Chlormethine Gel for the Treatment of Skin Lesions in All Stages of Mycosis … · 2021. 5. 21. ·...

REVIEW

Chlormethine Gel for the Treatment of Skin Lesionsin All Stages of Mycosis Fungoides Cutaneous T-CellLymphoma: A Narrative Review and InternationalExperience

Larisa J. Geskin . Martine Bagot . Emmilia Hodak . Ellen J. Kim

Received: February 26, 2021 / Published online: May 21, 2021� The Author(s) 2021

ABSTRACT

Mycosis fungoides (MF), the most commonform of primary cutaneous T-cell lymphoma, isa disease typically with an indolent course thatis initially characterized by localized patchesand plaques. In the early stages of the disease,treatment involves skin-directed therapies(SDTs) such as topical corticosteroids and reti-noids. Chlormethine gel (also known as

mechlorethamine) was the first SDT purposelydeveloped to treat MF and is currently endorsedby international guidelines for the treatment ofadult patients with MF as a first-line therapy.While chlormethine is an efficacious therapy,its usage may be complicated by the develop-ment of cutaneous reactions at the sites ofapplication. Herein, we discuss the supportiveguidelines for MF and the suitability ofchlormethine as a therapeutic option inpatients with MF. In addition, we present real-world experience on the use of chlormethinegel from clinics in the USA, Israel, and Francewith the aim of demonstrating the efficacy ofchlormethine gel in routine clinical practiceand outlining strategies that are being used tomanage emergent cutaneous reactions.

Keywords: Chlormethine gel; Cutaneous T-celllymphoma; Mycosis fungoides; Patientmanagement; Real-world

L. J. Geskin (&)Department of Dermatology, Columbia University,161 Fort Washington Ave, 12th Floor, New York, NY10032, USAe-mail: [email protected]

M. BagotDepartment of Dermatology, AP-HP, Universite deParis, Hopital Saint-Louis, Paris, Francee-mail: [email protected]

E. HodakDivision of Dermatology, Rabin Medical Center,Beilinson Hospital, Sackler Faculty of Medicine, TelAviv University, Tel Aviv, Israele-mail: [email protected]

E. J. KimDepartment of Dermatology, Perelman School ofMedicine at the University of Pennsylvania,Philadelphia, PA, USAe-mail: [email protected]

Dermatol Ther (Heidelb) (2021) 11:1085–1106

https://doi.org/10.1007/s13555-021-00539-3

http://crossmark.crossref.org/dialog/?doi=10.1007/s13555-021-00539-3&domain=pdf

https://doi.org/10.1007/s13555-021-00539-3

Key Summary Points

Mycosis fungoides (MF) is a cutaneousT-cell lymphoma typically with anindolent course that is initiallycharacterized by localized patches andplaques

Chlormethine gel is a therapeutic optionrecommended by international guidelinesfor patients with MF skin lesions; a rangeof retrospective, prospective, andobservational clinical data supports its usein all disease stages

While chlormethine is an efficacioustherapy, its usage may be complicated bythe development of cutaneous reactionsat the sites of application

Real-world experience from clinicalpractice in the US, Israel, and France hasshown that chlormethine gel is used as askin-directed therapy in the first- andsecond-line setting in patients with early-stage MF and as an adjunctive therapy inpatients with advanced-stage disease

The emergent cutaneous adverse reactionscan generally be managed throughchlormethine gel dose adjustments or theuse of topical steroids

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.14447193.

INTRODUCTION

Cutaneous T-cell lymphomas (CTCLs) are aheterogeneous family of T-cell lymphoprolifer-ative disorders, of which mycosis fungoides

(MF) is the most common. Early-stage MF fol-lows a slow, indolent course [1], with symptomspresent for extended periods of time. Due to theclinical similarity between benign skin diseases(such as eczema and psoriasis) and early-stageMF, as well as the lack of a singular diagnostictest or specific tumor markers, median timebetween MF symptom onset and biopsy-con-firmed diagnosis is 4–6 years [2]. Most patientswith early-stage MF have an average life expec-tancy following treatment but reduced qualityof life [3]. Median survival for those with stageIII or IV disease is low (\ 5 years), and C 50%die of their disease [4–7]. MF treatment goals aresymptom control and quality of life improve-ment [8], as there are no curative therapeuticoptions aside from allogeneic stem cell trans-plantation [9].

In this review, we will briefly present thetreatment guidelines for the management ofpatients with MF, discuss the role of topicalchlormethine gel as part of the treatmentparadigm, provide an overview of the clinicaldata demonstrating the effectiveness of the gel,and present real-world experience of chlorme-thine gel usage from four different dermatologypractices.

This review is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors. Informed consent wasprovided by the patient whose case wasincluded.

CLINICAL MANAGEMENTGUIDELINES FOR MF

MF treatment guidelines (European Society forMedical Oncology [10], European Organisationfor Research and Treatment of Cancer [11],National Comprehensive Cancer Network [12],and British Association of Dermatologists/UKCutaneous Lymphoma Group [13]) base theirrecommendations on disease stage [10–13].

For asymptomatic patients with early-stageMF (stage IA), ‘‘watch and wait’’ is considered anappropriate option. For symptomatic patients,those with adverse prognostic factors (such asplaque stage disease or large cell

1086 Dermatol Ther (Heidelb) (2021) 11:1085–1106

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https://doi.org/10.6084/m9.figshare.14447193

transformation), or those with extensive diseaseinvolvement (stage IB), skin-directed therapies(SDTs) should be initiated. The most commonlyused SDTs for treating early-stage MF are topicalcorticosteroids [8, 14], topical chlormethine orretinoids [15, 16], and phototherapy; superficialradiotherapy may also be employed. Patientswith advanced-stage disease generally receivesystemic single-agent or combination therapywith SDTs. Addition of an effective SDT canalleviate symptoms and shorten time toresponse compared with systemic therapy alone[11].

CHLORMETHINE AS TOPICALCHEMOTHERAPY FOR MANAGINGMF

All major guidelines recommend the use ofchlormethine for first-line treatment in adultpatients with MF [10–13]. Chlormethine is abifunctional alkylating agent that inhibitsrapidly proliferating cells by binding andcrosslinking DNA strands. The original aqueousand ointment formulations were not approvedas a therapy for MF, and it was subsequentlydeveloped as a topical gel [15, 17]. This formu-lation was approved by the US Food and DrugAdministration (FDA) in 2013 for treating stageIA and IB MF in patients who received priorSDT, has been registered in Israel since 2016 (forthe same indication as in the USA), wasapproved by the European Medicines Agency in2017 for treatment of adult patients with MF[18], and is now available commercially in anumber of European countries. Chlormethinegel has been available in France since 2014under a ‘‘temporary authorization for use’’ pro-gram that ended in July 2019, with 876 patientshaving participated [19].

The chlormethine gel (chlormethine 0.016%w/w, equivalent to 0.02% chlormethinehydrochloride) formulation was designed tomaximize efficacy and tolerability. Its non-aqueous nature imparts high stability, and theactive solvent, diethylene glycol monoethylether (Transcutol�), promotes delivery of thedrug to the epidermis [20–22], although there isno evidence of systemic absorption of

chlormethine following application [15]. Effi-cacy is enhanced by inclusion of the excipient,KlucelTM hydroxypropylcellulose (Ashland)[23], which results in a fast-drying, nongreasyformulation with a viscosity that is more likelyto remain at the administration site, whichmakes it easier to apply at home. The intrinsicantimicrobial nature of the active ingredients[24] removes the need for antimicrobial preser-vatives (which frequently cause skin reactions),thus potentially reducing the risk of allergy,although further investigations are required toconfirm this.

Chlormethine may be used as monotherapyin early-stage MF, in combination with systemictherapy in advanced-stage disease [25–27], andas maintenance treatment [11, 28]. Thechlormethine gel label indicates daily applica-tion; however, the frequency of applicationmay be reduced according to the patient’sneeds. For severe skin reactions, treatmentshould be suspended (in some cases perma-nently) and upon improvement can be restartedgradually up to daily frequency, if tolerated.

CHLORMETHINE IN MFMANAGEMENT: A REVIEWOF THE LITERATURE

There is a substantial body of prospective andretrospective evidence underlying the recom-mendation of chlormethine as a treatmentoption for patients with MF in all stages of thedisease (summarized in Table 1 [15, 17, 26,27, 29–44]). These studies have demonstratedthat chlormethine is efficacious, with a durableresponse that may be sustained for up to 8 yearsin some cases.

The pivotal registration 201 study evaluatedchlormethine gel versus chlormethine oint-ment for the treatment of patients with persis-tent or recurrent stage I or II disease whoreceived no concomitant corticosteroids.Response rates for chlormethine gel were con-sistently higher than those for the ointment forthe primary endpoint of Composite Assessmentof Index Lesion Severity (CAILS), and once-daily(QD) treatment with chlormethine gel met allprespecified criteria for noninferiority. In the

Dermatol Ther (Heidelb) (2021) 11:1085–1106 1087

Table

1Summaryof

efficacyandsafety

findingsof

studiesof

topicalchlorm

ethine

inthetreatm

entof

MF

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Priceet

al.

(1977)

[29]

Retrospective

case

analysis

51Topicalchlorm

ethine

as

adjuvant

therapyafterTSE

B

therapyvs.T

SEBtherapy

alone

Disease-freeinterval:25months

forchlorm

ethine

plus

TSE

B

therapyvs.1

7monthsfor

TSE

Btherapyalone

Relapse-freesurvival:37%

vs.

29%

Patientsreceivingadjuvant

topicalchlorm

ethine

hada

lowincidenceof

contact

allergy

Vonderheid

etal.(1979)

[30]

Retrospective

case

analysis

243

Topicalchlorm

ethine

givenasa

dilute

aqueoussolution

with

orwithout

system

ic

chem

otherapy

Disease-freeinterval:[

3years

in32

(13%

)patients

Equallyeffectiveas

historical

treatm

entwithTSE

B

NA

Priceet

al.

(1983)

[31]

Retrospective

case

analysis

43:stageIA,1

7;stageIB,2

2;

stageII,2

;stageIII,2

Topicalchlorm

ethine

ointment

CRoccurred

in26

patientsover

a42-m

onth

evaluation

period

Contact

derm

atitisoccurred

in

1of

31(3%)chlorm

ethine-

naivepatientsand3of

12

(25%

)previouslytreated

patients

Ram

sayet

al.

(1984)

[32]

Retrospective

case

analysis

76Topicalchlorm

ethine

Of64

patientswho

continued

therapy,43

(67%

)achieved

CRand12

(19%

)achieved

PR

Mediantimesto

CRforstageI,

II,and

IIIdiseasewere6,

32,

and22

months,respectively

Allergiccontacthypersensitivity

reactionsoccurred

in51

(67%

)patients

Nodifference

inresponse

betweenpatientswithor

without

contactsensitivity

Zachariae

etal.

(1985)

[33]

Retrospective

case

analysis

33(withearlyMFin

plaque

stage)

Topicalchlorm

ethine

14patientsin

CRand7in

PR,

witharelapse-free

survivalof

50%

after6and12

years,

respectively

3deaths

dueto

disease

3patientsdiscontinu

eddueto

treatm

ent-relatedcontact

derm

atitis

NohematologicAEs


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Hoppe

etal.

(1987)

[34]

Retrospective

case

analysis

123(m

edianage,59

years

[range

20–9

0];88%

White,

6%Black,5

%Hispanic,1%

Asian):stageIA,3

8;stage

IB,3

0;stageIIA,3

3;stage

IIB,1

3;stageIIIA,2

;stage

IIIB,7

Topicalchlorm

ethine

10–2

0mg/dl

giveneither

as

aqueoussolution

orointment

Efficacy

was

similarforaqueous

vs.o

intm

entform

ulations

ORRandCRrate:all,72%

and

32%;stageI,88%

and51%;

stageII,6

9%and26%

AmongthosewithCR,4

0%of

patientswithstageIdisease

and60%

withstageIIdisease

laterrelapsed

Subsequent

therapiesincluding

repeat

treatm

entswith

chlorm

ethine

weresuccessful

inachievinglaterskin

clearance

Long-term

remissionsnotedin

42%

ofpatientswithstageI

and31%

withstageIIdisease

NopatientswithstageIII

disease(n

=13)hadCR,and

allhadprogression

2of

9patientswithstageIV

diseasehadCR,but

both

later

relapsed

Whendeaths

occurred,they

weretypically

unrelatedto

diseasein

stageIpatients

Halfof

deaths

amongstageII

patientswereattributableto

disease

Among22

patientswithstage

IIIor

IVdisease,80%

were

attributableto

MF

Cutaneous

hypersensitivity

was

morecommon

withaqueous

than

withointment

form

ulation

14(11%

)patientsdeveloped

cutaneousmalignancies


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Ram

sayet

al.

(1988)

[35]

Retrospective

analysisof

medicalrecords

117(m

edianage,57

years;

56%

male):stageIA,2

8;

stageIB,3

5;stageIIA,1

2;

stageIIB,3

2;stageIIIA,1

;

stageIIIB,9

Chlormethine

10mgdissolved

in60

mlof

water

applied

QDun

til6

monthsafterCR,

tapering

over

thefollowing

18months;concom

itant

therapynotallowed

except

forlocalRT

forstageIII

disease

Mediantimeto

CR:stageI,

6.5months;stageII,

41months;stageIII,

39months

Clin

icallyapparent

remission

at

2years:stageI,76%;stageII,

45%;stageIII,49%

Delayed

hypersensitivity

reactions:58%

1patientdiscontinu

eddueto

hypersensitivity

Death

dueto

diseaseoccurred

in9cases,including3

unrelatedto

treatm

entand1

unknow

n

Vonderheid

etal.(1989)

[26]

Retrospective

analysisof

medicalrecords

331(m

eanage,

58±

0.7years;65%

male):

stageIA,8

9;stageIB,6

6;

stageIIA,4

6;stageIIB,3

9;

stageIII,37;stageIVA,3

8;

stageIVB,9

;lymphom

atoid

papulosis,7

Chlormethine

10–2

0mg

dissolvedin

40–6

0mlof

water

appliedQD

untilCR,

then

continuedQD

orEOD

depend

ingon

response;

adjunctive

therapyallowed

forslo

wlyresponsive,

extensivedisease,or

extracutaneous

involvem

ent

(e.g.,localRT,T

SEB

therapy,UVphototherapy,

methotrexate,or

other

alkylating

agents)

InitialCRdefin

edas

complete

disappearanceof

clinically

detectablediseaseC

2weeks

andconfi

rmed

byskin

biopsy:

stage1A

,80%

;stage

1B,68%

;

stageIIA,6

1%;stageIIB,

49%;stageIII,60%;stage

IVA,1

3%;stageIVB,1

1%

Sustainedremission

for4and

8years:65

and35

patients,

respectively

OfpatientswithCR[

8years,

12(35%

)experiencedACD


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Licataet

al.

(1995)

[39]

Retrospective

case

analysis

164(who

hadreceived

TSE

B

therapybetween1974

and

1990;medianage,59

years

[range

20–8

8];62%

males;

88%

White,1

0%Black)

Evaluated

effectsof

therapy

beyond

TSE

B,including

topicalchlorm

ethine

NA

6patientsdevelopedmalignant

melanom

a12–9

5months

afterTSE

Btherapy,

including2treatedwith

chlorm

ethine

Duringmedianfollow-upof

6years,no

patientdied

of

second

arycutaneous

malignancy

Additionaluseof

chlorm

ethine

followingTSE

Btherapywas

associated

withnonm

elanom

a

skin

cancer

Esteveet

al.

(1999)

[40]

Multicenter,p

rospective

study

52(m

ixed

population

of

patientswithCTCL

including35

withMF;

age

18–8

7years;67%

males)

Topicalchlorm

ethine

0.02%

givenas

aqueoussolution

NA

Follow-updata

from

43

patients

Intoleranceto

chlorm

ethine

developedin

23patients(14

males,9

females)4days

to

9monthsafterinitiation,

including15

of35

(43%

)

patientswithMF

12patientsoverallwereableto

resumechlorm

ethine

after

resolution

ofsymptom

s


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Foulcet

al.

(2002)

[36]

Open-label,prospective

study

39withCTCL(including

34

withMF:meanage,63

years

[range

31–8

2];59%

males:

stageIA,8

;stageIB,1

4;

stageIIA,3

;stageIIB,8

;

stageIVA,1

)

Topicalchlorm

ethine

0.2%

dilutedin

10mlsolventand

50mlwater

andgiveneither

QD

orinterm

ittently

Responseratewas69%,w

ithno

difference

betweenQD

and

interm

ittent

application

CRin

54%;PR

in15%

CRin

59%

withstageIA

orIB

CRin

45%

withstageIIA

or

IIB

How

ever,responsedecreased

withshort-term

application

vs.com

parisonwithliterature

Cutaneous

intoleranceoccurred

in19

of39

(49%

)patients,

including6withACDaftera

meanof

9weeks;theother

13patientsdeveloped

contactderm

atitisaftera

longer

period

(3weeks

to

17months)

Kim

etal.

(2003)

[37]

Single-center,

retrospectivecohort

analysis

203(withstageI–IIIdisease;

medianage,56

years[range

12–8

7];61%

males;86%

White):stageIA,1

03;stage

IB,7

4;stageIIA,1

8;stage

IIB,4

;stageIII,4

Topicalchlorm

ethine

10–2

0mg/100mlaqueous

solution

orointment

ORRandCRrate:all,83%and

50%;stageI,93%

and65%;

stageII,7

2%and34%

Mediantimeto

CR:all,

12months;stageI,

10months;stageII,

19months

Mediantimeto

relapse:

12months

Whenadministeredas

salvage

therapy,response

rateswere

similarto

initialtherapy

Efficacy

similarforaqueousvs.

ointmentform

ulations

Contact

hypersensitivity

reactionsoccurred

in\

10%

whenused

asointment

8(4%)patientsdeveloped

second

arycutaneous

malignancies,withnone

attributed

tochlorm

ethine

Nosignificant

toxiceffectswere

observed


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

deQuatrebarbes

etal.(2005)

[38]

Multicenter,p

rospective,

nonrandomized

study

64(new

lydiagnosed,

early-

stagedisease;meanage,

63years[range

7–82];67%

males):stageIA,3

3;stage

IB,2

6;stageIIA,5

Topicalchlorm

ethine

0.02%

aqueousgiventwiceweekly

followed

bybetamethasone

cream

over

6months

CRin

58%

afterameanof

4months,including61%

withstageIA

disease,58%

withstageIB,40%

withstage

IIA

disease

Relapse

in17

(46%

)patients

afterameanof

7.7months

58%

ofpatientsdidnot

experience

anyadverse

cutaneousreactions

Severe

cutaneousreactions

requiringdiscontinu

ation

developedin

18(28%

)

patients,including

erythema,

severe

pruritus,o

rburning

sensationin

11cases,and

eczematousreaction

in7cases

Lindahl

etal.

(2013)

[27]

Retrospective

analysisof

medicalrecords(116)

116:

stageIA,11;

stageIB,68;

stageIIA,1

0;stageIIB,1

3;

stageIII,9;

stageIVA,4

;

stageIVB,1

Chlormethine

ointment

(concentration

not

mentioned)

ORR,9

2%;CRrate,5

3%


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Lessinet

al.

(2013)

[15]

PhaseIImulticenter,

rand

omized,o

bserver-

blinded,

noninferiority

trialin

patientswith

persistent/recurrent

stageI–II

disease

260(m

edianage,58

years

[range

11–8

8];59%

male;

74%

Caucasian):stageIA,

141;stageIB,115;stage

IIA,

4

Chlormethine

0.02%

gelor

ointmentappliedQD

for

12months;no

concom

itant

corticosteroidswere

perm

itted

CAILS(severityscoreforB

5

lesions;CR,1

00%

improvem

entfrom

BL;

PR,C

50to\

100%

improvem

entfrom

BL:gel,

14%

CRand45%

PR;

ointment,12%

CRand36%

PR

Chlormethine

gelwas

noninferiorto

ointmentby

prespecifiedcriteria

Nodrug-related

severe

AEs

werereported

Drug-relatedskin

AEsinthegel

andointmentarmswere

reported

by62%

and50%

of

patients,respectively

These

included:skin

irritation

(n=32

vs.1

8);pruritus

(n=25

vs.2

0);erythema

(n=22

vs.1

8);contact

derm

atitis(n

=19

vs.1

9);

skin

hyperpigmentation

(n=7vs.9

);folliculitis

(n=7vs.5

)

11patientsoverallincluding3

ingelarm

and8in

ointment

arm

werediagnosedwith20

second

arynonm

elanom

askin

cancers

Kim

etal.

(2014)

[17]

PhaseIIextensionstudy

withpatientswho

completed

theLessin

2013

[15]

study

(12monthsof

treatm

ent)butdidnot

achieveCR(N

=98)

98(m

eanage,53

±14

years;

55%

male;68%

Caucasian)

Chlormethine

0.04%

gel

appliedQD

for7months

(applicationfrequencycould

bereducedfortoxicity)

CAILS(severityscoreforB

5

lesions,confi

rmed

C4weeks

later):CRin

6patientsand

PRin

20patients

Mild-to-moderatedrug-related

skin

AEswerereported

by31

(32%

)patients

Mostcommon

drug-related

skin

AEswereskin

irritation

(11%

),erythema(10%

),and

pruritus

(6%)


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Lindahl

etal.

(2014)

[41]

Population-based

cohort

study

303;

including110using

chlorm

ethine

(meanage,

69years[range

30–9

8];

69%

males:stageIA,1

4;

stageIB,3

9;stageIIA,8

;

stageIIB,25;

stageIIIA,15;

stageIV,9

)

Topicalchlorm

ethine

NA

Second

arycancerswerenot

significantlyincreased(H

R

0.8;

95%

CI0.5–

1.6)

in

patientsreceiving

chlorm

ethine

Subanalysesshow

edno

significantlyincreasedrisk

of

nonm

elanom

askin

cancers,

malignant

melanom

as,o

r

cancersof

therespiratory

organs

Mortalityandcause-specific

mortalitywerenotinfluenced

bytreatm

ent

Kim

etal.

(2020)

[42]

Prospective,

observational,

noninterventional

study

301(298

monitored)

stageIA–IIA:62%;stage

IIB–IV:8%

Topicalchlorm

ethine

gelin

combination

withother

therapies

ORRof

44%

inpatientswho

received

chlorm

ethine

gel

plus

corticosteroidsand/or

NBUVBphototherapy,o

ral

bexarotene,P

UVA,local

electron-beam

therapy,

topicalbexarotene,and

imiquimod

ORRof

45%

inpatientswho

received

chlorm

ethine

gelp

lus

anyothertreatm

ent

42%

experiencedC

1AE

Mostcommon

skin-related

AEs

were:derm

atitis(13%

);

pruritus

(10%

);skin

irritation

(7%);anderythema(5%)


Table

1continued

Firstauthor

(year)

Stud

ydescription

Patients,n

Treatment(s)

administered

Efficacy

findings

Safety

findings

Gilm

oreet

al.

(2020)

[43];

Alexand

er-

Savino

etal.

(2020)

[44]

PhaseII,nonrand

omized,

open-label,split-face,

two-arm

studyin

patientswithstageIA

andIB

disease

280.016%

w/w

topical

chlorm

ethine

gel(once

nightly)appliedover

a

minim

umof

8cm

2 ,over

a

4-month

period

0.016%

w/w

topical

chlorm

ethine

gel(once

nightly)plus

triamcinolone

0.1%

ointmentQD

applied

over

aminim

umof

8cm

2 ,

over

a4-month

period

CAILSscores

werecomparable

betweenthetwoarms

Additionof

triamcinolone

ointmentsignificantly

decreasedtheSC

ORAD

score

(p\

0.05)

32%

developedsevere

contact

derm

atitis

31%

developedACD

vs.6

6%

ofpatientsfrom

historical

data

usingaqueous

form

ulation

4%developedIC

D

The

trialswerecond

uctedun

dervaryingcond

itions,including

trialdesign,additionaltreatm

ents,and

responserates;AEscann

otbe

directlycomparedwithoneanotherandmay

not

reflect

theratesobserved

inclinicalpractice

ACD

allergic

contactderm

atitis;AEadverseevent;BLbaselin

e;CAILSCom

posite

Assessm

entof

IndexLesionSeverity;CIconfi

denceinterval;CRcompleteresponse;CTCL

cutaneousT-celllym

phom

a;EODeveryotherday;HRhazard

ratio;ICDirritant

contactderm

atitis;M

Fmycosisfungoides;NAdatanotavailable;NBUVBnarrow

band

ultravioletB;

ORRoverallresponserate;P

Rpartialresponse;PU

VApsoralen

andultravioletA;Q

Donce

daily;R

Tradiotherapy;SCORADSC

ORingAtopicDermatitis;T

SEBtotalskinelectron

beam

;UVultraviolet


efficacy-evaluable population, overall responserates (ORRs) were 77% and 59% for the gel andointment, respectively [15]. Additionally, the95% confidence interval of the CAILS score inthe efficacy-evaluable population not onlyexceeded the noninferiority threshold (C 0.75),but also lies entirely above 1. On the basis of apost hoc approach of switching from noninfe-riority to superiority testing, these results areconsistent with superiority (p\ 0.05) findingsfor chlormethine gel.

The gel formulation had a faster time toresponse (50% response in 26 weeks) than theointment (42 weeks). Response rates at 52 weekswere 76% for the gel and 56% for the ointment.Maximum response to chlormethine gel treat-ment occurred between 8 and 10 months,emphasizing the importance of continuedtreatment and close follow-up of patients tomaximize the response potential [15]. A follow-up 7-month extension study evaluated a higherdose of chlormethine gel (0.04%) in patientswho did not have a complete response (CR)after previously receiving chlormethine gel orointment for 12 months. In total, 27% ofpatients had a confirmed response, which couldoccur as late as 16 months after initiation of thelower-dose chlormethine treatment [17],thereby reinforcing the value of continuedchlormethine treatment.

In the 201 study,[50% of patients in eachgroup experienced a skin-related adverse event(AE). Irritant contact dermatitis (ICD) was mostcommon, although this was managed withtreatment adjustments, such as suspension orreduction of chlormethine treatment and theuse of emollients/oral antihistamines. Notreatment-related serious AEs were reported,and there was no evidence of systemic absorp-tion of chlormethine [15, 17].

The prospective, observational, noninter-ventional US-based PROVe trial was designed toprovide information on the use of chlormethinegel in a real-world practice setting(NCT02296164). Patients who were diagnosedwith any stage of MF and were being treatedwith chlormethine gel in combination withother MF therapies were enrolled. At12 months, the proportion of stage IA and IBresponders (defined as C 50% reduction from

baseline in body surface area [BSA] involve-ment) was 44% in patients who receivedchlormethine plus topical corticosteroids plusother treatment and 45% in patients whoreceived chlormethine plus other treatment. Apeak response occurred at 18 months forpatients with stage IA and IB disease in thechlormethine plus other treatment group(67%). Overall, 28% of patients experienced atreatment-related AE; the most common skin-related AEs deemed to be therapy related weredermatitis (12%), pruritus (7%), skin irritation(7%), and erythema (4%) [45].

Other studies using compounded formula-tions of chlormethine (ointment or solution)have reported response rates of 58–69% inpatients with early-stage disease [26, 30, 36–38]and 13–53% in patients with advanced disease[26, 30, 37]. Moreover, one trial has reported a10-year overall survival rate of 71% in patientswith mainly T1 or T2 disease (96%). For thosepatients who attained a CR with topicalchlormethine, a 5-year relapse-free survival rateof 42% was observed [37]. Another study foundthat the probability of achieving clinicallyapparent remission rates at 2 years was 76% forstage I MF, 45% for stage II, and 49% for stage IIIdisease [35].

REAL-WORLD EXPERIENCEOF CHLORMETHINE GELIN THE MANAGEMENTOF PATIENTS WITH MF (TABLE 2)

Penn Dermatology Cutaneous T-CellLymphoma Clinic

At the Penn Dermatology Cutaneous T-CellLymphoma Clinic (USA), * 200 patients withnewly diagnosed MF are seen annually; of these,70% have early-stage disease. This center useschlormethine gel as a first-line SDT in patientswith early-stage disease for whom topical cor-ticosteroids have failed. It is applied as a local-ized spot treatment or, for patients with more-extensive BSA involvement, as full-body treat-ment (from the neck down). In advanced-stagedisease, chlormethine gel is used as an


Table 2 Summary of the real-world experience from four centers

Characteristic PennDermatologyCutaneousT-CellLymphomaClinic, USA

Cutaneous OncologyClinic, ColumbiaUniversity, USA

Rabin Medical Center,Israel

Hopital Saint-Louis,France

Number of

patients

with MF

seen/year

* 200 [ 350 300 * 320

Disease stage

of patients

with MF

Mostly early stage Ranging from stage IA or

IB to Sezary syndrome

Early stage Early and advanced stages

Chlormethine

gel usage

Early stage:

treatment after

corticosteroids

failure

Advanced stage:

adjunctive

treatment to

systemic

therapies or

other SDTs

For patients with early

stage, skin-limited

disease

Advanced disease: in

combination with

systemic therapies

Second-line treatment in

patients for whom at

least 1 previous SDT

failed (topical steroids

or phototherapy)

Early stage: second-line

treatment after failure of

high-potency

corticosteroids, mainly

when phototherapy is

not possible or

contraindicated

Late stage: in combination

with systemic treatments

when insufficient effect is

observed on

patch/plaques lesions

Chlormethine

gel initial

application

frequency

Alternative

evenings or 2

nights/week

1–2 times/week,

alternating with topical

steroids

Gradually, up to a

maximum of QD,

sometimes with 1–2

times/week topical

steroids

3 times/week alternating

with topical steroids. If

well tolerated and PR,

increase to QD

Response time 4–6 weeks;

4–24 months

to achieve CR

1–2 months; 80% of

patients respond

NA Beginning of response:

1–2 months. CR:

9–12 months; in some

patients, 12–15 months

required to achieve CR

Incidence of

dermatitis

ICD/ACD:

20–25% of

patients in first

6 months

ICD: * 30%;

10% develop severe ICD

ICD is the most

commonly diagnosed

AE, and is usually mild

Mostly ICD (25% of cases)

Real ACD rare


adjunctive SDT to systemic therapy and otherSDTs. For at-home administration, patientsmust take appropriate precautions to avoidinadvertent mucosal exposure to chlormethinegel in other household members/pets.

Patients are instructed to apply chlorme-thine gel thinly, initially only every other nightor 2 nights/week, then slowly increase theapplication frequency as tolerance permits, tominimize irritant dermatitis. Patients may applytopical steroids every other day to the samearea, but this treatment is eventually tapered ifno AEs result from chlormethine gel treatment.Patients using full-body treatment are advisedthat they may notice new lesions during thefirst month; however, these are subclinical MFlesions unmasked by chlormethine gel, notnecessarily a sign of true disease progression.

In our experience, a response to chlorme-thine gel treatment can be expected within4–6 weeks. It takes 4–24 months to achieve aCR; the ORR is 70%, with 10% of these achiev-ing a CR and 90% achieving a partial response(PR). ICD or allergic contact dermatitis (ACD) isobserved in 20–25% of patients and occurs

mostly within the first 6 months of therapy.When dermatitis or other skin AEs occur, wetemporarily discontinue chlormethine geltreatment and apply potent topical steroids tothe affected area twice daily (BID) for 2–3 weeks.A ‘‘patch test,’’ where chlormethine gel isapplied daily to a small unaffected skin area, isthen performed. If dermatitis reappears, this issuggestive of ACD, and chlormethine gel isdiscontinued permanently. If no dermatitisappears, the prior reactions are most likely ICD,and chlormethine gel may be reintroducedslowly with applications every other night or 2nights/week. This practice of ‘‘starting low andgoing slow’’ with application frequency isanalogous to how we use other SDTs withknown irritant effects (e.g., topical retinoids).Patients who experience a moderate-to-severedermatitis reaction to chlormethine gel mayhave complete clearance of the original MFlesion once the dermatitis is cleared with potenttopical steroids, as has been observed in theliterature [46].

Table 2 continued

Characteristic PennDermatologyCutaneousT-CellLymphomaClinic, USA

Cutaneous OncologyClinic, ColumbiaUniversity, USA

Rabin Medical Center,Israel

Hopital Saint-Louis,France

Management

strategy for

dermatitis

Temporary

suspension of

treatment

Potent topical

steroids BID for

2–3 weeks

ICD: application of mid-

to-high-potency

ophthalmic steroid

(chlormethine gel

discontinuation if severe

ICD)

ACD: discontinue

chlormethine gel

Mild ICD: avoid

treatment

discontinuation if

possible; temporary

addition of topical

corticosteroids

Moderate-to-severe ICD:

topical steroid plus

temporary reduction or

discontinuation (only

for severe dermatitis)

Moderate-to-severe

dermatitis: chlormethine

gel discontinuation plus

topical steroids;

chlormethine gel

reintroduced after

reactions have

disappeared; and

frequency of application

has progressively increased

ACD allergic contact dermatitis; AE adverse event; BID twice daily; CR complete response; ICD irritant contact dermatitis;MF mycosis fungoides; NA data not available; PR partial response; QD once daily; SDT skin-directed therapy


The Cutaneous Oncology Clinicat Columbia University

At the Comprehensive Cutaneous OncologyClinic at Columbia University (USA), a range ofdisease stages are seen, from early-stage IA andIB MF-CTCL to stage IV disease, including Sez-ary syndrome. The patients are managedaccording to published algorithms in a stage-based approach. For patients with early-stageskin-limited disease, topical steroids, narrow-band ultraviolet B (NBUVB), and chlormethinegel are the first-line treatments. Based on theirschedule, personal preferences, or medical his-tory, and in consultation with their physician,patients choose a therapy that best fits theirlifestyle and disease state. Light therapy is aneffective way to treat cutaneous manifestationsof MF, but it may necessitate frequent visits tothe physician’s office and may not be conve-nient for people with busy work and familyschedules. Some of the benefits of chlormethinegel include the ability to apply the gel at home,reducing the need for office visits for lighttherapy in those patients unable to incorporatevisits into their daily schedule. Chlormethinegel treatment can continue away from home,provided refrigeration is available, so travelneed not interfere with the treatment schedule.Additionally, chlormethine gel is recommendedover NBUVB for patients with high risk of mel-anoma or nonmelanoma skin cancers, includ-ing patients with significant personal history ofthese diseases as well as light skin, numerousatypical nevi, or immunosuppression [47].Given that a link between chlormethine gel useand development of nonmelanoma skin cancershas been suggested, concurrent NBUVB andchlormethine gel treatment is not typicallyadvised in our patient population [48].

While chlormethine gel is FDA approved fortreating stage IA and IB MF in patients whoreceived one prior treatment, we also usechlormethine gel therapy in combination withsystemic therapies in more advanced disease,including Sezary syndrome.

At Columbia University, over 350 patientsper year are treated with chlormethine gel, allwith relatively low toxicity. The main AE isirritant dermatitis, seen in * 30% of treated

patients. ACD may be observed, and chlorme-thine gel should be discontinued in these cases.However, ICD is generally well controlled withmid- to high-potency topical steroid use, andchlormethine gel treatment can be continued inmost patients. Approximately 10% of patientsdevelop severe ICD, with lymphomatoid papu-losis observed in a few patients; this resolvesupon discontinuation of chlormethine gel [49].

Patients generally start chlormethine gelwith less frequent applications (one or twotimes/week, alternating with topical steroids). Ifthe patient can tolerate the gel without ICD orother concerns, the frequency is increased todaily use. In some patients, the gel may be usedBID depending on symptoms. In our experi-ence, response rates of up to 80% have beenseen in patients with early-stage disease. Initialresponse is typically observed 1–2 months afterstarting treatment, and therapy is continued for12 months in responders. Frequency can sub-sequently be reduced during the ‘‘maintenancephase,’’ which may last from several months toseveral years, or chlormethine gel can be dis-continued when cutaneous lesions disappearcompletely. A significant proportion of patientsuse skin-directed (mostly topical steroids) orsystemic agents in combination with chlorme-thine gel.

The Cutaneous Lymphoma Clinic at RabinMedical Center

In Israel, in daily practice the first-line treat-ment for early-stage MF (after topical steroids) isusually phototherapy, while chlormethine gel isused as a second-line treatment in patients forwhom phototherapy has failed or who havedeveloped intolerability. Chlormethine gel as afirst-line therapy (after topical steroids) isreserved for patients with early-stage MF whohave contraindications to phototherapy (e.g.,history of melanoma or multiple nonmelanomaskin cancers) or those who foresee adherenceproblems to phototherapy. Regional or whole-body application depends on the distribution oflesions and extent of cutaneous involvement.Since chlormethine gel has the potential tocause irritation, treatment initiation involves


gradually increasing the application frequencyup to the maximal tolerable frequency, but nomore than QD, to minimize the occurrence anddegree of irritation. The process is similar to thatadopted with other topical treatments withirritant potential (e.g., retinoids) [50]. The skinfolds and face are generally more susceptible toirritant reactions; hence, the maximal recom-mended application frequency is usually alter-nate days.

ICD is the most common AE and is usuallymild. In the case of mild irritation, patients maybenefit from temporary addition of topicalsteroids without a change in chlormethine gelapplication frequency, although in somepatients, emollients are sufficient to alleviatesymptoms. If irritation is moderate to severe,topical steroid application is advocated along-side temporary reduction (moderate irritation)or temporary discontinuation (severe irritation)of chlormethine gel application. Once irritationis under control or resolved, the applicationfrequency is gradually increased or chlorme-thine gel is reintroduced at the highest tolerablefrequency. In many patients, topical steroidsmay be withdrawn or minimized to once-weekly application. In the case of severe irrita-tion, reintroduction of chlormethine gel may beattempted but is initially limited to a small areato assess tolerability.

The main differential diagnosis of ICD isACD. Patch tests are not done routinely, andthe diagnosis is based solely on clinical judg-ment. Key diagnostic features are: (1) timing ofappearance, with delayed-type hypersensitivityoccurring at least 2–4 weeks following treat-ment initiation versus primary irritation, whichmay develop as early as a few days after appli-cation; (2) distribution, where extension ofdermatitis beyond treated areas indicatesdelayed-type hypersensitivity versus primaryirritation, which is localized to treated areasonly. ACD is suspected in few patients. If theallergic reaction is mild to moderate, the pro-tocol is the same as for severe irritation. Forpatients with severe ACD, permanent discon-tinuation is required. It is important that anytype of dermatitis is distinguished clearly fromthe unmasking effect of chlormethine gel,where new lesions are observed in the treated

areas; this is seen in a small fraction of patientsand usually occurs during the first month oftreatment. Patients should be encouraged tocontinue with treatment, and whole-bodyapplication should be considered.

Hopital Saint-Louis

Hopital Saint-Louis (France) sees * 320patients per year with cutaneous lymphomas ofany MF stage; * 80% have early-stage and 20%have advanced-stage disease. In patients withearly-stage IA MF, chlormethine gel is pre-scribed after failure of high-potency corticos-teroids, whereas for patients with stage IB,chlormethine gel may be prescribed as a first-line therapy, particularly in patients for whomphototherapy is not possible or contraindicated.In patients with late-stage disease, chlorme-thine gel is used in combination with systemictreatments when insufficient effect is observedon patch or plaque lesions. Response tochlormethine gel may occur 9 months aftertreatment initiation, but in some patients aperiod of 12 or 15 months may be required toachieve remission. In our experience, 19% ofpatients achieve a CR, and 66% have a PR.

The most common AE is skin reactions,mostly contact irritation versus real allergicdermatitis. When severe skin reactions areobserved (e.g., moderately severe to severe der-matitis), chlormethine gel is discontinued andtopical steroids are prescribed. Once the reac-tions have disappeared, chlormethine gel maybe applied to a limited zone with persistinglesions on the trunk or the limb, with a reducedschedule (one or two times/week). If the patientpresents with real sensitization, contact allergywill develop on the limited area, thereby indi-cating the patient has a true allergy, andchlormethine gel is contraindicated. In mostpatients, however, this limited application iswell tolerated, and it is possible to applychlormethine gel to the whole skin, up to threetimes/week, and often every day. Real patchtesting to determine whether the response isICD or ACD may be very informative in suchsituations.


A 58-year-old male with a history of mela-noma on his back presented with stage IB MF.The patient had disseminated pruriginous ery-thematosquamous patches and plaques,although there were no adenopathies or bloodinvolvement. A cutaneous biopsy demonstrateda band-like infiltrate with epidermotropism andatypical lymphocytes, and the patient wasdiagnosed with stage IB MF. Treatment withtopical clobetasol yielded no response, whiletreatment with phototherapy was not possibledue to the history of melanoma. Consequently,this patient was treated with chlormethine gelQD. Due to the dissemination of lesions,chlormethine gel was applied to the whole

body, except for the face and scalp, where nolesions were present. After 9 months ofchlormethine gel treatment, the patient was infull remission and treatment was stopped(Fig. 1).

CONCLUSIONS

Chlormethine gel is a therapeutic option forpatients with MF skin lesions, and a range ofretrospective, prospective, and observationalclinical data supports its use in all disease stages.Its validity as a treatment is supported byinternational guidelines, which all recommend

Fig. 1 Patient case images. a Epidermotropism and atypical lymphocytes, diagnostic of mycosis fungoides. b Skin lesions onthe patient’s legs before and after 3 and 6 months of once-daily chlormethine gel application


chlormethine gel as a first-line treatment forpatients with early-stage MF. In later stages ofMF, systemic treatments are usually indicatedand prescribed, although patch and plaquelesions in these patients may be only partiallyresponsive to systemic treatments; the additionof topical treatments, such as chlormethine gel,may be very useful in such cases. Moreover,chlormethine gel may be important as anadjunctive therapy in patients with late-stagedisease (especially for persisting patches andplaques) to palliate symptoms and to improvethe overall response and as a maintenancetreatment since systemic therapies do not typi-cally result in durable CRs.

Indeed, experience from clinical practice inthe USA, Israel, and France has shown thatchlormethine gel is used both as an SDT (oftenin the first line) in early-stage MF and as anadjunctive therapy in advanced-stage disease.The strategies employed by the centersdemonstrate that emergent cutaneous reactionscan be managed if the appropriate protocols arefollowed. Time to response varies slightlybetween centers, perhaps reflecting the diversityof patients who were seen (Table 2). ICD is themost frequently observed form of dermatitis,and all centers use topical steroids to managethis AE, although discontinuing chlormethinetreatment may be required for severe reactions.

Efforts are ongoing to gain a more in-depthunderstanding of the utility of chlormethine gelin patients with MF and the nature of theemergent skin reactions. The PROVe trial foundthat chlormethine gel is an effective treatmentacross all disease stages [45]. No chlormethinegel-related serious AEs occurred in the study,and the reported emergent skin-related AEswere manageable and less prevalent than in thepivotal clinical trial [15], possibly because offrequent dose adjustments and the co-adminis-tration of corticosteroids, which reflect the real-world experience reported herein.

The Mechlorethamine Induced ContactDermatitis Avoidance Study (MIDAS;NCT03380026), which evaluated the incidenceand severity of contact dermatitis followingtreatment with chlormethine gel alone or incombination with triamcinolone ointment inpatients with MF, aimed to gain a greater

understanding of chlormethine-related contactdermatitis. The study found that contact der-matitis with and without hypersensitivityresponses was seen, and histopathologyrevealed a superficial and deep lymphocyticinfiltrate with spongiosis and eosinophils simi-lar to arthropod assault [43, 44]. Evaluation ofthe patient samples is ongoing to provide moreinformation about the nature of the skin reac-tions, which should further help to guidemanagement of patients who develop contactdermatitis. Additional information that may beused to guide treatment and manage contactdermatitis in patients who receive chlormethinegel may come from the REACH trial (Study toDetermine the Aetiology of Chlormethine GelInduced-skin Drug Reaction in Early-stageMycosis Fungoides Cutaneous T Cell Lym-phoma; NCT04218825), which is currentlyrecruiting.

In conclusion, chlormethine gel is an effec-tive treatment for patients with all stages of MF.While contact dermatitis is an emergent skin-related AE, it can be managed effectively inmost cases if the appropriate strategies are inplace.

ACKNOWLEDGMENTS

Funding. Funding for this review the jour-nal’s and Rapid Service Fee were funded byHelsinn Healthcare SA, Lugano, Switzerland.

Medical Writing and/or Editorial Assis-tance. Editorial and medical writing assistancewas provided by Joanne Franklin, PhD, CMPP,from Aptitude Health, The Hague, The Nether-lands, funded by Helsinn Healthcare SA,Lugano, Switzerland.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.


Authorship Contributions. All authorsequally contributed to the concept, design, anddrafting of the manuscript.

Disclosures. Larisa J. Geskin has receivedresearch support from and was Principal Inves-tigator for BMS, Galderma, Helsinn, InnatePharma, Johnson & Johnson, Kyowa Kirin,Mallinckrodt, Merck, miRagen, Soligenix, andStratpharma. She was also a speakers’ bureaumember for Helsinn, a scientific advisory boardmember for Helsinn, Kyowa Kirin, Mallinck-rodt, Recordati, Regeneron Pharmaceuticals,and Takeda, and has consulted for RegeneronPharmaceuticals and Sanofi. Martine Bagot is ascientific advisory board member for Helsinn/Recordati, Innate Pharma, Kyowa Kirin, andTakeda. Emmilia Hodak was a scientific advisoryboard member for Actelion, Helsinn, andTakeda and a speakers’ bureau member forHelsinn, Rafa, and Takeda. Ellen J. Kim hasreceived clinical trial grants from Galderma,Innate, Kyowa Kirin, and Soligenix. She has alsoconsulted for Galderma and Helsinn.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors. Informed consent was pro-vided by the patient whose case was included.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,

visit http://creativecommons.org/licenses/by-nc/4.0/.

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