Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, is considered incurable. It represents about 4% of lymphomas in the United States. The median age at time of disease presentation is about 60 years, and there is a disposition towards male predominance. The majority of patients present with advanced-stage disease involving the bone marrow and peripheral blood, as well as diffuse lymphadenopathy. Some patients also present with splenomegaly and extranodal disease such as lymphomatous polyposis of the large bowel. Lymphoma- associated inflammatory or B symptoms such as fever, chills, and night sweats are common. Diagnosis is based upon biopsy of a lymph node or bone marrow showing sheets of monomorphic, small to medium-sized lymphoid cells. There are four cytologic variants, including small cell, mantle zone, diffuse, and blastoid variant. The pathognomonic feature of MCL is overexpression of cyclin D1 due to chromosomal translocation t(11;14)(q13;q32), a phenomenon observed in over 95% of cases. This determination can be made by immunohistochemistry or fluorescence in situ hybridization analysis. In cases where cyclin D1 is not overexpressed, cyclin D2 and D3 overexpression can be found. The initial patient workup should include complete blood count (CBC); comprehensive chemistry profile; lactate dehydrogenase (LDH) levels; bone marrow biopsy; and a CT scan of the neck, chest, abdomen, and pelvis—or alternatively, 18-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT. Endoscopic evaluation of the gastrointestinal tract should be considered, especially if the patient presents with clinical symptoms or anemia.
A 54-year-old man presented to a primary care office with a lump on the right side of his neck. He reported that the lump had existed for 2 months, and said he had experienced fever, chills, and night sweats for the past month. Upon examination of the patient, the primary care physician found swollen right cervical lymph nodes, bilateral axillary lymphadenopathy, and enlarged right inguinal lymph nodes. Furthermore, the CBC showed an increased white blood cell (WBC) count, with lymphocytosis and several unclassified cells. Pathology results from a core needle biopsy of the patient’s right axillary lymph node showed the blastoid variant type of MCL. The patient was then referred to a hematologist, who performed an FDG-PET scan. The scan showed increased standardized uptake values, as well as discrete masses in the right cervical neck region, bilateral axillary lymphadenopathy, retroperitoneal lymphadenopathy, increased uptake in the spleen, and right inguinal lymphadenopathy. A bone marrow biopsy revealed MCL involvement. The peripheral blood was submitted to flow cytometry, and immunophenotyping showed a phenotype that was CD19- , CD20- , and CD51-positive and CD10- , CD23- , and BCL6-negative. This patient was diagnosed with stage IVB MCL.
Unlike other types of lymphomas, treatment of MCL is not usually defined by Ann Arbor staging, since the majority of patients present with advanced-stage disease. Typically, the treatment of newly diagnosed MCL can be tailored toward younger patients (or those < 65 years old who can tolerate intensive chemotherapy) and elderly patients (or those > 65 years old who are ineligible for high-dose therapy). Clinical and biologic prognostic factors should also be taken into consideration when deciding on the timing of therapy and which treatment regimen to use.
Mantle Cell International Prognostic Index (MIPI). The MIPI was formulated by the European Mantle Cell Lymphoma Network; it uses age, Eastern Cooperative Oncology Group performance status, LDH levels, and WBC count to stratify patients into three different risk groups. Low-risk patients tend to do well, with a median overall survival (OS) time after diagnosis not reached and a 5-year OS rate of 60%. Intermediate-risk patients have a median OS of 51 months, and high-risk patients have a median OS of 29 months. This index has been validated by other groups, and variations have been used in retrospective and prospective trials. Besides the MIPI, the biomarkers SOX11, Ki-67, p53, and p16 have also been shown to have prognostic value. SOX11 is a transcription factor, and its absence has been associated with an indolent form of MCL. High Ki-67 proliferation and deletion of p53 and p16 have been shown to be associated with blastoid variant MCL, which has a worse OS outcome. Gene expression profiling (GEP) has identified preliminary molecular predictors. A recent study identified RAN, MYC, TNFRSF10B, POLE2, and SLC29A2 as predictors of survival in a small series of patients with MCL. Patients with increased expression of all five genes had inferior survival. Since GEP is not practical to perform on a large scale, this method needs to be explored further before it can be applied in clinical management. Although the genetic hallmark of MCL is cyclin D1 overexpression due to t(11;14) translocation, differential overexpression of cyclin D1 can be seen in various patient samples. Wiestner et al identified patients with a truncated cyclin D1 3' untranslated region as having inferior outcomes. This can be due to altered miR-16-1 regulation, as shown by Chen et al.
For younger, fit patients with MCL, the therapeutic strategy has been to use aggressive induction chemotherapy followed by autologous stem cell transplantation (ASCT). The benefit of consolidative ASCT has been shown by the European Mantle Cell Lymphoma Network. Their trial compared consolidative ASCT against maintenance treatment with interferon, and showed improved progression-free survival (PFS) in the ASCT arm (median PFS, 39 vs 17 months; P = .0108). Although the role of ASCT in younger patients with MCL is clear, the optimal induction chemotherapy has not been defined. Romaguera et al reported outcomes of the rituximab (R)-hyperCVAD regimen at the University of Texas MD Anderson Cancer Center. This multi-agent regimen contains hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose cytarabine and methotrexate for 6 to 8 cycles. The complete response (CR) rate was 87% and the overall response rate (ORR) was 97%, with a 3-year failure-free survival rate of 64% and OS rate of 82%. However, the results were not quite as favorable when tested in a multicenter setting, with a reported ORR of 86%, a CR rate of 55%, and an estimated 3-year PFS rate of 66%. In addition, 90% of the patients had grade 4 hematologic toxicities, and only 61% of the patients could finish the full course of treatment. Other alternatives to R-hyperCVAD include the Nordic regimen (R-Maxi-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] alternating with high-dose cytarabine without methotrexate). Geisler et al showed that this induction followed by ASCT yielded a 6-year PFS rate of 66% and OS rate of 70%. Delarue et al developed a regimen comprising 3 cycles of R-CHOP followed by 3 cycles of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by ASCT. The reported results are quite promising, with a CR rate of 57%, ORR of 93%, and 5-year OS rate of 75%. A recent Southwest Oncology Group (SWOG)-led US Intergroup trial compared R-bendamustine (RB) followed by ASCT vs R-hyperCVAD followed by ASCT in younger patients with untreated MCL. The results were reported in June 2015 at the 13th International Conference on Malignant Lymphoma in Lugano, Switzerland and updated at the 2015 American Society of Hematology (ASH) Annual Meeting. It was shown that, although treatment with RB vs R-hyperCVAD was associated with similar ORR, CR, 2-year PFS, and OS rates, patients who received R-hyperCVAD had significantly more instances of myelosuppression, including anemia (59% vs 9% with RB), neutropenia (65% vs 34%, respectively), and thrombocytopenia (71% vs 17%, respectively). R-hyperCVAD also resulted in more stem cell collection failures (29% vs 6%), and its use led to premature closure of the study. At this time, there are no clear data to show which induction regimen should be the standard of care in younger patients with MCL. However, the most appropriate strategy may be to choose the regimen associated with a high CR rate while sparing patients from treatment toxicity so that they can reach eligibility for ASCT.
Regarding older patients who cannot tolerate intensive chemotherapy or ASCT, there are a number of options. Historically, R-CHOP chemotherapy was used, with an ORR of 96%, a CR rate of 48%, and a PFS duration of about 17 months. R-CHOP has also been shown to be superior to R-FC (fludarabine and cyclophosphamide) by a group in Germany. In that study, the 4-year OS rate was 65% for R-CHOP vs 50% for R-FC. A recent study comparing R-CHOP vs VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) showed a 59% improvement in PFS, in favor of VR-CAP, and the median OS rate was not reached vs 56.3% with R-CHOP. Another option besides R-CHOP–based therapy is the use of bendamustine. Rummel et al studied the combination of RB in patients with untreated MCL, reporting an ORR of 75% and a CR rate of 50%, with minor hematologic toxicities. This regimen was then compared against R-CHOP in a large randomized noninferiority trial in Europe, which showed ORRs similar to those achieved with R-CHOP (93% vs 91%), as well as comparable CR rates (40% vs 30%); however, patients treated with RB had improved median PFS (70 vs 31 months), fewer hematologic toxicities (30% vs 68%), and fewer infections (37% vs 50%). Because of recent studies, many physicians are opting to use RB or VR-CAP rather than R-CHOP. Since elderly patients are not eligible to undergo ASCT, the role of maintenance therapy has been evaluated post induction. The study from Germany that compared R-CHOP vs R-FC also evaluated the role of maintenance rituximab vs interferon. The researchers found that the study arm with the best PFS and OS was R-CHOP followed by maintenance rituximab, with a 4-year OS rate of 87%. The role of maintenance rituximab has been confirmed further by meta-analysis of three large randomized trials showing an improvement in PFS with rituximab (hazard ratio [HR], 0.60 [95% CI, 0.44–0.82]). Although no studies have evaluated the role of maintenance rituximab post RB or VR-CAP, most physicians would administer maintenance therapy to patients regardless of the type of induction regimen used.
Besides combination chemotherapy induction regimens, another option exists for elderly patients who may choose not to undergo multi-agent chemotherapy. Ruan et al studied lenalidomide plus rituximab as initial treatment for MCL. This single-arm multicenter trial showed an ORR of 92%, a CR rate of 64%, and a 2-year PFS rate of 85%. Patients were treated with this regimen for at least 36 cycles or until disease progression. Although this was not a randomized trial comparing lenalidomide plus rituximab vs multi-agent chemotherapy, the ORR and PFS are certainly on par with historical controls. Table 1 shows a list of induction regimens discussed.
A small number of patients with MCL have indolent disease. Martin et al evaluated the watch-and-wait approach (similar to that followed in the management of patients with follicular lymphoma) for patients with asymptomatic disease or those who have low MIPI, or for elderly patients with MCL. The results show that the median time to treatment was about 12 months (range, 4–128 months), and the survival profile of the observation group appeared improved compared with that of the early treatment group. The majority of patients received an R-CHOP–like treatment at the time induction therapy was given. This outcome suggests that the watch-and-wait approach may be appropriate for a subset of patients with very indolent disease.
The patient in our initial case presentation received 6 cycles of RB followed by ASCT. He also enrolled on our trial using rituximab plus bortezomib as maintenance therapy post ASCT. He is currently doing well and still in remission.
Before the recent advances in novel therapeutics, patients with relapsed MCL were treated with multi-agent salvage chemotherapy, much like the treatment of diffuse large B-cell lymphoma (DLBCL), with regimens such as RICE (rituximab, ifosfamide, carboplatin, and etoposide), R-ESHAP (rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), R-DHAP, or gemcitabine-based strategies. RB has been used in the setting of relapsed disease and has been combined with cytarabine (R-BAC). The ORR of these agents appears to be high, at 80% to 90%, with a CR rate of 60% to 70%.[27,28] However, adverse events are common, including cytopenias.
A variety of novel therapies have been tested in recent years and have shown efficacy in relapsed MCL. Bortezomib, a proteasome inhibitor, has demonstrated an ORR of 33% and a CR rate of 8% in this setting, with the most common grade 3 or higher toxicity being peripheral sensory neuropathy in 13% of the patients. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, yielded an ORR of 41% and a CR rate of 4% in a phase II study of patients with relapsed/refractory MCL. Patients treated with the immunomodulatory agent lenalidomide were shown in a phase II trial to have an ORR of 35%, a CR rate of 12%, and median PFS of 9 months. Wang et al combined lenalidomide with rituximab in the setting of relapsed MCL and found that the regimen yielded an ORR of 58% and a CR rate of 33%. Perhaps the most exciting agent to gain approval from the US Food and Drug Administration in this setting is the Bruton tyrosine kinase inhibitor ibrutinib. It was shown to achieve a 68% ORR and a 21% CR rate in patients with relapsed/refractory MCL. These study results are similar to outcomes reported for patients with MCL who have received prior bortezomib vs those who have not, indicating that ibrutinib achieves a response in bortezomib-resistant patients. The median duration of response was 17.5 months, the 2-year PFS rate was 31%, and the 2-year OS rate was 47%. Overall, ibrutinib was well-tolerated; 16% of patients had grade 3/4 hematologic toxicities and 44% had grade 1/2 diarrhea. Although the approval of ibrutinib has benefited many patients with MCL, it has become clear with long-term follow-up that these patients can still experience disease progression while on treatment. The median PFS is 13 months.
Phosphoinositide 3 (PI3)-kinase inhibitors represent another class of drugs that have been investigated in relapsed/refractory MCL. In a phase I study, idelalisib, which like ibrutinib targets the B-cell receptor pathway, generated a 40% ORR, a CR rate of 5%, and a 3-month median duration of response. At the 2015 ASH Annual Meeting, results were presented from a phase I study of venetoclax, a drug that has generated some excitement in this setting. Gerecitano et al evaluated venetoclax, a B-cell lymphoma 2 inhibitor, in patients with relapsed/refractory MCL, follicular lymphoma, chronic lymphocytic leukemia, and DLBCL. Patients with relapsed/refractory MCL appeared to have the most favorable ORR at 75%, with a CR rate of 21%. We anxiously await the completion of that trial and the phase II trial in patients with MCL. At City of Hope, we will evaluate the combination of ibrutinib and venetoclax in patients with relapsed/refractory disease. Table 2 shows a list of novel therapeutics used in relapsed/refractory MCL.
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