alexa Invasive Mould Disease and#8211; Predictive Risk Factors in Acute Leukemia Patients Receiving Intensive Chemotherapy and its Impact on Survival | OMICS International
ISSN: 2155-9864
Journal of Blood Disorders & Transfusion

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Invasive Mould Disease – Predictive Risk Factors in Acute Leukemia Patients Receiving Intensive Chemotherapy and its Impact on Survival

Gee Chuan Wong1*, Jenny GH Low2, Nidhi L Chlebicka2 and Ban Hock Tan2

1Department of Haematology, Singapore General Hospital, Singapore

2Department of Infectious Diseases, Singapore General Hospital, Singapore

*Corresponding Author:
Gee Chuan Wong
Department of Haematology
Singapore General Hospital Outram Road
Singapore 169608
Tel: 65-6321-4855
Fax: 65-62250210
E-mail: [email protected]

Received date: May 30, 2013; Accepted date: September 17, 2013; Published date: September 20, 2013

Citation: Wong GC, Low JGH, Chlebicka NL, Tan BH (2013) Invasive Mould Disease – Predictive Risk Factors in Acute Leukemia Patients Receiving Intensive Chemotherapy and its Impact on Survival. J Blood Disord Transfus 4:156. doi: 10.4172/2155-9864.1000156

Copyright: © 2013 Wong GC, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Background: Invasive mould disease (IMD) after chemotherapy in patients with acute leukemia has traditionally caused much morbidity and mortality. Methods: We conducted a retrospective, matched case-control study of IMD in patients with acute leukemia managed in our institution from January 2004 to March 2007 to determine the incidence and clinical outcomes of IMD, including its impact on 1-year survival. Results: During this period, 172 patients with acute leukemia underwent chemotherapy with curative intent. A probable or proven IMD developed in 19 patients (cases), giving an incidence of 11%. Aspergillus was the commonest mould. Cases were more likely than controls to have prolonged neutropenia, fever that did not respond to carbapenems, a bacteremia and a longer length of stay. Three-month survival was 93.3% among both cases and controls, but one-year survival was 46.7% among cases and 93.3% among controls. Having an IMD appears to impart a higher risk of mortality at one year. Conclusion: The incidence of invasive mould disease in acute leukemia patients receiving chemotherapy is 11%. Absolute neutropenia more than 14 days is a risk factor for IMD. Itraconazole prophylaxis did not reduce the likelihood of an IMD and a change should be considered. Having an IMD appeared to predict mortality at 12 months.

Keywords

Invasive fungal infection; Acute leukemia; Invasive aspergillosis; Survival

Introduction

Invasive mould disease (IMD) after chemotherapy in patients with acute leukemia has traditionally caused much morbidity and mortality. Recent series, however, suggest an improved survival, attributed to the newer anti-fungal agents. Pagano et al noted that the attributable mortality of invasive aspergillosis (IA) in patients with acute myeloid leukemia fell from 48% in the 1987-1998 periods to 38% in the 1999- 2003 period [1]. In a more recent survey, the same investigators noted an attributable mortality of only 27% at 120 days [2]. Nivoix et al. in a series of mixed haematology-oncology patients found that survival was only 47% before 2002, but 60% after 2002 [3]. We conducted a retrospective, matched case-control study of IMD in patients with acute leukemia managed in our institution to determine the incidence and clinical outcomes of IMD, including its impact on one-year survival.

Materials and Methods

This was a retrospective, matched case-control study of IMD in patients with acute leukemia managed in our institution from 1st Jan 2004 to 31st Mar 2007. The Department of Haematology, Singapore General Hospital has had a Leukemia Registry from 2000. All patients with acute leukemia treated in our hospital were entered into the registry.

This registry was mined for all patients diagnosed with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and acute biphenotypic leukemia (ABL) within the study period. The following were excluded: patients who never received chemotherapy, and those who received only palliative chemotherapy. The case records (electronic and paper) of included patients were then reviewed-only those with ‘proven’ or ‘probable’ IMD were finally entered into our study as ‘cases’ [4]. Controls were patients with the same type of leukemia (according to WHO 2008 classification) who fulfilled the following criteria: their leukemia was diagnosed in the same month (± 1 month) as the case, and they were on chemotherapy at about the same time that the index case was diagnosed with IMD. The date of diagnosis of IMD was taken as the day on which an investigation yielded a result fulfilling a criterion for the diagnosis of IMD [e.g., a positive serum galactomannan (GM)]. For calculation of survival after IMD, the date of diagnosis in the control was the same as that in the matched case. The follow-up period for the purpose of the study was one year from the diagnosis of the IMD.

Paper and electronic records of cases and controls were reviewed for demographic, laboratory, and medication data. A diagnosis was captured from the casenotes and verified by the authors themselves. Computerised tomography scans of the thorax, abdomen and pelvis were ordered when chest x-rays (CXRs) were abnormal, when patients had persistent symptoms or signs despite normal CXR or for persistent febrile neutropenia beyond 96 hours of antibiotics treatment. All CT scans and X-rays were reviewed by two of the authors (BHT and GCW). Cut-offs for abnormal liver function tests and the oral bioavailability of itraconazole (ITC) were obtained from literature [5-7]. Neutropenia (unless otherwise specified) refers to an absolute neutrophil count (ANC) <500/mm3. Data were entered into a standardized data collection form. Episodes of IMD were counted. A patient with two episodes of IMD will contribute a count of two to the total number of IMD episodes. This study was approved by the hospital’s institutional review board (IRB). The setting up and maintenance of the Leukemia Registry were also approved by the hospital’s IRB.

During this period, patients undergoing chemotherapy were given ciprofloxacin as anti-bacterial prophylaxis. Most patients received oral itraconazole (ITC) for anti-fungal prophylaxis-the syrup formulation was recommended, but patients could receive the capsule formulation if they could not tolerate the syrup. The serum GM assay was not available in our hospital and was done at another laboratory [8]. The antibiotic protocol for the management of febrile neutropenia was amended slightly from the one we had previously published [9]. The recommended first-line antibiotic for febrile neutropenia was cefepime, with or without amikacin. If the patient was still febrile after 48 hours and cultures were negative, second-line antibiotics (imipenem or meropenem) could be started for patients who were unwell, after repeating a septic work-up. Vancomycin could be introduced if there was suspicion of line sepsis. Amphoterin B (amB) was the recommended anti-fungal agent for fever persisting beyond four days. The practice of sending bronchoalveolar lavage (BAL) fluid for GM was not routine then in our institution.

Statistics

Although 19 cases were found, only 15 had matched controls. For global data (baseline demographics and clinical features of IMD), data from all 19 cases are presented. Simple descriptive analyses were used for such purpose. For comparison data, only data from the 15 cases that had matched controls are presented. McNemar’s test and paired T-test for comparison of proportion and continuous variables were used for analysis of the 15 matched case-control pairs respectively. Survival analysis was carried out using Kaplan Meier test. Multivariate analysis for predictors of death was performed using Cox regression. A p-value of ≤ 0.05 was considered statistically significant.

Results

During this period, 19 cases of IMD were diagnosed. The demographics of cases and controls are shown in Table 1. The incidence of IMD in patients who received curative chemotherapy was 19/172 (11%); the incidence in patients receiving the first cycle of chemotherapy was 15/172 (8.7%).

  Cases(%) (n=19) Controls (%) (n=15)
Sex (male:female) 11:8 10:6
Age (median, range) 50.69 (19.0-62.8) 30.37(16.4-65.2)
Type of leukemia
AML
ALL

12(63.2)
7 (36.8)
    
10 (66.7)
5 (33.3)
Chemotherapy in admission in which IMI was diagnosed*^
Induction  
Consolidation
Mobilisation


15 (78.9)
4 (21.1)
0


9 (60.0)
5 (33.3)
1 (6.7)
Duration of neutropenia^
>/=14d
<14d

13 (86.7)
2 (13.3)

1 (6.7)
14 (93.3)
Duration ANC <100/mm3^  
>/=10d
<10d   
15 (78.9)
4 (21.1)
5 (33.3)
10 (66.7)
ANC at diagnosis of leukemia
>/=500/mm3 
<500/mm3 
8 (42.1)
11 (57.9)
13 (86.7)
2(13.3)
Absolute monocyte count #*
<120/mm3 
>120/mm3 
9 (47.4)
10 (52.6)

11 (73.3)
3 (20.0)
No. given FQ prophylaxis   9 (47.4) 9 (60)
No. given ITC prophylaxis 14 (73.7) 12 (80)
No. given syrup ITC 14 (73.7) 14 (93.3)
Anti-fungal prophylaxis >14days 5 (26.3) 8(53.3)
Median LOS (days) 46 (22-88) 23 (9-65)

Table 1: Baseline Demographics.

12 cases were ‘proven’ and 7 cases were “probable”. These are tabulated in Table 2. All cases underwent a diagnostic procedure, though the procedure was not yielding in all cases. A biopsy of suspicious skin lesions provided the diagnosis in 3 cases, a trans-bronchial biopsy in three, a trans-thoracic needle biopsy in four, a wedge resection of the lung in one, and a BAL in another. In nine of these cases, the procedure was performed after the platelet had risen above 80,000/mm3.

Patient No. Proven/Probable Criteria* met Additional comments
1 Proven Fusarium from skin biopsy Multiple skin nodules
2 Proven Fusarium from skin biopsy  
3 Proven Fusarium from blood culture A posthumous result -see text
4 Proven Aspergillus flavus from skin biopsy CT: Lung nodules with typical halo sign
5 Proven Blood and BAL fluid culture with Nodulisporum sp CT: Lung nodules with typical halo sign
6 Proven Lung biopsy with septate branching fungi CT: Lung nodules with cavitation
7 Proven Lung biopsy with septate branching fungi CT: Lung nodules with typical halo sign
8 Proven Lung biopsy with hyphae amidst necrotic lung Lung biopsy sample grew Conidiolobolus; hyphae also seen in microscopy of BAL fluid
9 Proven Lung biopsy with septate branching fungi, evidence of vessel invasion noted CT: Lung nodules with typical halo sign
10 Proven Lung biopsy: infarct with septate hyphae CT: Lung nodules with typical halo sign
11 Proven Lung biopsy with septate branching fungi CT: Lung nodules with typical halo sign
12 Proven Lung biopsy: infarct with septate hyphae CT: Lung nodules with typical halo sign
13 Probable Characteristic CT + serum GM  
14 Probable Characteristic CT + serum GM  
15 Probable Characteristic CT + BAL culture with Aspergillus  
16 Probable Characteristic CT + BAL culture with Aspergillus  
17 Probable Characteristic CT + BAL microscopy showing hyphae  
18 Probable Characteristic CT + serum GM  
19 Probable Characteristic CT + symptoms  

Table 2: Proven and probable cases of invasive mould disease [4].

The clinical features and treatment outcomes of patients with IMD are shown in Table 3. Treatment consisted of conventional amB or a lipid formulation started as part of a febrile neutropenia protocol in 13 case patients. When aspergillosis was considered, four case patients were given (voriconazole) VRC and three caspofungin (CAS). In six case patients (31.6%), defervescence was related to a rise in ANC to above 500/mm3. In two case patients (10.5%), defervescence was related to the introduction of VRC. In one patient (5.3%) it was related to the introduction of CAS and in another one (5.3%) it was related to control of bacterial infection. In seven patients (36.8%), defervescence was related to a combination of these factors.

  Cases (n=19)
Clinical
Fever not responding to 2nd-line antibiotics
Cough  
Pleuritic chest pain     
Breathlessness  
Hemoptysis  
Abnormal CXR without fever  
Hypotension
Asymptomatic- just a rising GM  
Sinusitis 
Pleural effusion on CXR or CT   
16 (84.7%)
8 (42.1%)
4 (21.1%)
5 (26.3%)
4 (21.1%)
1 (5.3%)
3 (15.8%)
1 (5.3%)*
1 (5.3%)
10 (52.6%)
MRI brain
Normal
Abnormal#   
Not done     
7 (36.8%)
3 (15.8%)
9 (74.4%)
Use of AmB or LAmB
Not given
Started as part of febrile neutropenia protocol 
Started when IMD considered
3 (15.8%)
13 (68.4%)
3 (15.8%)
Anti-fungal started when IMD [email protected]
AmB or Lamb
Voriconazole
Caspofungin
Combination
3 (15.8%)
4 (21.1%)
3 (15.8%)
1 (5.2%)
Further cycles of chemotherapy after IMD
0 ^
0?
1
2
3
>3
2 (10.5%)
3 (15.8%)
1 (5.3%)
2 (10.5%)
6 (31.6%)
5 (26.3%)
Delay in chemotherapy
No delay  
Delayed 2-4 weeks 
Delayed >4 weeks
8 (42.1%)
3 (15.8%)
6 (31.6%)
Eventual HSCT
Yes, autologous    
Yes, allogeneic   
4 (21.1%)
4 (21.1%)

Table 3: Clinical features of IMD in patients with acute leukemia.

Two case patients (10.5%) died in the index admission - both of these deaths were attributed to the IMD. One patient had Fusarium spp isolated from blood cultures posthumously. The other was receiving salvage chemotherapy when she developed pulmonary infiltrates. She died a few days after from massive pulmonary hemorrhage - histology (from a bronchoscopy performed a few days before death) revealed hyphae in the midst of necrotic debris.

Two patients (10.5%) did not have any outpatient antifungals for IMD-these were the 2 who died. Although 3 patients (15.8%) received oral VRC for entire duration of treatment, most of the others had VRC, CAS or amB followed by oral ITC. Oral ITC was continued for long periods (up to a year). One patient with disseminated fusariosis complicating ALL had oral POS as an outpatient, with LamB whenever she was admitted for chemotherapy.

When cases were compared with controls, neutropenia was a statistically significant risk factor for IMD (Table 4). In addition, no case patient had neutropenia of less than 10 days’ duration, and no control had neutropenia of more than 28 days’ duration. In fact, 14 of 15 controls had neutropenia <14 days’ duration. A bacteremia preceded the diagnosis of IMD more often in cases than in controls, but more cases than controls did not respond to broad-spectrum antibiotics.

  Cases (n=15) Controls (n=15) P-value
Age (Median) 50.69 30.37 0.14
ANC (/mm3)*
<500
≥ 500
9 (60%)
6 (40%)
2 (13.3%)
13 (86.7%)
0.05
Neutropenia duration^
≤14 days
>14 days
2 (13.3%)
13 (86.7%)
14 (93.3%)
1 (6.7%)
0.003
Absolute monocyte count# (/mm3)
<120
≥120
7 (46.7%)
8 (53.3%)
11 (73.3%)
4 (26.7%)
0.22
Steroid use in the year prior to the diagnosis of leukemia
Yes
No
0
15
1 (6.7%)
14 (93.3%)
1.00
DM
Yes
No
2 (13.3%)
13 (86.7%)
1 (6.7%)
14 (93.3%)
1.00
ITC prophylaxis^
Yes
No
11 (73.3%)
4 (26.7%)
12 (86.7%)
3 (13.3%)
1.00
ITC bioavailable daily dose^
≤200mg/day
>200mg/day
11α
0
14α
0
0.25
Bacteremia prior to diagnosis of IMI^
Yes
No
8 (53.3%)
7 (46.7%)
1 (6.7%)
14 (93.3%)
0.05
Fever unresponsive to 2nd line antibiotics
Yes
No
13 (86.7%)
2 (13.3%)
4 (26.7%)
11 (73.3%)
0.02
Cough
Yes
No
5 (33.3%)
10 (67.7%)
4 (26.7%)
11 (73.3%)
1.00
Length of stay
Mean, days
Range, days
51.8
29-88
27.2
9-65
0.01
Survival
At 3 months
At 12 months
14 (93.3%)
7 (46.7%)
14 (93.3%)
14 (93.3%)
0.007

Table 1: Baseline Demographics.

The one-year survival curves of cases and controls are shown in Figure 1. Because of the stark difference in mortality at 12 months (log-rank p value=0.007), we performed a Cox regression analysis to identify possible independent risk factors for mortality. On univariate analysis, factors that predicted death at 12 months included older age at diagnosis of leukemia, being a case (i.e. the presence of an IMD), prolonged neutropenia of ≥ 28 days, and the lack of an HSCT following the diagnosis of an IMD (Table 5). However Cox regression failed to identify variables that independently accounted for this difference in survival.

blood-disorders-transfusion-Kaplan-Meier-Survival

Figure 1: Kaplan-Meier Survival Curve of cases and controls.

Independent Risk Factors Mortality at 12 Months P-value
Death=9 (%) Alive=21 (%)
Age (yr) 53.6 ± 13.7 38.6 ± 15.0 0.02
Gender
Male 
5 (56) 15 (71) 0.43
Presence of at least one co-morbidity* 3 (33) 3 (14) 0.33
Neutropenia duration
³28 days
5 (56) 3 (14) 0.03
Development of new renal failure 0 (0) 2 (10) 1.00
Steroid use in the year prior to the diagnosis of leukemia 0 (0) 1(5) 1.00
steroids use > 3 wks in previous 60days 1 (11) 0 (0) 0.30
Any bacteremic  episode 5 (56) 7 (33) 0.42
ICU stay 2 (22) 1 (5) 0.21
Relapse disease 4 (44) 5 (24) 0.082
Received HSCT 1 11 0.05
IMD diagnosis 8 (89) 7 (33) 0.01

Table 5: Risk factors for death at 12 months (univariate analysis).

Discussion

This study allowed us to better understand the clinical characteristics and outcomes of IMD in patients undergoing chemotherapy for acute leukemia in our hospital.

We adopted the matched case-control approach because we had not, at that time, standardized our antifungal prophylaxis. In addition, we recognized that there were no definitive guidelines for anti-fungal therapy in febrile neutropenic patients then. Although we did not match for age, the difference in age between cases and controls was not statistically significant. Despite a seemingly difference in the ages of cases and controls in (Table 1), this table merely shows a pooled median age. The insignificant p value in Table 4 indicates that, on a matched basis (case vs. control) the age difference was not statistically significant. This study had 31 March 2007 as the end-date because a consensus on antifungal prophylaxis was reached in the department in the first quarter of 2007. For classification of proven and probable cases, we used the older EORTC/MSG guide as it was the prevailing guideline then; the newer guide was only published in 2008 (after the period covered by the study) [10].

We did not limit the infections studied to IA for several reasons. There were then increasing reports of non-Aspergillus moulds causing invasive disease in immune compromised persons [11-13]. Anecdotally, we knew that non-Aspergillus moulds surfaced time and again. This series validates our suspicions - of the proven cases, only one was culture positive for Aspergillus. On the other hand, if any microbiologic manifestation (serum GM, BAL cultures etc) was taken as evidence of IA, which is in line with guidelines, then 8 of the 19 cases were cases of IA [4,10]. This makes IA the commonest IMD in this series, a finding consistent with that of other series.

The clinical features of the cases point out several manifestations of IMD that may be diagnostically helpful. Only four cases had pleuritic chest pain, but no control had this symptom. Prolonged fever, not responding to carbapenems, was the commonest manifestation. In an era in which most experts advise restraint with antibiotic use, this point is worthy of re-emphasis because, in the absence of an outbreak of drug-resistant bacteria, it may be more prudent to search for a fungal infection than initiate a change of antibiotics. Prolonged neutropenia was a risk factor for the development of an IMD, as is well-known. Eight of the cases had neutropenia in excess of 28 days, and no control had neutropenia of this duration. A bacteremia preceded the diagnosis of an IMD more often in cases than controls. The best explanation for this is not known, but recent data suggest that there might be a genetic susceptibility to infection [14].

In this study, ITC did not protect our patients against IMD, even though ITC, in a meta-analysis, did reduce mortality from invasive fungal infections and the rate of IA, in patients treated for haematologic malignancies [7]. This could be due to the fact that none of our patients received a bioavailable daily dose in excess of 200 mg/day, a level found by investigators to be protective [7]. An Italian review of IA in patients with haematologic malignancies (prior to the availability of POS) similarly found that IA developed in two-thirds of patients given anti-Aspergillus prophylaxis [2]. ITC therapeutic drug monitoring is not available at our centre - its future availability may allow dose adjustments that may improve its efficacy. As a result of ward layout, very few patients were nursed in HEPA-filtered rooms. The provision of HEPA-filtered air has been recognized as an important measure in the prevention of IA in haematological patients [15,16].

Like other authors, we suspect that the low 12-week mortality in our series was related to the improved efficacy and tolerability of CAS and VRC. We based this on the fact that our patients who died did not receive either of these drugs. However, a bigger cohort of patients may help to elucidate this better. In an Austrian survey of IA, crude 12-week mortality was 34%. The authors noted that recipients of VRC had improved survival [17]. Pagano et al. similarly attributed lower mortality rates in more recent series to improved diagnostics and a better treatment armamentarium [2].

Although the 12-week survival among patients with IMD was quite good, this review shows that getting an IMD was associated with some degree of morbidity. Cases tended to have fever that did not respond to second-line antibiotics, required invasive procedures, stayed longer during the index admission, and required long periods of anti-fungal agents. A good proportion of patients had their chemotherapy delayed. These suggest that preventing an IMD, or detecting it early, will have benefits.

Despite the impressive 12-week survival, one-year survival was much poorer in cases than controls. To understand this, we analyzed a large variety of variables as predictors of death at 12 months. As mentioned, only older age at diagnosis of leukemia, prolonged neutropenia (≥ 28 days), the presence of an IMD, and the lack of an HSCT predicted death in the univariate analysis. None of these reached statistical significance as independent predictors of death on Cox regression but being a case trended towards a higher mortality risk. The small numbers in this series likely prevented a truly significant association to be found. We hypothesize that prolonged neutropenia contributed to IMD, which, by way of its difficult (and perhaps stormy) clinical course, may have led patients and their physicians to delay or even shy away from further intensive chemotherapy and HSCT. This could have contributed to the significance of ‘relapsed disease’ and ‘lack of HSCT’ in the univariate analysis.

The data suggest that most deaths caused by IA occur in the early weeks after diagnosis [18]. Although a three-month follow-up may be appropriate for evaluating the efficacy of an anti-fungal agent, a longer follow-up may be needed to understand the true impact of IMD on long-term outcomes in patients with acute leukemia. In this series, only two deaths were directly attributable to an IMD and both occurred early. This is consistent with the literature. What is of concern is the finding that patients with an IMD did poorly when followed up for one year. We are unable to tease out the factors contributing to this dismal one-year outcome. If indeed an IMD per se is contributory, then efforts to prevent an IMD become paramount in the management of patients with acute leukemia.

One limitation of this study is that mutations, with their well-known implications on survival in AML, were not factored into the survival analysis [19,20]. The reason that we were unable to include them is that they became available in our hospital at different times in the years covered by the study, hence they were not available for all patients. The full significance of the impact of these mutations on survival may be said to have been elucidated fairly recently. Given the small size of our study, it is doubtful if a statistically significant association could have been drawn between any of the mutations and survival.

While recognizing this non-inclusion of mutations in the survival analysis, we note that the studies of Shen et al. and Schlenk et al. did not consider the possible impact of an IMD on survival [19,20].

In summary, this review of IMD in patients with acute leukemia has shown that prolonged neutropenia is a risk factor for IMD and that Aspergillus was the commonest cause of an IMD in our patients. Although three-month survival in patients with an IMD was good, an IMD appeared to predict mortality at 12 months. A bigger study to understand the reasons for the observed poor outcome at 12 months is needed.

Conflicts of Interest

BH Tan has spoken at symposia organized by Pfizer and MSD. The others report no conflicts of interest.

Funding

NL Chlebicka was supported by the SingHealth Foundation. The other authors are employees of the Singapore General Hospital. The study per se was not funded.

References

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