Diffuse large B-cell lymphoma (DLBCL) (2023)

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Diagnostics

Method:
Anticoagulant:
Recommendation:

Method:Cytomorphology
Anticoagulant:EDTA
Recommendation:obligatory

Method:Immunophenotyping
Anticoagulant:EDTA or Heparin
Recommendation:obligatory

Method:Chromosome analysis
Anticoagulant:Heparin
Recommendation:facultative

Method:FISH
Anticoagulant:EDTA or Heparin
Recommendation:obligatory

Method:Molecular genetics
Anticoagulant:EDTA or Heparin
Recommendation:facultative

Classification
Subclassification
Diagnostic methods
Pathogenesis
Prognosis
Therapy

Diffuse large B-cell lymphoma not otherwise specified(DLBCL, NOS) is the most common malignant lymphoma andconstitutes 25-35% of adult non-Hodgkin lymphomas. The median age of onset of this aggressive neoplasm is 70-80 years, but it can also occur in children and young adults. Usually DLBCL arises de novo, but can also represent transformation of a less aggressive lymphoma (Swerdlow et al. 2017). In the case of transformation from chronic lymphocytic leukemia to DLBCL, this is referred to as Richter transformation or Richter syndrome (Rossi et al. 2018).

DLBCL: Classification

Diffuse large B-cell lymphomas are classified as mature B-cell neoplasms according to the WHO classification (2017); in addition to DLBCL, NOS, other subtypes of DLBCL are known:

primary diffuse large B-cell lymphoma of the central nervous system
primary cutaneous diffuse large B-cell lymphoma, leg type
EBV-positive diffuse large B-cell lymphoma, NOS
diffuse large B-cell lymphoma associated with chronic inflammation
fibrin associated diffuse large B cell lymphomaHHV8-positive diffuse large B-cell lymphoma

Subclassification of DLBCL

Based on morphology, DLBCL, NOS can be subdivided into: centroblastic, immunoblastic, anaplastic and other rare variants. However, the most important classification for DLBCL is the subtyping according to the cell of origin (COO). The neoplastic cells can originate from the germinal centre (germinal centre B cells, GCB) or the cells have already passed the germinal centre (post GCB or activated B cells, ABC(Basso et al. 2015, Chapuy et al. 2018). In accordance with the respective cell of origin, persistent somatic hypermutation can be detected in GCB-DLBCL, whereas this has already been completed in ABC-DLBCL.

In addition to somatic hypermutation, the processes of B-cell selection, class switching and terminal differentiation also take place in the germinal centre. All these steps are regulated by a finely tuned gene expression programme. For example, the transcriptional repressor BCL6 is expressed exclusively in the germinal centre (Basso et al. 2015). BCL6 suppresses cell cycle arrest as well as DNA damage recognition and repair. BCL6-mediated suppression of the proliferation factor MYC and the anti-apoptotic factor BCL2 (and other apoptosis factors) prevents uncontrolled proliferation in the germinal centre and maintains a pro-apoptotic state (Pasqualucci et al. 2018, Basso et al. 2010, Ci et al. 2009). Deregulation of these three genes, BCL6, BCL2 and MYC, contributes significantly to the pathogenesis of DLBCL.

Due to the prognostic relevance, the COO subtype of the disease should already be determined at diagnosis. The gold standard here would be gene expression analysis, but this is not used comprehensively in routine practice. However, 10-15% of cases cannot be assigned to a COO subtype (DLBCL, NOS unclassified) (Alizadeh et al. 2000, Rosenwald et al. 2002, Wright et al. 2003, Scott et al. 2015). Instead of gene expression analysis, mainly immunohistochemical approaches are used for subtype determination, e.g. the Hans algorithm checks the expression of the antigens IRF4/MUM1, CD10 and BCL6 and classifies cases into GCB and non-GCB (contains ABC-DLBCL and DLBCL, unclassified) (Hans et al. 2004). However, a meta-analysis showed that the classification according to immunohistochemical algorithms has no significant prognostic value (Read et al. 2014).

The two subtypes also differ in their tumour biology: a chronic, (auto)antigen-dependent activation of the B-cell receptor signalling pathway is characteristic for ABC-DLBCL (Davis et al. 2010). This also results in a constitutive activation of the downstream NF-kB signalling pathway, which is necessary for neoplastic cell survival in ABC-DLBCL. In contrast, neoplastic cells of the GCB subtype are dependent on tonic activation of the B-cell receptor. This weak, antigen-independent activation of B-cell receptor signalling is also normal-physiologically essential for B-cell survival. In both healthy and neoplastic cells, downstream signal transduction occurs via activation of the PI3K/AKT pathway (Chen et al. 2008, Efremov 2016, Myers et al. 2017). The GCB subtype therefore shows no dependence on the NF-kB signalling pathway (Efremov 2016).

Genetic characterisation of DLBCL is of increasing importance. Only 85-90% of DLBCL cases can be classified via the subtype determined by gene expression analysis. Using molecular genetic subclassification, this proportion can be significantly increased to 93.4% (Schmitz et al. 2018) and 96% (Chapuy et al. 2018) in two recent studies. In the study by Schmitz et al. DLBCL cases are classified into four genetically-defined groups as well as two groups defined by the COO subtype (other ABC and other GCB) and the unclassifiable cases (6.6%). In the study by Chapuy et al. cases are classified into a total of five clusters, 12 of 302 cases were unclassifiable. In both studies, the identified clusters/subgroups had prognostic relevance and overall allowed for a more refined risk stratification than the COO subclassification.

Diagnostics

In the diagnostics of lymphoma, the cytomorphology and in particular the histology are important for guiding the downstream diagnostics. In addition, blood and bone marrow smears can be used to assess blood lymphocytosis (rare in this lymphoma entity).

DLBCL: Pathogenesis

BCL2 expression

Aberrant expression of the anti-apoptotic molecule BCL2 occurs in both subtypes. However, the underlying genetic abnormalities differ for the two subtypes. While BCL2 translocations, such as t(14;18)(q32;q21.3), are detected in up to 40% of cases in the GCB subtype, BCL2 translocations are rare in the ABC subtype (Iqbal et al. 2004). Nevertheless, approximately 60% of patients with ABC-DLBCL show high BCL2 levels (Hu et al. 2013). Contributing factors are gains/amplifications of the locus (depending on the study, up to more than 55% of ABC-DLBCL cases) as well as aberrations that activate the NF-kB signalling pathway and thus lead to increased BCL2 expression (Iqbal et al. 2006, Iqbal et al. 2011, Davis et al. 2001).

BCL6 deregulation

Up to 35% of patients have genetic abnormalities of the BCL6 gene. In 1/3 of cases, translocations are the cause of aberrant BCL6 expression, here more frequently in the ABC subtype than in the GCB subtype (2:1) (Pasqualucci et al. 2018). Over 20 possible partner loci are known for the translocation leading to promoter substitution, with IG heavy- or light-chain loci most commonly involved in the rearrangement. Somatic BCL6 mutations also occur with high frequency; due to regulatory elements, the first 2 kb downstream of the transcription start site in particular represent a hotspot for mutations (75% of BCL6 mutations). A variety of indirect mechanisms also contribute to BCL6 downregulation (Pasqualucci et al. 2018).

MYC expression

Expression of the transcription factor MYC is associated with a proliferative phenotype (high Ki-67 proliferation index). In 10-14% of GCB-DLBCL cases, ectopic and constitutive MYC expression occurs, frequently caused by translocations with different partner loci, often involving IG loci (IGH, IGK, IGL) (Pasqualucci et al. 2018, Swerdlow et al. 2017).

If translocations of MYC and BCL2 and/or BCL6 occur simultaneously, these are referred to as double-hit or triple-hit lymphomas, respectively; according to the current WHO classification (2017), these are to be classified as "Highly malignant B-cell lymphomas (HGBL) with gene rearrangements". It is estimated that 3-10% of DLBCL patients have double- or triple-hit lymphoma (Rosenthal et al. 2017), a recent study (Scott et al. 2018) counts the proportion of HGBL in a cohort of 1228 DLBCL patients at 7.9%. HGBL occurred mainly in the GCB subtype and accounted for 13.3% of GCB-DLBCL cases, while the proportion of HGBL cases in ABC-DLBCL was 1.7% (Scott et al. 2018).

The so-called double-expressing phenotype, which shows co-expression of the MYC and BCL2 proteins, must be distinguished. According to WHO recommendations, such a phenotype is present if the MYC protein is detectable in more than 40% of the cells and the BCL2 protein in more than 50% of the cells in the immunohistochemical analyses. In many cases, no underlying chromosomal abnormalities is detectable. Double-expressing lymphomas are associated with the ABC subtype and a worse prognosis (Swerdlow et al. 2016, Pasqualucci et al. 2018).

Immune evasion

DLBCL is characterised by the absence of class I (60%) or class II (40-50%) MHC molecules (Pasqualucci et al. 2018). The variety of mechanisms underlying the lack of expression of MHC molecules include point mutations or losses of HLA loci (e.g. del(6p21.3)), epigenetic silencing, CD58 mutations, inactivating mutations of CIITA, and aberrations of the B2M gene (Pasqualucci et al. 2018). Overexpression of ligands of the programmed death 1 (PD1) factor can also contribute to the immunovascular phenotype. This is caused by copy number gains of the 9p24 region or, more rarely, translocations of PD1 ligands (Chapuy et al. 2016). Overexpression leads to reduced infiltration of cytotoxic T cells into the tumour tissue and a worsening of the prognosis (Rimsza et al. 2006, Rimsza et al. 2004).

Prognosis in DLBCL

The classification of DLBCL according to COO subtypes is of great relevance for the prognosis as well as a possible therapy, as the two subtypes differ significantly in their response to the R-CHOP regime (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The prognosis in GCB-DLBCL (with a 5-year survival of approx. 80%) is better than in ABC-DLBCL (5-year survival of approx. 50%) (Pon et al. 2016). Clinical parameters also have a prognostic influence. The "International Prognostic Index (IPI)" takes into account the patient's age, the lactate dehydrogenase level in the blood, the number of extranodal cases, the general condition of the patient, determined according to criteria of the ECOG (Eastern Cooperative Oncology Group), as well as the staging of the lymphoma according to the Ann Arbor classification. Stratification into four risk groups is based on the IPI risk score.

Several studies have shown an association of a less favourable prognosis and BCL2 gains in DLBCL and BCL2 translocations or BCL2 expression in GCB-DLBCL specifically (Barrans et al. 2003, Iqbal et al. 2011, Visco et al. 2013, Lu et al. 2015, Chapuy et al. 2018). Translocations of MYC have also been associated with worsening prognosis in some studies (Barrans et al. 2010, Copie-Bergman et al. 2015, Savage et al. 2009, Tzankov et al. 2014, Chapuy et al. 2018). Data on the prognostic significance of BCL6 translocation and MYC gain/amplification is inconsistent (Barrans et al. 2002, Iqbal et al. 2007, Shustik et al. 2010, Lu et al. 2015, Stasik et al. 2010, Testoni et al. 2011, Valentino et al. 2013, Yoon et al. 2008). Independent of genetic aberrations, simultaneous expression of MYC and BCL2 (so-called double-expressing lymphomas) is associated with an unfavourable prognosis (Swerdlow et al. 2016, Pasqualucci et al. 2018).

Mutations with a negative prognostic impact include mutations of the transcription factor FOXO1 (Trinh et al. 2013). TP53 losses/mutations are also associated with an unfavourable prognosis (Xu-Monette et al. 2012, Young et al. 2008), as are losses of the CDKN2A locus (Jardin et al. 2010), although Karube et al. demonstrated an independent prognostic effect only in the case of co-aberrations of both loci (Karube et al. 2018). In the same study, mutations in the KLHL6 and SGK1 genes were also negative prognostic indicators, independent of COO subtype and IPI score. When signalling pathways were considered, aberrations in the NOTCH pathway had a negative prognostic impact and alterations in the JAK-STAT pathway had a favourable prognostic impact (Karube et al. 2018).

Karube et al. also associate chromosomal alterations (gains in 5p15, 11q24, 12q14 as well as 12q15 and losses in 8q12) with a reduced rate of complete remission (Karube et al. 2018). Chapuy et al. demonstrated in another study that gains in 13q31.2/miR-17-92 and 18p and loss of 1q24.12 were associated with reduced progression-free and/or overall survival (Chapuy et al. 2018).

Diffuse large B-cell lymphoma prognosis calculation:

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Therapy for DLBCL

The R-CHOP regimen is currently the gold standard in the treatment of DLBCL, NOS. However, ABC DLBCL cases respond significantly worse to treatment with R-CHOP. Currently, however, the COO subtype does not influence treatment decisions (outside of trials) because the diagnostics required for this cannot be offered nationwide. With the knowledge of similarities and differences between the two subtypes, targeted therapies could possibly be used in the future to improve the treatment of DLBCL, NOS.

Potential targeted therapies for:

The high frequency of aberrations of BCL2 and BCL6 make them suitable therapeutic targets for inhibitors in both subtypes (Pon et al. 2016, Pasqualucci et al. 2018). While inhibition of BCL6 is the subject of preclinical research (Cerchietti et al. 2009, Cerchietti et al. 2010), results of initial phase I studies on the BCL2 inhibitor venetoclax are already available for use in refractory/relapsed non-Hodgkin's lymphoma (NHL). The DLBCL group showed the lowest overall response within the NHL patient groups. This was the case with venetoclax monotherapy (overall response of 18% compared to 75% in patients with mantle cell lymphoma) (Davids et al. 2017) and also in combined administration with bendamustine and rituximab (de Vos et al. 2018). Here, the overall response of 41% was significantly higher than for monotherapy, but significantly lower than the overall response of 75% in patients with follicular lymphoma or 100% in patients with mantle cell lymphoma (6 of 6 patients) (de Vos et al. 2018). Both studies did not differentiate between COO subtypes (Davids et al. 2017, de Vos et al. 2018). Further phase I/II trials of venetoclax combination therapy in DLBCL are currently being conducted or planned.

Cases in which immune evasion occurs through expression of PD1 ligands may benefit from PD:PD-L immune checkpoint inhibitors (Pasqualucci et al. 2018). CD19 CAR-T cells also represent a therapeutic option and target both subtypes. Initial clinical trials showed partial or complete responses in 82% (63 of 77 DLBCL patients) (Neelapu et al. 2017) and 50% (7 of 14 patients, 6 of 7 patients thereby with complete response), respectively (Schuster et al. 2017).

In addition to its immunomodulatory properties, the drug lenalidomide indirectly causes a reduced expression of IRF4, a central factor of the NF-kB signalling pathway (Lu et al. 2014, Kronke et al. 2014). 19% (Wiernik et al. 2008) and 28% (Witzig et al. 2011) of patients with refractory or relapsed DLBCL responded to monotherapy. Interestingly, depending on the therapeutic context, different patient subgroups benefit. When lenalidomide was combined with the R-CHOP regimen in newly diagnosed DLBCL in a phase II trial, this mitigated the negative prognostic impact of the non-GCB subtype (Nowakowski et al. 2015). In contrast, a phase III trial of the use of lenalidomide as maintenance therapy after R-CHOP treatment showed the strongest effects compared to placebo control in patients with GCB-DLBCL (Thieblemont et al. 2017).

The dependence of the ABC subtype on a constitutively activated B-cell receptor signalling pathway opens up ABC-DLBCL specific therapeutic options. For example, the Bruton tyrosine kinase BTK is a key interface between the B-cell receptor signalling pathway and the downstream NF-kB signalling pathway. The BTK inhibitor ibrutinib, currently used to treat CLL, mantle cell lymphoma and Waldenström's disease, is being evaluated in this context. However, preliminary studies on the use of ibrutinib in DLBCL are contradictory. In ibrutinib monotherapy of refractory or relapsed DLBCL, 37% of ABC-DLBCL patients responded in a phase II trial, but only 5% of patients with GCB-DLBCL did - consistent with the underlying biological characteristics (Wilson et al. 2015). In previously untreated non-GCB-DLBCL or ABC-DLBCL, the combination of ibrutinib and R-CHOP did not confer an advantage in event-free survival over placebo control in the overall group. Only the under-65 subgroup benefited in overall, event-free and progression-free survival from R-CHOP + ibrutinib combination therapy (Younes et al. 2018). Resistance to ibrutinib through compensatory mechanisms or mutations downstream of BTK may be a reason for the conflicting observations (Herman 2018, Pon et al. 2016). Ideal therapeutic targets are factors upstream of BTK, including, for example, the tyrosine kinase Src, which is upstream of both the NF-kB and PI3K/AKT pathways (Herman 2018). Clinical trials on the use of bortezomib, a proteasome inhibitor, provided conflicting data (Dunleavy et al. 2009, Leonard et al. 2017).

Inhibitors of the PI3K and mTOR pathways are attractive therapeutic targets in GCB-DLBCL. Everolimus, an mTOR inhibitor, was evaluated in a phase II trial for refractory/relapsed DLBCL, with 38% of patients showing response (Barnes et al. 2013). In particular, cases with GCB-DLBCL may also benefit from epigenetic therapeutics (Pasqualucci et al. 2018).

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Characteristic	Frequency
Characteristic	ABC-DLBCL	GCB-DLBCL
Rearrangements
BCL2 e.g. t(14;18)(q32;q21.3)	< 5%	40%
BCL6	25-30%	15%
MYC, single hit - without further rearrangements of BCL2 and/or BCL6, many possible translocation partners, mostly IG loci	5-8%	5-8%
Ligands of PD1	very rare	very rare
CIITA	very rare	very rare
TBL1XR1	0%	5%
Copy-number aberrations
Gain / amplification
2p16 (REL)	rare	30%
3q27	45%	15-20%
9p24.1 (CD274/PDCD1LG2)	rare	rare
18q21.3 (BCL2)	55%	15%
Deletions
1p36.32 (TNFRSF14)	10%	30%
6q21 (PRDM1)	45%	25%
9p21 (CDKN2A)	40%	20%

Characteristic	Frequency
Characteristic	ABC-DLBCL	GCB-DLBCL
Epigenetic factors
EZH2	very rare	20-25%
KMT2D	35%	40%
CREBBP	10%	30%
B-cell-migration
GNA13	very rare	25%
Tumor suppressor
TP53	25%	20%
Immune evasion
B2M	15-20%	20-25%
CD58	10%	10%
Signal transduction
STAT6	very rare	5%
CARD11	10-15%	10-15%
CD79B	20-25%	rare
MYD88	35%	rare
SOCS1	rare	10-15%
SGK1	5-10%	15-20%
TNFRSF14	very rare	30%
Terminal differentiation
PRDM1	15%	very rare
Transcription factors
MEF2B	5%	15-20%
FOXO1	3%	7%