In this issue of Blood, Thurner and colleagues from the European MCL Network report a subset of cases with B-cell receptor (BCR) reactivity against the self-antigen LRPAP1 (LDL receptor–related protein–associated protein 1), and that these patients have an improved clinical outcome.1 

In the 30 years since the identification of the hallmark molecular marker of mantle cell lymphoma (MCL), the t(11;14)(q13;q32) that leads to dysregulated expression of cyclin D1, the remarkable biologic and clinical complexity of the disease continues to amaze.2,3  Thurner et al, following up on their initial discovery,4  now have analyzed sera obtained during the Network’s phase 3 trials in previously untreated MCL. The MCL Younger Trial studied the role of high-dose cytarabine plus autologous stem cell transplant (ASCT) consolidation, and the MCL Elderly Trial assessed the role of maintenance rituximab after chemoimmunotherapy. Surprisingly, they found that patients with anti-LRPAP1 seropositivity experienced improved 5-year failure-free and overall survival (OS) independent of other established prognostic markers. The presence of LRPAP1 autoantibodies did not correlate with presenting clinical characteristics.

MCL patients may exhibit slow-paced disease that can be observed for months or years without therapy, while others have highly aggressive lymphoma with poor survival. Correlative research has established a number of MCL prognostic factors, most in the context of chemoimmunotherapy rather than agents that target the BCR or BCL2 pathways (see table). However, no biomarker nor the Mantle Cell International Prognostic Index (MIPI) scoring system currently is used in clinical practice to determine the timing or type of initial therapy, although the role of consolidative ASCT in TP53-mutated or deleted MCL has been questioned due to typically short remission durations in these patients.5  A high tumor cell proliferation rate is the common theme among those with poor treament outcomes, as demonstrated by a Ki-67 score >30%, blastoid morphology, or a high-risk MCL35 proliferation assay score.5,6 

Achieving a deep initial treatment response is emerging as the strongest single determinant of outcome, as reflected by the presence or absence of measurable residual disease (MRD) in peripheral blood and bone marrow upon completion of induction therapy. A recent study showed significantly improved progression-free survival and OS for MCL patients who were MRD negative by real-time quantitative polymerase chain reaction assays with a minimal sensitivity of at least 10−4 following completion of 4 cycles of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cis-platinum) and prior to ASCT consolidation.7  The ongoing ECOG-ACRIN EA4151 clinical trial (clinicaltrials.gov identifier NCT03267433) is prospectively testing risk-adapted postinduction ASCT consolidation based upon MRD status at completion of induction therapy; MRD-positive patients all proceed to ASCT consolidation followed by maintenance rituximab, while MRD-negative patients are randomized to ASCT plus maintenance vs maintenance rituximab alone. The results of this trial will inform the benefit of ASCT in patients who have already achieved deep clinical response by negative positron emission tomography imaging and MRD. Other MRD-based studies are exploring risk-adapted therapy to convert MRD-positive patients to negative utilizing anti-CD20 monoclonal antibody therapy and/or targeted agents.

What insights with regard to mantle cell lymphomagenesis are informed by LRPAP1 autoreactivity? It is well established that chronic active BCR signaling is integral to the pathogenesis of most B-cell lymphoproliferative malignancies. This activation may arise via mutations within the signaling pathway or by ligand binding of the tumor cell BCR. An external antigen may directly or indirectly engage the BCR, as in gastric mucosa-associated lymphoid tissue lymphoma with Helicobacter pylori infection, or it may bind to a “self” antigen as may arise during cellular apoptosis.4,8  LRPAP1 is the first such autoantigen clearly defined for MCL. Functional relevance was demonstrated by LRPAP1-induced MCL proliferation in cell lines and primary patient samples with LRPAP1-specific BCRs, and by induction of in vitro cell death in cells exposed to toxin-conjugated LRPAP1.4  The latter observation supports the idea that this receptor specificity may allow therapeutic targeting of LRPAP1-reactive MCL, as suggested by Thurman et al.

Further development of anti-LRPAP1 antibody detection as a biomarker for MCL will need to account for the recognition that serum LRPAP1 antibodies also may arise in patients with esophageal squamous cell cancer, colorectal carcinoma, and other solid tumors and in the setting of cardiovascular disease, including acute ischemic stroke or myocardial infarction.9  Additional analysis of this biomarker in MCL will be of particular interest utilizing samples from recent front-line MCL trials incorporating targeted agents in order to confirm whether or not anti-LRPAP1 remains prognostic in such therapeutic contexts. As noted, the potential of BCR with LRPAP1 specificity to serve as a therapeutic target or offer novel insights into MCL pathogenesis requires further exploration.

MCL thus continues to surprise. Initially identified as a difficult-to-diagnose and poor-prognosis non-Hodgkin lymphoma with only transient treatment response, recent advances have led to dramatic improvement in outcomes and survival with an array of therapeutic options for front-line and relapsed disease. Despite the universal presence of the t(11;14) translocation and cyclin D1 overexpression (or, rarely, cyclin D2 or D3) as the unifying molecular event, the clinical spectrum includes in situ MCL, the clinically indolent non-nodal leukemic subtype, as well as classical MCL and highly aggressive disease with blastoid transformation. The genomic and epigenomic abnormalities that underlie the MCL subtypes reveal a remarkably complex array of changes that in turn reflect the heterogeneity of clinical presentation and progression,10  holding promise for continued progress in predicting an individual patient’s course and informing treatment optimization.

MCL: prognostic factors at diagnosis

BiomarkerFavorableUnfavorable
MIPI or MIPI-c score Low High 
Ki-67 score <30% ≥30% 
Chromosome 17p Intact Deleted 
TP53 Wild-type Mutated 
Clinical/morphologic Leukemic/non-nodal subtype Blastoid or pleomorphic MCL 
Postinduction MRD Negative Positive 
MCL35 proliferation assay Low risk High risk 
Anti-LRPAP1 seropositive (proposed) Present  
BiomarkerFavorableUnfavorable
MIPI or MIPI-c score Low High 
Ki-67 score <30% ≥30% 
Chromosome 17p Intact Deleted 
TP53 Wild-type Mutated 
Clinical/morphologic Leukemic/non-nodal subtype Blastoid or pleomorphic MCL 
Postinduction MRD Negative Positive 
MCL35 proliferation assay Low risk High risk 
Anti-LRPAP1 seropositive (proposed) Present  

Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

1.
Thurner
L
,
Fadle
N
,
Bittenbring
JT
, et al
.
LRPAP1-autoantibodies in mantle cell lymphoma are associated with superior outcome
.
Blood
.
2021
;
137
(
23
):
3251
-
3258
.
2.
Williams
ME
,
Westermann
CD
,
Swerdlow
SH
.
Genotypic characterization of centrocytic lymphoma: frequent rearrangement of the chromosome 11 bcl-1 locus
.
Blood
.
1990
;
76
(
7
):
1387
-
1391
.
3.
Swerdlow
SH
,
Yang
W-I
,
Zukerberg
LR
,
Harris
NL
,
Arnold
A
,
Williams
ME
.
Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the BCL1/cyclin D1 gene
.
Hum Pathol
.
1995
;
26
(
9
):
999
-
1004
.
4.
Thurner
L
,
Hartmann
S
,
Fadle
N
, et al
.
LRPAP1 is a frequent proliferation-inducing antigen of BCRs of mantle cell lymphomas and can be used for specific therapeutic targeting
.
Leukemia
.
2019
;
33
(
1
):
148
-
158
.
5.
Maddocks
K
.
Update on mantle cell lymphoma
.
Blood
.
2018
;
132
(
16
):
1647
-
1656
.
6.
Rauert-Wunderlich
H
,
Mottok
A
,
Scott
DW
, et al
.
Validation of the MCL35 gene expression proliferation assay in randomized trials of the European Mantle Cell Lymphoma Network
.
Br J Haematol
.
2019
;
184
(
4
):
616
-
624
.
7.
Callanan
MB
,
Macintyre
E
,
Delfau-Larue
M-H
, et al
.
Predictive power of early, sequential MRD monitoring in peripheral blood and bone marrow in patients with mantle cell lymphoma following autologous stem cell transplantation with or without rituximab maintenance; Final results from the LyMa-MRD Project [abstract]
.
Blood
.
2020
;
136
(
suppl 1
). Abstract 120.
8.
Young
RM
,
Phelan
JD
,
Wilson
WH
,
Staudt
LM
.
Pathogenic B-cell receptor signaling in lymphoid malignancies: New insights to improve treatment
.
Immunol Rev
.
2019
;
291
(
1
):
190
-
213
.
9.
Sumazaki
M
,
Shimada
H
,
Ito
M
, et al
.
Serum anti-LRPAP1 is a common biomarker for digestive organ cancers and atherosclerotic diseases
.
Cancer Sci
.
2020
;
111
(
12
):
4453
-
4464
.
10.
Nadeu
F
,
Martin-Garcia
D
,
Clot
G
, et al
.
Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes
.
Blood
.
2020
;
136
(
12
):
1419
-
1432
.