(ESGICH) Consensus Document on the Safety of Targeted And

Accepted Manuscript

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an Infectious Diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4)

Lubos Drgona, Carlota Gudiol, Simone Lanini, Bernd Salzberger, Giuseppe Ippolito, Małgorzata Mikulska

PII: S1198-743X(18)30232-5 DOI: 10.1016/j.cmi.2018.03.022 Reference: CMI 1253

To appear in: Clinical Microbiology and Infection

Please cite this article as: Drgona L, Gudiol C, Lanini S, Salzberger B, Ippolito G, Mikulska M, ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an Infectious Diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4), Clinical Microbiology and Infection (2018), doi: 10.1016/j.cmi.2018.03.022.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT

Revised manuscript (CLM-17-12788.R1) [for AA publication]

Review paper

Title page

Complete title: ESCMID Study Group for Infections in Compromised Hosts (ESGICH)

Conse perspe

CD33,

Autho

Lubos

Małgor

1. D

2. D

3. D

4. D

5. D

• W

• N

• Number of references: 76

• Funding sources: This research was partially supported by Plan Nacional de I+D+I 2013-

2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de

Investigación Cooperativa, Spanish Ministry of Economy and Competitiveness, Spanish

Network for Research in Infectious Diseases (REIPI RD16/0016/0002) - co-financed by the

1 ACCEPTED MANUSCRIPT

European Development Regional Fund (EDRF) "A way to achieve Europe". M.F.R. holds a

clinical research contract “Juan Rodés” (JR14/00036) from the Instituto de Salud Carlos III,

Spanish Ministry of Economy and Competitiveness.

• Corresponding author: Małgorzata Mikulska, MD, PhD. Division of Infectious Diseases,

2 ACCEPTED MANUSCRIPT

Abstract (250 words)

Background: The present review is part of the ESCMID Study Group for Infections in

Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies.

Aims:

CD22, recom

Source therap

Conten inotuzu

Pneum for pat the ris

Patien zoster dacetu syndro therap lympho targete effect o herpes recom

Implica the severity of infectious complications associated to the reviewed agents.

Keywords: inotuzumab ozogamicin; moxetumomab pasedotox; brentuximab vedotin; gemtuzumab ozogamicin; daratumumab; lucatumumab; mogamulizumab; infection

3 ACCEPTED MANUSCRIPT

Introduction

The present review paper is part of a larger effort launched by the ESCMID (European Society of Clinical Microbiology and Infectious Diseases) Study Group for Infections in Compromised

Hosts (ESGICH) and aimed at analyzing, from an Infectious Diseases perspective, the safety profile of biological and targeted therapies By means of a set of unrestricted computer based

MEDL approp

In add

Medici

Method

[1]. Fo mecha expect the clin series

The p antigen malign antibod activat

Over t antibod treatm usually establi concomy p p yg disease. In fact, only RCTs allow to definitively establish the specific risk of a given agent.

However, caution must be exerted even if pivotal studies do not report an increased infectious risk. Indeed, in the past, most of the data on particular, and usually quite rare, infectious complications occurring during treatment with novel agents have been discovered only after

4 ACCEPTED MANUSCRIPT extensive post-marketing use, and reported either as case series or data from large observational studies.

The development status, therapeutic indications and the potential impact on the infectious risk of the reviewed agents are summarized in Table 1. The available data on infectious complications extracted from studies that included a control group are outlined in Table 2

Finally agents data a for con particu promp rare bu

CD22- and co

Mecha

The an

90% o

Theref unclea

(BCR) vivo an more e alone resultin hypera the superiority of epratuzumab compared to placebo [6].

In August 2017 the FDA granted approval for inotuzumab ozogamicin (Besponsa®, Wyeth

Pharmaceuticals) for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), currently being the only anti-CD22 agent approved for clinical use.

5 ACCEPTED MANUSCRIPT

Epratuzumab is a humanized IgG1 kappa monoclonal antibody targeting CD22 receptor on B- cells. It is being evaluated for the treatment of non-Hodgkin lymphoma (NHL) and ALL, and for autoimmune diseases such as SLE or Sjögren syndrome. Additionally, it has been also studied as a conjugate with SN-38, a topoisomerase I inhibitor with low nanomolar potency derived from the prodrug irinotecan [7]

Inotuzu via an

Microm surface the su signall

Moxetu contain fragme comple cleava the cyt thus in

Combo

(RFB4

The cl detaile

Expec

Accord cells, i

CD22 agents would be similar to those observed with anti-CD20 monoclonal antibodies such as rituximab. Peripheral blood kinetics of CD19+ B-cells were determined in clinical studies with epratuzumab. Approximately 90% of patients suffered from a reduction in B-cell levels of 75% or higher within 4 weeks from the initiation of therapy, with B-cell recovery occurring at 9 to 12 months after the last infusion. Serum immunoglobulin levels were measured before, during and

6 ACCEPTED MANUSCRIPT after drug exposure, and no significant decrease was documented [11,12]. In SLE patients a median reduction of 30-40% in peripheral blood B-cell levels was observed, although T-cell and serum IgA and IgG levels remained stable throughout therapy, whereas IgM levels decreased by 20% from baseline among epratuzumab-treated patients [6].

The number of circulating CD22+ B cells rapidly declined following the administration of inotuzu moxet the sus

Availab

Previo showe phase an ex popula

19]. In

(218 p

ALL. H

CD22- with s pneum

Liver inotuzu associ

Sugge

• In

monoclonal antibodies) and available data (mainly restricted to epratuzumab and

inotuzumab ozogamicin), therapy with CD22-targeted agents does not meaningfully

increase the risk of infection.

• No benefit is expected from the universal use of antibacterial, antiviral or anti-

Pneumocystis prophylaxis for patients receiving CD22-targeted therapy. However, infection

7 ACCEPTED MANUSCRIPT

risk should be individually evaluated at the light of patient’s co-morbidities and the

concomitant administration of other immunosuppressive agents.

• Screening for chronic and resolved hepatitis B virus (HBV) infection should be performed

before starting treatment with CD22-targeted agents. Antiviral prophylaxis while on therapy

ma be considered for hepatitis B s rface antigen (HBsAg) positi e patients for pre enting

CD30-

Mecha

Brentu human cleava synthe mollus conjug relapse

Expec

A mem a 120-

Sternb includi functio regulat effecto mediated cytoto c ty ( CC) a d e et a deete ous pact o u oa u ty

Available clinical data

In two pivotal phase 2 studies including 102 patients with in relapsed/refractory HL [24] and 58 with anaplastic large T-cell lymphoma [25], no specific infectious complications were observed, although approximately 20% of participants developed neutropenia. Likewise, in a RCT

8 ACCEPTED MANUSCRIPT evaluating brentuximab vedotin as a consolidation therapy for autologous hematopoietic stem cell transplant (HSCT) recipients with HL at high risk of relapse or progression, no increase in the rates of upper respiratory tract infection and severe infection was reported for 167 patients receiving brentuximab compared to 160 receiving placebo [26]. Neutropenia, peripheral sensory neuropathy thrombocytopenia pulmonary toxicity (when given in association with bleomycin) and an

Of note was m

Progre in pati difficul immun duratio brentu exposu nataliz

[2,27-2

Mitigat approp

The oc also re therap the nee

Conclu

• In

meaningfully increase the risk of overall infection, with observed rates comparable to those

expected for patients with relapsed or refractory lymphoma. However, the use of

brentuximab vedotin carries an additional risk of neutropenia, which might be associated

with typical pattern of infections.

• Anti-herpesvirus and anti-Pneumocystis prophylaxis should be administered to autologous

9 ACCEPTED MANUSCRIPT

HSCT recipients treated with brentuximab vedotin as consolidation therapy.

• PML is a life-threatening complication occasionally associated with the use of brentuximab

vedotin. The new onset of neurological symptoms among patients treated with brentuximab

should prompt suspicion of PML, early drug discontinuation and appropriate diagnostic

work p

• R

CD33-

Mecha

Gemtu

IgG4 k antibio

CD33 expres more haema derivat treatm

Author surviva the US the ba favora some countries (e.g., Japan) for relapsed AML.

Expected impact on the infection risk

CD33 is expressed on monocytes, granulocytes, mast cells and myeloid progenitors. Due to the cytotoxic effect exerted on immature myeloid cells, CD33-targeted therapy leads to profound

10 ACCEPTED MANUSCRIPT neutropenia and thrombocytopenia. The expected 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 (e.g., induction to remission cytotoxic therapies for AML).

Available clinical data

Result ozogam infectio specifi anecdo gemtu

Conclu

• In

• S

CD38-

Mecha

The h recogn has m leukoc bifunct intrace lympho myeloma cells express high levels of CD38 on their surface, similar to normal plasma cells [39].

Therefore, CD38 serves as an attractive therapeutic target, in particular for multiple myeloma and potentially for other CD38-positive disorders (i.e., NHL). The expression of CD38 on normal lymphoid and myeloid cells is low.

Daratumumab (Darzalex®, Janssen) is a fully human IgG1 kappa monoclonal antibody targeting

11 ACCEPTED MANUSCRIPT

CD38 that has been approved by the FDA and EMA for the treatment of relapsed and refractory multiple myeloma in adult patients, either in monotherapy (approval in 2015-2016) or in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone

(approval in 2017) [40]. Isatuximab (SAR650984, Sanofi Genzyme) is a chimeric anti-CD38

IgG1 monoclonal antibody not yet approved although clinical studies are ongoing for relapsed and/or

Expec

CD38 norma comple phagoc isatuxi and, i immun suppre

In view on the

Availab

Pooled grade

0.7% a infectio

22.8% of patie arms.

Combination therapy with daratumumab resulted in a slightly increased rate of grade 3-4 febrile neutropenia (5.7% versus 2.5% in the control group) [42,43].

The rate of varicella zoster virus (VZV) infection in the daratumumab arms of the pivotal studies for relapsed/refractory myeloma ranged from 2% to 5% [42,43]. This finding is likely explained by the inclusion of immunomodulatory agents, proteasome inhibitors and corticosteroids within

12 ACCEPTED MANUSCRIPT the combination regimens evaluated in these trials. In addition, it should be noted that the rate of infection among myeloma patients is higher for relapsed/refractory cases and those with progressive disease [44].

Isatuximab is another potent anti-CD38 monoclonal antibody, and several phase 2 studies are ongoing to evaluate its role in heavily pre treated myeloma patients Pneumonia and sepsis were d pneum and de

Conclu

• In

• C

• Se

CD40-

Mecha

CD40 upon i acts as a receptor on antigen presenting cells that plays an essential role in mediating a wide array of immune responses, including T cell-dependent immunoglobulin class switching, memory B-cell development, and germinal centre formation in spleen and lymph nodes.

Mutations affecting the gene encoding for CD40 are associated with autosomal recessive hyper-IgM immunodeficiency type 3 [49].

13 ACCEPTED MANUSCRIPT

Currently there are no approved CD40-targeted agents. Dacetuzumab is a humanized monoclonal antibody studied in phase 2 trials for relapsed diffuse large B-cell lymphoma, and in phase 1 trials for CLL and multiple myeloma. Lucatumumab is a fully human monoclonal antibody that has been evaluated in phase 2 trials for patients with refractory lymphomas and in phase 1 studies for CLL and multiple myeloma Its clinical development was discontinued by

Novart

Expec

As CD tissue, cytope hyper- to sev protozo

Crypto freque

Availab

A phas compli

Conclu

• In

• C

• Appropriate prevention strategies (including anti-Pneumocystis prophylaxis, regular

monitoring for CMV infection among CMV-seropositive patients or in presence of clinically

suspected CMV disease, and early diagnosis of opportunistic infections) might be needed

for patients receiving such therapy.

14 ACCEPTED MANUSCRIPT

CD319-targeted agents: elotuzumab

Mechanism of action, approved indications and off-label uses

Elotuzumab (Empliciti®, Bristol-Myers Squibb) is an immunostimulatory, humanized IgG1 monoclonal antibody targeted at the SLAMF7, previously known as cell-surface glycoprotein

CD2 s expres of SLA role in

(which antitum myelom killing o

The ac have b multipl been s efficac myelom thalido those investi high-ris nivolum

Expec

In add particular NK cells, NK-like T-cells, CD8+ T-cells, activated monocytes, and dendritic cells [63].

The most frequent adverse event reported in patients treated with elotuzumab is lymphopenia.

Since elotuzumab is mainly used in combination with other anti-myeloma drugs, it is difficult to discern if the observed infections may be directly attributable to the effect of elotuzumab. The

15 ACCEPTED MANUSCRIPT expected impact would be similar to that associated to usual anti-myeloma drugs, such as protease inhibitors, lenalidomide or dexamethasone.

Available clinical data

Grade 3-4 lymphopenia and neutropenia have been reported in 142 patients included in small, non-co lenalid compli of 47% elotuzu

A mod elotuzu over th drug e and de almost per 10

(but n infectio

Conclu

• In

• A

• In

peripheral blood lymphocyte subpopulation counts should be performed.

CCR4-targeted agents: mogamulizumab

Mechanism of action, approved indications and off-label uses

16 ACCEPTED MANUSCRIPT

Mogamulizumab (Poteligeo®, Kyowa Hakko Kirin) is a recombinant humanized IgG1 monoclonal antibody that targets CC chemokine receptor 4 (CCR4) and depletes CCR4- expressing cells by ADCC. Mogamulizumab was developed for the treatment of adult T-cell leukaemia/lymphoma (ATLL), which is an aggressive peripheral T-cell neoplasm characterized by the clonal proliferation of human T cell lymphotropic virus type 1 (HTLV 1) infected T cells since m cutane by ma large c

Additio highly cells a making subset allogen

Mogam for the treatm and C

(either identifi myelop curren

Expec

CCR4 cutaneous lymphocyte antigen (CLA)-positive skin-homing T-cells [67]. Infectious complications typical for patients with T-cell malignancies are to be expected with the use of mogamulizumab, and immunological exacerbation of response to infectious stimuli (mirroring the immune reconstitution inflammatory syndrome observed in HIV patients) might be hypothesised on the basis of the eventual impairment of Treg function.

17 ACCEPTED MANUSCRIPT

Available clinical data

Four phase 2 trials found no significant differences in the incidence of infections between study groups. In the first single-arm trial in 27 patients with relapsed ATLL, no data on infections were provided, although per protocol all the participants received prophylaxis with trimethoprim/sulfamethoxazole fluconazole and acyclovir [68] In the second single arm trial in

37 pa develo retinitis with ag patient infectio patient group had at in 38 p monot

2 patie

Post-m resolve

Mycob

In a r hepatit mogam none o compa mogam [ ] pp y infection have been reported [73,74]. One was successfully treated with entecavir [73]. In the other case, the progression to fatal fulminant hepatitis occurred despite entecavir treatment once mogamulizumab was started in a patient already diagnosed with high-HBV-DNA-level

18 ACCEPTED MANUSCRIPT

(>9.1 log copies/mL) reactivation after previous chemotherapy [74]. Finally, conventional anti-

Pneumocystis prophylaxis has been shown to be effective.

Conclusions and suggested prevention strategies

• In view of available data, therapy with mogamulizumab (which induces drug-related

• B

• P

• S

tre

19 ACCEPTED MANUSCRIPT

Figure legends

Figure 1. Mode of action of brentuximab vedotin, an antibody-drug conjugate targeting CD30.

Upon binding to CD30 on the surface of T-cell malignant cell, brentuximab vedotin is internalized via endocytosis. The exposure of protease-sensitive dipeptide linker to proteolytic lysoso intrace inducti

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Table 1. Description of the main agents targeting lymphoid and myeloid cell surface antigens.

Agent Mechanism of action Status s single Use as Cellular expression devel / first-line of app nation treatment

Epratuzumab Anti-CD22 monoclonal Phase es Yes B-cells (mature and antibody (also in folli malignant) conjugated with the lymph topoisomerase I ALL; p inhibitor SN-38) in SLE Inotuzumab Anti-CD22 monoclonal Appro es No ozogamicin antibody conjugated (2017 with a calicheamicin Studie agent agent with ri refrac relaps Moxetumomab Variable fragment of Phase o No pasudotox anti-CD22 monoclonal cell le antibody conjugated 1 stud with Pseudomonas and C exotoxin A trial in

Brentuximab Anti-CD30 monoclonal Appro es Yes Activated T- and B- vedotin antibody conjugated to (2012 ng trials cells, monocytes, anti-tubulin agent rutinib) activated NK and MMAE Reed-Sternberg cells

Gemtuzymab Anti-CD33 monoclonal Appro es No Monocytes, ozogamicin antibody conjugated (2000 granulocytes, mast with a calicheamicin reapp cells and myeloid agent EMA refused (2008) progenitors

Daratumumab Anti-CD38 monoclonal Approved, EMA Relapsed or Potentially lymphomas, Yes / yes No Plasma cells, early antibodies, enhancing (2016), FDA (2015) refractory MM amyloidosis, MDS T- and B-cells,

21 ACCEPTED MANUSCRIPT

Isatuximab antitumor activity, Phase 2 study in NA ALL, CD38-positive Yes / yes No activated T-cells and modulation of CD38 MM haematological germinal centre B- ectoenzyme function li i cells (immunomodulation)

Dacetuzumab Anti-CD40 monoclonal Phase Yes No B-cells, monocytes, antibody phase macrophages, CLL follicular DCs, fibroblasts and keratinocytes

Elotuzumab Anti-CD319 (SLAMF7) Appro es No Germinal centre B- monoclonal antibody (2016 cells, follicular DCs

Mogamulizumab Anti-CCR4 monoclonal Appro o (only Yes ATLL cells, highly antibody Minist oing immunosuppressive Labou s) Treg subset (2012

ALL: acute lymphoblastic leukaemia; ATLL: adult T-cell le DLBCL: diffuse large B-cell lymphoma; EMA: European Medicines Agency; FDA: Food and Drug Admi tic syndrome; MM: multiple myeloma; NA: not available; NHL: non-Hodgkin’s lymphoma; ODD: orphan

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Table 2. Summary of infectious events in patients treated with agents targeted different lymphoma and leukemia cells surface antigens across

RCTs and observational studies that included a control group.

Agent Type of study infection (novel agent vs. rator)

Epratuzumab Phase 2 RCT for SLE nfection: 24-51% vs. 40%; URTI: 0- 5%; UTI: 3-5% vs. 5%; viral n: 0-3% vs. 5%; pneumonia: 0% vs.

Phase 3 RCT for SLE nfection: 64-70% vs. 70%; serious n: 12-36% vs. 12% Two phase 3 RCTs fo nfection: 52-61% vs. 60%; URTI: [6] vs. 11-14%; UTI: 10-14% vs. 11- ZV: 1-4% vs. 2-3%

Inotuzumab Phase 3 RCT for relap neutropenia (grade 3-4): 11% vs. ozogamicin refractory ALL [15] eumonia: 4% vs. 1%; sepsis: 2% vs. tic shock: 1% vs. 1%

Brentuximab Phase 3 RCT for enia: 35% vs. 12%; URTI: 26% vs. vedotin consolidation therapy a vere infection: 7% vs. 6% allogenic HSCT in HL

Gemtuzumab RCTs for AML [35-37] infection (grade 3-4) in induction ozogamicin 44% vs 47%; febrile neutropenia in n phase: 24% vs. 26%

Daratumumab Phase 3 RCT for relap infection (grade 3-4): 21.4% vs. refractory MM [43] eumonia (grade 3-4): 8.2% vs. eutropenia (grade 3-4): 12.8% vs. ZV: 5% vs. 3% Phase 3 RCT for relapsed or Daratumumab plus lenalidomide 286 vs. 283 Serious infection (grade 3-4): 28.3% vs. refractory MM [42] plus dexamethasone vs 22.8%; pneumonia (grade 3-4): 7.8% vs. lenalidomide plus dexamethasone 8.2%; neutropenia (grade 3-4): 51.9% vs.

23 ACCEPTED MANUSCRIPT

37%; febrile neutropenia (grade 3-4): 5.7% vs. 2.5%;VZV: 2% vs. 2%

Dacetuzumab Phase 2 RCT for relap enia (grade 3-4): 33% vs. 24%; NHL after R-CHOP [54 eutropenia (grade 3-4): 16% vs. 9%; nia (grade 3-4): 19% vs. 16%

Elotuzumab Open-label phase 2 nfection: 67% vs. 53%; serious randomised trial for re n (grade 3-4): 21% vs. 13% or refractory MM [57] Phase 3 RCT for relap nfection: 81% vs. 74%; lymphopenia refractory MM [59] 3-4): 77% vs. 49%; neutropenia 3-4): 34% vs. 44%; rate of VZV: 4.1 per 100 pts-years

Mogamulizumab Phase 2 RCT for aggre nfection: 66% vs. 67%; CMV adult T-cell leukaemia- n: 14% vs. 0%; bacteremia: 14% vs. lymphoma [70] brile neutropenia: 90% vs. 88%; enia (grade 3-4): 100% vs. 92%; penia (grade 3-4): 97% vs 75%

AML: acute myeloid leukaemia; CMV: cytomeg RTI: lower respiratory tract infection; MM: multiple myeloma; NHL: non-Hodgkin lymphom hematosus; URTI: upper respiratory tract infection; UTI: urinary tract infection; VZV: varic

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Table 3. Summary of risk of infectious complications and possible management strategies for the reviewed targeted agents.

Group Agent Risk of Ris Risk of CMV Other infections neutropenia (an nfection to be considered pro (monitoring wa warranted)

CD22- Epratuzumab No No No ND targeted agents Inotuzumab No No No ND ozogamicin

CD30- Brentuximab Yes ND Yes PML targeted vedotin rec agents pro

CD33- Gemtuzumab No ND ND (patients received ND targeted ozogamicin sta standard prophylaxis agents for for AML)

CD38- Daratumumab Yes Ye No ND targeted (no data yet agents available for isatuximab)

CD40- Dacetuzumab Yes Po Possible Anticipated targeted (scarce data occurrence of OIs agents available for similar to hyper lucatumumab) IgM syndrome (PCP, CMV infection, IFI, protozoa)

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CD319- Elotuzumab No Yes (especially VZV) Possible (consider if ND (patients No ND targeted concomitant received standard agents

CCR4- Mogamulizumab Possible ND Yes ND targeted be agents to

AML: acute myeloid leukaemia; CMV: cytomegalovirus rus; HSCT: hematopoietic stem cell transplant; HSV: herpes simplex virus; IFI: invasive fungal infectio cii pneumonia; PML: progressive multifocal encephalopathy; VZV: varicella-zoster virus.

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Transparency declaration

• Conflict of interest disclosure: B.S. received personal fees from GSK, Sanofi-Aventis, AbbVie and

Chiesi. M.M. received an investigational grant and non-financial support from Gilead, as well as

person no

conflic the

submi

• Fundi and

Institu va,

Spanis ous

Diseas nal

Fund és”

(JR14 and

Comp

27 ACCEPTED MANUSCRIPT

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