Mantle cell lymphoma in 2023

1. MANTLE CELL LYMPHOMA
Dr Kunal Chhattani,
Clinical Hematologist, Nagpur

2.  Introduction
 History
 Pathogenesis
 Clinical Features
 Lab Features
 Work Up
 Treatment upfront
 Treatment Relapsed

3. INTRODUCTION
 Type of Mature B cell NHL
 5-10% of all NHLs.
 Generally Aggressive, although a subset behaves
indolently.
 Two to Seven fold more common in males
 Average age at diagnosis varies between 60-70yrs.
 Annual incidence is 4-8/million in US and Europe.

4. HISTORY
 In 1970, Kiel used the term Centrocytic lymphoma
whereas Berard and Dorfmann categorized it as
lymphocytic lymphoma of indeterminate
differentiation.
 In 1994 REAL classification, and 2001 WHO
classification onwards, MCL is recognized as a
distinct disease.

5. ESMO
Perceptorship on
Lymphoma,
Lugano 2018

8. PATHOGENESIS
 MCL, characterized by an alteration in the
regulation of the cellcycle, demonstrates cyclin D1
overexpression and increased replication.
 The tumor cells also demonstrate decreased
response to DNA damage and resistance to
apoptosis.
 The tumor cells originate from pre-B cells in the
bone marrow that can follow at least two different
molecular pathways of development.

9.  The classical MCL originates from a naive B cell
that has not entered the follicular GC, but has
SOX11 expression, lambda light chain restriction,
and limited or no immunoglobulin heavy chain
variable (IgVH) somatic mutations.
 The second subset of MCL, an indolent form
typically limited to peripheral blood and spleen,
originates from post-GC B cells. This MCL subset
has frequent IgVH mutations, typically lacks SOX11
expression, and has kappa light chain restriction.

11.  The three most common recurrent mutations in
MCL involve CCND1 (also known as Cyclin D1),
TP53, and ataxia telangiectasia mutated (ATM)
genes.

12. CLINICAL FEATURES
 The early symptoms usually include
 fevers,
 night sweats,
 unexplained weight loss,
 lymphadenopathy, and
 splenomegaly.
 Typically, the majority of patients present at an
advanced stage (III or IV).
 Splenomegaly is noted in 40% of patients.

13.  Involvement of the GI tract, frequently in the form of
lymphomatous polyposis, can be detected in up to
90% of patients; however, many patients do not
have any GI symptoms.
 Involvement of the central nervous system (CNS) is
rare but may be relatively more common with
blastoid MCL and relapsed disease.

14. LAB FEATURES
 Cytopenias are typically present secondary to bone
marrow involvement, whereas autoimmune
cytopenias are rare.
 Histologically, monomorphic proliferation of small-
to medium-sized lymphoid cells with an irregular
nuclear border, dispersed chromatin, and
inconspicuous nucleoli.
 The architectural patterns may include a vaguely
nodular, diffuse, mantle zone, or rarely follicular
growth pattern.
 Histologic transformation to large B-cell lymphoma
does not occur.

15.  Four Histological Variants:
1. Blastoid Variant
2. Pleomorphic Variant
3. Small cell Variant
4. Marginal Zone like Variant

16.  The characteristic immunophenotypic features of
MCL include expression of the B cell–associated
antigens CD19, CD20, CD22, and CD79a and
aberrant expression of the T cell–associated
antigens CD5 and CD43, and a lack of expression
of CD3, CD10, and CD23.
 The identification of t(11;14)(q13;q32) and CCND1
oncogene can further aid to diagnosis.
 The t(11;14) is seen in more than half of patients on
karyotyping and in virtually all the patients screened
with FISH.
 SOX11 is a very useful tool in cyclin D1-negative
cases.

17.  MCL has low to intermediate avidity for
fluorodeoxyglucose (FDG); however, the blastoid
variant is more FDG avid. Nonetheless, an
integrated FDG positron emission tomography
(PET) and CT scan is frequently utilized for staging
of patients with MCL.
 Lumbar puncture is not routinely performed but
should be done in patients with neurologic
symptoms.

19. WORK UP NCCN 2023

20. PROGNOSIS
 MCL international prognostic index (MIPI), based on age,
ECOG PS, LDH, and white blood cell count, is the most
important prognostic factors in MCL.
 In a large study, MIPI categorized MCL patients into low risk
(0–3 scores; OS not reached at a median follow-up of 32
months), intermediate risk (4–5 scores; median OS of 51
months), and high risk (6–11 scores; median OS of 29
months) categories with a significant difference in OS.
 MIPI separated the survival curves better than IPI utilized for
diffuse large B-cell lymphoma or follicular lymphoma (FLIPI).
 Cell proliferation (Ki-67), but not number of mitoses per
square millimeter, was an independent prognostic score.
 Ki-67 and MIPI have been shown to independently predict
PFS and OS in the studies
 -Hoster E, Dreyling M, Klapper W, et al: A new prognostic index (MIPI) for patients with advanced-stage
mantle cell lymphoma. Blood 111(2):558–565, 2008.

22. -Wang et al 2019

23. TREATMENT
 MCL combines the worst features of both follicular
lymphoma (noncurability) and diffuse large B-cell
lymphoma (aggressive course).

24. FIRST LINE TREATMENT
 Stage I, Nonbulky II
 Treatment with ISRT or CI + ISRT usually suffice.
Definite OS benefit with addition of RT.
 -Guru Murthy GS, Venkitachalam R, Mehta P: Effect of radiotherapy on the survival of patients with stage I and stage II
mantle cell lymphoma: analysis of the Surveillance, Epidemiology and End Results database. Clin Lymphoma
Myeloma Leuk 14(Suppl):S90–S95, 2014.

25.  Stage II bulky, Stages III and IV – Treatment has 3
phases –
1. Induction chemotherapy
2. Consolidation with Auto HSCT – not in Elderly/co-
morbidities
3. Maintenance with R

29. -Hermine ASH 2021

34. RELAPSED/REFRACTORY MCL
 Covalent BTKi form the cornerstone of 2nd line
therapy in MCL-
 Ibrutinib
 Acalibrutinib
 Zanubrutininb
 Lenalidomide and Venatoclax are other options

36. THIRD LINE TREATMENT OPTIONS
 The ZUMA-2 results led to U.S. Food and Drug
Administration approval of brexucabtagene
autoleucel in July 2020 for all patients with
relapsed/refractory mantle cell lymphoma.
 In the ongoing phase I TRANSCEND NHL001
study (NCT02631044) patients with
relapsed/refractory B-cell non-Hodgkin lymphoma
receive lymphodepleting chemotherapy followed by
one to two infusions of lisocabtagene maraleucel
(JCAR017), which is an anti-CD19 autologous CAR
T-cell product with a 4-1BB costimulatory domain.

37. NEWER DRUGS IN PIPELINE
1. Bispecific Antibodies-Glofitamab and Epcoritamab
2. Antibody-Drug Conjugate- Zilovertamab vedotin
3. Pirtobrutinib – approved Jan 2023
4. Parsaclisib

38. Kumar et al 2022

39. - NCCN 2023

40. TAKE AWAYS
 MCL combine non curability and aggressiveness.
 Cyclin D1 IHC and FISH for 11,14 translocation in all
patients.
 Histological transformation to large cell lymphoma does
not occur.
 MIPI –c most important prognostic factor.
 HD Cytarabine containing induction chemotherapy
regimens are preferred in young patients.
 All patients require maintenance.
 BR results better than RCHOP, preferred in older
patients.
 BTKi are still second line options in 2023.
 CART approved for 3rd line treatment.