Evolving Frontline Treatment Strategies in Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, accounting for approximately 30% of lymphomas. Up to 60% of patients can be cured with standard-of-care rituximab (Rituxan; Genentech), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the front line, but relapsed or refractory disease is still common in approximately 40% of patients.¹

Attempts to improve frontline therapy have historically involved escalation of chemotherapy beyond or addition of targeted agents to the R-CHOP backbone. More recently, substitution of polatuzumab vedotin-piiq (Polivy; Genentech) for vincristine (Pola-R-CHP), the addition of cellular therapies, and the application of nonchemotherapy-based regimens are being explored. This paper offers a review of updates in frontline DLBCL, including Richter transformation, over the past 3 years.

Bispecific Antibody Combinations

Use of CD3×CD20 bispecific antibodies (BsAbs) has expanded rapidly in relapsed DLBCL, both as monotherapy and in combination with other agents.² The phase 3 STARGLO trial (NCT04408638) introduced the idea of combining a BsAb with chemotherapy in the relapsed setting, and this is now being studied in the front line as well.³ Phase 2 trials have evaluated mosunetuzumab (Lunsumio; Genentech) in combination with CHOP or Pola-CHP, and glofitamab (Columvi; Genentech) in combination with R-CHOP or Pola-R-CHP in patients with newly diagnosed, untreated DLBCL.^4-6

Mosunetuzumab has been studied in multiple trials, including a phase 2, open-label study (NCT03677141) and a phase 1b/2 study (NCT03677141). These 2 trials enrolled adult patients to receive 6 cycles of standard chemotherapy with mosunetuzumab, followed by up to 11 cycles of monotherapy for patients without complete response (CR). Step-up dosing began with cycle 1. Primary prophylactic granulocyte colony-stimulating factor (G-CSF) was required during chemotherapy cycles, and mosunetuzumab replaced usual rituximab.^4,5

In contrast, the phase 1/2 COALITION study (NCT04914741) evaluated a slightly younger population (aged 18-65 years) with higher-risk disease.⁶ Glofitamab step-up began with cycle 2 and continued for 7 cycles (ie, 5 cycles with concomitant chemotherapy and 2 cycles of glofitamab monotherapy). Importantly, rituximab was also given to these patients, and glofitamab was administered on day 8 of cycles 3 through 6 to avoid same-day CD20-targeting agents.⁶ No patients received obinutuzumab (Gazyva; Genentech), but primary prophylactic G-CSF was required

Response rate and progression-free survival (PFS) outcomes (Table 1^4-6) appear comparable to standard R-CHOP and Pola-R-CHP, with a 3-year PFS of 85.0% (95% CI, 81.0%-89.0%) and a 2-year PFS of 76.7% (95% CI, 72.7%-80.8%), although cross-trial comparisons are limited.^7,8 Outcomes between Pola-M-CHP (polatuzumab vedotin, mosunetuzumab, cyclophosphamide, doxorubicin, prednisone) and Pola-R-CHP arms showed similar response rates and a slight trend toward higher PFS in the rituximab group. The end-of-treatment overall response rates (ORRs) were 72.5% (95% CI, 56.1%-85.4%) vs 77.3% (95% CI, 54.6%-92.2%), respectively. The estimated 24-month PFS was 70.8% (95% CI, 55.6%-86.1%) vs 81.8% (95% CI, 65.7%-97.9%).⁵ However, this trial was small and conducted exploratory comparisons only.

Larger, randomized-controlled studies will be vital to elucidate the impact of BsAbs on efficacy in the front line, and several important questions need to be answered. These include whether combining chemotherapy with a BsAb in the front line improves survival compared with sequential administration, whether a BsAb should replace rituximab as anti-CD20 therapy in combinations or be added to it, and what BsAb retreatment will look like, as well as how response rate at relapse is affected by prior exposure.

Across studies, grade 3 to 4 adverse effects (AEs) were frequent (86.8%, Pola-M-CHP; 87.5%, M-CHOP; 58.0%, glofitamab + R-CHOP; 58.0%, glofitamab + Pola-R-CHP), including high rates of neutropenia, febrile neutropenia, and other serious infections despite mandated primary G-CSF prophylaxis (Table 1).^4-6 The comparative rates of grade 3 AEs (86.6% vs 59.1%) and serious AEs (63.2% vs 13.6%) in Pola-M-CHP vs Pola-R-CHP suggest thoughtful consideration of which patients are best suited for a BsAb with chemotherapy in any line of therapy. Interestingly, rates of cytokine release syndrome (CRS) with mosunetuzumab combinations were higher than in monotherapy for relapsed disease (Pola-M-CHP, 68.4%; M-CHOP, 60.0%; mosunetuzumab monotherapy, 26.1%), but the rates for glofitamab were much higher (glofitamab plus chemotherapy, 21.0%; glofitamab monotherapy, 63.0%), possibly reflecting differences in timing of step-up dosing.^9-10

Most incidents of CRS across studies were grade 1, and immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 2.5% of patients (n = 1) with M-CHOP and 7.9% (n = 3) with Pola-M-CHOP.^4-5

A BsAb combined with chemotherapy is feasible in the frontline setting, but randomized data are critical for determining comparative efficacy, tolerability, and optimal integration with existing therapy.

POLARIX Trial

POLARIX (NCT03274492) was a phase 3, randomized-controlled trial comparing Pola-R-CHP with R-CHOP in patients aged 18 to 80 years with newly diagnosed DLBCL.⁸ The initial results showed a statistically significant improvement in 2-year PFS in favor of Pola-R-CHP, and similar overall survival (OS) that remained consistent at the 5-year follow-up (Table 2).^8,11-13 Exploratory subgroup analyses suggested greater benefit in patients with activated B-cell (ABC)–type disease, with limited benefit in germinal center B-cell–like (GCB)–type disease.^8,11,12

An age-based subgroup analysis suggested an enhanced benefit in PFS for patients older than 60 years, and a post hoc exploratory analysis further defined this trend.¹³ Importantly, formal statistical tests were not conducted for these age-based comparisons, and conclusions were limited by power and multiplicity.

These findings support the continued consideration of Pola-R-CHP for patients with newly diagnosed DLBCL, particularly for those with ABC-type disease. Furthermore, although Pola-R-CHP is undoubtedly an option for older patients, examination of the subgroup data cannot strongly conclude that R-CHOP is inferior or identify a specific age cutoff for enhanced benefit.

Other Combinations

Novel agents continue to be integrated into the R-CHOP backbone in attempts to improve outcomes with DLBCL. Some recent additions can be found in Table 3, which provides key clinical trial results, including their impact on safety and efficacy compared with standard R-CHOP therapy.^14-16

Richter Transformation

Richter transformation (RT) is an aggressive histologic change from chronic lymphocytic leukemia (CLL), most commonly to DLBCL. Risk of RT is primarily driven by disease biology and is higher in patients with relapsed/refractory CLL.¹⁷ Typical chemoimmunotherapy (CIT; ie, R-CHOP or rituximab, etoposide, prednisone, oncovin, cyclophosphamide, and hydroxydaunorubicin [R-EPOCH]) results in limited remissions (CR, 20%) and long-term survival rates (median OS, 6-12 months). No clear standard frontline therapy exists, and clinical trial enrollment should be prioritized. Emerging strategies include combinations with targeted therapies, checkpoint inhibitors, cellular therapy, and nonchemotherapy regimens.¹⁸

Early exploration of targeted monotherapy in RT focused on the intrinsic mitochondrial pathway of apoptosis, primarily driven by interactions between BCL-2 family proteins.¹⁸ Venetoclax (Venclexta; AbbVie) showed initial promise, leading to studies combining it with CIT.^19,20 The addition of venetoclax to R-EPOCH (VR-EPOCH) was evaluated in a phase 2 study of 26 patients (NCT03054896).²⁰ Cycle 1 consisted of standard R-EPOCH without venetoclax, followed by a venetoclax rapid ramp-up over 5 days prior to cycle 2. Venetoclax 400 mg was given for 10 days concurrently with cycles 2 through 6, with optional maintenance based on response. After a median follow-up of 17.0 months (range, 0.6-42.0), the combination led to an ORR of 62% and CR rate of 50%. TP53 alterations did not negatively impact CR. Median PFS and OS were 10.1 months and 19.6 months, respectively.

Hematologic toxicities were significant, with 65% of patients having grade 3 or higher neutropenia, 62% with grade 3 anemia, 50% with grade 3 or higher thrombocytopenia, and febrile neutropenia in 38% of patients. These toxicities limited the median number of cycles to 4.²⁰ In attempts to improve tolerability, an additional cohort of venetoclax plusR-CHOP (VR-CHOP) was studied, which demonstrated an ORR of 54% and a CR rate of 48%, with a median PFS of 14.9 months and a median OS not reached at time of publication.²¹ VR-CHOP appears more deliverable than VR-EPOCH, though the latter may be considered for fit patients with close monitoring. These results support venetoclax as a potential addition to multiagent treatment strategies, warranting further evaluation in prospective trials.

In addition to targeted therapies, antibody-based therapies have gained traction in RT due to the high expression of PD-1 protein in up to 80% of cases.¹⁸ Early data with monotherapy immune checkpoint inhibitors were positive, but larger studies of indicated combinations may be necessary for higher response data.²² In the phase 2 MOLTO trial (NCT04082897), the triplet regimen of venetoclax, atezolizumab, and obinutuzumab was evaluated in 25 patients with previously untreated RT, with the majority (71%) having untreated CLL. Treatment included obinutuzumab on days 1, 2, 8, and 15; venetoclax ramp-up starting day 15; and atezolizumab in cycle 1. This was followed by obinutuzumab and atezolizumab on day 1 of all subsequent cycles with continuous venetoclax.

At a median follow-up of 16.8 months, ORR was 68%, and CR was 29%. Median duration of response and OS were 11.7 and 31.6 months, respectively. Approximately half of patients had hematologic toxicities, and 24% experienced immune-related AEs.²³

Another antibody-based strategy was evaluated in the phase 2 BLINART study (NCT03931642), in which 24 patients who did not achieve CR after 2 cycles of R-CHOP received an 8-week induction of blinatumomab (Blincyto; Amgen) in a stepwise fashion (9 mcg/day in week 1, 28 mcg/day in week 2, then 112 mcg/day). ORR was 36%, including 20% CR, 16% partial response, and 24% stable disease. Median OS was 10.3 months. Common AEs were neurotoxicity (28%), fever (22%), and CRS (11%). These findings highlight the potential for chemotherapy-free options in RT.²⁴

Adding venetoclax to traditional multiagent chemotherapy and targeted combination therapies shows potential in RT but warrants further evaluation in prospective trials. As CLL therapy continues to evolve, especially with fixed-duration combinations, the applicability of study populations’ outcomes to current practice becomes increasingly complex. Optimal treatment depends on patient and disease factors, and continued data and individualized treatment regimens will be key to improving efficacy and safety in RT.

Conclusion

Advances in DLBCL and RT continue to build on traditional chemotherapy backbones with targeted therapies. Current data indicate that several of these approaches are feasible and capable of producing encouraging responses, although safety and optimal integration into existing standards remain important considerations. These updates offer meaningful progress, but definitive practice changes will depend on ongoing randomized trials.

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