Chemotherapy-related infectious complications in patients with Hematologic malignancies
Raluca Ana Rusu1, Dana Sîrbu2, Daniela Curşeu2, Bogdana Năsui2, Mădălina Sava3, Stefan Cristian Vesa4, Anca Bojan5, Cosmin Lisencu6, Monica Popa2
1 Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
2 Department of Hygiene, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
3 Department of Dermatology, University of Oradea, Oradea, Romania
4 Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
5 Department of Hematology, Iuliu Ha-ieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
6 Department of Oncologic Surgery and Oncologic Gynecology, Iuliu Ha-ieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
|Date of Submission||29-Oct-2017|
|Date of Decision||10-Mar-2018|
|Date of Acceptance||29-Apr-2018|
|Date of Web Publication||26-Jul-2018|
Dr. Stefan Cristian Vesa
23 Gheorghe Marinescu Street, Cluj-Napoca 400337
Source of Support: None, Conflict of Interest: None
Background: The objective of the present study was to determine the association between chemotherapy and infectious complications in patients diagnosed with Hematologic malignancies (HMs). Materials and Methods: The study included 463 patients diagnosed with HMs multiple myeloma (MM), Hodgkin's lymphoma (HL), non-HL (NHL), acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia, between January 2014 and June 2015. The patients were followed for 1 year after inclusion, to record the infectious complications. The collected data included age, sex, type of chemotherapy regimen, and several blood tests at admission. All patients received prophylactic treatment with antibiotics and antifungal agents. For each infection, we recorded the microbiological diagnosis and the day of occurrence since HMs diagnosis. Results: In patients with MM, we found that the treatment with growth factors (hazard ratio [HR] 2.2; confidence interval [CI] 95%: 1–4.6; P = 0.03) was associated with a higher chance of infectious complications. In patients with non-Hodgkin lymhoma (LNH), the following drugs were associated with a higher infectious incidence: cytarabine (HR: 2.3; CI 95%: 1–5; P = 0.03), methotrexate (HR: 2.1; CI 95%: 1.8–4; P = 0.01), dexamethasone (HR: 1.7; CI 95%: 0.9–3; P = 0.06), growth factors (HR: 1.7; CI 95%: 0.9–3.2; P = 0.001), and etoposide (HR: 2.5; CI 95%: 1.5–4.2; P = 0.002). Cytarabine (induction) (HR: 2; CI 95%: 1.1–3.7; P = 0.01), cytarabine (consolidation) (HR: 2.1; CI 95%: 1.3–3.5; P = 0.01), and growth factors (HR: 2.1; CI 95%: 1.3–3.5; P = 0.002) were often on the therapeutic plan of patients with AML, which developed infections. Conclusion: Regarding the chemotherapy regimen, the highest incidences of infectious complications were observed for growth factors and cytarabine.
Keywords: Chemotherapy, hematologic malignancies, infectious complications
|How to cite this article:|
Rusu RA, Sîrbu D, Curşeu D, Năsui B, Sava M, Vesa SC, Bojan A, Lisencu C, Popa M. Chemotherapy-related infectious complications in patients with Hematologic malignancies. J Res Med Sci 2018;23:68
|How to cite this URL:|
Rusu RA, Sîrbu D, Curşeu D, Năsui B, Sava M, Vesa SC, Bojan A, Lisencu C, Popa M. Chemotherapy-related infectious complications in patients with Hematologic malignancies. J Res Med Sci [serial online] 2018 [cited 2019 May 22];23:68. Available from: http://www.jmsjournal.net/text.asp?2018/23/1/68/237600
| Introduction|| |
The prevalence of Hematologic malignancies (HMs) has been constantly increasing in developed countries, due to earlier diagnosis and improved treatment efficacy and patient care. The treatment of HMs is based on a wide range of chemotherapeutics, small molecules, or antibodies, which are often associated by toxic side effects ranging from nausea and vomiting to diarrhea and mucositis to life-threatening myelosuppression. The extensive research carried out in the last decades has been translated in several breakthrough therapies, which have substantially transformed this field.
The introduction of chemoimmunotherapy (the fludarabine, cyclophosphamide, and rituximab regimen) for chronic lymphocytic leukemia (CLL) has shown excellent disease control, with a progression-free survival of 56.8 months., In the case of chronic myeloid leukemia (CML), the introduction of the first tyrosine kinase inhibitors (TKIs), imatinib, has drastically improved the prognosis of this disease. Moreover, second-generation TKIs (dasatinib, nilotinib, and bosutinib), and third-generation TKI (ponatinib) have further improved the outcome of treatment for refractory cases. In the case of Hodgkin's lymphoma (HL), conventional combination chemotherapy regimens such as doxorubicin, bleomycin, vinblastine, and dacarbazine or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone and radiotherapy attained a 20-year overall survival of approximately 80% in a Swedish HL cohort.
Acute forms of HMs, such as acute myeloid leukemia (AML), continue to have a rather poor prognosis. Despite several promising drugs which are currently evaluated in clinical trials, the classical approach based on intensive induction chemotherapy with 7 days of cytarabine and 3 days of an anthracycline (7 + 3), followed by consolidation chemotherapy or hematopoietic cell transplant (HCT), continues to remain the upfront treatment for AML.
Life-threatening infectious events due to malignancy and treatment-related immunosuppression are important factors that contribute to the mortality of HMs, especially in the case of acute HMs and patients who received HCT. Chemotherapy-induced neutropenia represents an important toxic side effect, which has been associated with increased morbidity, mortality, and treatment costs. Moreover, many neutropenic patients develop life-threatening infections with minimal symptoms and signs, due to their inability to respond immunologically. Infectious complications can be reduced using prophylactic antibacterial, antiviral, and antifungal agents in patients at significant risk, but the incidence of infections remains increased. Prophylactic therapy is especially recommended for high-risk patients such as those with anticipated prolonged (>7-day duration) and profound neutropenia (absolute neutrophil count ≤100 cells/mm3 following cytotoxic chemotherapy) and/or significant medical comorbid conditions including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. The risk of infectious complications depends on several factors including the prescribed chemotherapy, the type of HM, sex, and living conditions (rural/urban area).
The objective of the present study was to determine the association between chemotherapy and infectious complications in patients diagnosed with HMs.
| Materials and Methods|| |
A prospective, observational, analytical, longitudinal, cohort study was conducted at the “Ion Chiricuţă” Oncology Institute Cluj-Napoca, Romania. It included 463 patients admitted to the Department of Hematology, diagnosed with HMs, between January 2014 and June 2015. The study protocol was approved by the Ethics Committee of “Iuliu Hatieganu” University of Medicine and Pharmacy. The study protocol was in accordance with the Helsinki Declaration of 1975, as revised in 2000. All patients signed an informed consent form prior the study inclusion.
The inclusion criteria were age over 18 years, who provided written informed consent and were diagnosed with multiple myeloma (MM), HL, non-HL (NHL), AML, acute lymphocytic leukemia (ALL), CLL, and CML according to the current European LeukemiaNet guidelines. The exclusion criteria were the presence of autoimmune disorders or solid malignancy and patients who were only colonized with microorganisms without signs of infection.
The patients were followed for 1 year after inclusion, to record the infectious complications. The collected data included age, sex, type of chemotherapy regimen (including the goal of the chemotherapy: curative or relapse), and several blood tests at admission including complete blood count, blood urea, creatinine, aspartate transaminase, and alanine transaminase. All patients received prophylactic treatment with antibiotics and antifungal agents.
The infectious complications were diagnosed based on blood culture, sputum culture, throat swab culture, nasopharyngeal culture, vaginal culture, stool culture, central venous catheter tip culture, and by Galactomannan assay, chest X-ray, and clinical examination, in accordance with current guidelines. For each infectious complication, we recorded the microbiological diagnosis and the day of occurrence since HMs diagnosis.
Statistical analysis was performed using the MedCalc Statistical Software version 17.5.5 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2017). Nominal data were characterized by frequency and percent. Differences between groups were tested using Chi-square test or Fisher's test, whenever appropriate. The risk of infectious complications was estimated using Kaplan–Meier analysis. P < 0.05 was considered statistically significant.
| Results|| |
A total of 463 adult patients affected by HMs were collected (MM, n = 75; HL n = 32; NHL, n = 164, AML, n = 100; ALL, n = 26; and chronic leukemia [CL], n = 66).
The type and incidence of infectious complications, for each HMs, were in MM 42.7% total infectious complications, 26.7% bacterial infections, 9.3% fungal infections, 5.3% viral infections, and 17.3% infections of unknown etiology; in HL 34.4% total infectious complications, 21.9% bacterial infections, 9.4% fungal infections, 3.1% viral infections, and 6.3% infections of unknown etiology; in NHL 39.6% total infectious complications, 25.6% bacterial infections, 12.2% fungal infections, 3.7% viral infections, and 17.7% infections of unknown etiology; in AML 70% total infectious complications, 52% bacterial infections, 31% fungal infections, 1% viral infections, and 12% infections of unknown etiology; in ALL 73.1% total infectious complications, 53.8% bacterial infections, 30.8% fungal infections, 3.8% viral infections, and 11.8% infections of unknown etiology; and in CL 25.8% total infectious complications, 9.1% bacterial infections, 9.1% fungal infections, 3.0% viral infections, and 12.1% infections of unknown etiology.
Regarding the most frequent fungal infections, we recorded the following: Candida albicans was found more frequently in MM (5.3%), NHL (7.2%), AML (17.0%), ALL (26.6%), and CL (4.5%) and Aspergillus in NHL (3.6%), AML (6.0%), and ALL (15.4%). As for the most frequent bacterial infections, Escherichia More Details coli was more common in MM (5.3%), NHL (6%), AML (14%), ALL (15.4%), and CL (3.0%); Clostridium difficile in MM (5.3%), HL (9.4%), NHL (4.8%), AML (15%), and ALL (15.4%); and Klebsiella pneumoniae in NHL (6%) and AML (10%). Herpes simplex virus was more common in NHL (2.4%) and varicella-zoster virus in CL (3.0%).
In patients diagnosed with MM, we found that the treatment with growth factors, Adriablastin, and liposomal doxorubicin was associated with a higher chance of infectious complications of any type [Table 1].
|Table 1: Factors associated with infectious complications in multiple myeloma patients|
Click here to view
In patients diagnosed with HL, only vincristine was more likely to be associated with an infectious complication [Table 2]. This may be from the small number of HL cases.
|Table 2: Factors associated with infectious complications in Hodgkin lymphoma patients|
Click here to view
In patients with NHL, the following drugs were associated with a higher infectious incidence: cytarabine, methotrexate, dexamethasone, growth factors, etoposide, and cisplatin [Table 3].
|Table 3: Factors associated with infectious complications in non-Hodgkin's lymphoma patients|
Click here to view
Cytarabine, idarubicin, etoposide, dexamethasone, growth factors, and fludarabine were often on the therapeutic plan of patients with AML, which developed infections [Table 4].
|Table 4: Factors associated with infectious complications in acute myeloid leukemia patients|
Click here to view
In the patients diagnosed with CL that received growth factors, we recorded frequent infectious complications [Table 5].
|Table 5: Factors associated with infectious complications in CL patients|
Click here to view
For the drugs that were associated with infectious complications in previous analysis, we calculated the hazard ratio: growth factors (curative) in MM was 2.2 (confidence interval [CI]: 95% 1–4.6; P = 0.03); methotrexate (curative) in NHL was 2.1 (CI 95%: 1.8–4; P = 0.01); etoposide (curative) in NHL was 2.5 (CI 95%: 1.5–4.2; P = 0.002); cytarabine (relapse) in NHL was 2.3 (CI9 5%: 1–5; P = 0.03); dexamethasone (relapse) in NHL was 1.7 (CI 95%: 0.9–3; P = 0.06); growth factors (relapse) in NHL was 1.7 (CI 95%: 0.9–3.2; P = 0.001); cytarabine (induction) in AML was 2 (CI 95%: 1.1–3.7; P = 0.01); cytarabine (consolidation) in AML was 2.1 (CI 95%: 1.3–3.5; P = 0.01); growth factors (consolidation) in AML was 2.1 (CI 95%: 1.3–3.5; P = 0.002); and growth factors in CL was 3.5 (CI 95%: 1.3–9.3; P = 0.009). The treatment with etoposide and growth factors determined the highest chance of infections. Cytarabine and growth factors were correlated with infections in almost every HMs.
| Discussion|| |
Infectious complications represent an important issue for the patients diagnosed with HMs. The study showed that patients diagnosed with acute forms of leukemia had the highest incidence of infectious complications (AML – 70% and ALL – 73.1%), whereas in the case of chronic forms of leukemia (CL), the incidence was comparatively lower (9.1%).
The majority of the infectious complications were of bacterial etiology, a trend which was particularly obvious in the case of ALL, AML, and MM. Regarding specific nosocomial infections, the data show that, among patients diagnosed with acute HMs, the incidence of E. coli and C. dificille infections was around 27%–30%. A study conducted by Neofytus et al. with AML patients (48.4%) developed an invasive fungal infection. ALL patients developed 3.3% invasive aspergillosis.
Marin et al. found infections of C. dificille in 1.4% patients with HMs.
In a study regarding the use of supplements, as a trend toward a benefit, probiotics were indicated on hematologic and immunologic parameters in patients with pelvic malignancies.
Physicians must be aware of the infectious risks posed by chemotherapy-induced neutropenia and to promptly intervene with prophylactic antibiotics when needed. Often, fever can be the only sign of an underlying infection, since other symptoms are attenuated by the neutropenia. In the case of high-risk patients with fever, the Infectious Diseases Society of America guidelines recommend empirical intravenous therapy with antipseudomonal antibiotics such as cefepime, carbapenem, or Piperacillin-Tazobactam, whereas low-risk patients should receive combination ciprofloxacin plus amoxicillin-clavulanate, orally.
A study of Teh et al. identified the use of melphalan and cyclophosphamide, and cumulative doses of corticosteroids were independently associated with an increased risk of infection.
Fungal infections were dominated by C. albicans and Aspergillus, which represented around 30% of the total infection in acute HMs. In a study with HMs, patient that used of cytotoxic chemotherapy had 79.3% risk factor for invasive fungal infection.
Viral infections had a particular high incidence in MM patients (5.3%), and in those diagnosed with ALL (3.8%) and NHL (3.7%), with herpes simplex virus and Varicella-zoster viruses having the highest incidence. Patients with NHL who received chemotherapy had 24.45% infection with herpes zoster.
The severity of the neutropenia, which in turn influenced the risk for developing an infectious complication, was partly determined by the chemotherapy regimen. In the case of MM, the incidence of infectious complications was highest in patients treated with growth factors.
A study conducted by Pugliese et al. on patients with AML found that 55.4% had neutropenic episodes with infections after chemotherapy.
A similar situation was observed for patients diagnosed with LNH, the infectious complications being more frequent in the cases treated with methotrexate, etoposide, cytarabine, dexamethasone, and growth factors.
For AML, the incidence of the infectious complications was highest for cytarabine, which was 80% in the induction phase and 44.3% in the consolidation phase. Growth factors were associated with 65.7% infections in AML patients.
In a study, patients with CLL had 1.3% incidence of fungal infections, a lower risk comparative with MM (3.7%) and NHL (5.1%).
Chronic types of leukemia were characterized by a comparatively lower incidence of infectious complications, probably due to the lower intensity of the chemotherapy regimens, and an overall better performance status of the patients. The incidence of infectious complications was 52.9% in the patients treated with growth factors.
This is the first study from this region that evaluates the risk of infectious complications from chemotherapy in patients with HMs. The study included patients only from one important regional hematologic center, but it followed a moderate/high number of patients for a year.
| Conclusions|| |
In our study, the incidence of infections depended on the type of HMs and on the employed chemotherapy regimen. Bacterial, fungal, and viral infections had the highest incidence in the case of acute HMs (AML and ALL). Regarding the chemotherapy regimen, the highest incidences of infectious complications were observed for growth factors and cytarabine.
RAR contributed in the conception of the work, conducting the study, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work; DS contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work; DC contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work; BN contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work; MS contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work; SCV contributed in the conception of the work, performing the statistical analysis, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work; MP contributed in the conception of the work, drafting and revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dizon DS, Krilov L, Cohen E, Gangadhar T, Ganz PA, Hensing TA, et al.
Clinical cancer advances 2016: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2016;34:987-1011.
Sharma R, Tobin P, Clarke SJ. Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea. Lancet Oncol 2005;6:93-102.
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al.
Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74.
Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al.
Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: Updated results of the CLL8 trial. Blood 2016;127:208-15.
Shah NP, Kim DW, Kantarjian H, Rousselot P, Llacer PE, Enrico A, et al.
Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010;95:232-40.
Nicolini FE, Turkina A, Shen ZX, Gallagher N, Jootar S, Powell BL, et al.
Expanding nilotinib access in clinical trials (ENACT): An open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase. Cancer 2012;118:118-26.
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al.
Ponatinib in refractory Philadelphia chromosome-positive leukemias. N
Engl J Med 2012;367:2075-88.
Glimelius I, Diepstra A. Novel treatment concepts in Hodgkin lymphoma. J Intern Med 2017;281:247-60.
Tai E, Guy GP, Dunbar A, Richardson LC. Cost of cancer-related neutropenia or fever hospitalizations, United States, 2012. J Oncol Pract 2017;13:e552-61.
Neofytos D, Lu K, Hatfield-Seung A, Blackford A, Marr KA, Treadway S, et al.
Epidemiology, outcomes, and risk factors of invasive fungal infections in adult patients with acute myelogenous leukemia after induction chemotherapy. Diagn Microbiol Infect Dis 2013;75:144-9.
Mariette C, Tavernier E, Hocquet D, Huynh A, Isnard F, Legrand F, et al.
Epidemiology of invasive fungal infections during induction therapy in adults with acute lymphoblastic leukemia: A GRAALL-2005 study. Leuk Lymphoma 2017;58:586-93.
Marín M, Gudiol C, Ardanuy C, Garcia-Vidal C, Jimenez L, Domingo-Domenech E, et al.
Factors influencing mortality in neutropenic patients with haematologic malignancies or solid tumours with bloodstream infection. Clin Microbiol Infect 2015;21:583-90.
Mansouri-Tehrani HA, Rabbani-Khorasgani M, Hosseini SM, Mokarian F, Mahdavi H, Roayaei M, et al.
Effect of supplements: Probiotics and probiotic plus honey on blood cell counts and serum IgA in patients receiving pelvic radiotherapy. J Res Med Sci 2015;20:679-83.
] [Full text]
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.
Teh BW, Harrison SJ, Worth LJ, Spelman T, Thursky KA, Slavin MA, et al.
Risks, severity and timing of infections in patients with multiple myeloma: A longitudinal cohort study in the era of immunomodulatory drug therapy. Br J Haematol 2015;171:100-8.
Gayet-Ageron A, Iten A, van Delden C, Farquet N, Masouridi-Levrat S, Von Dach E, et al.
In-hospital transfer is a risk factor for invasive filamentous fungal infection among hospitalized patients with hematological malignancies: A matched case-control study. Infect Control Hosp Epidemiol 2015;36:320-8.
Cho SF, Wu WH, Yang YH, Liu YC, Hsiao HH, Chang CS, et al.
Longitudinal risk of herpes zoster in patients with non-Hodgkin lymphoma receiving chemotherapy: A nationwide population-based study. Sci Rep 2015;5:14008.
Pugliese N, Salvatore P, Iula DV, Catania MR, Chiurazzi F, Della Pepa R, et al.
Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia. Cancer Med 2017;6:1500-11.
Tisi MC, Hohaus S, Cuccaro A, Innocenti I, De Carolis E, Za T, et al.
Invasive fungal infections in chronic lymphoproliferative disorders: A monocentric retrospective study. Haematologica 2017;102:e108-11.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]