A Review of Standard of Care in DLBCL

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma that is considered diffuse because, under the microscope, the malignant lymphocytes are seen throughout the tumor sample. According to a recent review, the state-of-the-art treatment is immunochemotherapy, although various efforts are under way to improve on this standard.

Patients are typically treated with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Outcomes are poor for patients who experience treatment failure with R-CHOP, although treatment with secondary therapies may result in durable remissions, the review stated.

Diagnosis of DLBCL starts with examination of an exisional biopsy specimen, which is the removal of an entire lesion. Specialized diagnostic tests include immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), and molecular testing.

There are 2 distinct molecular subtypes of DLBCL: germinal center B-cell–like (GCB) subtype and activated B-cell–like (ABC) subtype. The ABC subtype has an inferior outcome with 3-year progression-free survival of roughly 40% to 50% vs 75% with GCB, according to the review.

An increasing understanding of molecular aberrations has led to proposals for new classifications of DLBCL that may yield greater potential for individualized therapies. MYC rearrangements are seen in 12% of cases and may be concurrent with BCL2 and BCL6 rearrangements, or both. These are considered double or triple-hit, high-grade lymphomas and are associated with poor outcomes post R-CHOP. In this setting, outcomes have been improved with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R).

Overexpression of MYC and BCL2 proteins occurs in roughly 30% of cases of DLBCL and is termed double-expressor lymphoma, which carries a worse prognosis.

Patients with DLBCL are typically in their mid-60s at time of diagnosis and 30% of patients are older than 75 years. Most patients (70%) present with advanced-stage disease.

Risk factors include genetic susceptibility, viral exposure, transplantation, autoimmune disorders, immunodeficiency, excess weight, and exposure to pesticides and ionizing radiation.

Allergies, blood transfusion, alcohol and vegetable consumption, and sun exposure are associated with decreased risk for DLBCL.

Disease Staging With PET-CT

Higher sensitivity of F-fluorodeoxyglucose positron-emission tomography with computed tomographic (PET-CT) has caused this to displace CT alone as a disease staging tool. Total tumor volume at diagnosis is thought to be of value in establishing prognosis, as is staging bone marrow biopsy, although PET-CT can suffice for this.

There is prognostic value to a PET-CT assessment after 2 to 4 cycles of treatment, although treatment modifications made on the basis of these findings have not been shown to alter outcomes; and recently, circulating tumor DNA is under investigation as a potentially useful interim response-assessment tool.

Patients who are event free at 2 years from diagnosis have an overall survival (OS) roughly equivalent to that of the general, age-matched population, although monitoring is advised.

The International Prognostic Index (IPI) helps to predict outcomes and stratify patients for risk who have received rituximab in combination with chemotherapy, as does the National Comprehensive Cancer Network IPI, although these are limited with regard to understanding biologic risk factors, which do correlate with outcomes.

The addition of rituximab to the CHOP chemotherapy regimen led to a significant improvement in OS, and a dose-intensive regimen with bleomycin (R-ACVBP) was the first and only improvement on R-CHOP in patients with a low IPI score of 1 (out of 3). Toxicities, however, have limited its use.

Six cycles of R-CHOP every 3 weeks has been confirmed as the standard of care.

Adding New Agents to R-CHOP

No value has been reliably demonstrated for the use of consolidative radiation therapy after immunochemotherapy. Several large trials have evaluated the addition of new agents to R-CHOP. No benefit was shown from the addition of the proteasome inhibitor bortezomib, and mixed findings resulted from the addition of ibrutinib, the Bruton tyrosine kinase inhibitor.

Initial hope resulted from a phase 2 trial of lenalidomide added to R-CHOP in unselected patients, who saw improvement in PFS and OS, but a phase 3 trial of patients with the ABC subtype failed to confirm any added value of lenalidomide. Meanwhile, post–R-CHOP maintenance with rituximab, enzastaurin, everolimus, and lenalidomide were inconclusive.

“Outside of clinical trials, R-CHOP has prevailed as the standard of care for DLBCL, regardless of the immunohistochemical profile or molecular subtype,” reviewers wrote. Better quality data and more-prompt testing and analysis could better elucidate the value of some of the above-mentioned experimental treatments, they said.

Approximately 30% of patients present with stage 1 or 2 (“limited stage”) disease and tend to have favorable outcomes, although delayed relapse patterns have been observed. To address these relapses and associated secondary cancers, recent efforts have focused on limiting radiation therapy and the number of chemotherapy cycles. The 5-year survival rate for patients with limited-stage disease is 85% to 95%.

Roughly 20% to 25% of patients are in poor condition owing to age, cardiac dysfunction, or comorbidities and are not candidates for frontline R-CHOP. Dose-reduced versions of R-CHOP may be appropriate in such cases, and pretreatment with glucocorticoids may reduce adverse events associated with treatment.

Relapsed or Refractory DLBCL

Approximately 10% to 15% of patients who receive R-CHOP will have an incomplete response or relapse within 6 months, and an additional 20% to 25% will relapse after an initial response, or within the first 2 years. “Outcomes remain poor for patients in whom frontline treatment fails,” reviewers said.

For patients with chemotherapy-sensitive relapsed or refractory disease, high-dose chemotherapy with autologous stem-cell transplantation “offers the best chance of cure.” Most relapsed or refractory patients, however, are transplant ineligible, and palliative treatment has involved rituximab, gemcitabine, and oxaliplatin. Chimeric antigen receptor (CAR) T-cell therapy has been a recent option with potential for durable disease remission.

Antibody-drug conjugates, which selectively deliver tumor-toxic payloads, have shown promise, such as polatuzumab vedotin, which in combination with bendamustine-rituximab has received regulatory approval. Various other agents also are under investigation.