Other ways to intensify therapy in MCL involve adding a second non-cross-resistant cytarabine-containing regimen to R-CHOP after remission, such as DHAP (dexamethasone, high-dose cytarabine, cisplatin), followed by consolidation with an autoSCT. A retrospective registry from the National Comprehensive Cancer Network sought to compare the efficacy of different treatment approaches in the frontline setting. They studied 167 patients with MCL and compared 4 groups: treatment with R-hyper-CVAD, either with or without autoSCT, and treatment with R-CHOP, either with or without autoSCT. This study found that in patients younger than 65, R-CHOP followed by autoSCT or R-hyper-CVAD without autoSCT resulted in similar PF and OS, but was superior to R-CHOP alone for newly diagnosed MCL patients.35 These data support more intensive regimens in younger and fitter patients. Several other prospective and randomized studies have demonstrated clinical benefit for patients with MCL undergoing autoSCT in first remission. Of particular importance is the seminal phase 3 study of the European MCL Network, which established the role of autoSCT in this setting.61 In this prospective randomized trial involving 122 newly diagnosed MCL patients who responded to CHOP-like induction, patients in CR derived a greater benefit from autoSCT.
More recent studies have demonstrated similar benefits using cytarabine-based autoSCT. The Nordic MCL2 study evaluated 160 patients using R-CHOP, alternating with rituximab and high-dose cytarabine, followed by autoSCT. This study used “maxi-CHOP,” an augmented CHOP regimen (cyclophosphamide 1200 mg/m2, doxorubicin 75 mg/m2, but standard doses of vincristine [2 mg] and prednisone [100 mg days 1–5]), alternating with 4 infusions of cytarabine at 2 g/m2 and standard doses of rituximab (375 mg/m2). Patients then received conditioning with BEAM and autoSCT. Patients were evaluated for the presence of minimal residual disease (MRD) and for the t(11;14) or clonal immunoglobulin heavy chain gene rearrangement with polymerase chain reaction (PCR). Patients with MRD were offered therapy with rituximab at 375 mg/m2 weekly for 4 doses. This combination resulted in 10-year OS rates of 58%.36 In a multicenter study involving 78 patients from the Cancer and Leukemia Group B (CALGB), R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT resulted in a 5-year OS of 64%.37 A single-arm phase 2 study from the Netherlands also tested R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT. Nonhematologic toxicities were 22% after high-dose cytarabine, and 55% after BEAM. The ORR was 70%, with a 64% CR rate and 66% OS at 4 years.38 The French GELA group used 3 cycles of R-CHOP and 3 cycles of R-DHAP in a phase 2 study of young (under age 66) MCL patients. Following R-CHOP, the ORR was 93%, and following R-DHAP the ORR was 95%. Five-year OSA was 75%.39 A large randomized phase 3 study by Hermine and colleagues of the EMCLN confirmed the benefit of this approach in 497 patients with newly diagnosed MCL. R-CHOP for 6 cycles followed by autoSCT was compared to R-CHOP for 3 cycles alternating with R-DHAP for 3 cycles and autoSCT with a cytarabine-based conditioning regimen. The addition of cytarabine significantly increased rates of CR, TTF, and OS, without increasing toxicity.40
CASE CONTINUED
The patient is treated with R-CHOP chemotherapy for 3 cycles followed by R-DHAP. His course is complicated by mild tinnitus and acute kidney injury from cisplatin that promptly resolves. Three weeks following treatment, a restaging PET/CT scan shows resolution of all lymphadenopathy, with no hypermetabolic uptake, consistent with a complete remission. A repeat bone marrow biopsy shows no involvement with MCL. He subsequently undergoes an autoSCT, and restaging CT/PET 3 months following autoSCT shows continued remission. He is monitored every 3 to 6 months over the next several years.
He has a 4.5-year disease remission, after which he develops growing palpable lymphadenopathy on exam and progressive anemia and thrombocytopenia. A bone marrow biopsy is repeated, which shows recurrent MCL. Restaging diagnostic imaging with a CT scan reveals lymphadenopathy above and below the diaphragm. An axillary lymph node biopsy also demonstrates recurrent MCL. At this time the patient is otherwise in fairly good health, except for feeling fatigued. His ECOG performance status is 1. He begins therapy with bortezomib at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 for 6 cycles. His treatment course is complicated by painful sensory peripheral neuropathy of the bilateral lower extremities. Restaging studies at the completion of therapy demonstrate that he has achieved a partial response, with a 50% reduction in the size of involved lymphadenopathy and some residual areas of hypermetabolic uptake. His peripheral cytopenias improve moderately.