ASIA-PACIFIC HEMATOLOGY CONSORTIUM
Fungal infections in hematology patients:
advances in prophylaxis and treatment
Vincent CC Cheng
MBBS (HK), MD (HK), PDipID (HK), MCRP (UK), FRCPath (UK),
FHKCPath, FHKAM (Path)
Department of Microbiology
Queen Mary Hospital
Mortality from invasive fungal infection in patients
with acute leukemia and HSCT
(40-50%)
(>70%)
Phases of opportunistic infections among allogeneic HCT recipients
Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238.
Concentrations of Amphotericin B deoxycholate in tissues of 13 cancer patients
Standard dose 1 mg / kg / day (BW 50 kg)
Liver
50 mg per day
Spleen
Kidney
Lung
MIC level
10 days
20 days
Antimicrob Agents Chemother. 1989 Mar;33(3):362-8.
Time line of development
of antifungal agents
Caspofungin
Voriconazole
Posaconazole
14
12
10
8
6
4
5-FC
2
0
1950
1960
1970
Micafungin
Anidulafungin
L-AmB
ABCD
ABLC
Terbinafine
Itraconazole
Fluconazole
Ketoconazole
Miconazole
1980
1990
2000
(1999 - 2007)
Persistent neutropenic fever
Prophylaxis
Known pathogen therapy
Liposomal Ampho B
Posaconazole
Voriconazole
vs
vs
vs
Ampho B deoxycholate
Fluconazole
Ampho B deoxycholate
(GVHD)
(Aspergillus)
Caspofungin
vs
Posaconazole
Caspo
Anidula
vs
vs
vs
Ampho B
Flucon
vs
Fluconazole or
itraconzole
(Candida)
(Candida)
Liposomal Ampho B
(AML / MDS)
Liposomal Ampho B
Voriconazole
Intermediate risk (high intermediate)
Fungal colonization at 1 site with neutropenia 0.1-0.5x109/L for 3-5 wk
Fungal colonization at > 1 site
AML
Total body irradiation
Allogeneic matched sibling donor BMT
Intermediate risk (low intermediate)
Neutropenia 0.1-0.5x109/L < 3 wk
Antibiotics + lymphopenia <0.5x109/L
Older age
Presence of a central venous catheter
Low risk
Autologous BMT
Lymphoma
Childhood AML
Transpl Infect Dis. 2009 Dec;11(6):480-90; Br J Haematol. 2000 Aug;110(2):273-84.
Degree of neutropenia, diagnosis, type of transplant, exposure to
corticosteroids, type of chemotherapy, and prior fungal colonization
were the major criteria used for stratification
Risk group stratification for development of invasive fungal infections in patients
with hematologic malignancies +/- hematopoietic cell transplant
High risk
Prolong neutropenia (<0.1x109/L for 3 wk and / or <0.5x109/L for 5 wk)
Allogeneic unrelated or mismatched BMT
GVHD
High dose Arabinose-C
Corticosteroids > 1/mg/kg with neutropenia <0.1x109/L over 1 wk
Corticosteroids > 2 mg/kg over 2 wk
Risk Based approach in antifungal treatment
Risk group
High
Intermediate
(high)
Intermediate
(low)
Low
Prophylaxis Pre-emptive
Yes
Empirical
Yes
Targeted
Yes
Yes
Yes
Yes
?
Yes
Yes
?
Yes
Yes
Degree of neutropenia, diagnosis, type of transplant,
exposure to corticosteroids, type of chemotherapy, and
prior fungal colonization
were the major criteria used for stratification
Br J Haematol. 2000 Aug;110(2):273-84.
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies
and Hematopoietic cell transplant
Study
Patients
Design
Regimen
Outcome
Fluconazole
Goodman et
al (1992)
356 (allo/
auto BMT)
RCT
(double
blinded)
FLU 400 mg qd po vs
placebo
IFI: FLU ↓
Mortality: FLU ↓
Winston et al
(1993)
257 acute
leukemia
patients on
chemo
RCT
(double
blinded)
FLU 400 mg qd po or
200 mg bd iv vs
placebo
IFI: No diff (3 cases
of Aspergillus in
both arms)
Mortality: no diff
Slavin et al
(1995)
300 (allo/
auto BMT)
RCT
(double
blinded)
FLU 400mg qd po vs
placebo
IFI: FLU ↓
Mortality: FLU ↓
Rotstein et al
(1999)
304 (44% auto
BMT)
RCT
(double
blinded)
FLU 400mg qd po vs
placebo
IFI: FLU ↓
Mortality: FLU ↓
Goodman JL, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326 (13): 845-851.
Winston DJ, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind, multicenter
trial. Ann Intern Med 1993; 7 (118): 495-503.
Slavin MA, 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 (6): 1545-1552.
Rotstein C, et al. Randomized placebo controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic
therapy. Clin Infect Dis 1999; 28 (2): 331-340.
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies
and Hematopoietic cell transplant
Study
Patients
Design
Regimen
Outcome
Itraconazole
Morgenstern
et al (1999)
445 (includes
autologous
and BMT) &
HM patients
Openlabel
Huijgen et al
(1999)
213 patients
RCT
(57% auto BMT; (double
31% HM on
blinded)
chemo
ITR 2.5 mg/kg
cyclodextrin solution
bd po vs FLU 100 mg
suspension qd po
IFI: No diff
Mortality: ITR ↓
ITR 100 mg bd po vs
FLU 50 mg bd po
IFI: No diff
Mortality: no diff
Harousseau et 557 HM
al (2000)
patients (5%
BMT)
RCT
(double
blinded)
ITR 2.5 mg/kg
IFI: No diff
solution bd po vs AMB Mortality: No diff
500 mg capsule qid po
Marr et al
(2004)
Openlabel
ITR 2.5 mg/kg
solution td po or 200
mg iv qd vs FLU 400
mg po or iv qd
304 (allo BMT)
IFI: ITR ↓
Mortality: No diff
Morgenstern GR, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological alignancies.
Br J Haematol 1999; 105 (4): 901-911.
Huijgens PC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999; 52 (5): 376-380.
Harousseau JL, et al. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a
randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother 2000; 44 (7): 1887-1893.
Marr KA, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103 (4): 1527-1533.
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies
and Hematopoietic cell transplant
Study
Patients
Design
Regimen
Outcome
Ullmann et al 600 (allo BMT)
(2007)
RCT
(double
blinded)
POS 200 mg
suspension td po vs
FLU 400 mg qd po
IFI: POSA ↓
Mortality: POS ↓
Cornely at al
(2007)
602 AML or
MDS
patients on
chemotherapy
RCT
(evaluator
blinded)
POS 200 mg
suspension td po vs
FLU 400 mg
suspension qd po or
ITR 200 mg solution
bd po
IFI: POSA ↓
Mortality: POS ↓
889 (46% auto
BMT, 54%
Allo BMT)
RCT
(double
blinded)
MICA 50 mg iv qd vs
FLU 400 mg iv qd
IFI: MICA↓
Mortality: No diff
Posaconazole
Micafungin
van Burik et
al (2004)
Ullmann AJ, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356 (4): 335-347.
Cornely OA, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356 (4): 348-359.
van Burik JA, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem
cell transplantation. Clin Infect Dis 2004; 39 (10): 1407-1416.
A randomized, double-blind trial comparing
voriconazole (200 mg twice daily) vs fluconazole (400 mg daily)
in allograft recipients >2 years of age considered to be at standard risk of IFI
Prophylaxis:
at least 100 days
extended to 180 days if
receiving prednisone (>1 mg/kg daily)
and/or CD4 cells <200/µL
Serum galactomannan levels &
intensive diagnostic process
Fungal-free survival:
78% with voriconazole (6 mo)
75% with fluconazole (6 mo)
64% with voriconazole (12 mo)
65% with fluconazole (12 mo)
Wingard JR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal
infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116: 5111–5118.
Patient risk stratification and treatment recommendations for primary antifungal
prophylaxis in haematology patients as per the ECIL-3 (3rd European Conference
on Infections in Leukemia) guidelines
Serum drug concentrations of posaconazole and itraconazole be
monitored to ensure therapeutic levels of these agents
Maertens J, 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 2011; 46: 709–718.
Empirical antifungal therapy: fever-driven approach
Empirical antifungal therapy:
• Targets haematology patients that have prolonged neutropenia
• Persistent or relapsing fever despite 4–7 days of adequate broad spectrum
antibiotics
• Absence of
other clinical symptoms/signs,
conventional radiological and laboratory findings
specific investigations aimed at documenting invasive fungal disease
(e.g. CT scan, detection of circulating fungal markers)
• Based on moderate evidence from clinical trials with small sample size and
debatable methodology/design
• May results in significant overtreatment, toxicity and expenditure
Klastersky J. Antifungal therapy in patientswith fever and neutropenia—more rational and less empirical?
N Engl J Med 2004; 351: 1445–7.
Measures of the Success of Empirical Antifungal Therapy with
Conventional or Liposomal Amphotericin B, Voriconazole, or Caspofungin
Liposomal Ampho B vs Ampho B deoxycholate
Liposomal Ampho B vs Voriconazole
Caspofungin vs Liposomal Ampho B
Walsh TJ, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-71.
Walsh TJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J
Med 2002; 346:225-34.
Walsh TJ, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med
2004;351:1391-402.
N Engl J Med. 2004 Sep 30;351(14):1445-7.
ECIL 3 guidelines on empirical antifungal treatment in
neutropenic patients with persistent or relapsing fever
Bone Marrow Transplant 2011; 46: 709–718.
Pre-emptive antifungal therapy: diagnostics-driven approach
The time period between fungal replication, invasion and appearance of signs and
symptoms represents a window of opportunity for earlier treatment.
However, there is as yet no consensus definition of preemptive antifungal therapy.
Such therapy should not be triggered by fever as a sole criterion, but should rest on:
(i) a clear identification of those patients who are at risk of fungal disease
(ii) utilization of sensitive techniques that facilitate rapid and early diagnosis of
invasive mould infections, e.g. galactomannan, b-D-glucan or PCR testing as
well as computerized radiological imaging techniques
Fever-driven approach:
Antifungal Rx: 41 of 136 episodes
Pre-emptive approach:
Antifungal Rx <25% episodes
(but identified 10 episodes of fungal
infection without fever or with the
presence of confounding febrile
conditions)
liposomal amphotericin B
No patient received mould-active
prophylaxis
(? improving the sensitivity of the
assay and favoring the pre-emptive
approach)
Clin Infect Dis. 2005 Nov 1;41(9):1242-50.
Antifungal prophylaxis was given according to
each center’s protocol
Amphotericin B deoxycholate (1 mg/kg/day)
Liposomal amphotericin (3 mg/kg/day)
Pre-emptive approach significantly reduced the use of
antifungal agents (39.2% vs 61.3%, P<0.001)
293 patients with haematological
malignancies (duration of
neutropenia ≥ 10 days)
17 patients developed an IFI:
4 (2.7%) in empirical group
13 (9%) in pre-emptive group
(P<0.02)
Overall survival rates:
2 weeks after neutrophil recovery
(95% vs 97%, P=0.12)
Duration of neutropenia < 15 days:
no difference
Prolonged neutropenia:
↑risk of fungal infection in the
pre-emptive therapy arm
Clin Infect Dis. 2009 Apr 15;48(8):1042-51.
Known pathogen therapy (Targeted therapy) of mould infections
Voriconazole:
first-line therapy of invasive aspergillosis based on
the results of a prospective, randomized clinical trial with amphotericin B deoxycholate
as comparative initial therapy in possible, probable or proven disease
149 (54%) of 277 patients were culture +ve for Aspergillosis
Potential concern of using voriconazole:
prior exposure to mould-active azoles, the concomitant use of contraindicated medication (e.g. sirolimus),
the risk of severe drug interactions, moderate to severe hepatic or renal impairment
Herbrecht R, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15.
Treatment of aspergillosis: clinical practice guidelines of IDSA
Condition
Primary Rx
Alternative Rx
Invasive pulmonary
aspergillosis
Voriconazole (6 mg/kg IV
every 12 h for 1 day,
followed by 4 mg/kg IV
every 12 h; oral dosage is
200 mg every 12 h)
L-AMB (3–5 mg/kg/day IV),
ABLC (5 mg/kg/day IV),
Invasive sinus aspergillosis
Tracheobronchial
aspergillosis
Chronic necrotizing
pulmonary aspergillosis
(subacute invasive
pulmonary aspergillosis)
Aspergillosis of the CNS
Caspofungin (70 mg day 1 IV
and 50 mg/day IV thereafter),
Micafungin (IV 100–150
mg/day; dose not established),
Posaconazole (200 mg QID
initially, then 400 mg BID PO
after stabilization of diseased),
Itraconazole (dosage
depends upon formulation)
Surgical debridement may be indicated
Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases
Society of America. Clin Infect Dis 2008; 46: 327–60.
Known pathogen therapy (Targeted therapy) of mould infections
Echinocandins in the primary therapy of invasive aspergillosis: limited data
non-comparative Phase II study in two different cohorts:
N=61
Favorable response: 33%
N=24
Favorable response: 42%
Viscoli C, et al. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological
patients. J Antimicrob Chemother 2009; 64: 1274–81.
Herbrecht R, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant
patients: an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant 2010; 45:
1227–33.
Choice of antifungal combination therapy
Caspofungin
Micafungin
Anidulafungin
Amphotericin B
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Trends Microbiol 2003;11:272–279.
Choice of antifungal combination therapy
Cancer. 2003 Feb 15;97(4):1025-32.
Cancer. 2003 Jul 15;98(2):292-9.
Choice of antifungal combination therapy
Patients (HSCT or hemic malignancies)
Pulmonary aspergillosis (proven or probable)
Failure with amphotericin B
Voriconazole
Caspofungin
P=0.048
* historical control
Observational study
of salvage therapy
Clin Infect Dis. 2004 Sep 15;39(6):797-802.
Antifungal treatment of other invasive mould infections
Fusarium and Scedosporium spp:
Voriconazole and lipid formulations of amphotericin B
+/-surgical debridement of necrotic tissue
Posaconazole can be used as salvage therapy for these infections
Invasive mucormycosis:
Lipid-based formulation of amphotericin B as first-line therapy
Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007; 20: 695–704.
Troke P, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob
Agents Chemother 2008; 52: 1743–50.
Spellberg B, et al. Clinical practice: recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009; 48: 1743–51.
J Clin Microbiol. 2009 Sep;47(9):2834-43.
Roll-plating of
allopurinol
Estimated number of preventable cases in HK
(1 year period)
54
60
50
12
30
20
10
36
18
40
Symptomatic cases
Asymptomatic cases
Total cases
18
6
Total cases
Asymptomatic cases
0
Symptomatic cases
Nov 08 to Feb 09
1 year
*Attack rate = (mucosal + invasive) / total = 6 / 18 = 33.3%
**Lives saved = 16 (only 1 / 8 = 12.5% symptomatic patients survived)