Fungal infections in hematology patients: advances in prophylaxis and treatment
1. 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
ASIA-PACIFIC HEMATOLOGY CONSORTIUM
2. Mortality from invasive fungal infection in patients
with acute leukemia and HSCT
(40-50%) (>70%)
3. Halo sign:
Nodular lesion surrounded by an
area of ground-grass attenuation
Air crescent sign:
Nodular lesion with internal
necrotic cavity
Invasive pulmonary aspergillosis
Profound neutropenia
to
Recovery of neutrophil
4. Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238.
Phases of opportunistic infections among allogeneic HCT recipients
5. Antimicrob Agents Chemother. 1989 Mar;33(3):362-8.
Concentrations of Amphotericin B deoxycholate in tissues of 13 cancer patients
Lung
Kidney
Spleen
Liver
Standard dose 1 mg / kg / day (BW 50 kg)
50 mg per day
10 days 20 daysMIC level
7. Risk group stratification for development of invasive fungal infections in patients
with hematologic malignancies +/- hematopoietic cell transplant
Transpl Infect Dis. 2009 Dec;11(6):480-90; Br J Haematol. 2000 Aug;110(2):273-84.
Degreeofneutropenia,diagnosis,typeoftransplant,exposureto
corticosteroids,typeofchemotherapy,andpriorfungalcolonization
werethemajorcriteriausedforstratification
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
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
8. Risk group Prophylaxis Pre-emptive Empirical Targeted
High Yes Yes Yes
Intermediate
(high)
Yes Yes Yes
Intermediate
(low)
Yes ? Yes
Low Yes ? Yes
Risk Based approach in antifungal treatment
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.
9. 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.
10. 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
Open-
label
ITR 2.5 mg/kg
cyclodextrin solution
bd po vs FLU 100 mg
suspension qd po
IFI: No diff
Mortality: ITR ↓
Huijgen et al
(1999)
213 patients
(57% auto BMT;
31% HM on
chemo
RCT
(double
blinded)
ITR 100 mg bd po vs
FLU 50 mg bd po
IFI: No diff
Mortality: no diff
Harousseau et
al (2000)
557 HM
patients (5%
BMT)
RCT
(double
blinded)
ITR 2.5 mg/kg
solution bd po vs AMB
500 mg capsule qid po
IFI: No diff
Mortality: No diff
Marr et al
(2004)
304 (allo BMT) Open-
label
ITR 2.5 mg/kg
solution td po or 200
mg iv qd vs FLU 400
mg po or iv qd
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.
11. Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies
and Hematopoietic cell transplant
Study Patients Design Regimen Outcome
Posaconazole
Ullmann et al
(2007)
600 (allo BMT) RCT
(double
blinded)
POS 200 mg
suspension td po vs
FLU 400 mg qd po
IFI: POS ↓
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: POS ↓
Mortality: POS ↓
Micafungin
van Burik et
al (2004)
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
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.
12. 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.
13. Marks DI, et al. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic stem cell transplanation.
Br J Haematol 2011; 155: 318–327.
A prospective, phase III, randomized, open label, multi-centre clinical trial
Eligible patients:
>12 years of age
allogeneic HCT for acute leukaemia, transformed CML, or failure of lymphoma therapy
Prophylaxis :
at least 100 days antifungal
continued until 80 days
if IFI risk factors persisted
Primary endpoint:
Success of antifungal prophylaxis at
day 180
(defined as fungal-free survival to day
180 without having discontinued
study treatment for >14 days in total
before day 100)
Survival outcome at Day 100, 180,
and 1 year (no difference)
14. 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.
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
15. 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.
16. N Engl J Med. 2004 Sep 30;351(14):1445-7.
Measures of the Success of Empirical Antifungal Therapy with
Conventional or Liposomal Amphotericin B, Voriconazole, or Caspofungin
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.
Liposomal Ampho B vs Ampho B deoxycholate
Liposomal Ampho B vs Voriconazole
Caspofungin vs Liposomal Ampho B
17. Bone Marrow Transplant 2011; 46: 709–718.
ECIL 3 guidelines on empirical antifungal treatment in
neutropenic patients with persistent or relapsing fever
18. 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
19. Diagnostic tools Advantages Disadvantages
Galactomannan assay • Noninvasive serum assay
• Biweekly testing may allow
earlier detection of IA
• With the cutoff OD index
reduced to 0.5 (from 1.5),
greater overall sensitivity
improved from 76% to 97%
• High percentage of false
positives; sensitivity 100%-33%
• Exposure to mold-active
antifungals considerably
reduces sensitivity
• Some serum reactivity in
patients on beta-lactam
antibiotics
(1, 3)-beta-Dglucan
antigen test
• Noninvasive serum assay
• Detects Candida and
Aspergillus species and other
opportunistic fungal
pathogens
• False-positive and false-
negative
• Sensitivity lower in patients
with localized Aspergillus
infection
• Does not usually detect
Cryptococcus species or
Zygomycetes
PCR assays • Highly specific and sensitive
• Negative result can rule out IA
and potentially limits empiric
therapy need
• No pan-fungal assay available
to date
• Lack of a standardized method
Eur J Haematol. 2011 Oct;87(4):289-301.
Advantages and disadvantages of major non-culture-based laboratory diagnostic methods for IFI
20. Clin Infect Dis. 2005 Nov 1;41(9):1242-50.
liposomal amphotericin B
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)
No patient received mould-active
prophylaxis
(? improving the sensitivity of the
assay and favoring the pre-emptive
approach)
21. Clin Infect Dis. 2009 Apr 15;48(8):1042-51.
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
Pre-emptive approach significantly reduced the use of
antifungal agents (39.2% vs 61.3%, P<0.001)
Antifungal prophylaxis was given according to
each center’s protocol
Amphotericin B deoxycholate (1 mg/kg/day)
Liposomal amphotericin (3 mg/kg/day)
22. 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
Herbrecht R, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15.
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
23. 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.
Treatment of aspergillosis: clinical practice guidelines of IDSA
Condition Primary Rx Alternative Rx
Invasive pulmonary
aspergillosis
Invasive sinus aspergillosis
Tracheobronchial
aspergillosis
Chronic necrotizing
pulmonary aspergillosis
(subacute invasive
pulmonary aspergillosis)
Aspergillosis of the CNS
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),
Caspofungin (70 mg day 1 IV
and 50 mg/day IV thereafter),
Micafungin (IV 100–150
mg/day; dose not stablished),
Posaconazole (200 mg QID
initially, then 400 mg BID PO
after stabilization of diseased),
Itraconazole (dosage
depends upon formulation)
Surgical debridement may be indicated
24. 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:
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.
N=61
Favorable response: 33%
N=24
Favorable response: 42%
25. Role of combination antifungal therapy
Clinical trials vs in-vitro basis
Efficacy
Toxicity
Interaction
Salvage therapy in refractory case
(Aspergillosis)
27. Choice of antifungal combination therapy
Cancer. 2003 Feb 15;97(4):1025-32.
Cancer. 2003 Jul 15;98(2):292-9.
28. Clin Infect Dis. 2004 Sep 15;39(6):797-802.
Choice of antifungal combination therapy
Patients (HSCT or hemic malignancies)
Pulmonary aspergillosis (proven or probable)
Failure with amphotericin B
P=0.048
Observational study
of salvage therapy
* historical control
Voriconazole Caspofungin
29. 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.
