considered!as!in!important!milestone!for!the!development!of!current!treatment!strategies!
for!younger!patients.!The!results!have!been!confirmed!in!the!randomized!trial!of!the!EMCL!in!
which!an!Ara>C!containing!regimen!was!compared!to!a!CHOP!based!induction,!each!followed!
by! HDT.! The! incorporation! of! Ara>C! clearly! improved! results! and! definitely! established! the!
role!of!this!agent!as!integral!part!of!first!line.!Other!results!have!underlined!its!role,!e.g.!the!
combination! of! BR! to! Ara>C(12).! Interestingly,! whereas! R>CHOP! followed! by! HDT! was!
superior!to!R>CHOP!alone,!the!results!were!comparable!to!HyperCVAD!without!HDT(13).!So!
again,!with!improved!induction!there!is!no!proof!of!additional!benefit!of!HDT!in!this!setting.!
Finally,! novel! agents! have! entered! the! field! of! MCL.! While! results! on! Ibrutinib! in! first>line!
combinations!are!pending,!Bortezomib!has!been!show!to!substantially!improve!the!results!of!
R>CHOP(14).!It!is!imaginable,!that!Ibrutinib!will!furthermore!
increase! response! rates,! PFS! and! OS! if! added! to! current! therapeutic! standards,! which! will!
further! reduce! the! chance! to! prove! any! benefit! of! HDT! in! the! future! in! the! context! of!
optimized!first>line!treatments.!
!
If! no! benefit! for! the! entire! population! of! patients! can! be! demonstrated,! are! there! data! to!
support!the!use!in!selected!–!high!risk!or!high!benefit!–!patient!groups.!For!the!most!relevant!
risk! factor! –! p53! mutation! –! treatment! intensification! clearly! failed! to! demonstrate! any!
benefit(15),! however,! retrospective! analysis! found! some! benefit! for! patients! with! blastoid!
morphology,!but!this!type!of!analysis!excludes!patients!who!did!not!enter!the!approach!due!
to! early! progression! or! refractoriness(6).! Analyzing! MRD! as! a! predictive! marker! failed! to!
demonstrate! conversion! of! a! negative! impact! of! MRD>positivity! at! the! end! of! induction!
treatment,!and!optimal!induction!likely!abrogates!any!beneficial!effect!of!HDT(16).!
!
Finally,!toxicity!of!different!treatment!approaches!needs!to!be!considered.!Although!HDT!is!
accepted! a! standard! procedure! acute! and! long>term! toxicities! are! well! known.! Treatment!
related! mortality! is! between! 1>! 5%,! with! high! rates! of! infections,! mucositis! and! other!
affections.!In!addition,!there!is!clear!evidence!of!late!sequalae!as!reduced!fertility,!cognitive!
disturbances,!skin!changes,!cardiovascular!problems!and!secondary!malignancies!associated!
to!HDT(17)!–!which!do!not!compare!favorably!with!the!recent!advances!in!treatment!in!MCL.!
!
As! MCT! is! a! fatal! disease! it! is! difficult! to! step! back! from! current! standards,! but! several!
indicators! argue! against! HDT! in! the! setting! of! first! line! treatment! of! MCL:! lack! of! curative!
potential,! no! proven! OS>benefit,! improvements! with! other! approaches,! no! defined! risk>
groups! benefitting! from! HDT! and! toxicities! which! are! substantial! in! the! light! of! lacking!
benefits.! Consequently,! at! this! time! the! value! of! HDT! needs! be! readdressed! and! the!
procedure!cannot!uniformly!be!recommended!to!every!patient.!Consequently,!the!EMCL!has!
embarked!on!a!clinical!trial!which!challenges!the!value!of!HDT!in!the!context!of!optimized!
induction!and!this!trial!will!help!to!finally!determine!the!role!of!HDT.!
!
References:(
1.!Stewart!DA,!Vose!JM,!Weisenburger!DD,!Anderson!JR,!Ruby!EI,!Bast!MA,!et!al.!The!role!of!high>
dose!therapy!and!autologous!hematopoietic!stem!cell!transplantation!for!mantle!cell!lymphoma.!
Annals!of!oncology!:!official!journal!of!the!European!Society!for!Medical!Oncology!/!ESMO.!
1995;6(3):263>6.!
2.!Khouri!IF,!Romaguera!J,!Kantarjian!H,!Palmer!JL,!Pugh!WC,!Korbling!M,!et!al.!Hyper>CVAD!and!high>
dose!methotrexate/cytarabine!followed!by!stem>cell!transplantation:!an!active!regimen!for!