Mantle-Cell Lymphoma C83.1

Mantle cell lymphoma is classified as indolent (cytic) B-cell lymphoma, but shows a heterogeneous, in some patients aggressive course. Pathognomonic is the chromosomal translocation t(11;14) with consecutive overexpression of cyclin-D1 (via bcl-1). The tumor cells show a co-expression of B-cell markers and CD5, but in contrast to CLL no CD23. The vast majority of patients is diagnosed in already advanced stages.

The staging is stage I to IV according to the Ann Arbor/Lugano classification of NHL. However, due to frequent KM involvement, an advanced stage is present in most cases.

• I: Involvement of a single lymph node region or presence of a single or localized extranodal focus.
• II: Involvement of two or more lymph node regions on one side of the diaphragm or presence of localized extranodal foci and involvement of one or more lymph node regions on one side of the diaphragm.
• III: involvement of two or more lymph node regions on both sides of the diaphragm or involvement of localized extranodal foci and lymph node involvement such that there is involvement on both sides of the diaphragm
• IV: disseminated involvement of one or more extralymphoid organs with or without involvement of lymph nodes.

The stages are given the suffix "A" in the absence, "B" in the presence of:

• unexplained fever >38°C
• unexplained night sweats (with change of clothes)
• unexplained weight loss (> 10% of body weight within 6 months)

5 to 7% of malignant lymphomas in Europe are classified as mantle cell lymphomas. The incidence is 2/100,000/year. m:w=4:1

Pathognomonic for mantle cell lymphoma is a chromosomal translocation between the immunoglobulin heavy chain gene on chromosome 14 and the cyclin D1 gene on chromosome 11. The translocation t(11;14)(q13;q32), which is found in approximately 95% of all cases, leads to aberrant overexpression of cyclin D1 and cell cycle activation. Additional genetic aberrations influence the clinical picture, with p53 mutations and deletions playing a central role.

The median age of onset is 65 years.

The clinical picture is heterogeneous, usually the disease is already in an advanced stage at first diagnosis. In the so-called leukemic, non-nodal, rather indolent (SOX11-negative) mantle cell lymphoma, the leukemic disease with splenomegaly is in the foreground. In the classic form, lymph node enlargement is common, splenomegaly and lymphocytosis also occur. Bone marrow infiltration is present in approximately 80-90%, with leukemic washout in 20-30% of cases. Extranodal manifestations (e.g. intestinal involvement, skin involvement) are more common than in other indolent lymphomas (Dreyling M et al. (2017).

The diagnosis is based on the histological examination of the affected lymph node. In the characteristic cytological picture, the cell nucleus is irregular and has a notch, the chromatin is dense, and the cytoplasm is narrow. In addition, there is a whole spectrum of variants in which the lymphoma cells appear more lymphocytic (as in CLL), pleomorphic or blastic. Immunohistochemical evidence of cyclin D1 overexpression or t(11;14) in fluorescence in situ hybridization (FISH) is obligatory to differentiate from other lymphoma subtypes. Ki67 should be determined obligatory, additionally at least p53 immunohistochemistry is recommended.

Since the therapy of mantle cell lymphoma depends on the stage of spread, a detailed diagnosis before starting therapy is essential (staging). This includes (initial examination):

• Anamnesis, especially of B-symptoms
• Physical examination
• Blood count: cell count, differential blood count
• Blood chemistry: LDH, β²-microglobulin, immunoglobulins quantitative, in case of suspicion of a monoclonal immunoglobulin: immunofixation, hepatitis-, HIV-serology
• Surface marker by FACS analysis (only in case of leukemic course)
• Bone marrow cytology, bone marrow histology
• Imaging:
• CT neck/thorax/abdomen
• (alternatively: sonography for follow-up)
• The performance of 18F-FDG positron emission tomography (PET-CT) is recommended in case of planned local radiotherapy in early stages due to the therapeutic consequences. Depending on the planned therapy, examinations of the lung function (high-dose consolidation) and the heart (CHOP, ibrutinib) are obligatory before the start of therapy.

The therapy of mantle cell lymphoma is usually carried out in therapy centers within the framework of studies.

The therapeutic goal for these patients is to achieve a long-term remission with prolonged survival. The therapy is mainly based on the general condition. Younger patients are treated with aggressive, cytarabine-containing chemotherapy followed by autologous stem cell transplantation with rituximab maintenance; in older patients, immunochemotherapy followed by rituximab maintenance therapy is recommended.

In disease relapse, an individualized assessment of appropriate therapy is made, taking into account clinical and biological factors and disease progression (POD 24). Options include renewed immunochemotherapy, targeted therapies, transplantation procedures and, currently, additionally CAR T-cell therapy. In early relapse (within the first 24 months after completion of first-line therapy, POD 24), targeted substances (BTK inhibitors) have been shown to be superior to conventional therapies.

Patients with mantle cell lymphoma should be treated in the setting of clinical trials whenever possible.

First-line therapy: For the minority of patients diagnosed in limited stage I-II with low tumor burden, shortened immunochemotherapy with consolidating radiotherapy or radiotherapy alone can be discussed. Patients in stage I-II with high tumor burden should be treated as patients in advanced stages.

In younger patients (≤65 years), a dose-intensified approach (induction plus high-dose consolidation with autologous stem cell transplantation) is the standard therapy because of significantly prolonged progression-free and overall survival (Dreyling M et al 2005). Cytarabine-containing induction therapy additionally leads to significantly prolonged progression-free survival [10]. Maintenance therapy with rituximab for 3 years prolongs progression-free and overall survival after autologous stem cell transplantation (Le Gouill S et al (2018).

In older patients, possible combination regimens include VR-CAP, R-bendamustine, or R-CHOP. However, due to the more aggressive disease course, the majority of patients relapse within a few years if maintenance therapy is not planned. Administration of bortezomib instead of vincristine (VR-CAP) results in prolonged progression-free and overall survival (Robak T et al 2018).

Note: In indolent clinical course with low tumor burden, leukemic presentation without nodal involvement) or biological markers (Ki67 <10%), a close-meshed "watch & wait" strategy can be followed initially and therapy initiated only in case of progression.

Recurrence: Especially in early recurrences, ibrutinib seems to be superior to re-chemotherapy. In relapses after a BTK inhibitor, an aggressive course is often observed. The recently approved CAR T-cell therapy achieves long-lasting remissions in this patient population. In older patients, venetoclax (which is not approved for MCL) can achieve remission in up to half of patients (Wang M et al 2020), but the duration of response is limited.

Prognosis can be estimated using the clinical MCL International Prognostic Index (MIPI) or established biological factors (blastic variant, Ki-67, p53 alteration(mutations in PCR or NGS, overexpression in immunohistochemistry). The MIPI-c merges the clinical prognosis estimation with the biological marker Ki-67, and allows a more sophisticated risk estimation. The median survival for all patients is about 5 years, with significant differences in the different risk groups. So-called blastoid mantle cell lymphoma has a poor prognosis (Jain P et al 2020).

Risk groups: The established clinical risk score (MIPI: MCL International Prognostic Index) includes the general condition and age of the patient as well as LDH and leukocyte levels (Hoster E et al. 2008). In addition, the proliferation marker Ki-67 (>30%) and the presence of p53 alterations (mutations or overexpression in immunohistochemistry; the significance of a deletion 17p has not yet been sufficiently clarified) have a high prognostic relevance for an unfavorable course (Aukema SM et al. 2018; Hoster E et al. 2016).

1. Aukema SM et al. (2018) Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network. Blood 131:417-420.
2. Dreyling M et al. (2005) Early consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 105:2677-2684.
3. Dreyling M et al. (2017) ESMO Guidelines Working Group. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28 Suppl 4:iv62-iv71.
4. Hoster E et al. (2008) A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111:558-565
5. Hoster E et al. (2016) Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma. J Clin Oncol 34:1386-1389.
6. Hermine OE et al. (2016) Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 388:565-575.
7. Jain P et al (2020) Blastoid Mantle Cell Lymphoma. Hematol Oncol Clin North Am 34:941-956.
8. Kim DH et al (2019) Mantle cell lymphoma involving skin: A clinicopathologic study of 37 cases. Am J Surg Pathol 43:1421-142
9. Le Gouill S et al (2018) Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 377:1250-1260
10. Robak T et al. (2018) Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study... Lancet Oncol 19:1449-1458.
11. Wang M et al (2020) KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma. N Engl J Med 382:1331-1342.