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

Mortality from invasive fungal infection in patients with acute leukemia and HSCT

(40-50%) (>70%)

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

Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238.

Phases of opportunistic infections among allogeneic HCT recipients

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 days MIC level

5-FC Miconazole Ketoconazole

Fluconazole Itraconazole

L-AmB ABCD ABLC Terbinafine

Time line of development of antifungal agents

02468

101214

1950 1960 1970 1980 1990 2000

Caspofungin Micafungin

Anidulafungin

Voriconazole Posaconazole

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.

Degree of neutropenia, diagnosis, type of transplant, exposure to corticosteroids, type of chem

otherapy, and prior fungal colonization w

ere the major criteria used for stratification

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

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.

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

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.

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.

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.

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)

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

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.

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

Bone Marrow Transplant 2011; 46: 709–718.

ECIL 3 guidelines on empirical antifungal treatment in neutropenic patients with persistent or relapsing fever

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

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

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)

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)

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

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

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%

Role of combination antifungal therapy

Clinical trials vs in-vitro basis

Efficacy Toxicity

Interaction

Salvage therapy in refractory case

(Aspergillosis)

Trends Microbiol 2003;11:272–279.

Amphotericin B

Caspofungin Micafungin Anidulafungin

Fluconazole Itraconazole Voriconazole Posaconazole

Choice of antifungal combination therapy

Choice of antifungal combination therapy

Cancer. 2003 Feb 15;97(4):1025-32.

Cancer. 2003 Jul 15;98(2):292-9.

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

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