: Significant predictors of FN were the number of chemotherapy lines received and IPI score. The median OS was significantly different between DLBCL patients who had at least one FN episode during the first-line chemotherapy and those who did not (P < 0,001). Significant predictors of OS in the multivariate analysis were the number of chemotherapy lines received, stage, Eastern Cooperative Oncology Group, and disease status.
CONCLUSION: Our study reveals that OS is significantly shorter in patients who had an FN episode than those who did not. Therefore, it is crucial to demonstrate all factors related to FN to prevent FN episodes. In our study, the number of chemotherapy lines received and IPI score was found to be significant predictors of FN. Close follow-up should be done in these patients as the risk of FN is higher.
Keywords: Diffuse large B-cell lymphoma, febrile neutropenia, neutropenic fever, R-CHOP
|How to cite this article:|
Bakirtas M, Yiğenoğlu TN, Başci S, Ulu BU, Yaman S, Çakar MK, Dal MS, Altuntaş F. Febrile neutropenia risk factors in actively treated diffuse large B-cell lymphoma patients. Iraqi J Hematol 2022;11:7-12
|How to cite this URL:|
Bakirtas M, Yiğenoğlu TN, Başci S, Ulu BU, Yaman S, Çakar MK, Dal MS, Altuntaş F. Febrile neutropenia risk factors in actively treated diffuse large B-cell lymphoma patients. Iraqi J Hematol [serial online] 2022 [cited 2022 Aug 14];11:7-12. Available from: https://www.ijhonline.org/text.asp?2022/11/1/7/346944
| Introduction|| |
The most common histologic subtype of non-Hodgkin lymphoma (NHL) is diffuse large B-cell lymphoma (DLBCL), and it accounts for almost 25% of all NHL cases.,, At presentation, the median age is 64 years and there is a male predominance.,
The initial standard treatment for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy and 3-year overall survival (OS) is between %50 and %95. Age, serum lactate dehydrogenase (LDH) concentration, Eastern Cooperative Oncology Group (ECOG) performance status, clinical stage, and the existence of extranodal disease sites are found to be related to the prognosis of DLBCL. Infection is also associated with reduced OS.
Infections are unfortunately widespread among patients with DLBCL who are receiving R-CHOP and R-CHOP-like chemotherapy; they are a cause of increased morbidity and mortality. In general, the incidence of febrile neutropenia (FN) was reported to be approximately 17% among cancer patients receiving chemotherapy.,
FN is a serious problem, especially in hematologic malignancies, and can cause high mortality rates and it occurs in 10%–20% of patients with lymphoma.,, As neutropenia is a strong predictor of FN, granulocyte colony-stimulating factors (G-CSF) are widely used to reduce neutropenia duration. International guidelines recommend primary prophylaxis with G-CSF when FN incidence is >20% for the chemotherapy regimen used in that treatment.
Lymphoma patients of geriatric age, especially with comorbidities, are recommended for primary prophylaxis with G-CSF after chemotherapy. Although previous studies have reported a reduced risk of neutropenia and FN with G-CSF, no significant effect on mortality was observed. DLBCL patients with comorbidities, low-performance status, and a high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score are at higher risk of infection.
The previous studies that evaluated the factors related to FN are inconsistent. Therefore, predicting the risk of infection in these patients is a challenge prior to the introduction of rituximab; a study conducted by Lyman and Delgado showed that age, LDH, albumin, neutropenia, and bone marrow involvement may predict hospitalization for FN. Pettengell et al. revealed that older age, low albumin, previous chemotherapy, and recent infection were predictive of FN in cycle one.
There is a lack of data on FN risk factors and the influence of FN on survival in DLBCL patients. The aim of this research is to assess risk factors for FN and the impact of FN on OS in patients with DLBCL.
| Materials and Methods|| |
Two hundred sixty-three DLBCL patients who were diagnosed and treated accordingly at our center between 2012 and 2021 were included. Patients at the age of 18 and older diagnosed with DLBCL by examining tissue biopsy with immunohistochemical analysis were included in the study. Hypertension, diabetes mellitus, ischemic heart disease, chronic renal failure, chronic respiratory disorder, and chronic liver disease were assessed as comorbidities.
This study was conducted in compliance with the ethical principles according to the Declaration of Helsinki, and it was approved by the local Institutional Review Board (No: 2021-01/964).
Data including gender, age, Ann Arbor stage, international prognostic score (IPI) score, immunohistologic subtype, treatment regimens, and response to treatment of any FN episode were recorded and analyzed. Patients were staged according to the Ann Arbor Staging. The staging was made according to computed tomography scans and/or positron-emission tomography.
Neutropenia is defined by absolute neutrophil count (ANC) <500 cells/μL or ANC <1000 cells/μL and predict to decrease until <500 cells/μL within 48 h later. FN is defined according to the definition of Infectious Diseases Society of America as a single oral body temperature more than 38.3°C or more than 38.0°C and continues 1 h with neutropenia.
IBM SPSS Statistics for Windows (Version 26.0. Armonk, NY, USA) was employed for analyses. Categorical data were presented as percentages and the numerical data were presented as median (minimum–maximum). The disease stages were categorized as early for Ann Arbor I-II and late for Ann Arbor III-IV, IPI score was categorized as IPI ≤3 and IPI >3, and the treatment response was categorized as remission and nonremission. Logistic regression analysis was done to evaluate the predictors of FN. Cox regression analysis was performed to analyze factors influencing survival. Variables with P ≤ 0.05 were included for the multivariate analysis. P ≤ 0.05 was considered statistically significant.
| Results|| |
There were 263 patients with DLBCL who received R-CHOP or R-CHOP-like chemotherapy. The median follow-up was 18 months. There were 137 (52.1%) males and the median age at diagnosis was 61 (17–87) years. Ninety-nine (37.6%) patients experienced at least one FN episode. The characteristics of the patients are given in [Table 1]. A significant relation was found in univariate analysis between FN and age, number of chemotherapy line, stage, IPI score, ECOG, and disease status. The FN incidence was significantly higher in patients – refractory to first-line chemotherapy – than patients who achieved remission after first-line chemotherapy (P < 0.001).
On the other hand, we could not demonstrate any relation between FN and gender, the number of comorbidities, histological subtype (germinal center B-cell like and activated B-cell like), body mass index (BMI), and radiotherapy history. Significant predictors of FN in the multivariate analysis were the number of chemotherapy lines received and IPI score. The predictors of FN in univariate and multivariate analysis are given in [Table 2]. There was a significant difference in FN incidence when patients were grouped as patients who were aged 65 years and older and under 65 years (P = 0.02). The median OS in patients with at least one FN episode during the first-line chemotherapy was 43 months.
|Table 2: The predictors of febrile neutropenia in patients with diffuse large B-cell lymphoma|
Click here to view
On the other hand, median OS was not reached in patients who did not have any FN episode during the first-line chemotherapy. The median OS was significantly different between DLBCL patients who had at least one FN episode during the first-line chemotherapy and those did not (P < 0.001). A significant relation was found in univariate analysis between FN and age, the number of chemotherapy lines, stage, IPI score, ECOG, and disease status. On the other hand, no relation was found between OS and gender and histological subtype (germinal center B-cell like and activated B-cell like). Significant predictors of OS in the multivariate analysis were the number of chemotherapy lines received, stage, ECOG, and disease status. The predictors of OS in univariate and multivariate analysis are given in [Table 3].
|Table 3: The predictors of survival in patients with diffuse large B-cell lymphoma|
Click here to view
| Discussion|| |
FN is a common cause of comorbidity in patients with hematologic cancers, especially in those receiving intense chemotherapies. According to the guidelines for the appropriate use of G-CSF, the incidence of FN in patients receiving myelosuppressive chemotherapy is 13%–21%. FN occurs in 10%–20% of patients treated for lymphoma.,, DLBCL is an aggressive lymphoma and FN commonly occurs after chemotherapy. It is crucial to determine all the factors related to FN to reduce the risk of FN. Therefore, in this study, we aimed to find out the incidence of FN during the first-line chemotherapy in patients with DLBCL and factors related to the risk of FN and its association with OS. In the study conducted by Dendle et al., among 325 patients with DLBCL, 206 (63.4%) patients experienced more than one infection. Previous randomized controlled trials reported rates of infectious episodes ranging from 10% to 42%.,, In our study, 37.6% of patients experienced at least one FN episode. In our center, we routinely administer primary prophylaxis with G-CSF in patients at the age of 65 years and older, and this may limit the number of FN episodes.
In several studies on NHL patients, being older than 60 or 65 years was related to FN., However, in other studies, age was not related to FN in NHL patients treated with CHOP., In one study, patients older than 70 years were classified into three age groups (70–74 years, 75–79 years, and >80 years of age) and researchers could not find a relation between age and FN. Instead, some studies have suggested that physiological age, as demonstrated by performance status, could be a better predictor of risk than chronological age itself. In our study, there was a significant difference in FN incidence when patients were grouped as patients who were aged 65 years and older and under 65 years (P = 0.02).
In the studies with NHL, the female gender was shown to be related to FN. Drugs are more slowly cleared in females. Therefore, myelosuppression in female patients treated with an R-CHOP regimen may be higher.,, However, in our study, we did not find any relation between FN and gender.
Although different cut points were analyzed, several studies have shown that low BMI or low body surface area is a risk factor for FN.,, However, in our study, we did not find any relation between FN and BMI (P = 0.325).
In previous studies, low-performance status and comorbidities were found to be related to FN. Salar et al. reported that old age and lower performance status were independent risk factors for FN in NHL patients treated with R-CHOP regimen. Dendle et al. reported that Charlson comorbidity score 3 or greater (reference category score of 2 or less), ECOG status of 1, 2, 3, or 4 (with zero the reference category) are related to an infectious episode. Lyman and Delgado reported that renal and cardiovascular diseases were associated with a higher FN risk. In our study, there was no relation between the number of comorbidities and FN. In univariate analysis, there was a significant difference regarding the rate of FN when patients with ECOG score 0–1 compared to patients with ECOG score 2, 3, and 4 (P < 0.001); however, no relation was found between FN and ECOG status in multivariate analysis (P: 0.2).
Advanced disease status was shown as a significant predictor of FN in studies with various cancers including NHL, breast, ovarian, lung, colorectal, and prostate cancer., Dendle et al. reported that low/intermediate or greater NCCN-IPI is associated with an infectious episode compared to low NCCN-IPI. Lyman and Delgado found that disease stage III–IV is related to FN. In our study, in multivariate analysis, no relation was found between FN and stage. However, a significant relation was found between FN and IPI score (P = 0.007).
In the study conducted by Dendle et al., infection was an independent predictor of survival. On the other hand, OS between patients never experienced FN and patients experienced at least more than one FN episode was not different statistically in the study conducted by Choi et al. The median OS in patients who had at least one FN episode during the first-line chemotherapy was 43 months. On the other hand, median OS was not reached in patients who did not have any FN episode during the first-line chemotherapy. The median OS was significantly different between DLBCL patients who had at least one FN episode during the first-line chemotherapy and those who did not (P < 0.001).
This study is limited due to its retrospective design and lack of data about the results of the cultures obtained during the fever. On the other hand, to the best of our knowledge, this is the first study that compared the rate of FN in patients with germinal center B-cell-like DLBCL to patients with activated B-cell-like DLBCL. No relation was found between FN and histological subtype (germinal center B-cell like and activated B-cell like) (P = 0.77).
| Conclusion|| |
Our study reveals that OS is significantly shorter in patients who had an FN than those who did not. Therefore, it is crucial to find out all factors related to FN to prevent FN episodes. In our study, the number of chemotherapy lines received and IPI score were significant predictors of FN. Close follow-up should be done and precautions such as antimicrobial prophylaxis and G-CSF prophylaxis may be considered in these patients as the risk of FN is higher.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006;107:265-76.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al.
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 Rev. ed., Vol. 2. Lyon: International Agency for Research on Cancer (IARC); 2017.
Shenoy PJ, Malik N, Nooka A, Sinha R, Ward KC, Brawley OW, et al.
Racial differences in the presentation and outcomes of diffuse large B-cell lymphoma in the United States. Cancer 2011;117:2530-40.
Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al.
An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014;123:837-42.
Yakushijin Y, Shikata H, Takaoka I, Horikawa T, Takeuchi K, Yamanouchi J, et al.
Usage of granulocyte colony-stimulating factor every 2 days is clinically useful and cost-effective for febrile neutropenia during early courses of chemotherapy. Int J Clin Oncol 2011;16:118-24.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al.
Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2015;33:3199-212.
Pettengell R, Aapro M, Brusamolino E, Caballero D, Coiffier B, Pfreundschuh M, et al.
Implications of the European Organisation for Research and Treatment of Cancer (EORTC) guidelines on the use of granulocyte colony-stimulating factor (G-CSF) for lymphoma care. Clin Drug Investig 2009;29:491-513.
Pettengell R, Johnsen HE, Lugtenburg PJ, Silvestre AS, Dührsen U, Rossi FG, et al.
Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma. Support Care Cancer 2012;20:647-52.
Bennett CL, Djulbegovic B, Norris LB, Armitage JO. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med 2013;368:1131-9.
Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer 2003;98:2402-9.
Pettengell R, Bosly A, Szucs TD, Jackisch C, Leonard R, Paridaens R, et al.
Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: Data from the INC-EU Prospective Observational European Neutropenia Study. Br J Haematol 2009;144:677-85.
Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al.
Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989;7:1630-6.
Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al.
Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011;52:e56-93.
Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al.
2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47:8-32.
Dendle C, Gilbertson M, Spelman T, Stuart RL, Korman TM, Thursky K, et al.
Infection is an ındependent predictor of death in diffuse large B cell lymphoma. Sci Rep 2017;7:4395.
Aurer I, Eghbali H, Raemaekers J, Khaled HM, Fortpied C, Baila L, et al.
Gem-(R)CHOP versus (R)CHOP: A randomized phase II study of gemcitabine combined with (R)CHOP in untreated aggressive non-Hodgkin's lymphoma – EORTC lymphoma group protocol 20021 (EudraCT number 2004-004635-54). Eur J Haematol 2011;86:111-6.
Watanabe T, Tobinai K, Shibata T, Tsukasaki K, Morishima Y, Maseki N, et al.
Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol 2011;29:3990-8.
Lyman GH, Morrison VA, Dale DC, Crawford J, Delgado DJ, Fridman M, et al.
Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 2003;44:2069-76.
Salar A, Haioun C, Rossi FG, Duehrsen U, Pettengell R, Johnsen HE, et al.
The need for improved neutropenia risk assessment in DLBCL patients receiving R-CHOP-21: Findings from clinical practice. Leuk Res 2012;36:548-53.
Ray-Coquard I, Borg C, Bachelot T, Sebban C, Philip I, Clapisson G, et al.
Baseline and early lymphopenia predict for the risk of febrile neutropenia after chemotherapy. Br J Cancer 2003;88:181-6.
Scott SD, Chrischilles EA, Link BK, Delgado DJ, Fridman M, Stolshek BS. Days of prophylactic filgrastim use to reduce febrile neutropenia in patients with non-Hodgkin's lymphoma treated with chemotherapy. J Manag Care Pharm 2003;9 Suppl 2:15-21.
Shayne M, Culakova E, Wolff D, Poniewierski MS, Dale DC, Crawford J, et al.
Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy. Cancer 2009;115:5319-28.
Choi YW, Jeong SH, Ahn MS, Lee HW, Kang SY, Choi JH, et al.
Patterns of neutropenia and risk factors for febrile neutropenia of diffuse large B-cell lymphoma patients treated with rituximab-CHOP. J Korean Med Sci 2014;29:1493-500.
Moreau M, Klastersky J, Schwarzbold A, Muanza F, Georgala A, Aoun M, et al.
A general chemotherapy myelotoxicity score to predict febrile neutropenia in hematological malignancies. Ann Oncol 2009;20:513-9.
Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 2014;90:190-9.
[Table 1], [Table 2], [Table 3]