I fattori di rischio per infezioni in ematologia: tra vecchie e nuove classificazioni Livio Pagano

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1 I fattori di rischio per infezioni in ematologia: tra vecchie e nuove classificazioni Livio Pagano Istituto di Ematologia Roma

2 Invited Speaker Consultant Research grants

3 New chemotherapic agents already in use or coming in Hematology AML 1. FLT3-inhibitors (Quizartinib, Midostaurin, Sorafenib) 2. Monoclonal antibodies anti-cd33 (Gentuzumab) 3. Arsenic Trioxide 4. IDH1-2 inhibitors 5. Combined liposomal cytarabine and daublastine (CTX1) Lymphomas (low and high grade) 1. BTK-inhibitors (Ibrutinib) 2. Monoclonal antibodies anti-cd20 (Rituximab, Ofatumumab) 3. PI3Kδ signaling- inhibitor (Idelalisib) Hodgkin s Lymphoma 1. Monoclonal antibodies anti-cd30 (Brentuximab) 2. IgG4 anti-pd-1 (Nivolumab) ALL 1. Monoclonal antibodies a. anti-cd19 (Blinatuzumab) b. anti -CD22 (Inotuzumab) 2. TK inhibitors (Imatinib, Nilotinib, Dasatinib, Ponatinib) Multiple Myeloma 1. IMIDS (Talidomide, Lenalidomide Pomalidomide) 2. Proteosome inhibitors (Bortezomib, Carfizomib) 3. Monoclonal antibodies a. anti-cd38 (Daratumumab) b. anti-cd319 (Elotuzumab) CLL 1. BTK-inhibitors (Ibrutinib) 2. Monoclonal antibodies anti-cd20 (Ofatumumab) 3. PI3Kδ signaling- inhibitor (Idelalisib) 4. Anti apoptotic BCL-2 (Venetoclax)

4 At the present time only for a few we have enough knowledge of infectious complications AML 1. FLT3-inhibitors (Quizartinib, Midostaurin, Sorafenib) 2. Monoclonal antibodies anti-cd33 (Gentuzumab) 3. Arsenic Trioxide 4. IDH1-2 inhibitors 5. Combined liposomal cytarabine and daublastine (CTX1) Lymphomas (low and high grade) 1. BTK-inhibitors (Ibrutinib) 2. Monoclonal antibodies anti-cd20 (Rituximab, Ofatumumab) 3. PI3Kδ signaling- inhibitor (Idelalisib) Hodgkin s Lymphoma 1. Monoclonal antibodies anti-cd30 (Brentuximab) 2. IgG4 anti-pd-1 (Nivolumab) ALL 1. Monoclonal antibodies a. anti-cd19 (Blinatuzumab) b. anti -CD22 (Inotuzumab) 2. TK inhibitors (Imatinib, Nilotinib, Dasatinib, Ponatinib) Multiple Myeloma 1. IMIDS (Talidomide, Lenalidomide Pomalidomide) 2. Proteosome inhibitors (Bortezomib, Carfizomib) 3. Monoclonal antibodies a. anti-cd38 (Daratumumab) b. anti-cd319 (Elotuzumab) CLL 1. BTK-inhibitors (Ibrutinib) 2. Monoclonal antibodies anti-cd20 (Rituximab, Ofatumumab) 3. PI3Kδ signaling- inhibitor (Idelalisib) 4. Anti apoptotic BCL-2 (Venetoclax)

5 How is relevant the problem of infectious Frequently too early complications? We do not know! Data regarding infectious complications only from registrative trials Attention focused above all on efficacy of anticancer drugs Low interest from Industry for complications Confounding data due to the combination with other drugs

6 but not only new chemotherapic agents, also new approaches More aggressive chemotherapies High doses of steroids Extensive use of HSCT procedures Multiple lines of chemotherapy Old drugs for new diseases (i.e. Bendamustine) Different schedule of chemotherapy, more intensive

7 Acute Myeloid Leukemia FLT3-Inhibitors (Midostaurin, Sorafenib) Arsenic Trioxide Gentuzumab (anti-cd33) Use of transplant procedure in refractory patients Increased use of aplo-identical HSCT Maintenance chemotherapy post-hsct All these procedures do not modify the already wellstated high risk of infections, above all IFI, but they can modify the antimicrobial prophylactic strategies for the drug-drug interactions

8 Cardenas et al, Environ Health Perspect 2015 High doses of inorganic arsenic are known to suppress IgM and IgG antibody formation Inhibit antigen-driven T-cell proliferation and macrophage activity Block the differentiation of monocytes into functional macrophages Decrease CD4+ splenic cell numbers Alter the development, activation, and proliferation of T cells

9 Pharmacokinetic interactions Alteration of the kinetic of the drug A related to the effect of the drug B 1) Absorption 2) Distribution 3) Metabolism 4) Excretion Roden DM, Nature (1) 2002

10 Interactions of antimicrobials with FLT-3 inhibitors: Pharmacokinetic data Drug Co-administration with strong CYP3A4 inhibitors Co-administration with moderate CYP3A4 inhibitors Co-administration with weak CYP3A4 inhibitors Co administration with CYP3A4 inducers Co-administration with P-gp inhibitors Midostaurin Avoid Avoid??? Avoid No dose adjustment required Sorafenib No implication No implication No implication No implication Dose adjustment? Take note that in the ongoing registrative Midostaurin trials the use of azoles prophylaxis is not authorized

11 BCL2 inhibitors - Venetoclax A toxicity close to induction when associated with HMA In first line therapy: 30% gr 3-4 febrile neutropenia, 1 IA and 1 candidiasis among 45 patients In salvage therapy: 19% IFI among 43 patients Concern about interactions: azoles increase plasma level of venetoclax 8-fold! Posaconazole is allowed after venetoclax a minimum 75% dose reduction DiNardo Lancet Oncol 2018; DiNardo AJH 2017; Agarwal Clin Ther 2017

12 Gentuzumab Ozogamicin Lass-Flörl et al, Mycoses 2013

13 Gentuzumab Ozogamicin Literature revision performed between said us that the impact of Gemtuzumab ozogamicin on the incidence of infection would be thus similar to that observed with other therapies inducing severe and long-lasting neutropenia Gemtuzumab + chemotherapy Chemotherapy Patients Grade 3-4 infections during induction phase Febrile neutropenia in induction phase 44% 47% 24% 26% Drgona, CMI 2018

14 Acute Lymphoblastic Leukemia TK-inhibitors (Imatinib, Dasatinib, Nilotinib, Ponatinib) Blinatuzumab (anti-cd19) Inotuzumab (anti- CD22) High doses of steroids AML-like treatments Actually antifungal prophylaxis with azoles is not indicated and other antifungal fail to demonstrate an efficacy to prevent IFI, but the main point is: must we wait in the next years an increased incidence of bacterial and fungal infections as observed in the past in AML without prophylaxis?

15 Blinatumomab Profound depletion in B cells, including early B and plasmocytes Subsequent hypogammaglobulinemia Lack of dialog with T-cells But neutropenia as well (38% vs 58% in chemo arm) No significant difference in infection rate (vs FLAG) More BSI due to route of administration: a gate for bacteremia/candidemia? Mikulska et al, CID 2018

16 So et al, Med J Hem Infect Dis 2018 Based on the results an anti-mold coverage when ANC < 500/μL in this patient population considering compromised host factors could be indicated. More data to support need to support a recommendation for anti- bacterial prophylaxis in this population, it may be prudent to individualize based on well-known risk factors. In relapsed or refractory disease, the ANC should be monitored closely post blinatumomab since neutropenia can unexpectedly develop after treatment.

17 Inotuzumab ozogamicin Depletion in B cells Few impact on immunoglobulin or T cells activity Neutropenia, among which febrile: 24% vs 49% for chemo arm No recommended prophylaxis Drgona, CMI 2018

18 Chronic Lymphocytic Leukemia/ Lymphomas low grade BKT-inhibitors (Ibrutinib) PI3Kδ signaling- inhibitor (Idelalisib) Rituximab - Ofatumumab (anti- CD20) High doses of steroids Combined treatments How is relevant the problem? Is necessary to start in all patients an anti-(bacterial, fungal, viral) prophylaxis?

19 Leuk & Lymphoma pts patients from 4 centers who received a total of 1095 bendamustine cycles were included. NHL in 65.4% (153/234), CLL/SLL in 28.2% (66/234) and MM in 6.4% (15/234). Of those with NHL, 70 (30%) were follicular lymphoma, 23 (10%) mantle cell lymphoma (MCL), 20 (8.5%) marginal zone lymphoma (MZL), 21 (9%) with DLBCL, eight (3.4%) with lymphoplasmacytic lymphoma, one with hairy cell leukemia (0.4%) and 10 (4.3%) with other low grade lymphomas

20 Pneumocystis jiroveci pneumonia in patients with non- Hodgkin s lymphoma after Rituximab-based regimens Xu-Oiu Jung et al, J Thorac Dis 2013

21 The combination «Monoclonal Antibody and PI3Kδ signalinginhibitor increases the risk of serious infections Above all CMV and Pneumocystis Pneumonia Jones JA et al, Lancet Oncol 2017

22 IBRUTINIB BTK is an indispensable component of the B-cell receptor signaling pathway. BTK is also found in neutrophils, monocytes and macrophages where it mediates pathways involving innate and adaptive immunity. ITK found in T-cells has significant homology with BTK and is irreversibly inhibited by ibrutinib, suggesting that ibrutinib may predispose patients to increased infections. BTK plays an important role in neutrophil differentiation and function. BTK plays an important role in TREM-1 mediated PMN activation, providing a potential mechanism for the frequently observed infectious complications in patients treated with ibrutinib.

23 Cryptococcosis in patients receiving ibrutinib Wang ML et al, Blood 2015 Byrd JC et al, New Engl J Med 2014 Okamoto K et al, Case Rep Infect Dis 2016 Messina JA et al, OFIDS 2916 Treatments aimed to block the function of Bruton s tyrosine kinase could pose a higher risk for cryptococcal infection Szmczak et al, MBio 2013

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25 Grommes & Younes et al, Cancer Cell 2017

26 Hodgkin s Lymphoma Monoclonal antibodies anti-cd30 (Brentuximab) IgG4 anti-pd-1 (Nivolumab) Intensified Treatments Great attention to the risk of non-infectious pneumonia during these treatments!!

27 Nivolumab cause PD-1 block with a reduced activity of T-lymphocyte. Usually administered in Hodgkin s relapsed/refractory Immunological mechanisms is related to pro-inflammatory activation of the innate immune system, mediated by effects on monocytes or macrophages and upregulation of nuclear factor kb The adaptive immune system is also affected leading to enhanced CD8 memory T-cell responses to foreign antigens, and the recruitment and activation of macrophages and other inflammatory cells possibly via a T-cell-mediated, delayed-type hypersensitivity mechanisms

28 Progressive Multifocal Leukoencephalopathy after Treatment with Nivolumab Martinot et al. Emerg Infect Dis case report plus other 4 cases from pharmacovigilance databases Very few data reported on the other 4 cases (not clear how many were affected by HM) No denominator!!

29 Checkpoint inhibitors improve T cell exhaustion in chronic infections

30 Checkpoint inhibitors improve T cell exhaustion in chronic infections

31 BRENTUXIMAB VEDOTIN Depletion of CD30 expressing activated T-cells could reduce immune surveillance Typically administered to patients with refractory Hodgkin Lymphoma, Mycosis Fungoides, Mastocytosis VERY LOW RISK OF INFECTIONS

32 Multiple Myeloma IMIDS (Talidomide, Lenalidomide Pomalidomide) Proteosome inhibitors (Bortezomib, Carfizomib) Monoclonal antibodies (Daratumumab - Elotuzumab) High doses steroids Multiple lines of chemotherapy (these patients can arrive to 5-6 different chemotherapic courses including autologous and/or allogeneic HSCT procedures)

33 Cellular immune defects in Multiple Myeloma Reduced CD4+ T cell numbers Abnormal Th1/Th2 cytokine profile Impaired cytotoxic T cell response Reduced B cell numbers, impaired B-cell differentiation and Ab response Reduced expression of tumor antigens and HLA cosrimulatory molecules with inadequate T-cell costimulation Upregulation of inhibitory surface ligands inducing T- cell anergy Recruitment of immunosuppressive cells (Tregs and MDCSs) Production of proinflammatory cytokines mediating the suppression of dendritic and T-cell activation Rodriguez-Otero et al., Haematologica 2017

34 More than patients evaluated, but no data are reported on the kind of infection observed Chen et al. Ann Hematol 2018

35 Frequency of infection by regimen and type of infection in patients receiving Daratumumab Johnsrud AJ et al, Br J Haematol 2018

36 Treatment-emergent infections in the FIRST trial: 26.5% The «Myeloma Paradigm 17% 13.5% 11% 10% 75% of all grade 3 infections occurred in the absence of neutropenia Dumontet C et al, Leukemia 2018

37 Chimeric Antigen Receptor (CAR) T-Cell Immunotherapy for Leukemia and other lymphoprolipherative diseases

38 Infectious complications of CD19-targeted chimeric antigen receptor-modified T cell immunotherapy 113 adult patients with ALL-NHL-CLL Hill et al, Blood 2017

39 Different Infectious risk with the new biological drugs DRUG Viral Bacterial Fungal Arsenic Trioxide Midostaurine/Quizartinib/Sorafenib Gentuzumab Imatinib/PonatiniB/Dasatinib/Nilotinib Inotuzumab/Blinatuzumab Idelalisib Ibrutinib Rituximab/Ofatumumab Talidomide/Lenalidomide/Pomalidomide Bortezomib Brentuximab Nivolumab CAR-T

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