In the first article of a 2-part series, Herbert A. Eradat, MD, discusses the research down that led to the use of the immunotherapy polatuzumab vedotin in combination with chemotherapy for patients with diffuse large B-cell lymphoma.
A 58-year-old retired schoolteacher presented with the chief complaint of swollen lymph nodes in his neck and groin, persistent fatigue, night sweats, and unintentional weight loss of 15 pounds over the last 2 months.
Targeted Oncology: How many cycles of chemotherapy treatment do you recommend for patients with DLBCL?
HERBERT A. ERADAT, MD: The other question, at the time, was [whether to give] 6 cycles vs 8 cycles of therapy, and I can tell you that there is really no advantage to the 2 additional cycles of therapy.1 The standard right now for chemotherapy backbone [therapy] is 6 cycles of therapy and we shouldn't be pushing beyond that to 8 cycles of anthracycline based therapy.
That's old news, but I would like to highlight that perhaps...there is some value to dose intensity and dose density for patients that have a higher IPI score. These [older] data were not comparing it with a 21-day cycle, but it [increased their event-free survival], suggesting that perhaps there is some value to dose density. However, I would caution this because this is not comparative data to 21-day cycle strategy.1
What data led to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a standard of care in this space?
The [phase 3] Alliance/CALGB 50303 trial [NCT00118209] compared dose adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin] vs R-CHOP. It demonstrated that these 2 regimens were essentially equivalent in terms of their outcomes.2 However, when you look at their toxicity profiles, in general, dose-adjusted R-EPOCH ended up being more toxic than R-CHOP, therefore, based on that Alliance data, for most patients, R-CHOP remained the standard.2
What study looked at adding immunotherapy to chemotherapy to treat these patients?
The POLARIX trial [NCT03274492] was a double-blind randomized study, so the patients in the experimental arm received R-CHP plus polatuzumab compared with R-CHOP.3 Each of the arms had a placebo drug, so it was a blinded randomized study, in that regard. The patients received 6 cycles of a chemotherapy backbone with the immunotherapy and then to make everything equivalent, everybody received 2 additional cycles of rituximab in cycles 7 and 8 with no cytotoxic chemotherapy. The primary end point was progression-free survival [PFS] as assessed by the investigators, and [there was also] secondary end points including EFS, overall survival [OS], and safety data. These were previously untreated patients with DLBCL who had to have an IPI score of 2 to 5, so they excluded patients with IPI 1. [This was also a] large study with 879 patients.3
What was the patient characteristics on this study?
Both arms were very well balanced. In terms of [patients’ stage of disease at the time of enrollment], about 90% of patients in both arms had stage III or IV disease, so a heavy burden of disease. Approximately 50% of patients had more than 2 extranodal sites.3 About 43% of patients in both arms had bulky disease, defined as more than 7.5 cm, so [this group showed a] reasonably heavy burden of disease. Around 62% of patients had IPI scores of 3 to 5.
Then looking at the various cell of origin, most of the patients had germinal-center B-cell like subtype, while about 30% of the patients at an activated B-cell phenotype, with an additional 10% to 15% who were unclassified. Looking at the subgroups of patients with double expressors and double-hit or triple-hit histology, about 5% to 7% of the patients had double-hit histology and about 35% to 40% of the patients had double over-expressor histology.3
What were the main efficacy outcomes with this treatment regimen?
There was indeed an improvement in PFS [with polatuzumab plus R-CHOP] that was statistically significant.3 The HR was 0.73 [95% CI, 0.57-0.95, P = .02], so that translates to a 37% reduction in the risk of disease progression in favor of the polatuzumab plus R-CHP strategy. In the EFS results, there was a similar trend in favor of the polatuzumab/R-CHP [HR, 0.75; 95% CI, 0.58-0.96; P = .02]. In terms of the OS...[these data] were not statistically significant in terms of having a P value of .75 [and a HR of 0.94 (95% CI, 0.65-1.37) when looking at both arms].3
1. Pfreundschuh M, Schubert J, Ziepert M, et al; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-16. doi:10.1016/S1470-2045(08)70002-0
2. Bartlett NL, Wilson WH, Jung SH, et al. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019;37(21):1790-1799. doi:10.1200/JCO.18.01994
3. Tilly H, Morschauser F, Sehn L, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022; 386:351-363. doi:10.1056/NEJMoa2115304