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Antibody-Drug Conjugates in Hematologic Malignancies

Lori A. Leslie, MD, and Anas Younes, MD

OVERVIEW

Antibody-drug conjugates (ADCs) are agents composed of a monoclonal antibody linked to cytotoxic molecules. By specifically delivering

cytotoxic agents to cells expressing surface antigens of interest, ADC technology allows for the targeted use of highly toxic agents

resulting in increased efficacy against malignant cells and decreased damage to normal tissue. Effector agents can be small molecules,

radioisotopes, proteins, or bacterially derived toxins. Over the past several decades, ADCs have been evaluated in a variety of

preclinical models of hematologic malignancies, as well as early-phase clinical trials with limited success. More recently, advancements

in linkage technology, improvements in cytotoxin selection, and use of smaller conjugates containing partial rather than complete

antibodies have drastically improved the potential clinical value of ADCs. In the future, ADC technology may be used to restore tumor

suppressor activity, target the microenvironment, or replace nonfunctional enzymes. In this review we will discuss select ADCs in

various stages of development for use in hematologic malignancies including lymphoma, multiple myeloma, and leukemia.

In the era of targeted therapy the goal is to develop highlyeffective, specifc agents with wide therapeutic indices.Most cancer therapies currently in use either target onco-

genic drivers specifcally with the risk of inducing tumor re-

sistance mechanisms or nonspecifcally target rapidly

dividing cells with the risk of toxicity to normal tissue. The

U.S. Food and Drug Administration (FDA) approval of the

anti-CD20 monoclonal antibody rituximab in 1997 sparked

an increased interest in using antibodies to target malignantcells. Recent advancements in conjugate technology have al-

lowed for the translation of antibody-drug conjugates

(ADCs) into clinical use.ADCs are bioconjugates composed of a monoclonal anti-

body, linker region, and effector molecule. Generally, the an-

tibody binds the target antigen or receptor on the surface of a

cell. The complex is endocytosed and transported to lyso-

somes where the effector molecule is released into the cyto-

plasm leading to cell toxicity. Because the large molecular

size of early ADCs limited delivery, modern ADCs use

smaller modifed antibodies or portions of antibodies.

Trials of early ADCs using classic chemotherapeutics as ef-fector molecules resulted in disappointing response rates be-

cause of low cytotoxicity at the deliverable dose. Through

bioconjugation, highly toxic agents can now be selectivelydelivered to target cells with a wide therapeutic index. Effec-

tor molecules currently in use include proteins and small

moleculessuch as theminor DNA-binding agent calicheami-

cin; tubulin depolymerization agents maytansinoids (DM1

or DM4) and auristatins (MMAE or MMAF); and bacterial

derived agents such as diphtheria or Pseudomonas exotoxins.

Linker selection is a crucial determinant of ADC effcacy.

Cleavable linkers such as hydrazones and disulfdes are acti-

vated in the acidic lysosomal environment or the reductive

cytosolic environment, respectively, but unintentional sys-

temic toxin release is relatively common because of the non-

specifc nature of these reactions. Dipeptide noncleavable

linkers are more stable in circulation because they are acti-vated by specifc lysosomal proteases, reducing the potential

for systemic release. Rather than releasing effector molecules

at the site of intended activity, thioethers are noncleavablelinkers in which intracellular degradation of the attached an-

tibody leads to effector activation. The number of effector

molecules linked to a single antibody determines properties

such as tendency to aggregate systemically, effcacy of endo-

cytosis, half-life, and ability to bind target antigens. For the

majority of ADCs, the ideal antibody drug ratio to maximize

effcacy and delivery is 1:4.

There are several additional factors to consider when de-

signing an ADC. Malignant cells typically do not expressnovel markers to avoid clearance by the hosts immune sys-

tem, but they may express aberrantly high concentrations

of normal surface markers ideal for targeting. Rapid inter-nalization of the antigen-antibody complex on binding is

another important target quality, as receptor-mediated en-

docytosis is necessary for the activity of most effectors.

Conjugate stability in circulation, timing of effector release,

From the Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center,New York, NY.

Authors disclosures of potential conflicts of interest are found at the end of this article.

Corresponding author: Anas Younes, MD, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 330, New York, NY, 10065, email:[email protected].

2013 by American Society of Clinical Oncology.

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and minimization of neutralizing antibody production mustalso be optimized. With these considerations in mind,

various ADCs have been designed for use in patients withhematologic malignancies, including lymphoma, multiplemyeloma, and leukemia.

LYMPHOMACD19CD19 is part of the B-cell receptor (BCR) complex. Similar toCD20, CD19 is expressed on the surface of B-lymphocytesthroughout development with loss of expression on plasmacells. Unlike CD20, CD19 is rapidly internalized on antigenbinding. In a phase I/II study of the CD19 monoclonal anti-body, MEDI-551, in patients with relapsed or refractory (RR)B-cell NHL, the objective response rate (ORR) was 26%.1

Given the activity of naked anti-CD19 monoclonal antibod-ies and its internalization on antibody binding, CD19 is a ra-tional target for cytotoxic ADCs.

A phase I study of the anti-CD19-DM4 conjugate,SAR3419, in RR B-cell non-Hodgkin lymphoma (NHL) re-

vealed a maximum tolerated dose of 55 mg/m2 weekly. Dose-limiting toxicities were reversible corneal changes andperipheral neuropathy. Other adverse events (AE) weregrades 1 to 2 hepatotoxicity and myelosuppression. Of the 22patients who received drug at the maximum tolerated dose,the ORR was 36% (complete remission rate (CRR) 14%) witha response duration of 6 to at least 12 months.2 Anotherphase I trial of SAR3419 in 39 patients with RR B-cell NHLestablished a maximum tolerated dose (MTD) of 160 mg/m2

every 21 days with similar dose-limiting toxicities. Of the 17

evaluable patients who received drug at the MTD, the ORRwas 24%. Of those with rituximab-refractory disease, 47% ex-perienced reduction in tumor size. The duration of responseat all dose levels was 13.9 to at least 33.1 weeks. 3

CD22CD22 is involved in inhibitory BCR signaling and preventionof autoimmunity. Similar to CD19, it is rapidly internalizedon antigen binding. The modest ORRs of 10% to 18%achieved with the naked anti-CD22 monoclonal antibody,epratuzumab, in B-cell NHL have drastically increased withCD22-directed ADCs.4,5

Inotuzumab ozogamicin (CMC-544), an anti-CD22-calicheamicin ADC, has shown promising single-agentactiv-ity in patients with RR indolent B-cell NHL. In a phase IIstudy of 43 patients with RR indolent or follicular lymphoma(FL) receiving 1.8 mg/m2 of inotuzumab ozogamicin every28 days, the ORR was 53% (CRR 19%) with a 6-monthprogression-free survival (PFS) rate of 59%. Of the 35 pa-tients with FL, the ORR was 66% and 6-month PFS rate was67%. Common AEs were cytopenias, nausea, fatigue, and in-creased liver enzymes.6 In a phase I/II trial of inotuzumabozogamicin and rituximab in patients with RR B-cell NHL,the combination was well-tolerated with manageable AEssimilar to those of inotuzumab ozogamicin and rituximabmonotherapies, with MTDs of 1.8 mg/m2 and 375 mg/m2,

respectively. In FL (39 patients), diffuse large B-cell lym-phoma (DLBCL, 42 patients), and aggressive NHL (30 pa-tients) the ORRs were 87%, 74%, and 20%, respectively.7

Preliminary results of a phase I/II trial of DCDT2980S, ananti-CD22 antibody linked to MMAE, revealed early evi-dence of clinical activity in 35 patients with RR indolent andaggressive B-cellNHL. TheMTD was 2.4mg/kg andthe mostcommon AEs were diarrhea, fatigue, nausea, neutropenia,and peripheral edema. Of the 3 patients with DLBCL treatedat the MTD, 2 patients (67%) had greater than 75% decreasein tumor burden with complete metabolic response on PET.

Two additional patients with DLBCL achieved a partial re-sponse (PR) and underwent autologous stem-cell transplan-tation (ASCT). One patient (9%) with FL achieved PR at adose level of 1.8 mg/kg. Enrollment in two expansion cohortsat the MTD is ongoing.8

CD30CD30 is a memberof the tumor-necrosis factorreceptorfam-ily, expressed on activated T and B-lymphocytes, and rapidlyinternalized on antigen binding. Expression is increased inanaplastic large cell lymphoma (ALCL), classic Hodgkinlymphoma (HL), select cases of NHL, and embryonal germ

cell tumors. Although studies of naked anti-CD30 monoclo-nal antibodies in CD30 lymphomas were disappointingwith ORRs of less than 10%,9 the development of CD30-directed ADCs is changing the treatment paradigm forCD30 lymphomas.

Brentuximab vedotin (SGN-35), an anti-CD30-MMAEADC, was granted accelerated approval by the FDA in 2011for patients with RR HL with ASCTfailure or ineligibility andpatients with ALCL after failure of at least one combined che-motherapy regimen. The approved dosage of brentuximab

vedotin is 1.8 mg/kg given every 21 days for a maximum of 16cycles.10 The most common AEs are peripheral neuropathy,

cytopenias, and fatigue. Approval for HL was on the basis of

KEY POINTS

Antibody-drug conjugates (ADCs) use the specificity of

monoclonal antibodies to deliver potent cytotoxic agents

with a wide therapeutic index.

Effector agents linked to antibodies are typically potentanticancer drugs that are too toxic for systemic use.

Selecting a cell surface target that is rapidly internalized

on antibody binding allows for intracellular delivery of

cytotoxins.

The anti-CD30 ADC brentuximab vedotin is an example of

an ADC that has been recently approved by the United

States Food and Drug Administration (FDA), has changed

the treatment paradigm of relapsed or refractory Hodgkin

lymphoma, and has promise for use in the upfront setting.

In the future, ADCs may be used to restore tumor

suppressor function or to replace nonfunctional enzymes in

a variety of disease processes.

PRESENT AND FUTURE OF ADCS IN HEMATOLOGIC MALIGNANCIES

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results from a multicenter phase II trial in which 102 patientwith relapsed HL after ASCT achieved an ORR of 73%, CRRof 32%, and partial response rate (PRR) of 40% with mediandurations of response 6.7, 20.5, and 3.5 months, respec-tively.11 Approval for ALCL was on the basis of a multicenterphase II trial of 58 patients with CD30-positive ALCL with

at least one prior multiagent chemotherapy regimen that

revealed an ORR of 86%, CRR of 57%, and PRR of 29%, withmedian durations of response 12.6, 13.2, and 2.1 months,respectively.12

Brentuximab vedotin has also shown activity in other NHLsubtypes. Interim results of a multicenter phase II trial ofbrentuximab vedotin in 53 patients with RR CD30-postive

NHL revealed an ORR of 33% (CRR 14%, PRR 19%) in 36

TABLE 1. Antibody-Drug Conjugates in Hematologic Malignancies

Target Antibody-Drug Conjugate Cytotoxic Conjugate Phase Disease CRR%PRR%(SD or MR) ORR% Ref

CD3 A-dmDR390-bisFv(UCHT1) Diphtheria toxin A I T-cell NHL 20 40 60 16

CD19 MEDI-551 I/II B-NHL 12 14 26 1

CD19 SAR3419 Maytansinoid, DM4 I/II NHL 14 22 36 2

I NHL 24

3

CD22 Epratuzumab I/II Indolent/FL 6 12 18 4

I/II Aggressive 6 4 10 5

CD22 Inotuzumab ozogamicin, CMC544 Calicheamicin II ALL 18 39 57 28

II Indolent/FL 19 34 53 6

I DLBCL 15 29

CD22 Inotuzumab ozogamicin with rituximab Calicheamicin I/II Indolent, FL 87 7

DLBCL 74

Aggressive 20

CD22 DCDT2980S MMAE I DLBCL 22 8

Indolent 9

CD22 CAT-3888, BL22 PE38 II HCL (1 cycle) 25 25 50

25

HCL (2 cycles) 47 25 82

CD22 Moxetumomab pasudotox , CAT-8015,HA22

PE38 I HCL 46 40 86 27

CD19 andCD22

RFB4 & HD37-dgRTA, Combotox DeglycosylatedRicin A

I B-cell ALL 0 6 6 30

CD30 MDX30 I/II HL, ALCL, orCD30 T-

NHL

8 (35) 8 9

CD30 Brentuximab vedotin, SGN-35, ADCETRIS MMAE II HL 32 40 73 11

ALCL 57 29 86 12

CD30 NHL 14 19 33 13

CD30 Brentuximab vedotin, AVD CHP MMAE I HL 92 4 96 14

I ALCL 88 12 100 15

CD33 M195 I 0 0(15) 0 20

CD33 Gemtuzumab ozogamicin, Mylortag Calicheamicin II AML 30 30 21

AML, Age60 26 26

CD33 AVE9633 Maytansinoid, DM4 I AML 2 2 4 23

CD33 Hum-195/rGel Gelonin I AML, MDS,CMML

0 0 (27) 0 24

CD56 Lorvotuzumab mertansine, IMGN901 Maytansinoid, DM1 I MM 0 7 (11) 18 18

CD74 Milatuzumab I MM 0 0 (19) 0 19

CD74 Milatuzumab-doxorubicin, hLL1-DOX Doxorubicin I/II MM CLL, NHL Ongoing

CD138 BT062 Maytansinoid, DM4 I/IIa MM 0 4 (48) 52 17Abbreviations: ALCL, anaplastic large cell lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocyticleukemia; CRR, complete response rate; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HCL, hairy cell leukemia; HL, Hodgkin lymphoma; MDS, myelodysplastic syndrome; MM,multiple myeloma; MMAE, monomethyl auristatin E; MR, minimal response; NHL, non-Hodgkin lymphoma; ORR, overall response rate; PE38, pseudomonas exotoxin; PRR, partial response rate; SD,stable disease.

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evaluable patients. Encouraging subtypes included nonpri-mary mediastinal DLBCL (15 patients, ORR 47%, completeremission rate (CRR) 20%, PRR 27%); angioimmunoblasticT-cell lymphoma (5 patients, ORR 60%, CRR 40%, PRR20%); and gray zone lymphoma (5 patients, PRR 40%). No-tably, the degree of CD30 expression did not correlate withlikelihood of response.13

Brentuximab vedotin is currently being evaluated in com-bination with chemotherapyin the upfront setting. In a phaseI study, 51 patients with untreated HL were given 0.6 mg/kgto 1.2 mg/kg of brentuximab vedotin with doxorubicin, bleo-mycin, vinblastine, and dacarbazine (BVABVD) or 1.2mg/kg of brentuximab vedotin with AVD (BVAVD) onday 1 and 15 of a 28-day cycle for up to 6 cycles. DTLs werenot observed at the maximum planned dose. Common AEswere similar to those with ABVD or brentuximab vedotinmonotherapies. Of note, 11 of 25 (44%) patients treated withBVABVD experienced pulmonary toxicity resulting in 2deaths, compared with 0% in the BVAVD group. PET-CT

after 2 cycles was obtained in 48 patients with complete met-abolic response observed in 100% (BVABVD) and 92%(BVAVD) of patients. At the end of treatment, the ORRwas 96% (CRR 95% for BV-ABVD, CRR 92% for BV-AVD).14A phase I study of 1.8mg/kg of brentuximab vedotingiven in combination with cyclophosphamide, doxorubicin,and prednisone (BV-CHP) for up to 6 cycles followed bymaintenance single-agent brentuximab vedotin in 26 pa-tients with untreated ALCL (19 patients) or other matureNK/T cell lymphomas (7 patients) revealed an ORR of 100%(CRR 88%, PRR12%). Grade 3 or higher AEs included febrileneutropenia, nausea, and pulmonary embolism.15 Random-

ized trials of BV-containing regimens compared with stan-dard ABVD in HL or CHOP in T-cell lymphomas areunderway. Further studies of brentuximab vedotin in com-bination with bleomycin-containing regimens should beavoided because of increased risk of life-threatening pulmo-nary toxicity.

CD3A component of the T-cell receptor (TCR) complex, CD3is a specifc surface marker expressed throughout T-cell de-

velopment and internalized on ligand binding. In a phase Itrial, the bivalent anti-CD3 antibody linked to diphtheria

toxin, A-dmDT390-bisFv(UCHT1), was administered to 12

patients with RR T-cell NHL. The MTD was not reached.AEs were dose-dependent and included transient fever,lymphopenia, CMV or EBV viremia, and liver function testabnormalities. Of the 10 evaluable patients, the CRR was 20%and PRR was 40%.16 A phase I/II trial in patients with CD3-positive refractory T-cell leukemia or lymphoma is currentlyin recruitment (NCT00611208).

MULTIPLE MYELOMACD138Among lymphoid cells, CD138 is a sensitive and specifcmarkerof plasmacytoid differentiationthat is internalized onligand binding. In a phase I/II study of BT062, an anti-CD138-DM4 ADC, in 32 patients with RR multiple my-eloma, the MTD was 160 mg/m2 and the dose-limitingtoxicity was mucositis. Common AEs were epithelial in na-ture, including stomatitis, hand-foot syndrome, xerophthal-mia, and blurred vision. Of the 27 evaluable patients, clinical

response rate was 52%, with 4% demonstrating PR and 48%demonstrating minimal response (MR) or stable disease(SD).17 The MTD cohort has been expanded, results are cur-rently unavailable.

CD56CD56, or neural cell adhesion molecule, is involved with cell-cell adhesion. It is expressed on a variety of normal and ma-lignant hematolymphoid cells, including NK cells, activatedT cells, myeloid leukemia, NK/T-cell lymphomas, and mul-tiple myeloma. Results from the expansion cohort of a phaseI study of the anti-CD56-DM1 ADC, lorvotuzumab mer-

tansine (IMG901), in 28 evaluable patients with RR CD56-positive multiple myeloma revealed an ORR of 18% (PRR7%, MRR 11%). The MTD was 112 mg/m2 and grade 3 AEswere fatigue, renal failure, and absence of deep tendon re-flexes.18 Considering that clinically signifcant myelosup-pression was not observed, a phase I study of lorvotuzumabmertansine in combination with lenalidomide and dexa-methasone in patients with RR multiple myeloma is ongoing(NCT00991562).

CD74CD74 is the invariant chain of the MHC class II complex

expressed on the surface of antigen presenting cells and

FIG 1. Target expression in hematologic malignancies.Abbreviations: HL, Hodgkin lymphoma, B-NHL, B-cell non-Hodgkin lymphoma, T-NHL, T-cell non-Hodgkin lymphoma, MM, multiple myeloma, CLL, chronic lymphocytic leukemia.



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lymphocytes, is internalized on ligand binding, and has ahigh degree of expression in multiple myeloma. In a multi-center phase I trial of the naked anti-CD74 monoclonalantibody, milatuzumab, in patients with RR multiple my-eloma the MTD was not reached, and 19% of patients re-ceiving the highest dose levels maintained stable disease.19

Phase I/II trials of the hLL1-DOX, a milatuzumab-

doxorubicin ADC, in patients with RR multiple myeloma(NCT01101594) and CLL or NHL (NCT01585688) are cur-rently in recruitment.

LEUKEMIACD33Although early phase trials of the naked CD33 monoclonalantibody, M195, yielded disappointing results in patientswith acute myelogenous leukemia (AML),20 ADCs targetingthe myeloid-specifc transmembrane receptor CD33 haveshown activity. Gemtuzumab ozogamicin (Mylortag), an

anti-CD33-calicheamicin ADC, was granted accelerated-approval by the FDA in 2000 for the treatment of RR AMLin patients over age 60 or those who are not candidates forstandard chemotherapy. Approval was on the basis of ag-gregate data from phase I and phase II studies revealing aCRR with complete hematopoietic recovery of 16% and aCRR with persistent thrombocytopenia of 14%, for an ORRof 30%. The ORR for patients over the age of 60 was 26%.The most common AEs were myelosuppression and hepato-toxicity.21 In 2009, a planned interim analysis of a follow-upphase III trial evaluating gemtuzumab ozogamicin in com-bination with standard induction chemotherapy revealedno improvement in CRR, relapse free survival, postconsoli-dation disease free survival, or overall survival. Notably,5.8% of patients in the gemtuzumab ozogamicin arm experi-enced fatal AEs compared with 0.8% in the control arm.22

Given safety concerns, it was voluntarily withdrawn from themarket in 2010, but its use in clinical trials as part of combi-nation therapy in AML continues with stringent safety mon-itoring.

Early results of other anti-CD33 ADCs have been disap-pointing. In a phase I study, AVE9633, an anti-CD33-DM4ADC, was administered to 54 patients with AML resulting in1CR (2%)and 1 PR(2%).23 A phaseI study of the anti-CD33-gelonin ADC, HuM195/rGel, in 28 patients with AML,

chronic myelomonocytic leukemia, or myelodysplastic syn-drome revealed an MTD of 7 mg/m2. Of the 22 evaluable pa-tients, there was no CR but 6 (27%) had a 50% decrease inblasts.24 With both agents, hypersensitivity was common butmyelosuppression was not observed.

CD22CD22 directed ADCs have also been evaluated in patients withleukemia. In a phase II study, the frst generation anti-CD22-Pseudomonas exotoxin ADC, CAT-3888 (BL22), was adminis-tered to 36 patients with RR hairy cell leukemia (HCL). After

onecycle (three doses)of 40/kg every 48 hours,ORR was 50%

(CRR 25%). Those that did not achieve CR (27 patients)received a second cycle of CAT-3888, resulting in an ORR of72% (CRR 47%, PRR 25%). Those with splenomegaly greaterthan 20 cm or a history of splenectomy were less likely to re-spond. The onlygrade 3 toxicityreported was hemolytic uremicsyndrome (HUS), occurring in 6% of patients.25

A second generation anti-CD22-PE38 ADC, moxetumomab

pasudotox (CAT-8015, HA22), demonstrated increased eff-cacy over CAT-8333 in animal models of hematologic malig-nancies.26InaphaseItrialof28patientswithRRHCL,theMTDwas not reached. AEs included reversible grade 1 to 2 HUS, hy-poalbuminemia, transaminitis, headache, hypotension, nausea,and fatigue. Responses were seen at all dose levels with an ORRof 86% (CRR 46%). The median disease-free survival had notbeen reachedat 26 months.27Phase I/II trials of moxetumomabpasudotox in patients with CLL, NHL, and acutelymphoblasticleukemia(ALL)areactive, twoof which havecompletedrecruit-ment with results pending.

The anti-CD22-calecheamicin ADC, inotuzumab ozo-gamicin (CMC544), has not only shown promising activityin NHL, but also has shown encouraging activity in patientswith ALL. A phase II study of inotuzumab ozogamicin in 49patients with relapsed or refractory ALL revealed an ORR of57%, with 19% achieving CR and 39% achieving marrow CRwith persistent cytopenias. Common AEs were fever, hypo-tension, and hepatotoxicity.28

CD19/CD22Similar to the concept of combination chemotherapy,using combinations of monoclonal antibodies linked tothe same effector molecules is an area of interest. An ADC

composed of anti-CD19/CD22 antibodies linked to de-glycosylated ricin A chain, Combotox, was evaluated in aphase I study of 17 patient with RR B-lineage ALL. Dis-appointingly, only one patient experienced a PR and wasable to undergo an autologous stem cell transplant. How-ever, all patients with circulating blasts experienced reduc-tion in blast counts with therapy. Similarly a phase I trialof DT2219ARL, an immunotoxin composed of CD19 andCD22 scFv ligands linked to diphtheria toxin, is currently re-cruiting adults with relapsed/refractory B-lineage leukemiaor lymphoma (NCT00889408).

FUTURE DIRECTIONSAs more is understood about the interaction between malig-nant cells and their surroundings, ADCs can be used not onlyto target cell surface antigens but also the microenvironment.In the future, it is possible that ADCs could be used to deliverfunctional enzymes intracellularly or to restore tumor sup-pressor function. With further developments in antigen, ef-fector, and linker technology, the specifcity and effcacy ofADCs will continue to improve, creating valuable agents forboth monotherapy and combination therapy in hematologicmalignancies. Additionally, further correlative biomarker

studies will be crucial to improve patient selection.

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Disclosures of Potential Conflicts of Interest

Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate

family member; those marked B are held by the author and an immediate family member. Relationships marked U are uncompensated.

Employment or Leadership Position: None. Consultant or Advisory Role: Anas Younes, Allos Therapeutics; Celgene; Gilead Sciences; Millennium;

Novartis; Sanofi; Seattle Genetics. Stock Ownership: None. Honoraria: None. Research Funding: Anas Younes, Affimed Therapeutics; Gilead Sciences;

Novartis; Seattle Genetics; Syndax. Expert Testimony: None. Other Remuneration: None.

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