ORIGINAL ARTICLE
Secondary Antifungal Prophylaxis in Pediatric Hematopoietic Stem Cell Transplants Fatih M. Azık, MD,* Hasan Tezer, MD,w Aslinur Ozkaya-Parlakay, MD,z Tekin Aksu, MD,* Cengiz Bayram, MD,* Ali Fettah, MD,* Betu¨l Tavil, MD,* and Bahattin Tunc¸, MD*
Summary: Invasive fungal infections (IFIs) constitute a leading cause of morbidity and infection-related mortality among hematopoietic stem cell transplant (HSCT) recipients. With the use of secondary prophylaxis, a history of IFI is not an absolute contraindication to allo-HSCT. However, still, IFI recurrence remains a risk factor for transplant-related mortality. In this study, of the 105 children undergoing HSCT between April 2010 and February 2013, 10 patients who had IFI history before transplantation and had undergone allo-HSCT were evaluated retrospectively to investigate results of secondary prophylaxis. In conclusion, our study shows that amphotericin B and caspofungin was successful as secondary antifungal prophylaxis agents with no relapse of IFI. In addition, after engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients that yielded good results. Key Words: invasive fungal infection, hematopoietic stem cell transplant, secondary antifungal prophylaxis, child
(J Pediatr Hematol Oncol 2015;37:e19–e22)
I
nvasive fungal infections (IFIs) remain a major concern of morbidity and mortality after hematopoietic stem cell transplantation (HSCT).1–3 After the introduction of fluconazole prophylaxis in the 1990s, the incidence of candidemia decreased, coinciding with the emergence of other IFIs such as invasive aspergillosis,1,4 non-Aspergillus molds, such as Zygomycetes, Fusarium species, and Scedosporium species.5–9 Secondary antifungal prophylaxis (SAP) is the prevention of recurrent IFI in patients who went through an IFI previously, and will take an additional deep immunosuppressive treatment phase, including high-dose chemotherapy or HSCT.10 The aim of SAP is to prevent the recurrence of a previous IFI or onset of another.
MATERIALS AND METHODS This study was a retrospective analysis of allo-HSCT patients treated in a tertiary referral center in central region of Turkey. Allo-HSCT patients were considered eligible for inclusion in the study if they had a history of possible, probable, or proven IFI that had been acquired during antecedent treatment, and if they had previously responded to antifungal treatment. Received for publication December 20, 2013; accepted April 23, 2014. From the *Pediatric Hematology Unit; zPediatric Infectious Disease Unit, Ankara Hematology Oncology Children’s Training and Research Hospital; and wGazi University Faculty of Medicine Pediatric Infectious Diseases Unit, Ankara, Turkey. The authors declare no conflict of interest. Reprints: Aslinur Ozkaya-Parlakay, MD, Ankara Hematology Oncology Children’s Training and Research Hospital, Pediatric Infectious Disease Unit, Diskapi 06110, Ankara, Turkey (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
IFIs were defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines.11 For definitions, a “proven diagnosis” required histopathologic or microbiologic documentation of a fungus from biopsied tissues, or positive results from culture of specimens obtained from a normally sterile site. A “probable infection” required host factors, clinical features including specific radiographic imaging signs and symptoms (halo sign etc.), and mycological evidence including an identified mold or a positive Galactomannan (GM) test (GM levels were studied by sandwich ELISA commercial kit [Platelia Aspergillus; Bio-Rad Laboratories, France] in accordance with the manufacturer’s instructions; GM levels were grade 2 etc), duration of immunosuppressive medication usage, and proof and type of fungal infection. In possible IFI cases, SAP was continued until engraftment. In probable and proven IFI cases, SAP duration was planned according to the type of fungal infection. As SAP agents, liposomal amphotericin B (3 mg/kg/d) and caspofungin (50 mg/m2/d) were used. Unfortunately, therapeutic drug monitoring was not available in our hospital to guide voriconazole therapy. During hospitalization, all the patients lived in single isolated rooms equipped with positive air pressure and high-efficiency air filters, and underwent daily clinical, biochemical assessment. Clinical symptoms, computed tomography scans, and GM levels were used to assess response to fungal treatments. All analyses were performed with SPSS v.16 (SPSS Inc., Chicago, IL). Significance was defined as P < 0.05.
RESULTS SAP was applied to 10 patients, 6 female and 4 male, aged between 7 and 16 years old (mean, 12.3 ± 3.4 y). Of all the patients, 5 were diagnosed with acute myelogenous leukemia, 2 were diagnosed with Fanconi aplastic anemia, 1 was diagnosed with acute lymphoblastic leukemia, 1 patient with biphenotypic leukemia, and 1 patient was diagnosed with mix-lineage leukemia. All patients had undergone alloHSCT. Except 1 patient who had 9/10 match, all recipients had full match (10/10) by means of HLA. Seven patients received cyclophosphamide and busulfan, 2 patients received fludarabine and cyclophosphamide and ATG, and 1 patient received cyclophosphamide and melphalan as conditioning regimens.
Volume 37, Number 1, January 2015
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e19
e20 | www.jpho-online.com
Copyright
Mix lineage AML
Fanconi AA Fanconi AA AML
6
8
r
Paranasal sinus
Lung
Lung
Lung
Lung
LungLiverspleen Lung
Torax CT
Torax CT
Torax CT
Torax CT
Torax CT
Proven Histopatologic
Probable
Possible
Probable
Possible
Possible
Torax CT Abd. USG
Torax CT Torax CT Torax CT
Method of Diagnosis
GM+
GM+
GM+
Mycological Criteria
Amphotericin B
Lipos.Amp B
Liposomal amphotericin B Liposomal amphotericin B Caspofungin
Voriconazole
Voriconazole
Voriconazole Voriconazole Voriconazole
Primary IFI Therapy
139
40
33
28
99
133
91
28 91 180
13
13
10
21
12
17
13
16 13 14
Duration of Engraftment
Liposomal amphotericin B Caspofungin
Liposomal amphotericin B Caspofungin
Liposomal amphotericin B Caspofungin
Liposomal amphotericin B
Caspofungin Caspofungin Liposomal amphotericin B
Secondary Prophylaxis
100
118
34
90
32
51
100
23 20 100
Duration of SAP (d)
No
No
Hepatotoxicity
Nephrotoxicity
No
No
No
No
Nephrotoxicity- Caspofungin Hepatotoxicity No No
No No No No Hypokalemia- Caspofungin nephrotoxicityangioedema No Caspofungin
Toxicity
_
+
_
+
_
+
_
_ +
+ +
Oral Voriconazole Usage as Change of SAP After Antifungal Engraftment Exitus
J Pediatr Hematol Oncol
AA indicates aplastic anemia; ALL, acute lymphoblastic leukemia; AML, acute myelegenous leukemia; CT, computed tomography; GM, Galactomannan; IFI, invasive fungal infection; SAP, secondary antifungal prophylaxis.
10
9
7
AML
AML
4
5
ALL AML Bipheno typic
1 2 3
Probable
Possible Possible Possible
Case Diagnosis IFI Site
Lung Lung Lung
IFI Proof
Primary Fungal Therapy Duration
TABLE 1. Characteristics of the Patients Regarding Secondary Antifungal Prophylaxis
Azık et al Volume 37, Number 1, January 2015
2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 1, January 2015
Before transplantation, 6 patients were categorized as having possible IFI, 3 patients as having probable IFI, and 1 patient as having proven IFI. As secondary prophylactic agents 5 patients received liposomal amphotericin B, and 5 patients received caspofungin. After engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients. Antifungal prophylaxis was continued between 20 and 118 days (mean, 66.8 ± 38.2 d) after HSCT. With secondary antifungal prophylaxis no fungal infection occurred. Patients were followed up between 68 and 600 days (mean, 298.8 ± 188.3 d). Of the 10 patients, 2 died: 1 because of chronic GVHD, and the other because of leukemia relapse. In follow-up of 3 patients, amphotericin B was discontinued because of side effects such as nephrotoxicity and hypokalemia, and caspofungin was initiated instead. In patients receiving caspofungin, nausea, vomiting, diarrhea, and hepatotoxicity were observed; however, these side effects could also be because of concomitant multidrug use as these symptoms recovered spontaneously while caspofungin therapy was going on. Compared with patients receiving amphotericin B (4/5), less side effects were observed in patients taking caspofungin (2/8) (not statistically significant that might be because of small sample size) (Table 1).
DISCUSSION A variety of antifungal agents have been found to be effective for SAP in allo-HSCT patients, including voriconazole, itraconazole, caspofungin, and liposomal amphotericin-B.12–16 Previous studies showed that broadspectrum agents, such as voriconazole, itraconazole, caspofungin, and micafungin, were more efficient in SAP than fluconazole.10 In our case, possible IFIs are more common than probable and proven cases, due to difficulty in diagnosis in children. Although these infections have been well characterized in adults, the incidence and analysis of risk factors, diagnostic tools, treatments, and outcomes have not been well described for large cohorts of pediatric patients. Unfortunately, radiologic studies are not as helpful as in adults.17 In adult pulmonary aspergillosis series, 50% of cases show cavitation with air crescent formation in 40%, whereas in pediatric age group usually no air crescents are observed and cavitation rate is as low as 20% to 25%.18 Use of antigenic tests such as GM in pediatric age group has some limitations. Cutoff value is not clear in children and false-positive values are more common in this age group, which might be because of the presence of GM in formulas and several other food.19 Furthermore, falsenegative values are more frequently observed in pediatric use, especially in chronic granulamotous disease.20 Researchers have defined a number of risk factors for the development of IFI after HSCT: prior fungal exposure or colonization, state of immunosuppression, status of underlying hematologic disease, GVHD/graft rejection, bacteremia, organ dysfunction, and HLA disparity of the graft and stem cell source.21–26 A high mortality rate (20% to 80%) is associated with IFI, particularly in patients experiencing a relapse.27–29 However, the widespread use of SAP has greatly decreased fungal-related mortality. In the first prospective multicenter clinical trial evaluating voriconazole as a SAP in allo-HSCT adult recipients with previous proven or probable IFI, Cordonnier et al16 Copyright
r
Secondary Antifungal Prophylaxis in Pediatric HSCT
reported only a single death from systemic fungal disease, and only a 3.6% 1-year cumulative incidence of IFI relapse. In another study,10 a 70.1% survival rate and a relatively low (8%) fungal-related mortality rate was observed. Because half of these patients were graded as being “possible” cases, a separate analysis was performed including data only from the 44 patients with a previous proven or probable IFI. This subsample of individuals experienced similar early recurrence rates (25%) and IFIrelated mortality rates (11.3%). It was also found that overall survival rates were higher in patients without recurrent IFI, reflecting the importance of SAP to decrease the risk of recurrence rate and improve overall survival. The results of our retrospective study suggest that alloHSCT can be safely and effectively performed in patients with previous IFI. Voriconazole was given to 5 patients in the treatment of primary IFI episode (4 possible, 1 probable aspergillosis patients) owing to ECIL and IDSA guidelines,30,31 before HSCT, which may have resulted with no recurrence of fungal infection after HSCT. Caspofungin and liposomal amphotericin B can be safely used as SAP.13,32,33 In a pediatric study evaluating amphotericin B and voriconazole, unless chronic GVHD, relapse of leukemia, or graft failure occurs, antifungal prophylaxis with aforementioned agents was found to be efficient.13 In our study, the limiting role of hypokalemia in patients receiving long-term amphotericin B was notable in 3 patients; yet SAP with amphotericin B or caspofungin resulted with no recurrence of IFI that occurred before HSCT. In possible IFI cases, SAP was continued until engraftment, whereas in probable and proven cases SAP was determined according to status of the patient and type of the suspected fungal infection. In patients having GVHD, both GVHD and immunosuppressive therapy usage could have negative effects on immune status of the patient. Therefore, SAP duration was planned according to underlying diseases and also the type of the suspected or proven fungal infection. In a previous study, duration of neutropenia, high-dose cytarabine, prior antibiotic therapy, a partial response to the first IFI therapy, and newly diagnosed acute myelegenous leukemia were defined as risk factors for breakthrough IFI,25 and therefore these criteria were evaluated before deciding SAP. Although sample size is low, less side effects were observed with caspofungin as SAP agent. In conclusion, our study shows that amphotericin B and caspofungin was successful as SAP agents with no relapse of IFI.
REFERENCES 1. Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100:4358–4366. 2. Singh N. Impact of current transplantation practices on the changing epidemiology of infections in transplant recipients. Lancet Infect Dis. 2003;3:156–161. 3. Wingard JR. Fungal infections after bone marrow transplant. Biol Blood Marrow Transplant. 1999;5:55–68. 4. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation: a prospective, randomized, double-blind study. J Infect Dis. 1995;171:1545–1552. 5. Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191:1350–1360.
2014 Wolters Kluwer Health, Inc. All rights reserved.
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Azık et al
6. Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:909–917. 7. Nucci M. Emerging moulds: Fusarium, Scedosporium and Zygomycetes in transplant recipients. Curr Opin Infect Dis. 2003;16:607–612. 8. Nucci M, Marr KA, Queiroz-Telles F, et al. Fusarium infection in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2004;38:1237–1242. 9. Garcia-Vidal C, Upton A, Kirby KA, et al. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis. 2008;47:1041–1050. 10. Liu F, Wu T, Wang JB, et al. Risk factors for recurrence of invasive fungal infection during secondary antifungal prophylaxis in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2013;15:243–250. 11. 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;46:813–1821. 12. Cordonnier C, Maury S, Pautas C, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004;33:943–948. 13. Allinson K, Kolve H, Gumbinger HG, et al. Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients. J Antimicrob Chemother. 2008;61:734–742. 14. Grigull L, Kuehlke O, Beilken A, et al. Intravenous and oral sequential itraconazole antifungal prophylaxis in paediatric stem cell transplantation recipients: a pilot study for evaluation of safety and efficacy. Pediatr Transplant. 2007;11:261–266. 15. Fabritiis P, Spagnoli A, Bartolomeo PD, et al. Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/ or systemic fungal infection. Bone Marrow Transplant. 2007;40: 245–249. 16. Cordonnier C, Rovira M, Maertens J, et al. Voriconazole for secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients: results of the VOSIFI study. Haematologica. 2010;95:1762–1768. 17. Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121:e1286–e1294. 18. Thomas KE, Owens CM, Veys PA, et al. The radiological spectrum of invasive aspergillosis in children: a 10-year review. Pediatr Radiol. 2003;33:453–460. 19. Herbrecht R, Letscher-Bru V, Oprea C, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol. 2002;20:1898–1906. 20. Walsh T, Schaufele R, Sein T, et al. Infectious Diseases Society of America, 2002, Alexandria, VA. Reduced expression of
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21.
22.
23. 24. 25. 26. 27. 28.
29.
30.
31.
32.
33.
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Volume 37, Number 1, January 2015
galactomannan antigenemia in patients with invasive aspergillosis and chronic granulomatous disease or Job’s syndrome (abstract 345), p. 105. Program and abstracts of the 40th annual meeting of the Infectious Diseases Society of America, Chicago, 2002. Martino R, Subira M, Rovira M, et al. Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients. Br J Haematol. 2002;116:475–482. Bow EJ, Loewen R, Cheang MS, et al. Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileukemic regimen. Clin Infect Dis. 1995;21:361–369. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk based, antifungal strategy in neutropenic patients. Br J Haematol. 2000;110:273–284. Mahfouz T, Anaissie E. Prevention of fungal infections in the immunocompromised host. Curr Opin Investig Drugs. 2003;4: 974–990. Anaissie EJ, Rex JH, Uzun O, et al. Predictors of adverse outcome in cancer patients with candidemia. Am J Med. 1998; 104:238–245. Cornely OA, Bohme A, Reichert D, et al. Risk factors for breakthrough invasive fungal infection during secondary prophylaxis. J Antimicrob Chemother. 2008;61:939–946. Offner F, Cordonnier C, Ljungman P, et al. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis. 1998;26:1098–1103. Fukuda T, Boeckh M, Guthrie KA, et al. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10yearexperience at a single transplant center. Biol Blood Marrow Transplant. 2004;10:494–503. Pagano L, Caira M, Nosari A, et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study—Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis. 2007; 45:1161–1170. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Infectious Diseases Society of America. 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–e93. ECIL 4—pediatric group considerations for fungal diseases and antifungal treatment in children. Available at: http://www. eortc.org/sites/default/files/ECIL.4.2011.Paediatric.guidelines. Fungi.and.antifungals.pdf. Accessed December 18, 2013. Kru¨ger WH, Ru¨ssmann B, de Wit M, et al. Haemopoietic cell transplantation of patients with a history of deep or invasive fungal infection during prophylaxis with liposomal amphotericin B. Acta Haematol. 2005;113:104–108. Vehreschild JJ, Sieniawski M, Reuter S, et al. Efficacy of caspofungin and itraconazole as secondary antifungal prophylaxis: analysis of data from a multinational case registry. Int J Antimicrob Agents. 2009;34:446–450.
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
Secondary Antifungal Prophylaxis in Pediatric Hematopoietic Stem Cell Transplants Fatih M. Azık, MD,* Hasan Tezer, MD,w Aslinur Ozkaya-Parlakay, MD,z Tekin Aksu, MD,* Cengiz Bayram, MD,* Ali Fettah, MD,* Betu¨l Tavil, MD,* and Bahattin Tunc¸, MD*
Summary: Invasive fungal infections (IFIs) constitute a leading cause of morbidity and infection-related mortality among hematopoietic stem cell transplant (HSCT) recipients. With the use of secondary prophylaxis, a history of IFI is not an absolute contraindication to allo-HSCT. However, still, IFI recurrence remains a risk factor for transplant-related mortality. In this study, of the 105 children undergoing HSCT between April 2010 and February 2013, 10 patients who had IFI history before transplantation and had undergone allo-HSCT were evaluated retrospectively to investigate results of secondary prophylaxis. In conclusion, our study shows that amphotericin B and caspofungin was successful as secondary antifungal prophylaxis agents with no relapse of IFI. In addition, after engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients that yielded good results. Key Words: invasive fungal infection, hematopoietic stem cell transplant, secondary antifungal prophylaxis, child
(J Pediatr Hematol Oncol 2015;37:e19–e22)
I
nvasive fungal infections (IFIs) remain a major concern of morbidity and mortality after hematopoietic stem cell transplantation (HSCT).1–3 After the introduction of fluconazole prophylaxis in the 1990s, the incidence of candidemia decreased, coinciding with the emergence of other IFIs such as invasive aspergillosis,1,4 non-Aspergillus molds, such as Zygomycetes, Fusarium species, and Scedosporium species.5–9 Secondary antifungal prophylaxis (SAP) is the prevention of recurrent IFI in patients who went through an IFI previously, and will take an additional deep immunosuppressive treatment phase, including high-dose chemotherapy or HSCT.10 The aim of SAP is to prevent the recurrence of a previous IFI or onset of another.
MATERIALS AND METHODS This study was a retrospective analysis of allo-HSCT patients treated in a tertiary referral center in central region of Turkey. Allo-HSCT patients were considered eligible for inclusion in the study if they had a history of possible, probable, or proven IFI that had been acquired during antecedent treatment, and if they had previously responded to antifungal treatment. Received for publication December 20, 2013; accepted April 23, 2014. From the *Pediatric Hematology Unit; zPediatric Infectious Disease Unit, Ankara Hematology Oncology Children’s Training and Research Hospital; and wGazi University Faculty of Medicine Pediatric Infectious Diseases Unit, Ankara, Turkey. The authors declare no conflict of interest. Reprints: Aslinur Ozkaya-Parlakay, MD, Ankara Hematology Oncology Children’s Training and Research Hospital, Pediatric Infectious Disease Unit, Diskapi 06110, Ankara, Turkey (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
IFIs were defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines.11 For definitions, a “proven diagnosis” required histopathologic or microbiologic documentation of a fungus from biopsied tissues, or positive results from culture of specimens obtained from a normally sterile site. A “probable infection” required host factors, clinical features including specific radiographic imaging signs and symptoms (halo sign etc.), and mycological evidence including an identified mold or a positive Galactomannan (GM) test (GM levels were studied by sandwich ELISA commercial kit [Platelia Aspergillus; Bio-Rad Laboratories, France] in accordance with the manufacturer’s instructions; GM levels were grade 2 etc), duration of immunosuppressive medication usage, and proof and type of fungal infection. In possible IFI cases, SAP was continued until engraftment. In probable and proven IFI cases, SAP duration was planned according to the type of fungal infection. As SAP agents, liposomal amphotericin B (3 mg/kg/d) and caspofungin (50 mg/m2/d) were used. Unfortunately, therapeutic drug monitoring was not available in our hospital to guide voriconazole therapy. During hospitalization, all the patients lived in single isolated rooms equipped with positive air pressure and high-efficiency air filters, and underwent daily clinical, biochemical assessment. Clinical symptoms, computed tomography scans, and GM levels were used to assess response to fungal treatments. All analyses were performed with SPSS v.16 (SPSS Inc., Chicago, IL). Significance was defined as P < 0.05.
RESULTS SAP was applied to 10 patients, 6 female and 4 male, aged between 7 and 16 years old (mean, 12.3 ± 3.4 y). Of all the patients, 5 were diagnosed with acute myelogenous leukemia, 2 were diagnosed with Fanconi aplastic anemia, 1 was diagnosed with acute lymphoblastic leukemia, 1 patient with biphenotypic leukemia, and 1 patient was diagnosed with mix-lineage leukemia. All patients had undergone alloHSCT. Except 1 patient who had 9/10 match, all recipients had full match (10/10) by means of HLA. Seven patients received cyclophosphamide and busulfan, 2 patients received fludarabine and cyclophosphamide and ATG, and 1 patient received cyclophosphamide and melphalan as conditioning regimens.
Volume 37, Number 1, January 2015
www.jpho-online.com |
e19
e20 | www.jpho-online.com
Copyright
Mix lineage AML
Fanconi AA Fanconi AA AML
6
8
r
Paranasal sinus
Lung
Lung
Lung
Lung
LungLiverspleen Lung
Torax CT
Torax CT
Torax CT
Torax CT
Torax CT
Proven Histopatologic
Probable
Possible
Probable
Possible
Possible
Torax CT Abd. USG
Torax CT Torax CT Torax CT
Method of Diagnosis
GM+
GM+
GM+
Mycological Criteria
Amphotericin B
Lipos.Amp B
Liposomal amphotericin B Liposomal amphotericin B Caspofungin
Voriconazole
Voriconazole
Voriconazole Voriconazole Voriconazole
Primary IFI Therapy
139
40
33
28
99
133
91
28 91 180
13
13
10
21
12
17
13
16 13 14
Duration of Engraftment
Liposomal amphotericin B Caspofungin
Liposomal amphotericin B Caspofungin
Liposomal amphotericin B Caspofungin
Liposomal amphotericin B
Caspofungin Caspofungin Liposomal amphotericin B
Secondary Prophylaxis
100
118
34
90
32
51
100
23 20 100
Duration of SAP (d)
No
No
Hepatotoxicity
Nephrotoxicity
No
No
No
No
Nephrotoxicity- Caspofungin Hepatotoxicity No No
No No No No Hypokalemia- Caspofungin nephrotoxicityangioedema No Caspofungin
Toxicity
_
+
_
+
_
+
_
_ +
+ +
Oral Voriconazole Usage as Change of SAP After Antifungal Engraftment Exitus
J Pediatr Hematol Oncol
AA indicates aplastic anemia; ALL, acute lymphoblastic leukemia; AML, acute myelegenous leukemia; CT, computed tomography; GM, Galactomannan; IFI, invasive fungal infection; SAP, secondary antifungal prophylaxis.
10
9
7
AML
AML
4
5
ALL AML Bipheno typic
1 2 3
Probable
Possible Possible Possible
Case Diagnosis IFI Site
Lung Lung Lung
IFI Proof
Primary Fungal Therapy Duration
TABLE 1. Characteristics of the Patients Regarding Secondary Antifungal Prophylaxis
Azık et al Volume 37, Number 1, January 2015
2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 1, January 2015
Before transplantation, 6 patients were categorized as having possible IFI, 3 patients as having probable IFI, and 1 patient as having proven IFI. As secondary prophylactic agents 5 patients received liposomal amphotericin B, and 5 patients received caspofungin. After engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients. Antifungal prophylaxis was continued between 20 and 118 days (mean, 66.8 ± 38.2 d) after HSCT. With secondary antifungal prophylaxis no fungal infection occurred. Patients were followed up between 68 and 600 days (mean, 298.8 ± 188.3 d). Of the 10 patients, 2 died: 1 because of chronic GVHD, and the other because of leukemia relapse. In follow-up of 3 patients, amphotericin B was discontinued because of side effects such as nephrotoxicity and hypokalemia, and caspofungin was initiated instead. In patients receiving caspofungin, nausea, vomiting, diarrhea, and hepatotoxicity were observed; however, these side effects could also be because of concomitant multidrug use as these symptoms recovered spontaneously while caspofungin therapy was going on. Compared with patients receiving amphotericin B (4/5), less side effects were observed in patients taking caspofungin (2/8) (not statistically significant that might be because of small sample size) (Table 1).
DISCUSSION A variety of antifungal agents have been found to be effective for SAP in allo-HSCT patients, including voriconazole, itraconazole, caspofungin, and liposomal amphotericin-B.12–16 Previous studies showed that broadspectrum agents, such as voriconazole, itraconazole, caspofungin, and micafungin, were more efficient in SAP than fluconazole.10 In our case, possible IFIs are more common than probable and proven cases, due to difficulty in diagnosis in children. Although these infections have been well characterized in adults, the incidence and analysis of risk factors, diagnostic tools, treatments, and outcomes have not been well described for large cohorts of pediatric patients. Unfortunately, radiologic studies are not as helpful as in adults.17 In adult pulmonary aspergillosis series, 50% of cases show cavitation with air crescent formation in 40%, whereas in pediatric age group usually no air crescents are observed and cavitation rate is as low as 20% to 25%.18 Use of antigenic tests such as GM in pediatric age group has some limitations. Cutoff value is not clear in children and false-positive values are more common in this age group, which might be because of the presence of GM in formulas and several other food.19 Furthermore, falsenegative values are more frequently observed in pediatric use, especially in chronic granulamotous disease.20 Researchers have defined a number of risk factors for the development of IFI after HSCT: prior fungal exposure or colonization, state of immunosuppression, status of underlying hematologic disease, GVHD/graft rejection, bacteremia, organ dysfunction, and HLA disparity of the graft and stem cell source.21–26 A high mortality rate (20% to 80%) is associated with IFI, particularly in patients experiencing a relapse.27–29 However, the widespread use of SAP has greatly decreased fungal-related mortality. In the first prospective multicenter clinical trial evaluating voriconazole as a SAP in allo-HSCT adult recipients with previous proven or probable IFI, Cordonnier et al16 Copyright
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Secondary Antifungal Prophylaxis in Pediatric HSCT
reported only a single death from systemic fungal disease, and only a 3.6% 1-year cumulative incidence of IFI relapse. In another study,10 a 70.1% survival rate and a relatively low (8%) fungal-related mortality rate was observed. Because half of these patients were graded as being “possible” cases, a separate analysis was performed including data only from the 44 patients with a previous proven or probable IFI. This subsample of individuals experienced similar early recurrence rates (25%) and IFIrelated mortality rates (11.3%). It was also found that overall survival rates were higher in patients without recurrent IFI, reflecting the importance of SAP to decrease the risk of recurrence rate and improve overall survival. The results of our retrospective study suggest that alloHSCT can be safely and effectively performed in patients with previous IFI. Voriconazole was given to 5 patients in the treatment of primary IFI episode (4 possible, 1 probable aspergillosis patients) owing to ECIL and IDSA guidelines,30,31 before HSCT, which may have resulted with no recurrence of fungal infection after HSCT. Caspofungin and liposomal amphotericin B can be safely used as SAP.13,32,33 In a pediatric study evaluating amphotericin B and voriconazole, unless chronic GVHD, relapse of leukemia, or graft failure occurs, antifungal prophylaxis with aforementioned agents was found to be efficient.13 In our study, the limiting role of hypokalemia in patients receiving long-term amphotericin B was notable in 3 patients; yet SAP with amphotericin B or caspofungin resulted with no recurrence of IFI that occurred before HSCT. In possible IFI cases, SAP was continued until engraftment, whereas in probable and proven cases SAP was determined according to status of the patient and type of the suspected fungal infection. In patients having GVHD, both GVHD and immunosuppressive therapy usage could have negative effects on immune status of the patient. Therefore, SAP duration was planned according to underlying diseases and also the type of the suspected or proven fungal infection. In a previous study, duration of neutropenia, high-dose cytarabine, prior antibiotic therapy, a partial response to the first IFI therapy, and newly diagnosed acute myelegenous leukemia were defined as risk factors for breakthrough IFI,25 and therefore these criteria were evaluated before deciding SAP. Although sample size is low, less side effects were observed with caspofungin as SAP agent. In conclusion, our study shows that amphotericin B and caspofungin was successful as SAP agents with no relapse of IFI.
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