Professor Dr. Markus Ruhnke Stiftungsprofessor f. onkologische Mykologie

- Charité

Universitätsmedizin -Medizinische Klinik u. Poliklinik II

Campus Charité

Mitte Berlin

Risk assessment in the hemato-onco patient

-

stem cell transplantation -6th Trends in Medical Mycology,

Copenhagen, 14.10.2013

Factors that increase the risk of infection among patients with hematological malignancies

Anaissie

& Kiwan

ASH (2006)

Environmentrelated

Host related

Treatmentrelated

Factors that increase the risk of infection among patients with hematological malignancies

Treatment-relatedProlonged neutropenia (>10 days)• CD4 cytopenia (<200 cells/ml)• Allogeneic BMT/ PBSCT if:1. matched unrelated or mismatch related2. T-cell depleted3. GVHD II-IV4. standard conditioning regimen (as opposed to non- myeloablative conditioning regimens)• Autologous BMT/ PBSCT if: CD34+ infused (autologous) <2.0 x 106/kg• Prior therapy with purine analogues and/or high-dose corticosteroids (>1 mg/kg/d for more than 2 weeks)

Anaissie

& Kiwan

ASH (2006)

European Group for

Blood

and Marrow Transplantation / ESH –

Handbook

2012

P. Ljungman, A. Gratwohl EBMT 2012http://www.ebmt.org/Contents/Resources/Library/EBMTESHhandbook/Pages/EBMT-ESH-handbook.aspx

Allo Auto Total

All 9661 15389 25050

AL 6784 1179 7963

AML 3020 811 3831

2006

Episodes of risk for IFD after allogeneic SCT

Gra

nulo

cyte

s (l

og10

1x 1

06 /L)

0.10.1

11

1010

3636

3737

3838

3939

4040

4141

Tem

pera

ture

°C

[days] [months]-7 0 7 14 21 12 6 9 12-14 628 8 10

[weeks]Transplantation

Aplastic phase ENGRAFTMENT

PRE-

TRANSPLANT

EARLY POST-

ENGRAFTMENT

LATE POST-

ENGRAFTMENT

Stem cellsacute GvHD

NeutropeniaNeutropenia CorticosteroidsCorticosteroids

chronic GvHDConditioning

1. phase 2. phase 3. phase> month 4until months 3-4

Adopted from HJ Adopted from HJ DornbuschDornbusch

and C. Cordonnierand C. Cordonnier

aspergillosis aspergillosis

Marr

et al., CID (2002)

The onset of infection was bimodal, peaking 16 and 96 days after transplant

Wald et al., JID (1997)

risk factors associated with IA early after TX (< 40 days) and after engraftment (41-180 days). Very late IA (> 6 months after transplantation) wasassociated with chronic GVHD and CMV disease

Marr

et al., Blood

(2002)

overall 1-year survival rate was equally poor (~20%)

Marr

et al., CID (2002)

The 1-year survival rate after proven and probable infectionwith Aspergillus species, Zygomycetes, Fusarium species, and Scedosporiumspecies.

Marr

et al. , CID (2002)

Pagano et al., JAC (2011)

Hematopoietic TX Allogeneic SCT Autologous SCTNeutropenia (depth&duration) + -Monocytopenia + -Lymphocytopenia + -Steroids + +Iron overload + -GvHd + -CMV infection + -Purine analogues or MAB -/+ -/+Renal failure + -Advanced age + -

risk factors

Pagano et al., JAC (2011)

Hematopoietic TX Allogeneic SCT Autologous SCTNeutropenia (recovery) + +Monocytopenia + -Lymphocytopenia + -Uncontrolled malignancy + -Steroid administration + -Probable/proven vs. Possible IA + +Uncontrolled GvHd + -Disseminated disease (incl. CNS) + +Renal failure + -Prior respiratory disease + -

Prognostic factors

Autologous stem cell transplantion

Auner

et al. Ann Hema

(2005)

Potential risk factors for the development of fever

Potential risk factors for failure of empirical first-line antibiotic therapy

Meyer et al., BMT (2007)

Data were taken from the GermanONKO-KISS multicenter surveillance project.- unrelateddonor allogeneic transplantation constituted a risk factor for pneumonia (P=0.012)

Gil et al., BMT (2009)

The incidence

of IA was comparable in NHL, HD and MM patients and not influenced by age, advanced disease or conditioning regimen. Factors significant for development of documented IA by univariate

analysis

treatment with fludarabine

or rituximabthe only factor predicting documented IA by multivariate analysis was treatment with fludarabine

(P=0.008).

Patients treated with fludarabine

or rituximab

in pretransplant

period are at risk of IA and require close

monitoring

and/or

anti-mould

prophylaxis.

Allogeneic stem cell transplantion

Cordonnier et al., CID (2006)

Seven factors assessed at diagnosis were determined to be strongly related to death due to IA:1)age of 12–35 years, 2)dissemination of IA, 3)presence of a pleural effusion, 4)monocyte

count of !120 cells/mm3,

5)Prolonged administration of steroids within the previous 2 months, 6)receipt of a dose 2 mg/kg at the time of diagnosis, 7)uncontrolled

graft-versus-host

disease.

Cordonnier et al., CID (2006)

Seven factors assessed at diagnosis were determined to be strongly related to death due to IA:1)age of 12–35 years, 2)dissemination of IA, 3)presence of a pleural effusion, 4)monocyte

count of !120 cells/mm3,

5)Prolonged administration of steroids within the previous 2 months, 6)receipt of a dose 2 mg/kg at the time of diagnosis, 7)uncontrolled

graft-versus-host

disease.

The concept

of nonmyeloablative hematopoietic

stem

cell

transplantation

Junghanss & Marr Curr Opin Inf Dis 2002

• Patients are „not the same“!

Junghanss

et al., BBMT (2002)

Neutropenia and mucositis are no more predominant!

Junghanss

et al., BBMT (2002)

The probability of overall survival is shown for all case and control patients for up to 100 days posttransplantation.Case patients had better 30-day (P = .02) and 100-day (P = .04) survival

Junghanss

et al., BBMT (2002)

• During the first year posttransplantation, invasive aspergillosis occurred at a similar rate (case patients, 15%; control patients, 9%;

Cumulative incidence of bacteremia

Fukuda

et al., Blood

(2003)

Cumulative incidence rates of invasive fungal infections among 163 patients after allogeneic HCT with nonmyeloablative conditioning

Comparison of invasive aspergillosis after nonmyeloablative and myeloablative HCT

Fukuda

et al., Blood

(2003)

Invasive fungal infections and GVHD

Fukuda

et al., Blood

(2003)

Overall survival after diagnosis of invasive mold infections among 25allogeneic transplant recipients with nonmyeloablative conditioning

Fukuda

et al., Blood

(2003)

The following variables were NOT significant:

- patient age, patient sex- underlying disease risk, - donor, stem cell source,- conditioning including fludarabine, - prior history of HCT, - pretransplant

CMV serostatus,

- season of transplantation, - neutropenia, and monocytopenia

Summary•

Invasive

aspergillosis

after

SCT is

still associated

with

a high fungal-related

mortality•

IA has a bimodal

distribution

(early

vs. late)

•

Major risk factors after allo-SCT are: •

receipt of a dose 2 mg/kg at the time of diagnosis, and

•

uncontrolled

graft-versus-host

disease.•

Non-myeloablative

SCT procedures

are

associated

with

fewer

bacterial

infections

but

not

IFD•

Patients treated with fludarabine

or rituximab

in the

pretransplant

period are at risk of IA after autologous SCT