Study Population (11,802 patients) LH 7% LMA 26% LNH 29% LLA 10% LMC 5% MM 14% LLC 9%

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2 SEIFEM-24 The aims of the study were: To know the incidence of documented fungal infection in patients with hematological malignancies admitted in the italian hematological wards between 1999 and 23 To evaluate the mortality rate in different hematological neoplasms (chronic and acute leukemia, lymphomas, multiple myeloma).

3 Study Population (11,82 patients) LNH 29% LH 7% LMA 26% MM 14% LLC 9% LMC 5% LLA 1%

4 % incidence cases Incidence of Invasive Fungal Infections Overall Incidence 4.6% All patients Fungal infections Incidenza (%) ,3 6,5 2,7 1,6,9,6,5 LMA LLA LMC LNH LH LLC MM AML ALL CML NHL HD CLL Myeloma underlying diseases Patologia di base

5 Incidence of Mould and Yeast Infections Incidence ,9% Muffe 1,6% Lieviti n 346 n 192

6 Incidence of various Moulds infections 3 2,6% Incidence (%) 2 1,1%,1%,8% Aspergillus (n 31) Mucor (n 13) Fusarium (n 15) Altro (n 7) * Scedosporium spp (n 3); Acremonium spp (n 2), Cladosporium spp (n 1); Penicillium spp (n 1).

7 Incidence of Yeast infections Incidence (%) 2 1,5 1,5 1,5,1,1,2 n 175 n 8 n 7 n 2 Candida Cryptococcus Trichosporon Others* * Rhodotorula spp (n 1), Hansenula (n 1)

8 Development of fungal infection over time Incidenzce(%) RR 1.1 (IC 95% ; p-value.452) Incidence (%) 3,5 3 2,5 2 1,5 1, Aspergillus Altre muffe Candida Altri lieviti

9 Incidence of aspergillosis in different hematological malignancies Incidence (%) % 3,8% 2,3%,8%,4%,4% AML n 213 ALL n 44 CML n 14 NHL n 27 CLL n 5 HD n 3 Hematological disease

10 Distribution of moulds in relation to underlying disease 5% 14% 2% 1% 9% 1% Aspergillosis 68% 7 casi 19% 1 caso 3% 3 casi 9% 25 casi 69% LMA LLA LMC LLC MM LNH LH Other moulds

11 Identified Aspergillus spp Speciated 41% 1% 2% A. Fumigatus A. Flavus A. Niger A. Terreus Others* 8% 27% 53% *A. Glaucus (n 2), A. Versicolor (n 1)

12 Development relation stage underlying disease n = 279 n = 253 1% 75% 5% 25% % 14% 19% 16% 51% 21% 8% 28% 43% Remission induction Salvage/refractory Relapse Complete remission

13 Classification of aspergillosis 258 pz possible/probable 2% probable 58% proven 28% % n cases in vivo post mortem

14 Evolvement in the distribution of Aspergillus spp N cases spp fumigatus flavus terreus niger RR 2.1 (IC 95% ; p-value.117)

15 Incidence of candidemia Incidence (%) ,1 AML n 124 1,9 ALL n 22,6,4,2,2,1 NHL n 21 HD n 3 MM n 3 CML n 1 CLL n 1 Hematological disease

16 Candida spp according subtype 15% 9% 43% albicans parapsilosis 12% 11% 1% glabrata krusei tropicalis others

17 Distribution of yeasts in relation to underlying disease LNH 3 Other yeasts LLA 4 LMA 1 Candida 1% 1% 2% 12% 2% LMA LLA LMC LLC MM LNH LH 12% 7%

18 Proportion C. albicans vs non-albicans N centers % Years 8% Topic Fluconazole Itraconazole 6% 4% 2% % albicans non albicans

19 Mortality related to invasive fungal infections 12 1 Mortality 1.8% N casi popolazione non trapiantati n decessi n casi Lethality 39% 29 n infezioni fungine n decessi

20 Letality of the various invasive fungal infections 4 42% 33% N casi % 53% 5% 29% Aspergillus Zigomicetes Fusarium Candida Criptococcus Tricosporon casi decessi

21 Letality aspergillosis % N casi % 5% 8% 75% 52% 67% LMA LLA LMC LLC MM LNH LH Aspergillosi Decessi 25 42% 2 N casi % 42% 27% 29% spp fumigatus flavus casi terreus niger decessi altro

22 Mortality in relation to site of infection 258 pz 1% 8% 6% 4% 67% 2% % 34% polmone (n 25) fegato (n 2) 25% 17% cute (n 4) seni (n 12) multiple (n 33) altro (n 2) * intestino (n 1), sangue (n 1) morti vivi

23 Mortality in relation to the stage of disease 258 pz 1% 8% 6% 4% 2% % 63% 28% 26% 21% Induz. Recid. Salv. RC fase di malattia morti vivi

24 Letality of Candida in relation of underlying disease and subspecies N casi % 36% 33% 19% LMA LLA LMC LLC MM LNH LH Candidemie Decessi 8 25% 6 N casi 4 2 6% 5% 52% 54% 12% albicans parapsilosis glabrata casi krusei decessi tropicalis altro

25 Incidence of non-aspergillus molds between 1987 and 23 N of cases

26 Cases of other moulds in patients with acute leukemia Casi tot casi LA casi Muffe morti Muffe RR.6 (IC 95% )

27 Incidence of infection by Aspergillus spp over time (periodo ) Casi

28 Aspergillosis in pazients with acute leukemia Casi tot casi LA casi Aspergillosi morti Aspergillosi Incidence: RR.81 (IC 95%.5-1.3) Lethality: RR 1.9 (IC 95% )

29 Incidence of fungal infection in transplanted patients 7.9% 1.2% allo auto 23 denominatori casi RR 6.39 (IC 95% ; p-value <.1)

30 Fungal infection in HSCT over time (both allo and auto) muffe lieviti RR.19 (IC95%.4-.82; p-value.1 )

31 Incidence di moulds and yeasts Incidenza (%) ,3 aspergillo 79,4 1,2 altre muffe 5 Allo-BMT candida 15 altri lieviti Eziologia Incidenza (%) ,3 aspergillo 7,8 altre muffe candida 15 Auto-BMT altri lieviti Eziologia

32 Lieviti N Candida C.albicans C. krusei C.tropicalis C.guillermondii C.parapsilosis C.zelanoides lieviti 15% muffe 85% Muffe N Aspergillus 79 A. spp 5 A. fumigatus 16 A. flavus 4 A. terreus 5 A. niger 4 Zigomiceti 1 Fusarium 3 Scedosporium 1

33 Fungal incidence with respect to the type of allohsct N casi % 9.4% MUD non MUD denominatore casi RR 1.92 (IC95% , p-value.56)

34 Conditioning regimen in allohsct: TBI vs non-tbi 45% 55% TBI non TBI

35 Onset of fungal infection 36% 64% <1 giorni >1 giorni

36 Letality due to candidemia 53% 47% allo auto casi decessi RR 1.14 (IC95% , p-value.72)

37 Mortality and letality for aspergillosis in allohsct n casi casi 1249 decessi 4.8% 6 n casi casi decessi

38 Lethality for Aspergillus subtypes di in allohsct % numero pz % 4% 4% 1% 1 spp fumigatus flavus terreus niger sottotipo casi decessi

39 Lethality aspergillosis over time in allohsct decessi vivi RR:.69 (IC95% ; p-value.47)

40 AML versus allohsct: incidence of aspergillosis 8, 7% 6,3% Incidenza (%) 6, 4, 2,, LMA ALLO RR.89 (IC95% , p-value.379)

41 AML versus allohsct: lethality of per Aspergillus infection 25 2 N casi 15 1 N 8 N 6 N 6 casi morti 5 LMA allo RR 2.2 (IC95% , p-value <.1)

42 Partecipating centers S.MARTINO HOSP.-GENOVA 2. REGGIO CALABRIA HOSP. 3. REGGIO EMILIA HOSP. 4. NIGUARDA HOSP.-MILANO 5. BARI UNIV. 6. UDINE UNIV. 7. S.GIOVANNI HOSP- ROME 8. FIRENZE UNIV. 9. PARMA UNIV. 1. ANCONA UNIV. 11. FEDERICO II UNIV.-NAPOLI 12. S.MATTEO HOSP.-PAVIA 13. CUNEO HOSP. 14. PALERMO UNIV. 15. S.GIOVANNI ROTONDO HOSP. 16. CATHOLIC UNIV.- ROME 17. LA SAPIENZA UNIV.-ROME 18. PERUGIA UNIV.