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In general, MCL is still considered incurable and most patients follow an aggressive clinical course. However, 10 to 15 percent of patients may exhibit a more indolent evolution and may not require therapy for several years. These cases are commonly characterized by a nonnodal leukemic presentation with only marrow involvement and splenomegaly.4 Sox-11 negativity may also identify some of these more indolent cases, although its role is controversial, as additional p53 mutations may cause an aggressive clinical evolution (see Fig. 100–1).25 Thus, the reliable diagnosis of indolent cases is difficult, and a short, watchful, waiting period under close observation seems to be appropriate in cases with low tumor burden.26
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Localized disease with low tumor burden is rare. A small retrospective review has suggested long-term remissions after involved-field radiotherapy (30 to 36 Gray).27 In contrast, in a randomized trial all patients relapsed within a year.28 Thus, a shortened chemotherapy induction followed by radiation consolidation seems to be most appropriate.
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Conventional Chemotherapy
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Because of the typical aggressive clinical presentation, anthracycline-containing chemotherapy has usually been applied to MCL in the past, although a small randomized trial did not confirm a major clinical benefit.29 Complete remission rates are only 30 to 40 percent with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), typically with a short duration of response of 10 to 12 months.30,31
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Combined Immunochemotherapy
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Rituximab monotherapy achieves low response rates of approximately 25 percent, and should be used only in medically unfit patients who are not able to tolerate cytotoxic therapy (Fig. 100–3).32 On the other hand, addition of rituximab to chemotherapy has been shown to significantly improve complete response rates, overall response rates, and overall survival in a systematic meta-analysis, making immunochemotherapy the standard of care, both in first-line and relapsed settings for patients with advanced stage MCL (Table 100–2).33–43 In patients with an overt leukemic phase and high lymphocyte counts of greater than 50 × 109/L, the first dose of rituximab should be delivered with caution because of the risk of tumor lysis syndrome or cytokine-release syndrome.
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In a randomized trial, rituximab with CHOP considerably improved response rates (94 percent vs. 75 percent), and time to treatment failure in comparison to CHOP chemotherapy alone.34 In contrast, rituximab with cyclophosphamide, vincristine, and prednisone (R-CVP) resulted in significantly inferior response rates and progression-free survival (PFS), and cannot be recommended in patients with MCL.44 Similarly, fludarabine combinations result in prolonged cytopenias, and resulted in overall survival rates significantly inferior (46 percent vs. 62 percent at 4 years) to those achieved with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in a large prospective European trial.39 In contrast, a bendamustine-based combination resulted in similar response rates (93 percent vs. 91 percent) and PFS in two randomized trials, but a more favorable toxicity profile, particularly with regard to alopecia and peripheral neuropathy, making the bendamustine and rituximab (BR) regimen the most commonly administered regimen currently, especially in elderly patients.41,44 Finally, an intensified approach combining bendamustine with cytarabine resulted in impressive response rates (100 percent), but significant thrombocytopenia, suggesting that this regimen should be used only in young, fit patients.42
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In conclusion, BR and R-CHOP represent the current standard approaches in older patients who represent the majority of MCL patients (see Fig. 100–3). Based on clinical presentation, BR may be preferable, especially in patients with CLL-like presentation, whereas CHOP seems to be appropriate in the more-aggressive cases with elevated LDH. Especially in blastoid variants, one might consider cytarabine-containing regimens based on the improved results in younger patients.45 However, such an individualized approach has never been tested in a prospective fashion.
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Maintenance/Consolidation
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The concept of regular rituximab maintenance, previously established in follicular lymphoma, has also been investigated in MCL.39 After conventional R-CHOP induction, continuous antibody maintenance results in an impressive prolongation of both PFS (58 percent vs. 29 percent at 4 years) and overall survival (79 percent vs. 67 percent at 4 years) so that rituximab maintenance is now generally recommended.
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Alternatively, radioimmunotherapy consolidation has been tested after a shortened R-CHOP induction. Again, survival rates seem to be prolonged with a median time to treatment failure of 31 months, but results seem to be inferior to ongoing rituximab maintenance, possibly because of the single-application scheme used with radioimmunotherapy.40
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Intensive Chemotherapy with and without Stem Cell Transplantation
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In several studies, either intensified upfront therapy or the addition of high-dose consolidation followed by autologous stem cell transplantation (ASCT) resulted in impressive survival rates (Table 100–3).45–56 A randomized trial has proven that ASCT prolongs PFS in comparison to CHOP-like induction therapy alone (3.3 vs. 1.4 years).46 In a subsequent meta-analysis, overall survival was also significantly prolonged by ASCT, independent of the addition of rituximab.57 “In vivo purging” with a rituximab-containing induction regimen was shown to further improve long-term survival. Various studies have investigated the potential benefit of cytarabine-containing induction regimens (Table 100–3). Most importantly, a randomized trial demonstrated that the median PFS was almost doubled by the administration of the R-CHOP/DHAP (dexamethasone, high-dose cytarabine, and cisplatinum) regimen (7.6 vs. 3.8 years) compared to administration of R-CHOP alone prior to ASCT.45 In contrast, a phase II study suggested that high-dose methotrexate (MTX) adds significant organ toxicity, but similar long term remissions could be also achieved with considerably reduced doses.47
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A study-to-study comparison suggests a benefit of a total-body irradiation (TBI)–containing high-dose consolidation in patients with only partial remission after induction, whereas such benefit was not observed for the addition of conventionally dosed radioimmunotherapy.58,59 An interim analysis has suggested a benefit from subsequent rituximab maintenance, but further followup is necessary to confirm the superiority of this approach.53
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Alternatively, upfront dose intensification may be applied. The rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) regimen has achieved high complete response rates and long-term remissions in various trials.54,55,56 However, this regimen is hampered by significant therapy-associated toxicity, including secondary malignancies, and should only be considered in young, fit patients.
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RECURRENT AND REFRACTORY DISEASE
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The inherent resistance of MCL to conventional doses of chemotherapy becomes especially apparent in relapsed disease. Conventional immunochemotherapy options, some of them highly effective in first line treatment, achieve only short term remissions in relapsed disease. (Table 100–4).42,60,61,62,63,64 Thus, consolidation with ASCT deserves consideration if not already employed in the frontline setting. Unfortunately, long-term results of this approach in recurrent/refractory MCL are rather sobering.
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In younger patients responding to salvage therapy, it is recommended to discuss the option of potentially curative allogeneic transplantation, based on the observed graft-versus-lymphoma activity in MCL. Reduced intensity conditioning may be applicable also in patients older than age 60 years, but is hampered by delayed toxicities, including chronic graft-versus-host disease and 20 to 25 percent treatment-related mortality.65,66,67,68
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In elderly patients, one might consider rituximab maintenance if not administered previously. Alternatively, radioimmunotherapy consolidation has achieved long-term remissions in some patients, although efficacy as a single approach is limited with a median time to progression of only 5 months.69,70
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Chemotherapy alone has only short-term activity in relapsed disease, and therefore a number of targeted approaches have been investigated, especially in relapsed MCL, both as single agents and in combination with chemotherapy (see Tables 100–4 and 100–5).71–97
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Proteasome Inhibitors Bortezomib, a first-generation proteosome inhibitor, is thought to exert its effect in part through alterations in the nuclear factor-κB (NF-κB). In relapsed disease, this single agent has shown response rates of 30 to 40 percent with a median PFS of approximately 6 months, which led to the first Federal Drug Administration approval of a targeted drug in relapsed MCL.71,72,73 In subsequent trials, bortezomib was evaluated in combination with different chemotherapy regimens to further improve remission rates and avoid cumulative side effects (see Table 100–4).88,89,90,91,92,93 Based on the encouraging data, a first-line trial has been completed. Substituting bortezomib for vincristine (within R-CHOP) led to an almost doubling of PFS.98 In such a combined approach, bortezomib should be administered on only days 1 and 4 of each cycle to avoid cumulative thrombocytopenia.
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Immunomodulatory Drugs Based on its oral formulation and its favorable tolerability, lenalidomide represents an attractive option, especially in the context of continuous treatment. After long-term efficacy was observed in multiple myeloma, various studies confirmed its benefit in relapsed MCL as well, with a response rate of 35 to 50 percent.75,76,77,78 In a randomized phase II trial, this approach was superior to monochemotherapy (response rate 40 percent vs. 11 percent).78 Other studies have investigated combining lenalidomide with chemotherapy.94
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Mammalian Target of Rapamycin Inhibitors Temsirolimus has been registered by the European Union based on a randomized phase III trial proving its superiority compared to monochemotherapy in a highly refractory patient population (response rate, 22 percent vs. 2 percent).81 Combining temsirolimus with chemotherapy resulted in objective responses in all evaluable patients in a phase I trial.96
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B-Cell Receptor Pathway Small molecules targeting the B-cell receptor have achieved remarkable response rates in relapsed MCL. The Bruton tyrosine kinase (BTK)-inhibitor, ibrutinib, exhibited a response rate of 68 percent in relapsed disesase.84 Combination with rituximab led to a response in all cases with low Ki-67, whereas in highly proliferating disease, this approach was only effective in half of the patients.85 The compound is very well tolerated with only slight immunosuppression, bleeding, and atrial fibrillation being the predominant side effects. However, early relapses with a highly aggressive course have been observed. Combinations of ibrutinib with chemotherapy are being tested in the frontline setting.
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Idelalisib achieves similar high response rates of 62 percent in MCL, although many of the remissions are short-lived.86