Pocket Oncology (Pocket Notebook Series), 1st Ed.

MANTLE CELL LYMPHOMA

Zachary H. Word and Andrew D. Zelenetz

Epidemiology

• Represents ∼6% of lymphomas

• ↑ Incidence w/↑ age, male sex (∼3:1 ratio), Caucasian race

Biology/Pathology

• Derived from a mature, naïve, or postgerminal center B-cell. MCL most often presents histologically as an infiltrate of small lymphocytes w/notched nuclei

• Several histologic variants include the blastoid & pleomorphic variants w/c have a poor prognosis & small cell variant w/c is morphologically similar to CLL/SLL

• Typically expresses B-cell Ags (CD-19 & CD-20) & the T-cell Ag CD-5 (aberrant expression, also seen in CLL/SLL), but not CD-10 or CD-23 w/c are more typical of FL & CLL/SLL respectively

• The hallmark cytogenetic abnormality is the t(11;14)(q13;q32). It juxtaposes the Cyclin D1 gene (CCDN1) w/the Ig heavy chain locus

• A large majority of cases have evidence of the t(11;14) by FISH, karyotype, or IHC (=BCL-1 stain)

• Rare CCND1(-) cases have Cyclin D2 or D3 lesions. Difficult to diagnose; must be distinguished from CD23(-) CLL

• Clinical behavior is intermediate between indolent & aggressive lymphomas

• Proliferative index measured by Ki-67 is the most powerful individual prognostic factor in MCL (<30% vs. ≥30%) (Ann Oncol 2010;21:133)

Staging

• Ann Arbor Staging w/Cotswolds modifications (J Clin Oncol 1989;7:1630)

WorkUp

• Incisional or excisional bx preferred for initial dx, as w/other lymphomas

• Cross-sectional imaging w/CT of chest/abdomen/pelvis and/or PET. PEx to evaluate peripheral nodal areas

• Marrow involvement ± leukemic phase are common. BM bx should be included in initial staging

• GI tract commonly involved. Panendoscopy will better define extent of disease but may be deferred in asx pts

• LP to evaluate for CNS involvement in pts w/blastic morphology or CNS sx

Treatment-Localized Disease

• Localized MCL is rare (<5%). Endoscopic evaluation of GI tract (EGD & colonoscopy w/blind biopsies) bilateral BM bx (or single bx ≥2 cm) & PET are indicated to r/o more adv stage

• Management of truly localized cases is controversial; the most typical approaches are IFRT alone or combined modality Rx: 4–6 cycles of combination chemotherapy (eg, R-CHOP) w/IFRT

• Localized Rx alone preserves future tx options

Treatment: Asymptomatic Patients

• Observation appears to be safe in selected pts (J Clin Oncol 2009;27:1209)

• Most observed pts will require Rx w/in 9 mos, but ∼15% may have a prolonged indolent course

• Low proliferative index by Ki-67 staining (<10%), & absence of SOX11 have been suggested as markers of an indolent course but require validation

Initial Treatment: Transplant Eligible Patients

• No generally accepted standard of care; clinical trial enrollment encouraged

• In pts who require Rx & can tolerate it, an upfront autologous transplant approach is favored by most groups based on results of prospective randomized trials. Various protocols exist, w/similar structure:

Figure 23-1 Treatment Paradigm for Mantle Cell Lymphoma

• The A & B chemotherapy regimens are each given for several cycles, w/alternating (eg, R-Hyper-CVAD (J Clin Oncol 2005;23:7013) & Nordic MCL-2 (Blood 2008 112:2687)) or sequential (eg, R-CHOP → R-ICE (Ann Oncol2010;21:133)) schedules in various regimens

• Chemotherapy A is usu an R-CHOP-like regimen

• Inclusion of high-dose cytarabine (alone or in combination) as part of chemotherapy has been shown to improve outcomes

• Rituximab is typically included in both chemotherapy A & B

Initial Treatment: Transplant Ineligible Patients

• No generally accepted standard of care; clinical trial enrollment encouraged

• Pts will have a multiply relapsing course

• Multiple active regimens include rituximab in combination w/CHOP, bendamustine, CVP, EPOCH, & Cladribine

• C/w R-CHOP, R-Bendamustine confers longer PFS w/less tox (ASH Annual Meeting 2009;Abstract 405 & ASH Annual Meeting 2012;Abstract 902)

• Maintenance rituximab improves OS after response to R-CHOP but not R-FC (NEJM 2012;367:520). Thus, cannot be extrapolated to all regimens

Relapsed disease

• No generally accepted standard of care; clinical trial enrollment encouraged

• The above described initial Rx regimens are typically also active in the relapsed setting if not already used. Other cytotoxic regimens, including fludarabine-based combinations are also active

• Bortezomib has been approved for salvage Rx based on a single agent ORR of 33% w/8% CRs (J Clin Oncol 2006;24:4867). It is being combined w/other agents in various ongoing studies

• Lenalidomide (± rituximab) is active in several lymphoid malignancies including relapsed MCL (ASH Annual Meeting 2012;Abstract 905)

• Long-term disease control can be achieved w/allogeneic SCT. Compared to autologous SCT, allo SCT is a/w increased tox, but improved disease control

Prognosis

• Classically considered incurable w/standard therapies, though long-term remissions have been reported w/upfront transplant approaches

• Median survival typically reported at 4–5 y. Longer OS w/various tx approaches in several recent trials

• Outcomes in relapsed/refractory pts remain poor due to the development of chemoresistant disease

• The MIPI has been shown to predict outcome more accurately than the standard IPI (Blood 2008;111:558). MIPI RFs are age, ECOG PS, LDH, & WBC. “Combined” version also considers proliferative index. Calculation typically requires an electronic calculator