Original Study
Patterns of Infection in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia Receiving Azacitidine as Salvage Therapy. Implications for Primary Antifungal Prophylaxis Jose F. Falantes,1 Cristina Calderón,1 Francisco J. Márquez-Malaver,1 Manuela Aguilar-Guisado,2 Almudena Martín-Peña,2 María L. Martino,1 Isabel Montero,1 Jose González,1 Rocío Parody,1 Jose A. Pérez-Simón,1 Ildefonso Espigado1 Abstract Patients treated with azacitidine who previously received intensive chemotherapy are at a highest risk for fungal infection (invasive aspergillosis; P [ .015). Incidence, etiology, and outcome of infectious episodes in patients with myeloid neoplasms receiving azacitidine are uncertain, with no prospective data available in this group of patients. The aim of the current study was to analyze the incidence and factors related to the probability of infection in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with azacitidine who did not receive any type of antimicrobial prophylaxis. Significantly, the group of patients who received prior intensive chemotherapy had more infectious episodes (P ¼ 10-4), and particularly, invasive aspergillosis (P ¼ .015), than patients who received frontline azacitidine. Primary antifungal prophylaxis might be recommended in MDS and AML patients receiving azacitidine as salvage therapy after intensive regimens. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 1, 80-6 ª 2014 Elsevier Inc. All rights reserved. Keywords: Acute Myeloid Leukemia, Aspergillosis, Azacitidine, Myelodysplastic Syndrome, Prophylaxis
Introduction Infection is a recurrent cause of morbidity and mortality in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) undergoing intensive chemotherapy (IC) (idarubicin combined with cytarabine).1 Most of these patients routinely receive antimicrobial prophylaxis (AIP) with fluorquinolones or 1 Department of Hematology, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Sevilla, Spain 2 Clinical Unit of Infectious Diseases, Clinical Microbiology and Preventive Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain
Submitted: Jul 3, 2013; Revised: Sep 7, 2013; Accepted: Sep 24, 2013; Epub: Oct 1, 2013 Address for correspondence: Jose F. Falantes, MD, Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/ CSIC/Universidad de Sevilla, Avenida Manuel Siurot s/n, Sevilla, 41013, Spain E-mail contact: [email protected]
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antifungal agents according to the current guidelines for the prevention of infection in neutropenic patients with cancer.2-7 Hypomethylating agents (HMAs) are considered the standard of care in higher-risk MDS (intermediate-2 and high risk according to International Prognostic Scoring System (IPSS)) and AML patients with low blast counts for whom allogeneic stem cell transplant (AlloSCT) is not suitable.8 In addition, there is an increasing use of HMAs in patients with relapsed or refractory disease after IC who are not candidates for reinduction therapy and patients for whom these agents are intended as an alternative approach to classic induction regimens prior to AlloSCT.9-11 However, the role of AIP in patients treated with azacitidine (AZA) or decitabine has not been widely analyzed.12 Lee et al. reported an incidence of 11.5% febrile episodes requiring hospitalization per AZA course (15/131 courses of treatment) in a cohort of MDS patients treated with decitabine.13 Antimicrobial prophylaxis
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.09.014
was administered in 72.5% of decitabine courses. In this study, the incidence of febrile episodes was higher in patients who did not receive prophylaxis (22.2% vs. 7.4%; P ¼ .017) and in patients with platelet or neutrophil count after each course of therapy < 50 109/L or < 0.5 109 cells/L, respectively. Recently, a multicenter retrospective study conducted in Israel including 184 higher-risk MDS and AML patients reported a high incidence of documented bacterial infections (59% among cases with microbiological analysis available), with a significant proportion of these cases with febrile episode requiring hospitalization (74.5%). In this study, only 10% of the patients received prophylaxis.14 Again, peripheral cytopenias, particularly platelet count < 20 109/L and adverse karyotype, significantly influenced the risk of infection in multivariate analysis. Interestingly, both studies included patients who received AZA or decitabine as frontline therapy either for MDS or AML. In summary, the incidence and etiology of infections in MDS and AML receiving AZA is not well characterized, and the role of antimicrobial prophylaxis is not clearly defined. The aim of this study was to evaluate the incidence and pattern of febrile episodes (FE) attributable to both clinically and microbiological documented infections occurred in a cohort of
MDS and AML patients treated with AZA who did not receive antimicrobial prophylaxis. The secondary objectives were to analyze factors related to an increased probability for infection and to identify a subset of these patients who could possibly benefit from prophylaxis.
Design and Methods Patients This is a retrospective study including consecutive patients with MDS and AML treated with AZA at our institution. Only patients receiving at least 2 courses of AZA were included in the study. Sixtyfour patients with MDS and AML were analyzed for a total of 523 AZA courses administered. All patients were diagnosed according to World Health Organization (WHO) Classification15 at Hospital Universitario Virgen del Rocío (Seville, Spain) between 2009 and 2012. Median age was 68 years (range: 29-83 y). Forty-three patients had MDS and 21 patients had AML. The demographic, clinical, and biological characteristics of patients at the time of diagnosis are shown in Table 1. All higher-risk MDS (defined as bone marrow blasts > 10% or IPSS categories intermediate-2 or high risk) and AML patients received AZA at a recommended dose
Table 1 Patient Characteristics Global Series (n [ 64) Age, years, median (range) Number of AZA courses, n (median) WHO, n (%)
68 (29-83) 6 (1-50) RARS: 2 (3.2) RCMD: 9 (14) CMML: 3 (4.7) RAEB-1: 3 (4.7) RAEB-2: 26 (40.6) AML: 21 (32.8)
Prior IC (n [ 18; 28.1%) 66 (29-78) 6 (2-16)
Frontline AZA (n [ 46; 71.9%) 68 (35-83) 9 (2-50)
Int-1
1 episode (range: 1-5). Most of the patients having an FE required hospitalization according to treatment physician criteria (n ¼ 26; 81% from the group of patients with FE). The median duration of hospitalization was 14 days (range: 4-80 d), and 10 patients required > 1 hospital admission. The median duration of neutropenia (< 0.5 109/L) until AZA treatment was 1 month for the group that received frontline AZA therapy, compared with 7 months in patients who received prior IC (P ¼ .02). FE mainly occurred during the first 3 courses of AZA (86%, n ¼ 62) (Fig. 1 shows the incidence of FE after consecutive courses of AZA). Pneumonia and infections from the upper respiratory tract were the most common type of infection (35%) followed by soft tissue and urinary tract infections.
Parameters Related to the Probability of Infection The cumulative incidences of infection estimates for different risk factors were analyzed: previous IC versus frontline AZA therapy, type of disease (AML vs. MDS), adverse karyotype vs. other, bone marrow (BM) blast percentage (cutoff: 10%), peripheral cytopenias
Figure 1 Incidence of Febrile Episodes in Each Course of Azacitidine
Jose F. Falantes et al at the initiation of AZA therapy (cutoff values for hemoglobin concentration, absolute neutrophil count [ANC], and platelet count: 10 g/dL, 0.5 109/L, and 30 109/L, respectively) and achievement of complete response (CR) after a fourth course of AZA vs. any other response, including progressive disease. Interestingly, there was no difference in the probability of infection in patients with (ANC) above or below 0.5 109 cells/L at baseline (P ¼ .158). Only prior IC vs. up-front AZA therapy influenced the probability of infection (P ¼ .007) (Fig. 2A). Table 2 shows the cumulative incidence of infection with estimates at different times. Although no correlation among infection and BM blast percentage, peripheral cytopenias, or achievement of CR were documented, is noteworthy that the incidence of infection reached a plateau after
Figure 2 Cumulative Incidence Estimates From Competing Risks Data (Estimates at Different Time Points). (A) Patients Treated With Prior Intensive Chemotherapy vs. Patients Receiving Frontline Azacitidine Therapy; (B) Patients With Absolute Neutrophil Count > 0.5 3 109/L vs. Patients With Absolute Neutrophil Count > 0.5 3 109/L After 3 Courses of Azacitidine Therapy
4 to 6 courses of AZA among patients with < 10% BM blasts and less severe cytopenias as compared with those with > 10% BM blasts or profound cytopenias at the time of initiation of therapy. This finding was noted when we evaluated the probability and the cumulative incidence of infection in patients recovering from severe neutropenia. Patients with a durable ANC > 0.5 109 cells/L had a significantly lower probability of infection than patients with persistent neutropenia, or 0.5 109/L) after 3 courses of AZA was included as a time-dependent covariate in the multivariate analysis, we observed a significant trend toward a lower risk of infection for the patients achieving durable ANC > 0.5 109/L (hazard ratio, 0.34; 95% CI, 0.98-1.190; P ¼ .07) (Table 4).
Comparison Between Patients Receiving Frontline AZA Therapy and Patients Previously Treated With IC: Etiology and Outcome of Infectious Episodes The group receiving AZA as frontline therapy had fewer incidences of FE per course of therapy than the previous IC treatment group (44/420 AZA courses [10.4%] vs. 44/103 AZA courses [27%]; OR, 3.181 [1.849-5.43]; P ¼ 10-4) Patients previously treated with IC had more episodes of hospital admission (11/18 patients [61%] vs. 15/46 patients [32.6%], respectively; P ¼ .04), although there was no significant difference in the median duration of hospitalization (13 and 14 days, respectively; P ¼ .9). Overall, there were 23 microbiological isolations in 17 patients with microbiologically documented infections. Of those 17 patients, 12 had bacteremia and 10 (15%) had pneumonia, 6 of the cases being fungal pneumonia caused by Aspergillus species. Pneumocystis jirovecii (n ¼1), Enterococcus faecium (n ¼1), and Escherichia coli (n ¼1) were each isolated in 1 of 3 patients with pneumonia. A diagnosis of pneumonia was established when clinical (fever and respiratory symptoms) and radiographic (infiltrate or cavitation in x-ray or computed tomography scan) criteria were present. Bacterial infections were the most frequent (E. coli, n ¼ 6), followed by fungal infection (Aspergillus species n ¼ 5, Candida species n ¼ 2). All cases of invasive aspergillosis were probable according to EORTC criteria. Of 17 infections, 5 were polymicrobial. Microbiological isolation occurred more frequently in patients with prior IC (50% vs. 16%; P ¼ .007). The rate of fungal infection was higher in the group of patients that received prior IC (P ¼ .038). In particular, invasive aspergillosis occurred in 5 of 20 in this group compared with 1 of 44 in the AZA frontline group (Risk difference, 22.4%; OR, 12 [1.524-308.2]; P ¼ .015) for an 8.3% overall incidence of invasive aspergillosis. Evaluating the incidence of probable IFI caused by Aspergillus species, we found that the group of patients receiving AZA as frontline therapy had a 2.7% incidence of aspergillosis. With the estimated absolute risk difference, the NNT was 4. There was no difference in the rate of
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Invasive Aspergillosis in MDS and AML Treated With Azacitidine Table 2 Cumulative Incidence of Infectiona (AZA Courses) [Cumulative Incidence Estimates in %] Parameter
b
Previous IC Frontline AZA therapy MDS AML Adverse karyotypec Other BM blast % >10 BM blast % 0.5 109 cells/Lc Ptl 10d ANC 0.5 109 cells/L after 3 courses of azacitidine as a time-dependent covariate. d Measured at the time of initiation of azacitidine therapy.
However, there is no prospective trial evaluating the need for prophylaxis in patients receiving HMA, and approaches to prophylaxis differ among institutions. Moreover, data on the risk of infection in patients previously treated with IC who receive AZA as salvage therapy are lacking. Results from a recent multicenter retrospective analysis on 184 patients with MDS and AML who were treated with AZA have shown an incidence of FE in 54.3% of them (100/184). In this cohort, only 20 patients (10.8%) received AIP. Data similar in terms of FE (11.5%) have been described in a group of MDS patients, most with lower-risk MDS, treated with decitabine.13 Of these patients, 54 received antifungal prophylaxis. In the current study, we found a similar incidence of FE and similar timing of infection. On the contrary, none of the patients from our study received prophylaxis, and a significant proportion of them received intensive regimens prior to initiation
of AZA therapy, all of them being refractory or relapsed after standard IC, even patients who received prior IC as per institution practice did not received prophylaxis. As AZA represents a novel and attractive alternative for patients with very limited therapeutic options, information on the patterns of infection in this setting is of great value, as this group of patients might be offered primary antifungal prophylaxis considering the morbidity and mortality of this complication, which could exclude them from the possibility of AlloSCT as a potential curative intervention. Interestingly, the severity of neutropenia and thrombocytopenia as surrogates for bone marrow reserve has been identified as important risk factors for FE in recent studies. By contrast, in our study, this relationship between severe cytopenias at the initiation of AZA therapy and the onset of FE was not so evident, while other variables emerged as the most important risk factors to be considered to properly monitor these patients. In this regard, the facts that most infections occurred during the first courses of AZA and that the probability of infection was higher in patients not achieving neutrophil recovery indicate that marrow failure is a significant factor for the risk of infection. As patients achieve some degree of hematological improvement, the risk of infection tends to decline, supporting the recommendation of a very close follow-up of these patients in the initial months after starting therapy. Furthermore, compliance with AZA treatment is critical during the first courses of therapy.27 As infections occurred mainly during this period, and considering that once an infection occurs, treatment must be delayed or even stopped, identification of individuals at higher risk for fungal infection might help to improve outcomes in these patients. Data from our study, although limited to a relatively reduced and retrospective analysis of patients receiving AZA therapy, together with the implementation of approaches for selecting patients for
Table 5 Comparison Between Groups: Data on Microbiological Isolation and Outcome Global (n [ 64)
Prior IC (n [ 18)
AZA Frontline (n [ 46)
FE per AZA course, n (%)
73/523 (13.95)
28/98 (18.7%)
45/425 (10.7%)
Hospital admission, n (%)
26/64 (40.6%)
11/18 (61%)
15/46 (32.6%)
14 (4-80) 17/64 (26.6)
13 (4-80) 9/18 (5%)
14 (5-57) 8/46 (17.4%)
Hospital stay, d, median (range) Patients with microbiological isolation, n (%)
Type of isolation,a n
Fungal isolation, n
Cause of death, n (%)
Bacterial: 6 Fungal: 4 Both: 4 Other: 1 Aspergillus spp: 6 Candida spp: 2
Progression: 21 (58.4) Infection on AZA: 2 (5.5) Other: 14 (36.1)
Bacterial: 3 Fungal: 2 Both: 4 Other: Aspergillus spp: 5 Candida albicans: 1
Bacterial: 3 Fungal: 2 Both: Other: 1 Aspergillus spp: 1 Candida parapsilosis: 1
Progression: 11 (79) Infection on AZA: 1 (7) Other: 3 (14)
Progression: 10 (46) Infection on AZA: 1 (4) Other: 11 (50)
P Value 10-4 Risk difference: 18% OR: 3.36 (1.955-5.757) .04 Risk difference: 18% OR: 3.18 (1.025-10.41) .9 .01 Risk difference: 32% OR: 4.61 (1.378-16.07) Fungal: .038 Risk difference: 22% OR: 4.9 (1.089-27.37) .015 Risk difference: 22.4% OR: 12 (1.524-308.2) NNT¼4 .56
Abbreviations: AZA ¼ azacitidine; FE ¼ febrile episode; IC ¼ intensive chemotherapy; OR ¼ odds ratio; NNT ¼ number needed to treat. P values denote differences between the group that received previous IC and the group that received frontline AZA therapy for the corresponding parameter (Mid-I exact test and c2). a 5 of the cases were polymicrobial.
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Invasive Aspergillosis in MDS and AML Treated With Azacitidine antifungal therapy based on risk profile and a close follow-up of infectious episodes as described by Aguilar-Guisado et al., have the potential benefits of both identifying patients more likely to develop a fungal infection and avoiding overtreatment and toxicity among those with a lower probability for this event. Based on the results of our study, primary antifungal prophylaxis should be recommended in patients receiving AZA therapy after previous IC, especially during the first courses of treatment, until hematopoiesis is restored. Considering the expected increase in the use of AZA in MDS and AML cases, not only in elderly patients but also in other clinical settings, randomized prospective studies are needed to better address this issue. In contrast, the risk for fungal infection was very low among patients receiving frontline AZA therapy. The latter group would not require antifungal prophylaxis.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Neofytos D, Lu K, Hatfield-Seung A, et al. Epidemiology, outcomes, and risk of invasive fungal infections in adult patients with acute myelogenous leukemia after induction therapy. Diagn Microbiol Infect Dis 2013; 75:144-9. 2. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356: 348-59. 3. Cornely OA, Böhme A, Buchheidt D, et al. Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematologica 2009; 94:113-22. 4. Vehreschild JJ, Rüping MJ, Wisplinghoff H, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort. J Antimicrob Chemother 2010; 65: 1466-71. 5. Freifeld AG, Bow EJ, 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. 6. Maertens J, Marchetti O, Herbrecht R, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3-2009 Update. Bone Marrow Transplant 2001; 46:709-18. 7. National Comprehensive Cancer Network. NCCN Guidelines for Supportive Care: Prevention and Treatment of Cancer-Related Infections, version 1.2013. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 8. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol 2009; 10:223-32.
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9. Quintás-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012; 120:4840-5. 10. Van der Helm LH, Scheepers ER, Veeger NJ, et al. Azacitidine might beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients. J Hematol Oncol 2013; 6:29. 11. Field T, Perkins J, Huang Y, et al. 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2010; 45: 255-60. 12. Fenaux P, Bowen D, Gatterman N, et al. Practical use of azacitidine in higher-risk myelodysplastic syndromes: an expert panel opinion. Leuk Res 2010; 34:1410-6. 13. Lee JH, Lee KH, Lee JH, et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res 2011; 35:499-503. 14. Merkel D, Filanovsky K, Gafter-Gvili A, et al. Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective multicenter study. Am J Hematol 2013; 88:130-4. 15. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC; 2008. 16. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813-21. 17. Cisneros JM, Espigado I, Rivero A, et al. Empirical antifungal therapy in selected patients with persistent fever and neutropenia. Enferm Infecc Microbiol Clin 2005; 23:609-14. 18. Aguilar-Guisado M, Martín-Peña A, Espigado I, et al. Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach. Haematologica 2012; 97:464-71. 19. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for the modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108:419-25. 20. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel on behalf of the European LeukemiaNet. Blood 2010; 115:453-74. 21. Dean AG, Sullivan KM, Soe MM. OpenEpi: open source of epidemiologic statistics for public health, version 2.3.21. Available at: www.OpenEpi.com.Accessed: October 17, 2012. 22. Wang R, Lagakos SW, Gray RJ. Testing and interval estimation for two-sample survival comparisons with small sample sizes and unequal censoring. Biostatistics 2010; 11:676-92. 23. Chatellier G, Zapletal E, Lemaitre D, et al. The number needed to treat: a clinically useful nomogram in its proper context. BMJ 1996; 312:426-9. 24. Pagano L, Caira M, Candoni A, et al. Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study. Haematologica 2010; 95: 644-50. 25. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006; 24:3895-903. 26. Steensma DP, Stone RM. Practical recommendations for hypomethylating agent therapy of patients with myelodysplastic syndromes. Hematol Oncol Clin North Am 2010; 24:389-406. 27. Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 2011; 117:2697-702.
Patterns of Infection in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia Receiving Azacitidine as Salvage Therapy. Implications for Primary Antifungal Prophylaxis Jose F. Falantes,1 Cristina Calderón,1 Francisco J. Márquez-Malaver,1 Manuela Aguilar-Guisado,2 Almudena Martín-Peña,2 María L. Martino,1 Isabel Montero,1 Jose González,1 Rocío Parody,1 Jose A. Pérez-Simón,1 Ildefonso Espigado1 Abstract Patients treated with azacitidine who previously received intensive chemotherapy are at a highest risk for fungal infection (invasive aspergillosis; P [ .015). Incidence, etiology, and outcome of infectious episodes in patients with myeloid neoplasms receiving azacitidine are uncertain, with no prospective data available in this group of patients. The aim of the current study was to analyze the incidence and factors related to the probability of infection in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with azacitidine who did not receive any type of antimicrobial prophylaxis. Significantly, the group of patients who received prior intensive chemotherapy had more infectious episodes (P ¼ 10-4), and particularly, invasive aspergillosis (P ¼ .015), than patients who received frontline azacitidine. Primary antifungal prophylaxis might be recommended in MDS and AML patients receiving azacitidine as salvage therapy after intensive regimens. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 1, 80-6 ª 2014 Elsevier Inc. All rights reserved. Keywords: Acute Myeloid Leukemia, Aspergillosis, Azacitidine, Myelodysplastic Syndrome, Prophylaxis
Introduction Infection is a recurrent cause of morbidity and mortality in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) undergoing intensive chemotherapy (IC) (idarubicin combined with cytarabine).1 Most of these patients routinely receive antimicrobial prophylaxis (AIP) with fluorquinolones or 1 Department of Hematology, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Sevilla, Spain 2 Clinical Unit of Infectious Diseases, Clinical Microbiology and Preventive Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain
Submitted: Jul 3, 2013; Revised: Sep 7, 2013; Accepted: Sep 24, 2013; Epub: Oct 1, 2013 Address for correspondence: Jose F. Falantes, MD, Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/ CSIC/Universidad de Sevilla, Avenida Manuel Siurot s/n, Sevilla, 41013, Spain E-mail contact: [email protected]
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antifungal agents according to the current guidelines for the prevention of infection in neutropenic patients with cancer.2-7 Hypomethylating agents (HMAs) are considered the standard of care in higher-risk MDS (intermediate-2 and high risk according to International Prognostic Scoring System (IPSS)) and AML patients with low blast counts for whom allogeneic stem cell transplant (AlloSCT) is not suitable.8 In addition, there is an increasing use of HMAs in patients with relapsed or refractory disease after IC who are not candidates for reinduction therapy and patients for whom these agents are intended as an alternative approach to classic induction regimens prior to AlloSCT.9-11 However, the role of AIP in patients treated with azacitidine (AZA) or decitabine has not been widely analyzed.12 Lee et al. reported an incidence of 11.5% febrile episodes requiring hospitalization per AZA course (15/131 courses of treatment) in a cohort of MDS patients treated with decitabine.13 Antimicrobial prophylaxis
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.09.014
was administered in 72.5% of decitabine courses. In this study, the incidence of febrile episodes was higher in patients who did not receive prophylaxis (22.2% vs. 7.4%; P ¼ .017) and in patients with platelet or neutrophil count after each course of therapy < 50 109/L or < 0.5 109 cells/L, respectively. Recently, a multicenter retrospective study conducted in Israel including 184 higher-risk MDS and AML patients reported a high incidence of documented bacterial infections (59% among cases with microbiological analysis available), with a significant proportion of these cases with febrile episode requiring hospitalization (74.5%). In this study, only 10% of the patients received prophylaxis.14 Again, peripheral cytopenias, particularly platelet count < 20 109/L and adverse karyotype, significantly influenced the risk of infection in multivariate analysis. Interestingly, both studies included patients who received AZA or decitabine as frontline therapy either for MDS or AML. In summary, the incidence and etiology of infections in MDS and AML receiving AZA is not well characterized, and the role of antimicrobial prophylaxis is not clearly defined. The aim of this study was to evaluate the incidence and pattern of febrile episodes (FE) attributable to both clinically and microbiological documented infections occurred in a cohort of
MDS and AML patients treated with AZA who did not receive antimicrobial prophylaxis. The secondary objectives were to analyze factors related to an increased probability for infection and to identify a subset of these patients who could possibly benefit from prophylaxis.
Design and Methods Patients This is a retrospective study including consecutive patients with MDS and AML treated with AZA at our institution. Only patients receiving at least 2 courses of AZA were included in the study. Sixtyfour patients with MDS and AML were analyzed for a total of 523 AZA courses administered. All patients were diagnosed according to World Health Organization (WHO) Classification15 at Hospital Universitario Virgen del Rocío (Seville, Spain) between 2009 and 2012. Median age was 68 years (range: 29-83 y). Forty-three patients had MDS and 21 patients had AML. The demographic, clinical, and biological characteristics of patients at the time of diagnosis are shown in Table 1. All higher-risk MDS (defined as bone marrow blasts > 10% or IPSS categories intermediate-2 or high risk) and AML patients received AZA at a recommended dose
Table 1 Patient Characteristics Global Series (n [ 64) Age, years, median (range) Number of AZA courses, n (median) WHO, n (%)
68 (29-83) 6 (1-50) RARS: 2 (3.2) RCMD: 9 (14) CMML: 3 (4.7) RAEB-1: 3 (4.7) RAEB-2: 26 (40.6) AML: 21 (32.8)
Prior IC (n [ 18; 28.1%) 66 (29-78) 6 (2-16)
Frontline AZA (n [ 46; 71.9%) 68 (35-83) 9 (2-50)
Int-1
1 episode (range: 1-5). Most of the patients having an FE required hospitalization according to treatment physician criteria (n ¼ 26; 81% from the group of patients with FE). The median duration of hospitalization was 14 days (range: 4-80 d), and 10 patients required > 1 hospital admission. The median duration of neutropenia (< 0.5 109/L) until AZA treatment was 1 month for the group that received frontline AZA therapy, compared with 7 months in patients who received prior IC (P ¼ .02). FE mainly occurred during the first 3 courses of AZA (86%, n ¼ 62) (Fig. 1 shows the incidence of FE after consecutive courses of AZA). Pneumonia and infections from the upper respiratory tract were the most common type of infection (35%) followed by soft tissue and urinary tract infections.
Parameters Related to the Probability of Infection The cumulative incidences of infection estimates for different risk factors were analyzed: previous IC versus frontline AZA therapy, type of disease (AML vs. MDS), adverse karyotype vs. other, bone marrow (BM) blast percentage (cutoff: 10%), peripheral cytopenias
Figure 1 Incidence of Febrile Episodes in Each Course of Azacitidine
Jose F. Falantes et al at the initiation of AZA therapy (cutoff values for hemoglobin concentration, absolute neutrophil count [ANC], and platelet count: 10 g/dL, 0.5 109/L, and 30 109/L, respectively) and achievement of complete response (CR) after a fourth course of AZA vs. any other response, including progressive disease. Interestingly, there was no difference in the probability of infection in patients with (ANC) above or below 0.5 109 cells/L at baseline (P ¼ .158). Only prior IC vs. up-front AZA therapy influenced the probability of infection (P ¼ .007) (Fig. 2A). Table 2 shows the cumulative incidence of infection with estimates at different times. Although no correlation among infection and BM blast percentage, peripheral cytopenias, or achievement of CR were documented, is noteworthy that the incidence of infection reached a plateau after
Figure 2 Cumulative Incidence Estimates From Competing Risks Data (Estimates at Different Time Points). (A) Patients Treated With Prior Intensive Chemotherapy vs. Patients Receiving Frontline Azacitidine Therapy; (B) Patients With Absolute Neutrophil Count > 0.5 3 109/L vs. Patients With Absolute Neutrophil Count > 0.5 3 109/L After 3 Courses of Azacitidine Therapy
4 to 6 courses of AZA among patients with < 10% BM blasts and less severe cytopenias as compared with those with > 10% BM blasts or profound cytopenias at the time of initiation of therapy. This finding was noted when we evaluated the probability and the cumulative incidence of infection in patients recovering from severe neutropenia. Patients with a durable ANC > 0.5 109 cells/L had a significantly lower probability of infection than patients with persistent neutropenia, or 0.5 109/L) after 3 courses of AZA was included as a time-dependent covariate in the multivariate analysis, we observed a significant trend toward a lower risk of infection for the patients achieving durable ANC > 0.5 109/L (hazard ratio, 0.34; 95% CI, 0.98-1.190; P ¼ .07) (Table 4).
Comparison Between Patients Receiving Frontline AZA Therapy and Patients Previously Treated With IC: Etiology and Outcome of Infectious Episodes The group receiving AZA as frontline therapy had fewer incidences of FE per course of therapy than the previous IC treatment group (44/420 AZA courses [10.4%] vs. 44/103 AZA courses [27%]; OR, 3.181 [1.849-5.43]; P ¼ 10-4) Patients previously treated with IC had more episodes of hospital admission (11/18 patients [61%] vs. 15/46 patients [32.6%], respectively; P ¼ .04), although there was no significant difference in the median duration of hospitalization (13 and 14 days, respectively; P ¼ .9). Overall, there were 23 microbiological isolations in 17 patients with microbiologically documented infections. Of those 17 patients, 12 had bacteremia and 10 (15%) had pneumonia, 6 of the cases being fungal pneumonia caused by Aspergillus species. Pneumocystis jirovecii (n ¼1), Enterococcus faecium (n ¼1), and Escherichia coli (n ¼1) were each isolated in 1 of 3 patients with pneumonia. A diagnosis of pneumonia was established when clinical (fever and respiratory symptoms) and radiographic (infiltrate or cavitation in x-ray or computed tomography scan) criteria were present. Bacterial infections were the most frequent (E. coli, n ¼ 6), followed by fungal infection (Aspergillus species n ¼ 5, Candida species n ¼ 2). All cases of invasive aspergillosis were probable according to EORTC criteria. Of 17 infections, 5 were polymicrobial. Microbiological isolation occurred more frequently in patients with prior IC (50% vs. 16%; P ¼ .007). The rate of fungal infection was higher in the group of patients that received prior IC (P ¼ .038). In particular, invasive aspergillosis occurred in 5 of 20 in this group compared with 1 of 44 in the AZA frontline group (Risk difference, 22.4%; OR, 12 [1.524-308.2]; P ¼ .015) for an 8.3% overall incidence of invasive aspergillosis. Evaluating the incidence of probable IFI caused by Aspergillus species, we found that the group of patients receiving AZA as frontline therapy had a 2.7% incidence of aspergillosis. With the estimated absolute risk difference, the NNT was 4. There was no difference in the rate of
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Invasive Aspergillosis in MDS and AML Treated With Azacitidine Table 2 Cumulative Incidence of Infectiona (AZA Courses) [Cumulative Incidence Estimates in %] Parameter
b
Previous IC Frontline AZA therapy MDS AML Adverse karyotypec Other BM blast % >10 BM blast % 0.5 109 cells/Lc Ptl 10d ANC 0.5 109 cells/L after 3 courses of azacitidine as a time-dependent covariate. d Measured at the time of initiation of azacitidine therapy.
However, there is no prospective trial evaluating the need for prophylaxis in patients receiving HMA, and approaches to prophylaxis differ among institutions. Moreover, data on the risk of infection in patients previously treated with IC who receive AZA as salvage therapy are lacking. Results from a recent multicenter retrospective analysis on 184 patients with MDS and AML who were treated with AZA have shown an incidence of FE in 54.3% of them (100/184). In this cohort, only 20 patients (10.8%) received AIP. Data similar in terms of FE (11.5%) have been described in a group of MDS patients, most with lower-risk MDS, treated with decitabine.13 Of these patients, 54 received antifungal prophylaxis. In the current study, we found a similar incidence of FE and similar timing of infection. On the contrary, none of the patients from our study received prophylaxis, and a significant proportion of them received intensive regimens prior to initiation
of AZA therapy, all of them being refractory or relapsed after standard IC, even patients who received prior IC as per institution practice did not received prophylaxis. As AZA represents a novel and attractive alternative for patients with very limited therapeutic options, information on the patterns of infection in this setting is of great value, as this group of patients might be offered primary antifungal prophylaxis considering the morbidity and mortality of this complication, which could exclude them from the possibility of AlloSCT as a potential curative intervention. Interestingly, the severity of neutropenia and thrombocytopenia as surrogates for bone marrow reserve has been identified as important risk factors for FE in recent studies. By contrast, in our study, this relationship between severe cytopenias at the initiation of AZA therapy and the onset of FE was not so evident, while other variables emerged as the most important risk factors to be considered to properly monitor these patients. In this regard, the facts that most infections occurred during the first courses of AZA and that the probability of infection was higher in patients not achieving neutrophil recovery indicate that marrow failure is a significant factor for the risk of infection. As patients achieve some degree of hematological improvement, the risk of infection tends to decline, supporting the recommendation of a very close follow-up of these patients in the initial months after starting therapy. Furthermore, compliance with AZA treatment is critical during the first courses of therapy.27 As infections occurred mainly during this period, and considering that once an infection occurs, treatment must be delayed or even stopped, identification of individuals at higher risk for fungal infection might help to improve outcomes in these patients. Data from our study, although limited to a relatively reduced and retrospective analysis of patients receiving AZA therapy, together with the implementation of approaches for selecting patients for
Table 5 Comparison Between Groups: Data on Microbiological Isolation and Outcome Global (n [ 64)
Prior IC (n [ 18)
AZA Frontline (n [ 46)
FE per AZA course, n (%)
73/523 (13.95)
28/98 (18.7%)
45/425 (10.7%)
Hospital admission, n (%)
26/64 (40.6%)
11/18 (61%)
15/46 (32.6%)
14 (4-80) 17/64 (26.6)
13 (4-80) 9/18 (5%)
14 (5-57) 8/46 (17.4%)
Hospital stay, d, median (range) Patients with microbiological isolation, n (%)
Type of isolation,a n
Fungal isolation, n
Cause of death, n (%)
Bacterial: 6 Fungal: 4 Both: 4 Other: 1 Aspergillus spp: 6 Candida spp: 2
Progression: 21 (58.4) Infection on AZA: 2 (5.5) Other: 14 (36.1)
Bacterial: 3 Fungal: 2 Both: 4 Other: Aspergillus spp: 5 Candida albicans: 1
Bacterial: 3 Fungal: 2 Both: Other: 1 Aspergillus spp: 1 Candida parapsilosis: 1
Progression: 11 (79) Infection on AZA: 1 (7) Other: 3 (14)
Progression: 10 (46) Infection on AZA: 1 (4) Other: 11 (50)
P Value 10-4 Risk difference: 18% OR: 3.36 (1.955-5.757) .04 Risk difference: 18% OR: 3.18 (1.025-10.41) .9 .01 Risk difference: 32% OR: 4.61 (1.378-16.07) Fungal: .038 Risk difference: 22% OR: 4.9 (1.089-27.37) .015 Risk difference: 22.4% OR: 12 (1.524-308.2) NNT¼4 .56
Abbreviations: AZA ¼ azacitidine; FE ¼ febrile episode; IC ¼ intensive chemotherapy; OR ¼ odds ratio; NNT ¼ number needed to treat. P values denote differences between the group that received previous IC and the group that received frontline AZA therapy for the corresponding parameter (Mid-I exact test and c2). a 5 of the cases were polymicrobial.
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Invasive Aspergillosis in MDS and AML Treated With Azacitidine antifungal therapy based on risk profile and a close follow-up of infectious episodes as described by Aguilar-Guisado et al., have the potential benefits of both identifying patients more likely to develop a fungal infection and avoiding overtreatment and toxicity among those with a lower probability for this event. Based on the results of our study, primary antifungal prophylaxis should be recommended in patients receiving AZA therapy after previous IC, especially during the first courses of treatment, until hematopoiesis is restored. Considering the expected increase in the use of AZA in MDS and AML cases, not only in elderly patients but also in other clinical settings, randomized prospective studies are needed to better address this issue. In contrast, the risk for fungal infection was very low among patients receiving frontline AZA therapy. The latter group would not require antifungal prophylaxis.
Disclosure The authors have stated that they have no conflicts of interest.
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