New Directions in Mantle Cell Lymphoma PDF

New directions in Mantle cell lymphoma. Supervised by DR. ALA`A ALKHAZZAR PRESENT ED B Y NOOR SABAH KADHIM 2nd year hematopathology student  Ob j ec tiv e s * over view of mant le cell lymp homa * C linical m anifestati ons * Diagnos tic approach of MCL *Deference between M C...

New directions in Mantle cell lymphoma. Supervised by DR. ALA`A ALKHAZZAR PRESENT ED B Y NOOR SABAH KADHIM 2nd year hematopathology student  Ob j ec tiv e s * over view of mant le cell lymp homa * C linical m anifestati ons * Diagnos tic approach of MCL *Deference between M CL and CLL * Man tl e cell l ymp h oma In tern ation al p rogn osti c in dex (M IP I) * N ew str ate gie s fo r tre atme nt - N AÏ V E ma ntle c ell lymp homa  Overview of mantle cell lymphoma _ Mantle cell lymphoma (MCL): is a chronic B-lineage lymphoproliferative disorder characterized by variable cytological and histological features, but with a distinctive cytogenetic and molecular genetic defect. _ Although histologically low-grade, It has an intermediate prognosis between other low- grade B-cell lymphomas and high-grade lymphomas, with a median survival of only 3-4 years. _ The disease is generally considered incurable and shows an increased incidence associated with family history of mantle cell lymphoma or other non-Hodgkin lymphomas. - Mantle cell lymphoma is characterized by the t(11;14) translocation, leading to cyclin D1 overexpression. - Despite this common genetic feature, MCL exhibits significant clinical and biological heterogeneity. - It can range from indolent non-nodal leukemic variants to highly aggressive blastoid variants. Risk stratification at diagnosis is critical for determining optimal treatment approaches.  CLIN ICAL PRESENTA TION - Mant le cell lymp ho ma prim arily af fects m id dle-aged an d old er in dividu als, with a median ag e o f 60 years an d a marked male predo min an ce , present ation is usu ally with advanced stag e d isease, m ost o ft en exhibit in g lymp haden op at hy and sp lenom egaly. - Extran od al invo lvemen t is co mm en, in clud in g Waldeyer's rin g, lun g, pleura, and th e gastro in test in al t ract. - Periph eral blo od in vo lvem ent o ccurs in abou t t wo -th irds of patien ts an d h as been associated w it h a wo rse p rog nosis, Ho wever, leukemic n on-no dal man tle cell lymp ho ma, usually in vo lvin g t he spleen , tend s t o b e clinically ind olent. - Cen tral nervou s system disease may be mo re likely in p at ients wit h perip heral blo od in volvement.  D I A G N OS I S P e rip he ral b lo od : * Th ere can be cyto pen ias d ue to m arro w infilt ration an d t here m ay b e circulatin g lymp ho ma cells visible.Ho wever, th e p resent ation can be wit h a fr ank leu kaemic ph ase. * Mantle cell lymphoma ce lls exhibit signi fi cant pl eom or phism, typically medium-sized w ith ir reguler nuclei. * som e calls show inconspicuous nucleoli or pronounced nuclear i ndentati ons or clefts. Cytopl asmic v acuoles may be present, and rar ely, cytoplasm ic granules. The chr om ati n patter n can vary,w ith some cel ls showi ng e di ffuse pattern. * in the blastoid vari ant , which com pr ises 10-20% of cases, cells predom inantl y have a di ffus e chr om atin pattern and may r esemble acute l ymphoblastic l eukem ia (ALL)cell s or show som e more m ature features.  _PB film in mantle cell ly mphoma. The c ells are ma rk edly pleom orphic. _PB film in blastoid var ian t of m antle cell lymp hom a sho win g med iu m-sized cells with a high n ucleocyt oplasm ic r atio; som e have a diffu se chro m atin p atter n and o ther s s how som e deg ree of ch ro matin co nden sation. Som e cells have distinct sm all o r me dium -sized n ucleoli. _PB film fr om a p atient wit h blastoid var ian t of m antle cell lym p ho ma sho win g pleom o rp hic cells r angin g fro m m atu re lymp ho cyt es to b last -like cells. Som e cells have cleft n uclei an d som e have cytop lasm ic vacu oles.  B one m a r ro w & his to lo gic a l find in gs : * Bone marrow infiltration is common in mantle cell lymphoma, observed in up to 80% of patients. The infiltration pattern is usually interstitial or focal, with either nodules or irregularly shaped infiltrates. Paratrabecular infiltration is uncommon. * in trephine biopsy sections, lymphoma cells may have regular round nuclei or irregular and cleaved nuclei with relatively dense chromatin and inconspicuous nucleoli. * The blastoid variant may show a 'starry sky' appearance. * Lymph node histology can display mantle zone, nodular,or diffuse pattern of infiltration,with the mantle zone pattern potentially representing the earliest stage of involvement.  I mm u n o ph e n o t y p e: _ The characteristic immunophenotype of mantle cell lymphoma includes expression of B - cell-associated antigens (CD19, CD20, CD22, CD24, CD79a), CD5, CD79b, FMC7, and BCL2. _ Notably, CD10, CD11C, CD103, and BCL6 are typically not expressed. CD20 expression is strong, often stronger than CD19. _ While CD5 is usually expressed, 10-15% of patients may lack CD5 expression. CD23 expression is variable and generally weak when present. The immunophenotype is crucial for distinguishing mantle cell lymphoma from other B-cell malignancies. P os it iv e m ar ke r s N eg ati ve m ar ker s CD19, CD 20, CD22, CD24, CD 79a, CD 5, CD79b, FMC7, CD10, CD1 1c, CD103 , BCL6 BCL2. Var iabl e ma rke rs Diagnostic m arker s CD23 (we ak whe n pr ese nt), CD38 , CD43 Cyclin D1, SOX11(useful for cyclin D1 _negative cases)  Cytogenetic Abnormalities : _ The hallmark cytogenetic abnormality in mantle cell lymphoma is t(11;14) (q13.3;932), which leads to dysregulation of the CCNDI gene encoding cyclin D1. This translocation brings CCNDI into proximity with the IGH locus, resulting in cyclin D1 overexpression. _ This rearrangement is not specific to mantle cell lymphoma,being reported also in multiple myeloma; however, this translocation is considered diagnostic in the appropriate clinical and histological context. _ Fluorescence in situ hybridization (FISH) techniques are highly sensitive in detecting this rearrangement. Additional cytogenetic abnormalities are common, including deletions in chromosomes 1p, 6q, 9p. 11q, and 13q, as well as gains in chromosomes 3 and 12. Primary abnormality t(11;14) (q13.3;q32) Gene invo lved CCND1 (cyclin D1) Detection metho d FISH, PCR Common secon dary abn ormalities del(1p),del(6q),del(9p),del(11q),del(13q),+3, +12 * Molecular genetic features: _ Mantle cell lymphoma cells typically show unmutated IGHV genes, indicating a pre- germinal center origin. _ However, a significant minority exhibit IGHV somatic hypermutation, which correlates with predominantly non-nodal disease and can include a subgroup of patients with indolent disease. _ Secondary genetic abnormalities are common, including gains of MYC, CDK2, CDKNIB, and MDM2, as well as losses of RB1, CDKN2A, ATM, and TP53. _ Mutations in TP53, CDKN2A, and CDKN2C are particularly associated with the blastoid variant and worse prognosis. _ ATM function may be lost through point mutation or deletion, often affecting both alleles in cases with del(11)(q23)  Pitfalls :- * Man tle cell lymp hom a ( MCL ) is an impo rtant d if ferential d iagn osis f or CLL/SLL du e t o sh ared CD5 p ositivit y. Most MCL cases are com po sed o f in termed iat e lymph ocytes an d centrocyt es with irregular n uclear cont ours, which is a key disting uishing featu re. * Ho wever, some MCL cases can b e co mpo sed of small -sized cells t hat resem ble CLL/SLL , m aking t he distinction ch allenging. _PB fi lm from a pati ent w ith mantle cell lym phom a showi ng a range of cells from sm all ly mphocytes resembling those of CLL to larger cells w ith irregular nuclei and ill-defined nuc leoli; there are s om e sm ear cells. * Im munophenotyping and ge ne tic a na lys is are crucial for ac curate dia gnosis. * MCL is typic ally positive for cyc lin D 1 a nd SOX11, which a re negativ e in CLL/SLL. * The t(11:1 4) translocation, charac teristic of MCL, is absent in CLL/SLL.  * C D 23 - p o s it iv e m an t le c e l l ly mp h om a * Wh ile CD23 p ositivity is typically associated with CL L/SL L, a subset of m ant le cell lym pho ma (MCL) cases can exp ress CD23, com plicating the d ifferen tial diag nosis. * Stu dies h ave shown th at ap proxim at ely 13% of MCL cases are weakly positive for CD23. Th ese CD23-po sitive MCL cases often present wit h increased leukocyte coun t, bon e marro w involvement, and leukemic presentation, sim ilar to CLL. * Imp ortan tly, CD23-po sitive MCL is mo re f requ en tly asso ciated wit h CD200 po sitivit y an d w eak SOX11 expression. * Despite th e leukem ic p resen tation , patients w ith CD23-po sitive MCL tend to have a better pro gnosis than those with CD23 -negative MCL. *C D 200 Exp re ss ion in man tle c ell l ymp ho ma _ CD200 is typically considered a m arker for CLL/SLL, b ut recent studies have shown that a sm all subset of mantle cell lymphom a (MCL) cases can express CD200, further complicating the differential diagnosis. _ Approximately 4% of MCL cases are CD200-positive, and most of these ( 76%) are also positive for CD23. _ CD200-positive MCL cases have distinct characteristics: only 24% express SOX11, 39% exhibit round nuclear contours similar to CLL, and 44% present as a non -nodal leukemic variant of MCL. _ These cases are often associated with IGHV- mutated status, which is typically seen in a small subset of MCL with a more indolent clinical cou rse.  Mantle Cell Lymphoma International Prognostic Index (MIPI) - Th e MIPI is a key progno stic too l for MCL. It incorporates ag e, ECOG Performance Status, lactate d eh ydrog en ase level, and white cell count to stratify patients int o low, interm ed iate, an d h ig h-risk grou ps. - Th e simp lified MIPI (s -MIPI) was created for rou tine clin ical use. T he biological MIPI ( MIPI-b) adds th e Ki67 proliferation index for en han ced p ro gnostic power. - Five-year overall survival (OS) rates patients of low, intermediate, and high -risk MIPI groups were 83%, 63% , and 34%, respectively,  - The European Mantle Cell Lymphoma Network developed the combined MIPI (MIPI-c) , which integrates the Ki67 index with the standard MIPI score. - This modification provides greater discriminatory power, separating patients into four risk groups: low, low-intermediate, high-intermediate, and high risk. - The 5-year overall survival rates for these groups are 85%, 72%, 43%, and 17%, respectively, demonstrating improved stratification compared to the MIPI alone. * TP53 A be rr ati on i n MC L : in cl udin g d ele tion s (d el 17 p) a nd/o r muta tion in TP5 3 g ene , ar e imp orta nt p ro gnos tic fac tor s in MC L. _ Hi gh T P53 e xpr e ss ion by im mu nohi stoc he mi str y is as so ci ate d wi th in fe r ior tim e-to-tr ea tme nt fa ilur e an d ov e ra ll sur v iva l. _ Pati ents ha r bor ing a TP5 3 m uta tion we re e nri ch ed for Ki6 7 ind ex gr ea te r th an 30 %, bla s to id mor pho logy , and a high-r isk MIPI , ha v ing s hor t me di an OS of o nly 1.8 ye a rs. _ How ever, on mu ltivariab le an alysis, on ly th e MIPI -c hig h-risk gr ou p an d T P53 m ut atio n g rou p retain ed in dep end ent pr og no stic sig nif ican ce fo r OS.  Ea rly dis ease progre ssion in MC L - pr ogr es si on of dis ea se withi n 2 4 m onths ha s bee n s hown to be a str ong ne ga ti ve pr ogno stic fac tor for OS in both y oun ger pa tien ts tr ea ted with hig h dos e cy tar ab ine-ba se d in duc tion a nd in ol der pa tie nts w ho a re una ble to r e ce ive s tand ar d im muno che mo th er ap y. - A re ce nt s tudy an aly zing pati ent o utcom es a cc or ding to tim e-to- r ela ps e a fter inte ns ive in duc ti on a nd auto logou s s tem ce ll tra ns pla ntatio n. - The im pa ct of r e lap se wa s g re ate st for pa tie nts w hos e d ise as e re la pse d with in 6 mo nths.  Prognostic factors in Relapsed /Re fractory MC L - Se veral f act o rs a re ass oc ia ted w it h po o r o u t co m es in relap se d/r ef ract o ry MCL t rea ted w it h BT K in hib it o rs. - T h ese in clu d e : h ig h-risk s-MIP I sco re, b las to id m o rp h olo g y, an d T P5 3 m u ta tio n s. - p at ien ts w it h th es e fe atu re s h ad ov erall r esp o ns e rat es ( O RR) of ab o u t 55% , 50 % , 55% res pe ctiv ely, an d m ed ian pr o gr essio n-f ree su r vival ( PF S ) rat es w er e 6.5 m o n t hs , 5 m on t h s, an d 4 m o n th s, r esp ect ively. - Pa tien t s w it h K i67 in d ex g reat er t h an o r eq u al t o 50% asso ciat ed w it h in fe rio r o u tc om e s, in clu din g lo w er re sp on se rat es an d sh o rt er su rv ival.  NEW STRA TEGIES FOR TREATMENT -NA ÏVE MANTLE CELL LYMPHOMA - Chem oim mu no th erapy reg im ens co mp rise t he st andar d first -line treat men t op tio ns fo r pat ien ts wit h m ant le cell lym ph om a. - Alth oug h a sub set o f pat ien ts wit h ind olent disease may un derg o o bservat io n, m ost p atient s ultim ately requ ire th er apy. - Mult ip le st ud ies are in corp oratin g BTK inh ib ito rs in to f ron tlin e MCL t reat ment wit ho ut ch emo th erap y. T he com binat ion o f ib rut in ib and rit uxim ab fo r 2 years, fo llowed by ibru tinib co nt inu at ion , sh ow ed a 96% o verall resp on se rat e in patient s >65 years old. -Beyon d BTK Inh ibitio n: n ew th erapies are need ed f or p atient s who pro gress o n th ese agen ts,includ e: 1_CAR T -cell t herap y 2_ bisp ecif ic an tib od ies. 3_ant ibo dy -dr ug co nju gat es 4_next -gen erat io n sm all m olecu le inh ibit ors. -Th ese th erapies of fer d istinct mech anism s o f act io n an d overco m in g resist ance to cur rent treat men ts. Nov el Thera peut ic Approac hes for Rela pse d/Refra ct ory Mant le Ce ll Lym phom a  References * Barbara J. Bain, Leukemic Diagnosis, Fifth Edition. * HEMATOLOGIC MALIGNANCIES.New Directions for Mantle Cell Lymphoma in 2022 Anita Kumar, MD; Toby A. Eyre, MD²; Katharine L. Lewis; Meghan C. Thompson, MD³; and Chan Y. Cheah, MD34. * Journ al of clinical and exp erimental hematopatho log y.Vol. 60 No.4, 124 -129,2020 Review Article Differen tial diagn osis of chronic lymp hocyt ic leu kemia/ small lym pho cytic lymp hom a and other indo lent lymph omas, inclu ding mantle cell lym pho ma Tadash i Yoshin o, Takehiro T an aka, Yasuharu Sato.