New England Journal of medicine
`v. 372, no. 4 (Jan. 22 2015)
`General Collection
`W1 NE388
`2015-01—2810238132
`
`
`
`ENGLAND
`
`
`
`
`
`JOURNAL ofMEDICINE
`
`
`
`VOL. 31"2
`
`
`NO. 4
`
`ESTABLISH Iii) IN I312
`
`JANUARY 22, 201';
`
`rut-ammo;
`
`T10
`
`30!
`
`30%
`
`30h
`
`308
`
`3‘1]
`
`32!]
`
`3‘31
`
`341
`
`THIS WEEK AT NEJMJZIRG
`
`PERSPECTIVE
`
`
`
`'[‘reating Millions for l [W —- The Adherence CIUbS
`I W'.
`':_.|l'||."|f|"
`Othayelitsha
`
`Demediealizing AIDS Prevention and Treatment
`II] Africa
`l
`Ilirrml:
`
`Foreseeahle Risks? informed Consent for Studies
`within the Standard of Care
`furl.
`‘3.i-'|<:'. nirl f. .l' Wm H-II
`
`Bridging the I lospitalist—Primary Carr Divide through
`fill I:I(.]Ir1ii
`ii-rl LIP. Hunt
`Collaborative Care
`
`ORIGINAL ARTICLES
`
`PD-l Blockade with Nivoluntab in Relapsed
`
`or Refractory l-Iodgkin’s Lymphoma
`Blvl Fair-mil anti ('ltlii-rn
`
`Nivolumab in Previously Untreated Melanoma
`without BRAF Mutation
`i.
`i-'r1l1['ri
`.Iriti ()iiitjf‘»
`
`Causes and Timing oi'Death in Extremely
`Premature lnfants from 2000 through 2011
`Lil-«l l'.lll'l .|.-I[i C'Ii'itg-r'n
`
`’l‘BXti Null Variants and a Common llypomorphic
`
`Allele in Congenital Scoliosis
`l-.l Wn .intl i'JIliel
`
`35]
`
`36"}
`
`6'5
`
`364
`
`374
`
`371')
`
`332
`
`38';
`
`3‘14
`
`2:14
`
`305
`
`REVIEW AR'rICLE
`
`Origins onystic Fibrosis Lung Disease
`DA. Stoltz. D.i(. Meyerlaolr, and M .l. Welsl'.
`IMAGES IN CLINICAL MEDICINE
`
`Bilateral Lower Palpebral MALT Lymphoma
`|.
`|
`.‘ilya and H. Marisouri
`Acute Colonic Pseudo-Obstruction
`
`F. Alaiitiab and S Saligram
`CASE RECORDS OF THE MASSACHUSETTS
`GENERAL HOSPITAL
`
`A Woman with Abdominal Pain, Dyspuea.
`and Diplopia
`W5. and and Other";
`
`EDITORIAL
`
`Release the l [ounds! Activating the T-Cell Response
`to Cancer
`
`M. Sznnl .ll'lLI D.L. iongo
`HEALTH POLICY REPORT
`
`
`institute ofMedicine Report on GM *'
`for Reform
`
`lK igic‘i'intl
`
`CLINICAL IMPLICATIONS or BASIC RESEARCH
`
`A Biologic Velcro Patch
`
`j.'lolrn'.‘-nitl_J.F.Wa§1ner
`CORRESPON DENCE
`
`Rituximab or Azathioprine Maintenance
`in ANCA-Associated Vasculitis
`
`Cost-Effectiveness ofCT Screening
`in the National Lung Screening 'l'rial
`
`integration ofAcid—Base and Electrolyte Disorders
`
`Hidden Formaldehyde in E—Cigarette Aerosols
`CORRECTI . .
`
`Genome & Co. v. Univ. of Chicago
`
`PGR2019-00002 UNIV. CHICAGO EX. 2055
`
`(NEJM
`GROUP
`
`{Itwml & pulalislrrri lru IIII' masmtil 1er li'i'I's s. t: I .‘lICA I. sum 1E'1‘Y
`20: S. all rights mrrml. ISSN ooze-41:9 ;_
`
`as
`///iit\\\\
`NAI IONAI
`[ [BRARY Oi
`M EDICINF.
`
`Int-Mu. man-mum Hum:
`
`PROPERTY OF THE
`NATIONAL
`
`LIBRARY OF
`MEDICINE
`
`:Ill\f|t
`
`

`

` The NEW ENGLAND
`
`JOURNAL of MEDICINE
`
`Subscription and
`Business Information
`
`The New Englandjournal ofMedicine is a publication of NEJM Group, a division ofthe Massachusetts Medical Society.
`
`CUSTOMER SERVICE
`
`SUBSCRIPTIONS
`
`NEJM Customer Service
`PD. Box 54803
`Waltham. MA 02454-0803
`Telephone: SOG-THE-NEJM {300-843-6356}
`Fax:
`781-893-0413
`Email: neimcust@mms.org
`Web:
`nejm.orgy’contact-nejrn
`
`BUSINESS OFFICE ADDRESS
`
`The New Englandjournal of Medicine
`860 Winter Street
`Waltham. MA 02451-1413
`
`ADVERTISING SALES
`DISPLAY ADVERTISING
`
`Telephone: 800-635-6991
`Email: salessupport©nejm.org
`Web:
`neimorgirfadvertising
`CLASSIFIEDADVERTISING
`
`Telephone: 300—635—6991
`Email: ads@nejmcareercenter.org
`Web:
`recruiters.nejmcareercenterorg
`
`INSTITUTIONAL SALES
`
`Telephone: 781-434-7135
`Email:
`institution sales®neimorg
`Web:
`neirn.orgfrfinstitutions
`
`CORPORATE SALES
`
`Telephone: 781-434-7041
`Email: corporatesales®nejmorg
`Web:
`nejm.orgir,linstitutions
`
`PERMISSIONS
`
`Email: permissions©nejm.org
`Web:
`nejm.orgiripermissions
`
`EDUCATIONAL anssnoom use
`
`Copyright Clearance Center (CCC)
`222 Rosewood Drive. Danvers. MA 01923
`Telephone: 978-750-8400
`Fax:
`973—750-4470
`
`Web: copyrightcom
`
`ARTICLE REPRINTS
`
`Telephone: 877-241-7159
`Email: reprints@nejm.org
`Web:
`nejm.orgfry’reprints
`
`MEDIA RELATIONS
`
`Telephone: 731-434—7847
`Email: mediasupport@nejm.org
`Web:
`nejm.org{media
`
`Individual one-year NEJM subscriptions include weekly print issues. aCcess to:
`NEJM.org [1990 to present). the NEJM iPad Edition, 20 free online CME exams.
`and 50 free 1812'1989 Archive views, Online-only subscriptions are also available.
`USA RATES
`
`Individual Print + Online + iPad
`Physician: $1?9
`Resident: $69
`Student:
`$65
`
`Institutional Print-Only: $1.150. Contact Institutional or Corporate Sales for onlinc
`Site License rates.
`
`SUBSCRIBE OR RENEW
`
`Contact Customer Service or go to my.neim.orgisubscribe or my.nejm.orgfrenew_
`
`ACTIVATE SUBSCRIPTION AT NEJM.0RG
`
`Activate your individual subscription to get access to subscriber content at
`NEJM.org and the NEJM iPad Edition. Go to my.nejm.orgy’activate. You'll need your
`customer number. which is located on your address label, or inquire with Customer
`Service.
`
`ADDRESS CHANGE
`
`Advise Customer Service of changes to your delivery address four to six weeks in
`advance to ensure uninterrupted service. Provide current mailing label information
`{including customer number). new address, and effective date ofchange. lfa pOstal
`ofiice advises us that your issues are undeliverable, we will have no further obligation
`unless we receive a corrected address within one year.
`
`REPLACING MISSING OR DAMAGED ISSUES
`
`Please notify Customer Service within three months of the missed or damaged issue for
`replacement without charge. Provide issue dateIs) and a copy ofa mailing label.
`SINGLE COPY AND VOLUME PURCHASE
`
`Single copies of print issues may be purchased for $6.00 and print unbound volumes
`(26 issues.jan—lune orJuly—Dec] are available for $179. Prepayment is required: tentact
`Customer Service to order. Copies are provided subject to their availability. Issues are
`only retained for three years.
`
`DISPLAY ADVERTISING
`
`All advertising material is expected to conform to ethical. medical. and business standards.
`Acceptance ofdisplay advertising does not imply endorsement by NEJM. Please contact
`Display Advertising Sales for more information about advertising policies.
`PERMISSIONS
`
`Requests to reproduce articles from NEJM for educational classroom use should be
`directed to the Copyright Clearance Center {CCC}. For additional permissions information_
`please visit nejmprgiry’permissions.
`
`LIST RENTAL
`
`The NEJM subscriber mailing list is available to select approved third parties for rental on
`a controlled basis. Please contact Customer Service ifyou prefer to have your name
`withheld from such rentals and not to receive promotional material. We do not sell or
`rent your email address to any third parties. List rental requests should be directed to
`List Manager: Mike Rovello, Infogroup Targeting Solutions, Telephone: 402-836-5531
`Email: Mike.Rovello®infogroup.org.
`
`COPYRIGHT
`
`Copyright @2015 Massachusetts Medical Society. All rights reserved.
`
`
`
`

`

`This material may be protected by Copyright law mile 17 us. Code]
`
`
`
`
`The NEW ENGLAND
`
`JOURNAL of MEDICINE
`
`ESTABLISHED IN 1812
`
`IANUARY 22, 2015
`
`VOL. 372 N0. 4
`
`PD-l Blockade with Nivolumab in Relapsed or Refractory
`Hodgkin’s Lymphoma
`
`Stephen M. Ansell. MD. Ph.D.. Alexander M. Lesokhin. M.D.. Ivan Borrello. M.D.. Ahmad Halwani. M.D.,
`Emma C. Scott. M.D.. Martin Gutierrez. M.D.. Stephen]. Schuster. MD. Michael M. Millenson, M.D..
`Deepika Cattry. M.S.. Gordonj. Freeman, Ph.D.. Scott]. Rodig. MD. Ph.D.. Bioern Chapuy. M.D.. Ph.D..
`Azra H. Ligon, Ph.D.. Lili Zhu. M.S..Joseph F. Grosso. Ph.D.. So Young Kim. M.D.. Ph.D..
`John M. Timmerman. M.D.. Margaret A. Shipp. M.D., and Philippe Armand. MD. PhD.
`
`ABSTRACT
`
`nacxnaouuo
`
`Preclinical studies suggest that Reed—Sternberg cells exploit the programmed death 1
`(PD-1} pathway to evade immune detection. In classic Hodgkin’s lymphoma. altera-
`tions in chromosome 9p24.1 increase the abundance ofthe I’D-1 ligands. PD—Ll and
`PD-LZ, and promote their induction through Janus kinase [JAK}—signal transducer
`and activator oftranscription [STAT] signaling. We hypothesized that nivolumab, a
`PD-l—bloeking antibody. could inhibit tumor immune evasion in patients with re-
`lapsed or refractory Hodgkin’s lymphoma.
`"canons
`
`In this ongoing study, 23 patients with relapsed or refractory Hodgkin’s lymphoma
`that had already been heavily treated received nivolumab (at a dose of 3 mg per ki—
`logram of body weight} every 2 weeks until they had a complete response, tumor
`progression, or excessive toxic effects. Study objectives were measurement of safety
`and efficacy and assessment ofthe PDLI and PDL2 (also called C0274 and PDCDILGZ.
`respectively) loci and I’D-1.1 and PD-L2 protein expression.
`RESULTS
`
`Of the 23 study patients, 78% were enrolled in the study after a relapse following
`autologous stem-cell transplantation and 78% after a relapse following the receipt
`of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3
`occurred in 78% and 22% of patients, respectively. An objective response was re-
`ported in 20 patients (87%), including 17% with a complete response and 70% with
`a partial response; the remaining 3 patients {13%} had stable disease. The rate of
`progression-free survival at 24 weeks was 86%; 11 patients were continuing to par-
`ticipate in the study. Reasons for discontinuation included stem-cell transplanta-
`tion (in 6 patients}. disease progression {in 4 patients], and drug toxicity (in 2 pa—
`tients}. Analyses of pretreatment tumor specimens from 10 patients revealed
`copy-number gains in PDLI and PDLZ and increased expression of these ligands.
`Reed—Sternberg cells showed nuclear positivity of phosphorylated STATB. indica-
`tive of active JAK—STAT signaling.
`CONCLUSIONS
`
`From the Mayo Clinic. Rochester, MN
`(EMA); Memorial Sloan Kettering Can-
`cer Center {A.M.L.. DC} and Weill Corv
`neII Medical College {A.M.L.} — both in
`New York; Johns Hopkins University
`School of Medicine and the Sidney Kim-
`rnel Comprehensive Cancer Center. Balti-
`more {LB.}; University of Utah Hunts-
`man Cancer
`Institute. Salt Lake City
`{A.H.}: Oregon Health and Science Uni-
`versity and the Knight Cancer Institute.
`Portland [E.C.S.}: John Theurer Cancer
`Center. Hackensacl: University Medical
`Center. Hackensacl-t (MG). and Bristol—
`Myers Squibb. Lawrenceville (L.Z..J.F.G..
`S.Y.K.:I — both in Newjersey: Abramson
`Cancer Center. University of Pennsylva-
`nia {33.5.}. and Fox Chase Cancer Center
`(M.M.M.} — both in Philadelphia; Dana—
`Farber Cancer
`Institute
`(G.J.F.. B.C..
`M.A.S.. RA.) Brigham and Women's
`Hospital
`[S.j.R.. A.H.|...). and Harvard
`Medical School (G.J.F.. B.C.. M.A.S.. P.A..
`SJ.R.. A.H.L.) —— all in Boston: and Jons-
`son Comprehensive Cancer Center. Uni-
`versity of California. Los Angeles. Los
`Angeles U.M.T.}. Address reprint
`re—
`quests to Dr. Ansell at the Mayo Clinic.
`200 First St. SW. Rochester. MN 55905.
`or at ansell.stephen@mayo.edu; or to
`Dr. Armand at the Dana—Farber Cancer
`Institute. 450 Brookline Ave. Boston.
`MA 02215. or at philippe_armand@
`dfci.harvard.edu.
`
`Drs. Ansell and Lesokhin and Drs. Shipp
`and Armand contributed equally to this
`article.
`
`This article was published on December 6.
`2014. at NEJM.org.
`
`Nivolumab had substantial therapeutic activity and an acceptable safety profile in
`patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma.
`(Funded by Bristol-Myers Squibb and others; ClinicalTrialsgov number, NC'IDIS‘JZ370.)
`
`N Eng” Med 2015;331:3113.
`DDI: 10.10561NEJM03141108?
`Copyright © 201‘ Massachusetts Medical Society.
`
`NENGLJMED3?2.‘4 NEJM.ORG JANUARY22.2015
`
`311
`
`

`

`'l’llr NEW ENGLAND JOURNAL nj'MEDIClNE
`
`Il*"'i'_"-.HE. PROGRAMME!) DEATH 1 (PD—1) PATH—
`r' way serves as a checkpoint to limit T-ceil—
`1 mediated immune responses.‘ Both I’D-1
`ligands, PD—Ll and I’D-1.2, engage the DID-1 recep—
`tor and induce I’D-1 signaling and associated T—cel]
`“exhaustion," a reversible inhibition ofT—cell acti—
`vation and proliferation.1 By expressing PD-l 11-
`gands on the cell surface and engaging PD—I re-
`ceptor—positive immune effectOr cells, tumors can
`co-opt the I’D-1 pathway to evade an immune
`.
`8.2
`meillziJJI—rlsflblocking antibodies have been used to
`enhance immunity in solid tumors and obtain
`durable clinical responses with an acceptable
`safety profile?6 Preliminary data also. support
`empirical PD-l blockade as a therapeutic strate-
`gy in certain hematologic cancers."'”- Adverse
`events that are commonly associated wrth I’D-1—
`blocking antibodies include pruritus, raeh, and
`diarrhea.“ Immune-mediated pneumonitis, coh-
`tis, hepatitis, hypophysitis, and thytmditis are
`less common toxic effects of PD-l blockadefl’”
`Classic Hodgkin’s lymphomas include small
`numbers of malignant Reed—Sternberg cells
`within an extensive but ineffective inflammatory
`and immune-cell
`infiltrate.“"5 The genes en-
`coding the PD—l
`ligands, PDLI and PDLZ (also
`called C0274 and PDCDILGZ, respectively}, are key
`targets of chromosome 9p24.1 amplification, a
`recurrent genetic abnormality in the nodular-
`sclerosis type of Hodgkin’s lymphoma.” The
`9p24.1 amplicon also includes JAKZ, and gene
`dose-dependent JAK-STAT activity further induces
`I’D-1 ligand transcription.“ These cepy-numbere
`dependent mechanisms and less frequent ch romo-
`somal rearrangements” lead to overexpression
`of the I’D-1 ligands on Reed—Sternberg cells in
`patients with Hodgkin's lymphoma. Epstein—Barr
`virus [EBV} infection also increases the expres—
`sion of I’D-1 ligands in EBV—positive Hodgkin’s
`
`_
`lymphomas."
`The complementary mechanisms of I’D-1 li-
`gand overexpression in Hodgkin’s
`lymphoma
`suggest that this disease may have genetically
`determined vulnerability to I’D-1 blockade. Coam-
`plification of PDLI and PDLZ 0n chromosome
`9p24.1 suggests receptor rather than selective
`ligand blockade as a treatment strategy. For these
`reasons, Hodgkin’s lymphoma was included as a
`cohort-expansion group in a phase 1 study of
`nivolumab (Bristol—Myers Squibb and Ono Phar-
`
`maceutical), a fully human monoclonal lgG4 an-
`tibody directed against PD-l,
`in patients with
`relapsed or refractory hematologic cancer.
`
`
`METHODS
`
`PATIENTS
`
`To be eligible for participation in this study, pa-
`tients had to be at least 18 years of age, have
`histologically confirmed evidence of relapsed or
`refractory Hodgkin’s lymphoma with at least one
`lesion measuring more than 1.5 cm {as defined
`by the Revised Response Criteria for Malignant
`Lymphomas“) (see the Supplementary Appendix,
`available with the full text oFthis article at NEJM
`
`.org]. an Eastern Cooperative Oncology Group
`[ECOle performance-status score of 0 or 1 (on a
`scale from 0 to 5, with 0 indicating no symptoms
`and higher scores indicating increasing disabili-
`ty], previous treatment with at least one chemo-
`therapy regimen, and no autologous stem-cell
`transplantation within the previous 100 days. Key
`exclusion criteria were a history of cancer involving
`the central nervous system, a history of or active
`autoimmune disease, a concomitant second cancer,
`and previous organ allograft or allogeneic bone
`marrow transplantation.
`
`STUDY DESIGN
`
`This phase 1 study consisted of dose-escalation
`and expansion cohorts.
`In the dose-escalation
`cohort, patients with relapsed or refractory he-
`matologic cancers were treated with nivolumab
`at a dose of 1 mg per kilogram of body weight,
`with escalation ofthe dose to 3 mg per kilogram.
`Since the maximum tolerated dose was not reached,
`a dose of 3 mg per kilogram was chosen for the
`expansion cohorts. Patients with relapsed or re-
`fractory Hodgkin’s lymphoma received nivolu-
`mab at a dose of 3 mg per kilogram at week 1,
`week 4, and then every 2 weeks until disease pro-
`gression or complete response or for a maximum
`of 2 years.
`The primary objective was to evaluate the safety
`and side-effect profile of nivolumab. Secondary
`objectives included characterizing the efficacy of
`nivolumab and assessing PD—l ligand loci integrity
`and expression of the encoded ligands.
`Adverse events were assessed throughout the
`study and for 100 days after the last dose was
`administered, according to the National Cancer
`
`N2
`
`N ENGLJ MED 372:4 NEJMDRC.
`
`jANUARY 22. 20:5
`
`

`

`NIVDI.UMAB IN RILLAI’SElD OR REFRACTORY HODUKIN'S LYMI‘I-iOMfl
`
`Institute Common Terminology Criteria for Ad-
`verse Events, version 4.20 Patients were evaluated
`for efficacy at weeks 4, 8, 16, and 24 and every
`16 weeks thereafter. All the patients underwent
`computed tomography [CT] and ‘xF-fluorodeoxy—
`glucose—positron-emission tomography {FOG-PET]
`at screening, subsequent CT (as described above},
`and FDG-PET scanning for confirmation of a com»
`plete response.
`
`srunv ovensmI-rr
`
`The protocol was approved by the institutional
`review board at each center, and the study was
`conducted in accordance with the Declaration of
`Helsinki and the International Conference on
`Harmonisation Guidelines for Good Clinical
`
`the patients provided written in—
`Practice. All
`Formed consent before study entry. The principal
`investigators,
`in collaboration with the sponsor
`[BristohMyers Squibb], were responsible for the
`design and oversight of the study and develop-
`ment ot‘the protocol, available at NEJM.org. The
`sponsor was responsible for the collection and
`maintenance of the data. Initial drafts of the
`
`manuscript were prepared by the authors, with
`subsequent editorial assistance paid for by the
`sponsor. All
`the authors made the decision to
`submit the manuscript for publication and vouch
`For the accuracy and completeness of the data
`reported and adherence to the protocol.
`
`slouanxea assessnem
`
`Fluorescence in situ hybridization (FISH) was
`performed on Hodgkin’s lymphoma tissue sec-
`tions to assess copy number on chromowme
`9p24.1. The bacterial artificial chromosome
`probes {CI-lORI; www.chori.org] RPll—599H20,
`which maps to 9p24.1 and includes CD274 (en-
`coding PD-Ll,
`labeled with Spectrum Orange],
`and RPM—635N121, which also maps to 9p24.1
`and includes PDCDILGZ {encoding I’D—L2, labeled
`with Spectrum Green), were cohybridized. A con-
`trol centromeric probe. Spectrum Aqua—labeled
`CEP9 (Abbott Molecular] that maps to 9p11-q11,
`was hybridized according to the manufacturer‘s
`recommendations. Malignant Reed—Sternberg cells
`were identified by means of nuclear morphologic
`features, and all such cells were analyzed. Nuclei
`with a target:control probe ratio of at least 3:1
`were classified as amplified, those with a probe
`ratio of‘more than 1:1 but less than 3:1 were clas-
`
`sified as relative copy gain, and those with a
`probe ratio of 1:1 but with more than two copies
`of each probe were classified as polysomic for
`chromosome 9p. Immunohistochemical staining
`was performed by means ot'an automated stain-
`ing system {BOND-ill, Leica Biosystems), with
`the use oi‘a double-staining technique for PD—Ll
`{405315111} and PAXS (24ll’ax—‘3, Bl) Bioscienees),
`
`and for PD-L2 (36609135) and phosphorylated
`S'l‘ATB (psm’r3; 03M, Cell Signaling Technolo-
`gy). The methods are detailed in the Supplemen-
`tary Appendix.
`
`STATISTICAL ANflL‘I’SIS
`
`All the patients who received at least one dose of
`nivolumab were included in the safety and effi-
`cacy analyses. The database was locked on June
`16, 2014. Adverse effects were coded with the use
`
`of the Medital DictionaryforRegularoryAtrtvines, ver-
`sion 17.0, and tabulated.
`
`The principal investigator at each site evalu—
`ated efficacy assessments using the Revised Re-
`sponse Criteria for Malignant Lymphomas” [see
`the Supplementary Appendix). The best overall
`response was defined as the best response be—
`tween the date ot‘ the first dose and the last effi-
`
`cacy assessment before subsequent therapy. The
`objective response rate was defined as the pro—
`portion of the total number of patients whose best
`overall response was either a partial or a complete
`response. A complete response was defined as tu-
`mor regression to 1.5 cm or less in greatest div
`ameter, ifthe tumor measured more than 1.5 cm
`
`before therapy, or a decrease in previously in-
`volved nodes measuring 1.1 to 1.5 cm in greatest
`diameter to 1 cm or less or a decrease of more
`
`than 75%, with negative results on PET scan-
`ning {see the Supplementary Appendix].
`Progression-free survival was defined as the
`time from the date of the first dose of study
`medication to the date of first disease progres-
`sion or the date of death. Progression-free sur-
`vival was estimated with the use of Kaplan—
`Meier methods. The time to a
`response was
`defined as the time from the date of the first
`
`dose to the date of the first response. The dura-
`tion ofa response was defined as the time be-
`tween the date of the first response and the date
`of first progression or the date of death. Plots of
`the percentage changes in tumor burden over
`time for each patient are presented graphically.
`
`N ENGL] MED 3:2:4 NEJMJJRG JANUARY 22. 2015
`
`313
`
`

`

`The NEW ENGLAND ]0URNAL of MEDICINE
`
`
`RESULTS
`
`pulsars
`
`Since enrollment started in August 2012, a total
`
`of 23 patients with relapsed or refractory Hodg—
`kin‘s lymphoma have been enrolled in the study.
`Results are reported through lune 16, 2014. The
`baseline characteristics of the patients are pre—
`sented in Table 1. The median age was 35 years
`
`
`
`Table 1. Characteristics ofthe 23 Patients at Baseline.
`
`Characteristic
`Value
`
`Age —— yr
`
`Median
`35
`
`
`
`Range
`Male sex -— no. {%J
`
`20—54
`12 {52]
`
`Race — no. (%)*
`White
`
`Black
`
`Other
`
`ECOG performance-status score — no. (96H-
`0
`
`l
`
`Histologic findings —- no. (‘36)
`Noduiar sclerosis
`
`Mixed cellularity
`
`No. of previous systemic therapies — no. (96}
`2 or 3
`
`4 or 5
`
`26
`
`Previous treatment — no. [96}
`
`20 (3?)
`
`2 (9)
`
`1 {4)
`
`5 (26)
`
`17 (74]
`
`22 [96)
`
`1 {4)
`
`8 (35}
`
`7 {30)
`
`8 [35)
`
`Brentuximab vedotin
`
`18 (73)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(range, 20 to 54}, and 17 patients [74%] had an
`ECOG performance-status score of 1. All the pa-
`tients had been extensively pretreated, with 87%
`having received three or more previous treatment
`regimens; 78% of the patients had received bren-
`tuximab vedotin (hereafter referred to as bren—
`
`tuximab) previously, and 78% had undergone
`autologous stem—cell transplantation. Extranodal
`disease involving bone, lung, pelvis, peritoneum,
`or pleura was found in 17% of the patients. With
`one exception, all the patients had the nodular-
`sclerosis type of Hodgkin‘s lymphoma; the remain-
`ing patient had mixed cellularity. The most common
`first—line chemotherapy was ABVD {doxorubicim
`bleornycin, vinblastine, and dacarbazine], which
`was administered in 20 patients (87%).
`
`SAFETY
`
`Among the 23 patients, adverse events of any
`grade were reported in 22 (96%}. Grade 3 or 4
`adverse events occurred in 12 patients {52%).
`Grade 3, 4, or S adverse events, listed according
`to whether they were deemed by the investigators
`to be related or unrelated to the study drug, are
`included in Table 81 in the Supplementary Ap—
`pendix. Drug—related adverse events
`that oc-
`curred in at least 5% ofthe patients are listed in
`Table 2. Overall, drug-related adverse events were
`reported in 18 patients (78%]. The most common
`were rash (in 22%) and a decreased platelet count
`(in 17%}. Drug—related grade 3 adverse events,
`Which were reported in 5 patients (22%), includ-
`ed the myelodysplastic syndrome, panereatitis,
`pneumonitis, stomatitis, colitis, gastrointestinal
`inflammation, thrombocytopenia, an increased
`lipase level, a decreased lymphocyte level, and
`leukopenia. There were no drug-related grade 4
`or 5 adverse events. Three patients had one seri-
`ous drug-related adverse event each [grade 3 pan—
`creatitis, grade 3 myelodysplastic syndrome, and
`grade 2 lymph-node pain} (Table 2). The patient
`with the myelodysplastic syndrome had under—
`gone six previous systemic chemotherapies, rav
`diation therapy, and autologous stem-cell trans-
`plantation but had not received bendamustine
`previously. There were no treatment—related
`deaths.
`
`Of the 12 patients (52%} who discontinued
`treatment, 2 patients [9%] had toxic effects {the
`myelodysplastic syndrome and thrombocytopenia
`
`
`
`
`
`Autologous stem-cell transplantation
`
`13 [73)
`
`19 [33}
`Radiotherapy
`4 [1?)
`Extranodai involvement -— no. (96]:
`
`
`
`* Race was either self-reported or reported by investigators.
`1‘ Eastern Cooperative Oncology Group {ECOG} scores indi-
`cate the performance status of patients with respect to ac-
`tivities of daily living on a scale from 0 to 5, with higher num-
`bers indicating greater disability. A score of 0 indicates that
`the patient is fully active and able to carry out all predlsease
`activities without restriction, and a score of 1 indicates that
`the patient is restricted in physically strenuous activity but is
`ambulatory and able to carry out work of a light nature.
`1: Sites of extranodal disease were bone. lung, pelvis, peri-
`toneum. and pleura.
`
`
`314
`
`N ENGLJ MED 312”, mimosa jANUAlIY 22. 2015
`
`

`

`NIVOI.UMAB IN RELAI’SED 0R REFRACTORY HODGKIN‘S LYMPIIOMA
`
`
`
`Table 2. Drug-Related Adverse Events in the 23 Patients.“
`
`
`
`Any Grade
`
`Grade 3
`
`no. ofpatients {96)
`
`13 (3'8)
`
`5 (22]
`
`Event
`
`Any adverse event
`
`Drug-related adverse events reported in 25%
`of patients
`
`Rash
`
`Decreased platelet count
`
`Fatigue
`Pyrexla
`
`Diarrhea
`
`Nausea
`
`Pruritus
`
`Cough
`
`Hypothyroidism
`Decreased lymphocyte count
`
`Hypophosphatemia
`
`Hypercalcemia
`
`Increased lipase level
`
`Stomatitls
`
`Drug-related serious adverse events
`
`Myelodysplastic syndrome
`
`5 [22)
`
`4 (17]
`
`3 [13)
`3 (13]
`
`3 (13}
`
`3 [13)
`
`3 (13}
`
`2 (9]
`
`2 (9)
`2 {9]
`
`2 [9}
`
`2 (9)
`
`2 {9}
`
`2 (9)
`
`1 (4::
`
`
`
`Oi—IOGOODOOOO
`
`1 (41
`
`1 l4)
`
`1 l4}
`
`1 l4}
`
`in 1 patient and pancreatitis in 1 patient). 4 pa—
`tients
`(17%) had progressive disease during
`treatment, and 6 patients (26%) elected to un-
`dergo either allogeneic stem-cell transplantation
`{in ‘5 patients} or autologous stem-cell transplan-
`tation [in 1}. Adverse events were reversible in all
`
`the patients except the 2 who discontinued treat—
`ment. As of June 16, 2014, a total of 11 patients
`(48%] were continuing to participate in the study.
`The median number of nivolumab doses that
`
`patients received was 16 (range, 6 to 37), admin-
`istered over a median treatment duration of 36
`
`weeks (range. 13 to 77}, with 15 patients {65%)
`receiving 90% or more of the intended Overall
`dose. Nine patients {39%) had at least one dose
`delay (five delays because of nonhematologic
`drug-related adverse events, five delays because
`of infections unrelated to treatment, and one
`delay because of inclement weather). All the pa-
`tients who had delayed doses were able to restart
`treatment. Two patients (9%) had infusion inter-
`ruptions that were due to grade 1 hypersensitiv—
`ity reactions.
`
`CLINlCAI. METW'IT‘I‘r
`
`The response rate was 87% {95% confidence in—
`terval [CI], 66 to 97}, with a complete response
`occurring in 4 patients {1.7%}. a partial response
`in 16 patients (70%}, and stable disease in 3 pa-
`tients (13%} [Table 3). Of the 4 patients with
`complete responses, 3 had not received previous
`treatment with brentuximab. Results are also
`
`summarized according to three subgroups: pa-
`tients in whom previous autologous stem—cell
`transplantation and brentuximab treatment
`failed,
`those in whom brentuximab treatment
`had failed but who did not undergo autologous
`stem-cell
`transplantation before brentuxitnab
`treatment, and those who did not receive bren-
`
`tuximab (Table 3]. Among 15 patients who had
`disease recurrence after autologous stem-cell
`transplantation and brentuximab treatment, the
`response rate was 87% {95% CI, 60 to 98). Of
`these patients, 1 {7%) had a complete response,
`12 (80%) had a partial response, and 2 (13%} had
`stable disease. For the 3 patients who did not
`undergo autologous stem-cell
`transplantation
`before brentuximab treatment, the response rate
`was 100% (95% CI, 29 to 100), with all 3 patients
`having a partial response. Among the 5 patients
`
`Lymph-node pain
`Pancreatitis
`
`1 [4}
`1 (4)
`
`
`* No grade 4 or grade 5 drug-related adverse events were reported. Decisions
`about whether the adverse event was related to the study drug were made by
`the investigators. A more detailed list of adverse events is provided in Table
`51 in the Supplementary Appendix.
`
`who did not receive brentuximab, the response
`rate was 80% (95% CI, 28 to 99), with 3 patients
`{60%) having a complete response, 1 [20%] a par-
`tial response, and 1 (20%) stable disease.
`Of the 20 patients who had a complete or
`partial response, 12 patients [60%) had the first
`response by 8 weeks (range, 3 to 39 weeks) (Fig.
`1A). The rate of progression-free survival at 24
`weeks was 86% (95% CI, 62 to 95}. As of this
`
`writing, 6 patients chose to undergo stem-cell
`transplantation at the time of the best overall
`response, and 11 patients continued to have a
`response (Fig. 1A). The median overall survival
`had not been reached. The median duration of
`
`follow—up was 40 weeks (range, 0 to 75).
`Figure 13 shows the maximum reduction in
`
`N ENGL] MED 312:4 NEJM.ORG JANUARY 22.2015
`
`315
`
`

`

`
`
`Thr NEW ENGLAND IOURNAL of MEDICINE
`
`Table 3. Clinical Activity in Nivolumab-Treated Patients.*
`Failure of Both Stem-Cell
`Transplantation and Brentuxirnab
`{N=15}
`
`Variable
`
`All Patients
`[N=23}
`
`
`
`No Stem-Cell Transplantation No Brentuximab
`and Failure of Brentuximab
`Treatment
`{N=3]
`[N=5]'i'
`
`Best overall response — no. (96]
`
`Complete response
`
`Partial response
`Stable disease
`
`Progressive disease
`
`Objective response
`
`No. of patients
`
`Percent of patients (95% Cl}
`
`ProgressionAfree survival at 24 wk
`——% (95% OH:
`Overall survival — wk
`
`4 l1?)
`
`15 l70l
`3 l13l
`
`0
`
`20
`
`3? (66—9?)
`
`36 {62—95}
`
`1 (3’)
`
`12(301
`2 {13]
`
`0
`
`13
`
`3? [50—98)
`
`35 [52—96)
`
`Median
`
`NR
`
`NR
`
`0
`
`3 {100}
`0
`
`0
`
`3
`
`100 {29-100)
`
`NC§
`
`NR
`
`3 (60)
`
`1 [20)
`1 [20]
`
`0
`
`4
`
`30 (28—99)
`
`30 (20—9?)
`
`NR
`
`
`
`21-35 21-?5 32—55Range at data cutoff‘ 30—50
`
`
`
`
`
`
`
`.1. NC denotes not calculated. and NR not reached.
`1‘ In this group, two patien ts had undergone autologous stem-cell transplantation and three had not.
`? Point estimates were derived from KaplanPMeier analyses; 95% confidence intervals were derived from Greenwood's formula.
`lculated when the percentage of data censoring was above 25%.
`E The estimate was not ca
`
`1 Responses were ongoing in 11 patients.
`
`tumor burden from baseline for each patient,
`Progression—free survival for the entire cohort is
`shown in Figure 81 in the Supplementary Ap—
`pendix.
`
`ANALYSIS OF I'D-1 LIGAND LOCI AND EXPRESSION
`
`In the subgroup of 10 patients with available tu-
`mor samples, PDL] and P012 copy numbers in
`Reed—Sternberg cells were assessed with the use
`of fixed tumor-biopsy specimens and a three-
`probe FISH assay (PDLI IL'D274], PDLZ [PDCDILGZ],
`and control centromeric probe] (Fig. 2A). In all
`tumors analyzed by means of FISH, tumor cells
`had 3 to 15 copies of PDLI and PDLZ in patterns
`characterized by amplification,
`relative copy
`gain. or polysomy of chromosome 9p (Fig. 2D,
`and Table 82 and Fig. 52 in the Supplementary
`Appendix). In all the samples, Reed—Sternberg
`cells, which were identified by their characteris-
`tic morphologic features and staining for PAXS,
`expressed PD-Ll and PD—L2 proteins (Fig. 2C and
`2D, and Table 33 and Fig. S2 in the Supplemen-
`tary Appendix). Tumor cells were also positive
`for nuclear pSTAT3, indicative ofactivc JAK-STAT
`
`signaling (Fig. 2C and ZD, and Table S3 and Fig.
`32 in the Supplementary Appendix). Infiltrating
`'1' cells in the available Hodgkin’s lymphoma bi—
`opsy specimens largely expressed low levels of
`the I’D-1 receptors (Table S4 and Fig. 83 in the
`Supplementary Appendix). Together, these data
`indicate that all the patients with Hodgkin’s lym-
`phoma in this study who could be evaluated had
`numeric alterations of the PD-l
`ligand loci and
`associated protein expression.
`
`DISCUSSION
`
`In this study, we found that nivolumab-mediated
`PD—l blockade was a highly effective therapy in
`patients with Hodgkin‘s lymphoma, a disease
`with a genetic basis for I’D-1 ligand overexpres-
`sion and a marked but ineffective inflammatory
`and immune-cell infiltrate. In heavily pretreated
`patients with relapsed or refractory Hodgkin’s
`lymphoma, the majority of whom had had a re—
`lapse after autologous stem-cell transplantation
`and brentuximab treatment,
`the use of nivolu—
`mab was associated with an overall response rate
`
`316
`
`NENGLJMED372;4 NEJMDRG jANUAR‘r 22.2015
`
`

`

`NIVULUMAB IN RELAPSl-ZD OR. REFRACTORY HODGKIN‘S LYMI‘HL)MA
`
`I ASCT failure and
`brentuximab failure
`
`I No ASCT and
`brentuximab failure
`
`I No brentuximab
`
`A Response Characteristics
`
`Patient No.
`
`
`20 -
`r -.
`.
`.
`.
`a First complele responSe
`
`
`.-
`2-
`19 .
`" First partial response
`18 -m— . s
`' The“?! duration
`I Transplantaticm
`1? an“ F
`,_ 0n -
`
`
`gomg response
`1f,
`.
`15
`o a-
`14
`13
`
`
`12
`ll
`10
`
`b
`
`o I-
`
`-
`
`a
`
`
`Hnmfimmumw
`
`of 87% and a rate of progression-free survival of
`86% at 24 weeks. Adverse events were mainly of
`grade 1 or 2. The rate of adverse events was sim-
`ilar to that in trials ofnivolumab in patients with
`solid tumors.4 Given the limited therapeutic op-
`tions for patients with Hodgkin’s lymphoma
`whose disease progresses after autologous stem-
`cell transplantation’1‘"3 and the relatively short-
`lived responses t