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DLBCL: Frontline Advances
How I’m Adapting My Frontline DLBCL Approaches Based on Recent Advances

Released: March 03, 2022

Expiration: March 02, 2023

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In this commentary, I will address how diffuse large B‑cell lymphoma (DLBCL) looks at presentation, discuss how current frontline treatment varies among patient subgroups, and review recent data supporting polatuzumab vedotin plus R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as an improvement vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

DLBCL: Clinical Presentation
DLBCL is the most common form of lymphoma seen in clinical practice. DLBCL is considered an aggressive lymphoma, but it is potentially curable with standard-of-care therapy; this is usually the goal in initial patient discussions. Most patients present with symptoms that vary quite a bit from case to case. Patients may have B symptoms (eg, fevers, night sweats, or weight loss), pain due to growing lymphadenopathy, or organ failure due to organ involvement. That said, DLBCL can come to medical attention in many ways.

Frontline Therapy for DLBCL: One Size Does Not Fit All
How DLBCL is managed in clinical practice depends on the disease subtype, as well as staging results and patient‑specific factors. Approximately one third of patients will present with limited‑stage disease, which is Ann Arbor stage I or II, and are candidates for an abbreviated course of chemotherapy. A very common current strategy, based on the SWOG 1001 study, is 2 cycles of standard R‑CHOP chemotherapy followed by PET imaging. If the PET scan is negative, meaning the patient is in a complete metabolic response, patients often receive just 2 more cycles. Patients who remain PET positive after 2 cycles usually will received combined modality therapy with R-CHOP followed by involved field radiation. We expect to cure 80%-90% of patients with limited stage DLBCL.

Patients with advanced‑stage disease typically receive 6 cycles of R‑CHOP chemotherapy and approximately 60% to 70% will be cured. Certain subtypes may receive alternative regimens. For example, if a patient has primary mediastinal DLBCL, many centers, including ours, tend to administer dose‑adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab. This regimen also is used for patients with so‑called double‑hit DLBCL, now called high‑grade B‑cell lymphoma with rearrangements of MYC and BCL2 or BCL6 genes.

Patients who are older, who are frail, or who have significant comorbidities may not be suitable for full‑dose R‑CHOP chemotherapy. This population can be treated with what’s called R‑mini-CHOP chemotherapy, which uses dose modifications of the various cytotoxic agents to increase tolerability. Perhaps 35% to 40% of patients are cured with that approach, so it is a viable strategy for older, frail patients who cannot receive standard R‑CHOP.

Beyond R-CHOP for DLBCL: What’s Next?
R‑CHOP chemotherapy has been the standard frontline treatment in DLBCL for approximately 20 years. There have been numerous attempts to improve upon outcomes with R-CHOP, and until very recently, all had failed. This is in part because the bar is set fairly high―R‑CHOP chemotherapy cures a majority of the patients. Several trials looked at dose intensification of R‑CHOP chemotherapy. Studies have investigated giving R-CHOP every 2 weeks, using dose‑adjusted EPOCH-R instead, or incorporating stem cell transplant, but none of those meaningfully improved outcomes for patients. Other studies in the frontline setting looked at adding novel anti‑CD20 monoclonal antibodies such as obinutuzumab or adding novel agents such as bortezomib, lenalidomide, or ibrutinib, often based upon cell of origin testing. These strategies also did not show benefit beyond R-CHOP. Results from the phase III POLARIX study presented at the 2021 American Society of Hematology (ASH) Annual Meeting, however, did show improved progression-free survival (PFS) with polatuzumab vedotin plus R-CHP vs R-CHOP in patients with DLBCL. Polatuzumab vedotin is an antibody–drug conjugate that targets CD79b, which is expressed on DLBCL and other mature B-cell lymphoma cells. In POLARIX, patients were randomized to standard R‑CHOP plus placebo vs polatuzumab vedotin plus R-CHP, with placebo substituted for vincristine. The rationale is that substitution is that vincristine is probably the least valuable of the 5 drugs in R-CHOP, so a more potent anti–microtubule agent could potentially improve the regimen. As the phase II data for single‑agent polatuzumab vedotin suggested, it may be more potent than vincristine, so it was a rational drug to test.

POLARIX enrolled approximately 880 patients with newly diagnosed DLBCL and high‑risk disease (International Prognostic Index IPI score 2‑5). In the results presented at ASH, median PFS was significantly better with polatuzumab vedotin plus R-CHP compared with R‑CHOP (HR: 0.73; 95% CI: 0.57-0.95; P = .02). The 2-year PFS rate was approximately 77% for polatuzumab vedotin plus R-CHP vs approximately 70% for R‑CHOP. This is approximately a 7% improvement in absolute terms, which isn’t a gigantic benefit―but clinically significant, nevertheless. Results from this study also demonstrated that substituting polatuzumab vedotin for vincristine in R-CHOP resulted in no real change in adverse event profile. Of note, the risk of peripheral neuropathy was about the same with polatuzumab vedotin plus R-CHP vs R-CHOP (any grade: 52.9% vs 53.9%; grade 3/4: 1.6% vs 1.1%), as was the risk of myelosuppression (any grade neutropenia: 30.8% vs 32.6%; any grade anemia: 28.7% vs 26.0%). There was slightly more neutropenic fever in the polatuzumab vedotin plus R-CHP group, but this did not appear to be clinically significant. At this time, there is no difference in the overall survival between the two regimens.

POLARIX demonstrated that polatuzumab vedotin plus R-CHP provides an improvement in PFS efficacy over R-CHOP with no worsening in toxicity. If polatuzumab vedotin plus R-CHP receives FDA approval, it will likely become the new frontline standard of care for patients with DLBCL and IPI scores of 2‑5. Of note, although the trial does not show an overall survival difference at this time, one could emerge with longer follow-up. Even if that does not happen, I still think polatuzumab vedotin plus R-CHP will become the new standard of care because it helps an additional 7% of patients avoid relapse and the subsequent need for autologous stem cell transplant or CAR T‑cell therapy. Preventing relapse is an important goal in DLBCL treatment.

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If polatuzumab vedotin is approved as first-line therapy for DLBCL, based on PFS improvements in the POLARIX trial, will this change the standard of care in your clinic?
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