Between 30% and 40% of patients with advanced stage DLBCL will either fail to attain a remission with primary therapy (referred to as primary induction failure) or will relapse. In general, for those with progressive or relapsed disease, an updated tissue biopsy is recommended. This is especially true for patients who have had prior complete remission and have new lymph node enlargement, or those who have emergence of new sites of disease at the completion of first-line therapy.
Patients with relapsed disease are treated with systemic second-line platinum-based chemoimmunotherapy, with the usual goal of ultimately proceeding to auto-HCT. A number of platinum-based regimens have been used in this setting such as R-ICE, R-DHAP, R-GDP, R-Gem-Ox, and R-ESHAP. None of these regimens has been shown to be superior in terms of efficacy, and the choice of regimen is typically made based on the anticipated tolerance of the patient in light of comorbidities, laboratory studies, and physician preference. In the CORAL study, R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin) seemed to show superior PFS in patients with the GCB subtype.58 However, this was an unplanned subgroup analysis and R-DHAP was associated with higher renal toxicity.
Several studies have demonstrated that long-term PFS can be observed for relapsed/refractory DLBCL patients who respond to second-line therapy and then undergo high-dose therapy with auto-HCT. The Parma trial remains the only published prospective randomized trial performed in relapsed DLBCL comparing a transplant strategy to a non-transplant strategy. This study, performed in the pre-rituximab era, clearly showed a benefit in terms of DFS and OS in favor of auto-HCT versus salvage therapy alone.59 The benefit of auto-HCT in patients treated in the rituximab era, even in patients who experience early failure (within 1 year of diagnosis), was confirmed in a retrospective analysis by the Center for International Blood and Marrow Transplant Research. In this study, a 44% 3-year PFS was seen in the early failure cohort versus 52% in the late failure cohort.60
Some DLBCL patients are very unlikely to benefit from auto-HCT. The REFINE study focused on patients with primary induction failure or early relapse within 6 months of completing first-line therapy. Among such patients, primary progressive disease (defined as progression while still receiving first-line therapy), a high NCCN-IPI score at relapse, and MYC rearrangement were risk factors for poor PFS following auto-HCT.61 Patients with 2 or 3 high-risk features had a 2-year OS of 10.7% compared to 74.3% for those without any high-risk features.
Allogeneic HCT (allo-HCT) is a treatment option for relapsed/refractory DLBCL. This option is more commonly considered for patients in whom an autotransplant has failed to achieve durable remission. For properly selected patients in this setting, a long-term PFS in the 30% to 40% range can be attained.62 However, in practice, only about 20% of patients who fail auto-HCT end up undergoing allo-HCT due to rapid progression of disease, age, poor performance status, or lack of suitable donor. It has been proposed that in the coming years, allo-HCT will be utilized less commonly in this setting due to the advent of chimeric antigen receptor T-cell (CAR T) therapy.
CAR T-cell therapy genetically modifies the patient’s own T lymphocytes with a gene that encodes an antigen receptor to direct the T cells against lymphoma cells. Typically, the T cells are genetically modified and expanded in a production facility and then infused back into the patient. Axicabtagene ciloleucel is directed against the CD-19 receptor and has been approved by the US Food and Drug Administration (FDA) for treatment of patients with DLBCL who have failed 2 or more lines of systemic therapy. Use of CAR-T therapy in such patients was examined in a multicenter trial (ZUMA-1), which reported a 54% complete response rate and 52% OS rate at 18 months.63 CAR-T therapy is associated with serious side effects such as cytokine release syndrome, neurological toxicities, and prolonged cytopenias. While there are now some patients with ongoing remission 2 or more years after undergoing CAR-T therapy, it remains uncertain what proportion of patients have been truly cured with this modality. Nevertheless, this new treatment option remains a source of optimism for relapsed and refractory DLBCL patients.
Primary Mediastinal Large B-Cell Lymphoma
Primary mediastinal large B-cell lymphoma (PMBCL) is a form of DLBCL arising in the mediastinum from the thymic B cell. It is an uncommon entity and has clinical and pathologic features distinct from systemic DLBCL.64 PMBCL accounts for 2% of all NHLs and about 7% of all DLBCL.20 It typically affects women in the third to fourth decade of life.