Brentuximab vedotin is an anti-CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkin’s lymphoma.

We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II–deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I– and MHC-II–negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. Significance: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin–specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination. See related commentary by Velcheti et al., p. 472. This article is highlighted in the In This Issue feature, p. 453

Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Presently Hodgkin's lymphoma can be cured in at least 80% of patients. The major challenge to the clinician in 2005 is how to cure the disease while inducing the least irreversible toxicity. This review focuses on clinical trials and institutional experiences to identify the best choice of treatment, individualized to the stage of the lymphoma permitting minimization of late toxicity such as infertility, premature menopause, cardiac disease, and most importantly, risk of second neoplasms. More than 90% of patients with limited Hodgkin's lymphoma can be cured with either short-course chemotherapy alone or even briefer chemotherapy followed by involved-field radiation. Accumulating evidence suggests that chemotherapy alone is suitable for the large majority of patients with limited disease. For the 80% of patients with advanced disease but without a large number of adverse prognostic factors, standard multi-agent chemotherapy with the well-established ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) provides the best balance of effectiveness and minimization of toxicity. More intensified regimens currently under investigation are appropriate for the 20% with numerous adverse prognostic factors. In 2005 it is insufficient to focus solely on cure of Hodgkin's lymphoma. The treatment program must maximize chance of cure and minimize late toxicity. Fortunately, brief chemotherapy alone or with radiation for patients with limited disease and standard ABVD chemotherapy for patients with advanced disease offer the appropriate balance of these two requirements. Patients with advanced disease plus multiple indicators of a poor prognosis and patients with disease that persists despite optimized primary treatment require specially intensified treatment.

Background: Primary bone lymphoma (PBL) is a distinct clinicopathological entity. Although PBL has been reviewed in several small studies, few reflect recent improvements in primary treatment. Methods: We used the British Columbia Cancer Agency Lymphoid Cancer Database to identify all patients with PBL (1983–2005). All were staged in a uniform manner and treated with era-specific protocols. Results: We identified 131 patients with a median age of 63 years (18–87). One third had disease in long bones and another one third had disease in the spine, of which half presented with spinal cord compression. Patients with diffuse large-cell lymphoma (DLCL) (n = 103, 79%) had 5- and 10-year overall survivals (OS) of 62% and 41%, respectively. Multivariate analysis identified three prognostic groups: age <60 with International Prognostic Index (IPI) 1–3 (n = 43), age ≥60 with IPI 0–3 (n = 23) and age ≥60 with IPI 4–5 (n = 33), with markedly different 5-year OS of 90%, 61% and 25%, respectively (P < 0.0001). Neither primary site nor pathological fracture at presentation had an impact on OS. The 3-year progression-free survival in patients who received rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOPR) chemotherapy was 88% compared with 52% in those who received CHOP-like chemotherapy without rituximab (P = 0.005). The 10-year OS for those with advanced-stage disease who received irradiation plus chemotherapy was 25% versus 56% for those who received chemotherapy alone (P = 0.025). Patients received irradiation if spinal cord compression was present or residual disease at the end of chemotherapy was thought to require it. Conclusions: PBL is usually of DLCL type and has an improved outcome with CHOPR. Younger patients with good IPI score have a favorable prognosis.

PURPOSE: This randomized, prospective trial compares outcomes for patients with advanced Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid regimen or alternating MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: Three hundred one patients with advanced Hodgkin's disease were randomized to receive MOPP/ ABV hybrid regimen or alternating MOPP/ABVD after stratification for prior treatment, B symptoms, and treatment center. Eligible patients were either previously untreated and found to have stage IIIB, IVA, or IVB disease or previously treated with wide-field irradiation. Responding patients received a minimum of eight cycles of chemotherapy. Those with residual disease in a localized region received irradiation between the sixth and seventh cycle of treatment. RESULTS: Response rates to the two regimens were similar. Five-year overall survival rates were 81% and 83% for MOPP/ABV hybrid and alternating MOPP/ ABVD, respectively (P = .74; 95% confidence interval [CI] for the difference, -11% to 7%). Five-year failure-free survivals were 71% and 67% for MOPP/ABV hybrid and alternating MOPP/ABVD, respectively (P = .87; 95% CI for the difference, -9% to 17%). Significantly more episodes of febrile neutropenia and stomatitis were observed with the MOPP/ABV hybrid regimen; there was no significant difference in fatal toxicity. Patients with predefined, high-quality partial responses (PR-1s) had results similar to those with complete responses (CRs). Planned subset analysis showed no significant difference in outcome between the two arms of the trial for patients with newly diagnosed disease (5-year failure-free survival rates were 70% for MOPP/ABV hybrid and 59% for alternating MOPP/ABVD; P = .180), but superiority of alternating MOPP/ABVD for patients with prior irradiation (5-year failure-free survival 94% v 73%; P = .017). CONCLUSION: MOPP/ABV hybrid and alternating MOPP/ABVD regimens are equally effective for patients with advanced Hodgkin's disease.