Invasive Fungal Infection Following Reduced-Intensity Cord Blood Transplantation for Adult Patients with Hematologic Diseases

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Data Collection
  • Transplantation Procedures and Supportive Cares
  • Management of Infections
  • Diagnostic Criteria for IFI
  • Endpoints and Statistical Analysis
• Results
  • Clinical Outcomes after RICBT
  • Incidence and Clinical Features of IFI
  • Risk Factors of IPA
• Discussion
• References
• Copyright

Abstract 

Invasive fungal infection (IFI) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT); however, we have little information on its clinical features after reduced intensity cord blood transplantation (RICBT) for adults. We reviewed medical records of 128 patients who underwent RICBT at Toranomon Hospital between March 2002 and November 2005. Most of the patients received purine-analogbased preparative regimens. Graft-versus-host disease (GVHD) prophylaxis was a continuous infusion of either tacrolimus 0.03 mg/kg or cyclosporine 3 mg/kg. IFI was diagnosed according to the established EORTC/NIH-MSG criteria. IFI was diagnosed in 14 patients. Thirteen of the 14 had probable invasive pulmonary aspergillosis and the other had fungemia resulting from Trichosporon spp. Median onset of IFI was day 20 (range: 1-82), and no patients developed IFI after day 100. Three-year cumulative incidence of IA was 10.2%. Four of the 13 patients with invasive aspergillosis (IA) developed grade II-IV acute GVHD, and their IA was diagnosed before the onset of acute GVHD. The mortality rate of IFI was 86%. Multivariate analysis revealed that the use of prednisolone >0.2 mg/kg (relative risk 7.97, 95% confidence interval 2.24-28.4, P = .0014) was a significant risk factor for IA. This study suggests that IFI is an important cause of deaths after RICBT, and effective strategies are warranted to prevent IFI.

Key Words: Invasive aspergillosis, Graft-versus-host disease, Corticosteroid

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Introduction 

Cord blood transplantation (CBT) is an attractive alternative for patients with hematologic diseases who lack a matched related or unrelated donor. The usefulness of CBT using myeloablative preparative regimens has been confirmed for pediatric patients [1, 2]. Myeloablative CBT for adult patients achieves engraftment in 90% of the patients, but carries 50% risk of transplant-related mortality (TRM), mostly resulting from infection [3, 4]. We and other groups have reported the feasibility of CBT using reduced-intensity regimens (RICBT) for adult patients with advanced hematologic diseases [5, 6].

Because of delayed immune recovery and graft-versus-host disease (GVHD), infection is the leading cause of TRM after CBT using myeloablative preparative regimens [2, 3, 4, 7]. However, studies on immune recovery following RICBT gave us hope that RICBT recipients may less frequently experience GVHD and infectious complications. Invasive fungal infection (IFI) has been 1 of the most feared infectious complications in conventional allogeneic marrow or peripheral blood stem cell (PBSC) transplantation [8, 9], whereas we have little information on IFI following RICBT. We investigated its incidence and clinical features in patients who underwent RICBT for advanced hematologic diseases.

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Patients and Methods 

Data Collection 

We reviewed medical records of 128 recipients who underwent first reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) using cord blood (CB) between March 2002 and November 2005 at Toranomon Hospital. Their characteristics are shown in Table 1. Of the 128 patients, 101 had high-risk diseases including acute myelogenous leukemia (AML) in relapse or the second and higher complete remission (CR; n = 42), acute lymphoid leukemia (ALL) except those in the first CR (n = 12), chronic myelogenous leukemia (CML) in blastic phase (n = 4), myelodysplasia except refractory anemia (n = 10), refractory lymphoma (n = 30), idiopathic myelofibrosis (n = 1), plasma cell leukemia in relapse (n = 1), and chronic myelomonocytic leukemia (n = 1).

Table 1. Patients’ Characteristics and Transplantation Procedures

Variables	Number
Patients Characteristics
Age, median (range)	56 (17-71)
Sex, male/female	80/48
Primary diseases
AML/MDS	63
Malignant lymphoma	33
Acute lymphoblastic leukemia	17
Severe aplastic anemia	6
Chronic myelogenous leukemia	6
Chronic myelomonocytic leukemia	1
Plasmacytic leukemia	1
Idiopathic myelofibrosis	1
Risk of underlying diseases,⁎1 high/low	101/27
Prior autologous stem cell transplant, yes/no	9/119
Transplantation procedures
Conditioning regimen
Flu + Mel + TBI 2 Gy or 4 Gy/8 Gy	112/2
Flu + BU + TBI 4 Gy/8 Gy	8/1
Others	5
GVHD prophylaxis, cyclosporine/tacrolimus	64/64
Number of infused nucleated cell, median (range) ×107/kg	2.7 (1.6-4.8)
HLA disparity (antigen), 2/1/0	108/17/3
Transplantation outcomes
Neutrophil engraftment	99/128
Complete donor chimerism⁎2	90/99
Grade II-IV acute GVHD⁎2	45/99
Chronic GVHD⁎3⁎4	11/40
CMV antigenemia⁎3	48/93
CMV disease	10
Relapse⁎2	24/98

AML indicates acute myelogenous leukemia; MDS, myelodysplastic syndromes; ULN, upper limit of normal; GVHD, graft-versus-host disease; CMV, cytomegalovirus.

Transplantation Procedures and Supportive Cares 

Transplantation procedures were shown in Table 1, and we previously reported details of the procedures [6]. GVHD prophylaxis was either tacrolimus 0.03 mg/kg or cyclosporine 3 mg/kg continuous infusion starting on day −1. Trough blood levels of these drugs were monitored 2-3 times a week and the dosage were modified to maintain the target level of 10-15 ng/mL for tacrolimus and 200-400 ng/mL for cyclosporine [10, 11, 12]. Immunosuppressants were tapered off from day 100 until day 150. If grade II-IV acute GVHD (aGVHD) developed, 1-2 mg/kg/day of methylprednisolone was added to cyclosporine or tacrolimus, and tapered from the beginning of clinical response.

The diagnosis and management of preengraftment immune reactions were reported previously [13].

Management of Infections 

Patients were managed in reverse isolation laminar airflow-equipped rooms. All patients received tosufloxacin 450 mg/day from the start of conditioning until neutrophil engraftment. Fluconazole 200 mg/day or micafungin 150 mg/day, and acyclovir 600 mg/day were given from the start of conditioning until the discontinuation of GVHD prophylaxis, which were restarted when patients developed GVHD and were treated with steroids and immunosuppressants. They received prophylaxis with trimethoprim-sulfamethoxazole against Pneumocystis jirovecii infection from the start of conditioning until the discontinuation of immunosuppressants or disappearance of chronic GVHD (cGVHD). When patients develop neutropenic fever, tosufloxacin was changed to broad-spectrum antibiotics [14]. Intravenous administration of amphotericin B at a dose of 0.5 mg/kg/day was added when the fever persisted for more than 5 to 7 days. If the diagnosis of aspergillus infection was confirmed, the dosage of amphotericin B was increased to 1.0 mg/kg/day. We used blood tests, enzyme-linked immunosorbent assay for galactomannan antigen, (1-3)-beta-D glucan assay, and chest computed tomography for the early diagnosis of invasive aspergillosis (IA), as previously reported [15]. Because most patients had been heavily treated and received multiple transfusions prior to transplantation, anti-CMV antibodies were not examined before transplantation. All patients were monitored for cytomegalovirus pp65 antigenemia once a week. When CMV antigenemia exceeded 10/50,000, patients preemptively received foscarnet 30 mg/kg intravenously twice daily.

Diagnostic Criteria for IFI 

Invasive fungal infection was diagnosed according to the established EORTC/NIH-MSG criteria [16]. Briefly, we diagnosed patients as having proved IFI when any 1 of the following examinations was positive: histopathologic or cytopathologic examinations for hyphae or yeasts in needle aspiration or biopsy specimens, fungal cultures obtained from normally sterile sites by sterile procedures, and Cryptococcus antigen in cerebrospinal fluid. Probable IFI was diagnosed when a patient satisfied at least 1 host factor, microbiologic criteria, and clinical criteria. Possible IFI was not included in this study. The day of diagnosis of IFI was defined as the day when the first diagnostic test was performed.

Endpoints and Statistical Analysis 

The cumulative incidence of IA was evaluated using Gray’s method, considering death without IA as a competing risk [17].

Potential confounding factors considered in the analysis of risk factors of IA were age, sex, disease status, previous stem cell transplantation, conditioning regimens, HLA mismatch, stem-cell dose (all nucleated cells, and CD 34-positive cells), GVHD prophylaxis, grade II-IV aGVHD, and use of prednisolone. Proportional hazard modeling was used to evaluate the influence of these factors on the incidences of IA treating the development of aGVHD and the use of prednisolone as time-dependent covariates. Factors associated with at least borderline significance (P < .10) in the univariate analyses were subjected to a multivariate analysis using backward stepwise proportional-hazard modeling. P-values of <.05 were considered statistically significant. Survival was estimated by the Kaplan-Meier method. Median follow-up of surviving patients was 628 days (range: 26-1347 days).

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Results 

Clinical Outcomes after RICBT 

Ninety-nine (77%) patients achieved primary engraftment at a median of day 20 (range: 9-53 days). Of the remaining 29 patients who failed to achieve primary engraftment, 4 patients received second RICBT, and the other 25 patients died before engraftment. Their causes of death included bacteremia (n = 22), invasive pulmonary aspergillosis (IPA) (n = 1), and progression of primary disease (n = 2). Of the 99 engrafted patients, 45 and 22 patients developed grade II and grade III-IV aGVHD, respectively. The median onset of grade II-IV aGVHD was day 28 (range, 11-92). Eleven of 40 patients (28%) who survived longer than 100 days without disease progression developed cGVHD. Estimated 3-year overall survival was 33% (95% confidence interval (95% CI), 24%-42%). Causes of deaths comprised nonrelapse mortality (n = 31) and disease progression (n = 23). Infection was the leading cause of nonrelapse mortality (n = 20). Autopsy was performed in 5 patients (3.9%) in this series of patients.

Incidence and Clinical Features of IFI 

Invasive fungal infection was diagnosed in 14 patients. Their clinical features are shown in Table 2. Thirteen of the 14 patients had probable IA, and the other had fungemia from Trichosporon spp. Three-year cumulative incidence of probable IA was 10.2% (Figure 1). Median onset of IFI was day 20 (range: 1-82), and no patients developed IFI after day 100. IFI was diagnosed after day 30 in 1 patient. Prophylactic uses of antifungal agents included fluconazole (n = 12) and micafungin (n = 1) among the 13 patients with IA. Of the 63 patients who survived 100 days or longer, none developed IFI after day 100. Four of the 13 patients with IFI developed grade II-IV aGVHD, and their diagnosis of IFI was before the onset of aGVHD (Table 2).

Table 2. Clinical Characteristics of Patients with Invasive Aspergillosis

UPN	Age	Sex	Primary Disease	Disease Status at Transplant	No. of Prior Regimens	Neutrophil Engraftment Day	Grade II-IV Acute GVHD Onset Day	PSL Started	Invasive Fungal Infection (IFI)*1	Onset (Day)	Other Infectious Complication	Overall Survival (Day)	Outcomes of IFI	Causes of Death
286	57	M	AML	PIF	3				Probable IA	4		4	dead	IFI
365	69	M	AML	RL1	3				Probable IA	3		14	dead	IFI
411	56	F	ML	PD	1			11	Probable IA	19	Bacteremia	24	dead	Bacteremia complicated with IA
196	61	M	AML	PIF	2	11	22		T. cutaneum fungemia	1		28	dead	IFI
202	62	M	AML	RL1	4	21	21	8	Probable IA	21	Bacteremia	28	dead	Bacteremia complicated with IA
344	55	F	ML	PD	1	19			Probable IA	4	Bacteremia	30	dead	IFI
262	59	M	AML	PIF	1			10	Probable IA	20		31	dead	PD
151	52	F	MDS	RAEB	3	20		7	Probable IA	12		33	improved	GI bleeding
114	52	F	ML	PD	4	13		0	Probable IA	23		39	dead	PD
153	70	M	AML	1stCR	2	14	30		Probable IA	29	Bacteremia	46	dead	IP
197	33	M	MDS	RA	0				Probable IA	28	Bacteremia	47	dead	Bacteremia complicated with IA
160	66	M	ML	PD	2	14	29	9	Probable IA	25		75	dead	MOF
120	70	F	SAA		0	13			Probable IA	82		1308+	improved
127	20	M	SAA		3	31	55	12	Probable IA	3		1347+	improved

AML indicates acute myelogenous leukemia; MDS, myelodysplastic syndromes; CR, complete remission; GI, gastrointestinal; IA, invasive aspergillosis; IFI, invasive fungal infection; SAA, severe aplastic anemia; RA, refractory anemia; PD, progressive disease; PIF, primary induction failure; RARB, refractory anemia with excess of blasts; MOF, multiple organ failure.

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• Figure 1. 

  Cumulative incidence of invasive aspergillosis (IA) considering death without IA as a competing risk. Black line indicates incidence of death with IA, and gray line indicates incidence of death without IA.

Seven patients were given prednisolone >0.2 mg/kg/day for the treatment of preengraftment immune reactions, of whom 5 developed grade II-IV aGVHD. Twelve of the 14 patients with IFI died, and the mortality rate was 86%. IFI was the primary cause of deaths in 4 patients.

Risk Factors of IPA 

Table 3 shows the results of univariate and multivariate analyses. Reactivation of cytomegalovirus (CMV) is a well-known risk factor of IA [18, 19]. However, it was not included in the analysis of this study, because the onset of IFI was earlier than the onset of CMV antigenemia. Use of prednisolone >0.2 mg/kg (relative risk [RR], 7.97; 95% CI, 2.24-28.4; P = .0014) was a significant risk factor in multivariate analysis.

Table 3. Univariate and Multivariate Analyses for the Incidence of IA

	Incidence of IPA (95% CI)	P Value
Univariate analysis
Pretransplantation factors
Age		.30
<55	7%
≥55	13%
Sex		.94
Female	11%
Male	10%
Disease risk		.63
Standard	16%
High	9%
Previous ASCT		.55
No	11%
Yes	0%
Regimen		.72
FM-based	11%
FB-based	10%
HLA mismatch		.076
0 or 1 antigen	0%
2 antigens	12%
Cell dose		.42
ANC <2.5 × 107/kg	8%
ANC ≥2.5 × 107/kg	12%
Cell dose		.03
CD34 <0.8 × 106/kg	5%
CD34 ≥0.8 × 106/kg	16%
GVHD prophylaxis		.42
Cyclosporine	13%
Tacrolimus	8%
Fungal prophylaxis		.99
Fluconazole	10%
Micafungin	10%
Posttransplantation factors (time-dependent covariates)
Acute GVHD		.96
Grade 0-I	1.00
Grade II-IV	1.06(0.12-9.40)
Prednisolone		.001
<0.2 mg/kg/day	1.00
≥0.2 mg/kg/day	7.97(2.24-28.4)
Multivariate analysis
Prednisolone		.0014
<0.2 mg/kg/day	1.00
≥0.2 mg/kg/day	7.97(2.24-28.4)

GVHD indicates graft-versus-host disease; ASCT, autologous stem cell transplantation.

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Discussion 

The present study demonstrated that IFI early after RICBT is a significant complication. Among IFI, the incidence of IA was high, which was consistent with the studies on reduced intensity stem cell transplantation (RIST) using other stem cell sources [9, 19]. Our results contrasted with the previous reports that the incidence of infection because of non-Candidia albicans species was high in myeloablative allogeneic stem cell transplantation [20]. The observations may be associated with the milder gastrointestinal mucosal toxicity by conditioning regimens in RIST than in myeloablative transplantation [21] and the less frequent and milder GVHD following CBT. Because gastrointestinal mucosal toxicity is milder in RICBT than in myeloablative transplantation, the incidence of infection from non-Candida albicans species as part of the gastrointestinal normal flora might be low, and hence aspergillus infection might become the majority of IFI.

The median onset of IFI was day 20 (range: 1-82) in the present study; the majority developed IFI early after RICBT. Majority of the patients who developed IFI died of causes other than fungal infection (Table 2), as reported previously by Saavedra et al. [7]. Our results were consistent with a previous report on CBT [18], and contrasted to reports on RIST using marrow or peripheral blood [19, 22, 23], in which IA develops late after transplantation. The low incidence of IA after day 100 would be related to the low incidence of cGVHD. The short duration from RICBT to IFI development suggests aggravation of latent infection, which would have existed before transplantation. These findings were consistent with a recent report by Martino et al. [23]. Given the possibility, several issues need to be addressed in the management of IFI following RICBT. First, selection of RICBT candidates would have to include accurate evaluation for the risk of fungal infection [24] and high-risk patients might need to be excluded from the indication of RICBT. Pretransplant CT scan of the chest and sinus would be useful in the screening of IA following RICBT, and bronchoalveolar lavage should be performed in patients with abnormal findings. Second, the importance needs to be stressed in prophylactic antifungal agents with antiaspergillus activity and attempts for early diagnosis of aspergillosis such as methods using molecular techniques [25], antigen tests [26], and imaging tests [15, 22]. Third, the way of steroid use after RICBT requires further investigations. The present study showed that the administration of steroids 0.2 mg/kg and more was a strong risk factor of IA (RR, 7.97; 95% CI, 2.24-28.4; p = .0014). Our observation that the use of small-dose steroids was a risk factor of IFI after RICBT supports the previous results of severe immunosuppression early after RICBT [27]. In RICBT using our regimens, immunologic reactions such as a preengraftment immune reaction frequently develops in addition to GVHD, requiring steroid administration early after RICBT [13]. Because steroids suppress phagocyte activities and cellular immunity [28], the risk of fungal infection early after RICBT may be increased.

The incidence of late IFI was not high in the present study. Of 102 patients who survived longer than 30 days, 1 patients developed IFI after day 30. None of 63 patients who survived longer than 100 days developed IFI after day 100. Our results contrast with the previous reports on BMT and PBSC transplantation where improvement in fungal management decreased early IFI and late IFI became the majority of IFI [8, 19, 22, 29]. In myeloablative CBT, late infection is considered a significant complication [4], whereas study results focused on fungal infection have not been published. Some hypotheses can explain the low incidence of late IFI after RICBT. First, cGVHD after RICBT is uncommon and mild. There is minimal effect of cGVHD on delay in immune recovery following RICBT. Second, steroids are not frequently administered late after RICBT for the treatment of complications such as GVHD. The incidence of cGVHD was 28% in the present study, and none of them required steroid treatments. Further studies are awaited for the clinical features of late IFI after RICBT.

The present study demonstrated clinical features of fungal infections after RICBT, leaving several issues to be investigated. First, the present study is a small-sized retrospective 1 . Unrecognized bias might affect the study results, and we obtained little information on rare fungal infections such as Fusarium and Zygomycetes. Large-sized prospective studies are awaited. Second, the diagnostic yields of IFI need to be addressed. Most of the diagnoses in our study were made based on EORTC/MSG criteria [16] using clinical, laboratory, and imaging findings. Although the clinical usefulness of the diagnostic criteria has been established, pathologic diagnosis of IFI was not confirmed in many patients and the diagnostic yields remain unclear. Underestimation of IFI incidence also remains possible, because postmortem examinations were not obtained in most patients who died without diagnosis of IFI. Because such limitations cannot be avoided in studying deep fungal infections [30], clinicians need to be aware of the limitations.

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