ECIL ESCMID Aspergillus Guidelines

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2 ECIL ESCMID Aspergillus Guidelines

3 Recommendation and Quality of evidence>> Grading system >> ESCMID Strength of the ESCMID Recommendation and Quality of Evidence. Two parts: Strength of a Recommendation (SoR) and Quality of Evidence (QoE) Strength of a recommendation Grade A Grade B Grade C Grade D Quality of Evidence Level I Level II* Level III Strongly supports a recommendation for use Moderately supports a recommendation for use Marginally supports a recommendation for use Supports a recommendation against use Evidence from at least one properly designed randomized, controlled trial Evidence from at least one well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from >1 centre); from multiple time series; or from dramatic results of uncontrolled experiments Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports of expert committees *Added index: r: Meta-analysis or systematic review of randomized controlled trials. t: Transferred evidence, that is, results from different patients cohorts, or similar immune-status situation. h: Comparator group is a historical control. u: Uncontrolled trial. a: Published abstract (presented at an international symposium or meeting). Ullmann AJ, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clin Microbiol Infect Dec;18 Suppl 7:

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7 Profilassi delle IFI Ø Acute leukemias

8 ESCMID Guidelines 2014: PROPHYLAXIS (1) Intention: lower the incidence of IA Population Intervention Strength of recommendation Hematologic malignancies (AL with prolonged neutropenia) POSA 200 mg TID A I ABLC 3 mg/kg 3x/w C II ITRA L-AmB 10 mg/kg q7d 50 mg qod 15 mg/kg q14d 12.5 mg biw nebulized D II C II

9 10 mg/kg q7 d 50 mg qod 15 mg/kg q14 d 12.5 mg biw

10 ECIL-5 (2013) Recommendations on antifungal prophylaxis in patients with acute myeloid leukaemia undergoing intensive chemotherapy DRUG and DOSAGE FLUCONAZOLE 400 mg qd ITRACONAZOLE 2.5 mg bid POSACONAZOLE oral solution 200 mg q8h; tablet 300 mg q24h following a loading dose 300 mg q12h Voriconazole 200 mg bid RECOMMENDATION B I B I A I B II

11 ECIL-5 (2013). Recommendations on antifungal prophylaxis in patients with acute leukaemia undergoing induction chemotherapy ANTIFUNGAL DRUG ECHINOCANDINS IV LIPOSOMAL AmB Lipid associated AmB AmB deoxyc. iv Aerosolized Liposomal AmB Aerosolized AmB deoxyc. GRADING C-II C-II C-II A-II against B-I A-I against

12 Blood 2017

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14 Recommendations on antifungal prophylaxis in patients with neutropenia excluding allogeneic HSCT DRUG and DOSAGE RECOMMENDATION Posaconazole oral suspension 200 mg tid Posaconazole tablet 300 mg qd L-AmB 12.5 mg biw inhalation Caspofungin 50 mg qd iv Fluconazole 400 mg qd Itraconazole tab, susp, iv L-AmB 50 mg q48h iv Voriconazole 200 mg bid A I (AML/MDS remission-induction chemotherapy) A II (AML/MDS remission-induction chemotherapy) B II C I C I C I C II C II Ann Hematol 2014

15 Patterson TF et al. Clin Infect Dis 2016 Antifungal prophylaxis of IA in high risk patients DRUG and DOSAGE Posaconazole oral suspension 200 mg tid Posaconazole tablet 300 mg qd RECOMMENDATION Strong-Rec/ HighQ-Evid Voriconazole 200 mg bid Strong-Rec/ Mod Q-Evid Micafungin mg/d Weak-Rec/ Low Q-Evid Caspofungin 50 mg qd iv Weak-Rec/ Low Q-Evid Itraconazole tab, susp, iv Strong-Rec/ Mod Q-Evid

16 Profilassi delle IFI Ø Stem Cell Transplantation

17 ESCMID Guidelines 2014: PROPHYLAXIS (2) Intention: lower the incidence of IA Population Intervention Strength of recommendation Autologous HSCT Any antifungal agent D III Allogeneic HSCT (until neutrophil recovery) Allogeneic HSCT (after neutrophil recovery and no GVHD) Allogeneic HSCT (with GVHD and/or intensified immunosuppression) POSA 200 mg TID VORICO 200 mg BID ITRA 400 mg/d MICA 50 mg/d Any antifungal agent POSA 200 mg TID VORICO 200 mg BID ITRA 400 mg/d MICA 50 mg/d B II C I D I C II D III A I C II C II C III

18 ECIL-5 (2013). Recommendations on antifungal prophylaxis in allogeneic HSCT recipients Antifungal Prophylaxis Pre-engraftment Low risk for moulds Pre-engraftment High risk for moulds GVHD FLUCONAZOLE A-I A-III against A-III against ITRACONAZOLE B-I B-I B-I VORICONAZOLE B-I B-I B-I POSACONAZOLE B-II B-II A-I MICAFUNGIN B-I C-I C-II CASPO/ANIDULA No data No data No data LIPOSOMAL AmB C-II C-II C-II Aerosilized AmB + Fluconazole C-III B-II No data

19 Ullmann et al. Ann Hematol 2016

20 Girmenia C et al BBMT 2014 High Risk Early Phase Day 0-40 Active acute leukemia Cord blood MMRD-UD + agvhd II-IV Steroids>2mg/Kg CMV dis/infec Neutropenia>3 w Iron overload Late Phase Day Posaconazolo agvhd III-IV A I Voriconazolo B I L-AmB C III Caspofungin C III Micafungin C III Areosol L-AmB C III Steroid refractory/dependent GVHD Very Late Phase > D 100 Extensive cgvhd after agvhd MMRD-UD+ agvhd II-IV Mold-active Antifungal prophylaxis Standard Risk Low Risk Patients not included in HR category Limited cgvhd Candida active No patient considered at low risk NO GVHD NO steroids NO prophylaxis

21 Aspergillus>> IDSA>> Prophylaxis Recommended prophylactic regimens for patients with Graft-Versus-Host Disease SoR QoE Comment Posaconazole strong high For allogeneic HSCT recipients with GVHD who are at high risk for IA Voriconazole strong Moderate In high-risk patients but did not show improved survival in clinical trials Itraconazole strong high Limited by tolerability and absorption Continuation of antifungal prophylaxis throughout the duration of immunosuppression is raccomanded in patients with chronic immunosuppression associated with GVHD (corticosteroid equivalent of >1 mg/kg/day of prednisone for >2 weeks and/or the use of other anti-gvhd therapies, such as lymphocyte-depleting agents, or TNF-α inhibition, for refractory GVHD) (strong recommendation; high-quality evidence). AmBisome currently has NO indication for prophylaxis treatment and is currently NOT promoted for such use. Patterson TF, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis Aug 15;63(4):e1-e60. 21

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23 Terapia delle IFI

24 Grade Comments Voriconazole A I Daily dose: 2x6 mg/kg on day 1 then 2x4 mg/kg (Initiation with oral therapy: C III) Isavuconazole A I As effective as voriconazole and better tolerated Liposomal amphotericin B B I Daily dose: 3 mg/kg Amphotericin B lipid complex B II Daily dose: 5 mg/kg Amphotericin B colloidal dispersion C I Not more effective than d-amb but less nephrotoxic Caspofungin Itraconazole ECIL-6 recommendations for first-line Combination voriconazole + anidulafungin Other combinations treatment of invasive aspergillosis. (Tissot et al, Haematologica 2017) d-amb A I against Less effective and more toxic C II C III C I C III

25 Targeted therapy (IA, only pulmonary): Choice of antifungal agents for first line therapy (I) May 10, 2014 *:TDM is discussed in an extra guideline

26 Targeted therapy (IA, only pulmonary): Choice of antifungal agents for first line therapy (II) May 10, 2014 Population Intention Intervention SoR QoE 1 QoE 2 QoE 3 Reference Comment 1 Neutropenia (non- allo HCT recipients) 2 Allo-HCT (during neutropenia) 3 Allo-HCT (w/o neutropenia) To increase response and survival rate camb mg/kg ABLC 5 mg/kg ABCD 4-6 mg/kg Voriconazole 6/4 mg/kg bid after one week oral possible (300mg bid) + Anidulafungin 200/100 mg D I II t II t Herbrecht NEJM 2002 C III III III Ito BMT 2005 D I II t II t Bowden CID 2002 C II a II t,a II t,a Marr ECCMID 2012 No difference compared to voriconazole. This is a RCT but not yet peerreviewed & fully published; TDM* *:TDM is discussed in an extra guideline Other combinations, e.g. camb plus 5-FC D III III III Caillot Cancer 2007 Efficacy unproven; camb plus 5-FC too toxic and PK erratic

27 Patterson TF et al. Clin Infect Dis 2016 Recommendations for primary treatment of IPA Voriconazole Liposomal-AmB Isavuconazole Lipid AmB Voriconazole+Echino Strong Rec High-Q Evid Strong Rec Moderate-Q Evid Strong Rec Moderate-Q Evid Weak Rec Low-Q Evid Selected patients with documented IPA Weak Rec Moderate-Q Evid Echinocandin NOT recommended: Strong Rec Moderate-Q Evid Ø Early initiation of antifungal therapy in patients with strongly suspected IPA is warranted while a diagnostic evaluation is conducted (strong rec; high-q evidence). Ø We recommend that treatment of IPA be continued for a minimum of 6 12 weeks

28 Patterson et al, Treatment of IPA be continued for a minimum of 6 12 weeks, largely dependent on the degree and duration of immunosuppression, site of disease, and evidence of disease improvement (strong recommendation; low quality evidence). For patients with successfully treated IPA who require subsequent immunosuppression, secondary prophylaxis should be initiated to prevent recurrence (strong recommendation; moderate-quality evidence).

29 Patterson et al, Colony-stimulating factors may be considered in neutropenic patients with diagnosed or suspected IA (weak recommendation; low-quality evidence). There is insufficient evidence regarding the value of granulocyte colony-stimulating factor vs granulocyte macrophage colony-stimulating factor (GM-CSF) in this setting. Granulocyte transfusions can be considered for neutropenic patients with IA that is refractory or unlikely to respond to standard therapy, and for an anticipated duration of more than one week (weak recommendation; low-quality evidence)

30 Patterson TF et al. Clin Infect Dis 2016 Diagnosis of IA When PCR assays are used, results should be considered in conjunction with other diagnostic tests and the clinical context (strong recomm; moderate-quality evid.). Serum and BAL galactomannan (GM) is recommended as an accurate marker for the diagnosis of IA in adult and pediatric patients when used in certain patient subpopulations (hematologic malignancy, HSCT) (strong recomm; high-quality evid). GM is not recommended for routine blood screening in patients receiving mold-active antifungal therapy or prophylaxis, but can be applied to bronchoscopy specimens from those patients (strong recomm; high-quality evid). Serum assays for (1 3)-β-D-glucan are recommended for diagnosing IA in high-risk patients (hematologic malignancy, allogeneic HSCT), but are not specific for Aspergillus (strong recomm; moderate-quality evid). We recommend performing BAL in patients with a suspicion of IPA (strong recomm; moderatequality evid). Routine use of contrast during a chest CT scan for a suspicion of IPA is not recommended (strong recomm;moderate-quality evid). Contrast is recommended when a nodule or a mass is close to a large vessel (strong recomm; moderate-quality evid).

31 Patterson TF et al. Clin Infect Dis 2016 Patient response to therapy Serial monitoring of serum GM can be used in the appropriate patient subpopulations (hematologic malignancy, HSCT) who have an elevated GM at baseline to monitor disease progression and therapeutic response, and predict outcome (strong recommendation; moderate-quality evidence). (1 3)-β-D-glucan has not been extensively studied in IA to predict outcome (weak recommendation; low-quality evidence). Treatment of pediatric patients Treatment of aspergillosis in children uses the same recommended therapies as in adult patients; however, the dosing is different and for some antifungals is unknown (strong recommendation; high-quality evidence).

32 Terapia antifungina empirica

33 Patterson TF et al. Clin Infect Dis 2016 Empiric antifungal therapy is recommended for high-risk patients with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotic therapy. Antifungal options include a lipid formulation ofamb (strong recommendation; highquality evidence), an echinocandin (caspofungin or micafungin) (strong recommendation; high-quality evidence), or voriconazole (strong recommendation; moderate quality evidence).

34 Ø For high-risk ptients without prior systemic antifungal prophylxis, mold-active empirical antifungal therapy is recommended, if fever persists for >96h or if fever relapses despite adequate antibacterial therapy (AI) Ø For patients receiving vori or posa prophylaxis, a switch may be judicious in the setting of persisting FUO (CIII) Ø But if a patient shows no clinical sign of IFI despite adequate diagnostic work-up, GM is neg, and levels of posa or vori are within the target range, unmodified continuation of oral antifungal prophylaxis is reasonable Ø For empirical mold-active antifungal therapy CASPO and L-AmB are approved, but L-AmB is preferred in patients at increased risk of IFI with non-aspergillus molds (AI)

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36 TARGET THERAPY in EMATOLOGIA Blinatumumab CD19 Leucemia linfoblastica acuta Target Indicazioni/Uso in Ematologia Checkpoint Inhibitors Nivolumab - Pembrolizumab PD-1 Melanoma mts, NSCLC, Hodgkin, LNH mediastino Ipilimumab Anti CTLA-4 Melanoma avanzato Bruton s Tyrosine Kinase Inhibitors Ibrutinib BTK CLL, MCL, Waldenstrom, MZL, chronic GVHD PI3K Inhibitors Idelalisib PI3K CLL, linfoma follicolare Proteasome Inhibitors Bortezomib proteasoma Mieloma, linfoma follicolare, MCL Carfizomib proteasoma Mieloma, linfoma follicolare Anti BCL2 Venetoclax BCL2 CLL, LNH MoAb Brentuximab CD30 Hodgkin, linfoma anaplastico Polatuzumab CD79 (B cell) DLBCL Obituzumab CD20 CLL, linfoma follicolare

37 PD-1 Pathway Checkpoints inhibitors: nivolumab, pembrolizumab, ipilimumab PD-1 is expressed on the surface of activated T cells Its ligands, PD-L1 and PD-L2, are overexpressed in certain tumor cells (PMBCL, LH) Binding of PD-1 to its ligands inhibits T-cell activation, allowing tumors to evade the immune response

38 Anti-CTLA4 Antibodies (Ipilimumab) Anti-cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) antibody, acts to up-regulate antitumor immunity First agent to be associated with an improvement in overall survival in patients with resistant melanoma Infections Risk of opportunistic infections: 7.3%, case reports of aspergillosis, CMV. Role of prophylactic antiviral/antifungal therapy in this setting unclear Immune related events 21% (one death; NEJM 2016 Davids MS, Ipilimumab for patients with relapse after allogeneic transplantation; no major infections)

39 7.8% CID 2016

40 Idelalisib Ibrutinib Venetoclax

41 IBRUTINIB Grade >3 infections occurred in 10-13% of 60 treatment-naive patients and 24-52% of 407 relapsed/refractory patients on ibrutinib monotherapy - Viral - Mycobacterial HZV, CMV, HBV: occasional TB: occasional Anti mould prophylaxis recommended when Ibrutinib is - PJP Associated several to reported steroids cases: unclear TDM required whether infection with azoles rate is due to - Fungal higher than usual in patients with chronic lymphoid malignancies cryptococcus: occasional cases Aspergillus: risk seems to be significantly increased if co- administered with steroids Non-Aspergillus moulds: occasional Yeasts: no reported cases drug-drug interactions

42 Infectious complications >grade 3: 36% 2 deaths due to AEs: pneumonia Aspergillosis Miklos D et al. Blood in press

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44 I+R+Benda I+R I+R+Benda GS-US : A Phase 3, Randomized, Double Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib in Combination with Bendamustine and Rituximab for Previously Untreated CLL GS-US : A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib in Combination with Rituximab for Previously Treated inhl GS-US : A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib in Combination with Bendamustine and Rituximab for Previously Treated inhl PJP: relative risk 12.5% (no correlation with CD4+ count prophylaxis with TMP-SMZ now recommended CMV: CMV-PCR at least every month

45 IDELALISIB Pneumonia and pneumonitis Infectious pneumonia is common during idelalisib use with a reported incidence of approximately 20%. Non-infectious pneumonitis was seen in 3%maily during the first 6 months Of idelasib therapy De Weerdt I et al Haematologica 2017

46 sepsi 5% Polmonite 4% IFI, n=9 (3%); n=1 mucor 2/45 decessi per sepsi e shock settico

47 Interactions of mold-active azoles with coadministered chemotherapic agents and target therapies COADMINISTERED AGENT INTERACTION MECHANISM EFFECT RECOMMENDATIONS AND ACTIONS Vincristine Inhibition CYP3A4 Increased neurotoxicity Avoid combo Cyclophosphamide (CTX) Inhibition CYP3A4/2C9 hepatotoxicity activation to hydroxy-ctx Monitor Avoid combo Ibrutinib Inhibition CYP3A4/2C9 Ibrutinib exposure 420 mg standard dose 280 mg if Fluco; 140 mg if Posa/vori Idelalisib Inhibition CYP3A4/Pgp AUC Monitor for side effect Ruxolitinib Inhibition CYP3A4/2C9 Ruxolitinib exposure dose 50%; monitor cytopenias Imatinib Inhibition CYP3A4 Imatinib exposure Avoid combo Dasatinib Inhibition CYP3A4 D. exposure, QT interval Avoid combo, monitor ECG Nilotinib Inhibition CYP3A4 N. exposure, QT interval Avoid combo, monitor ECG ponatinib Substrate CYP3A4 TKI dosage Avoid combo sorafenib Inhibition CYP3A4 No effect Monitor QTc Midostaurin Inhibition CYP3A4 adverse reaction Avoid combo, monitor QTc Quirzatinib Inhibition CYP3A4 Quirzatinib exposure dose (induc 40 mg ->20 mg) Lestaurtinib? efficacy????

48 Eyes are useless when the mind is blind Grazie