Subgroup Analysis Improves Understanding of Frontline DLBCL Options

Brian T. Hill, MD, PhD

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and while many trials have failed to change the standard of care and improve outcomes, new opportunities for targeted treatment are growing, according to Brian T. Hill, MD, PhD, who presented during the 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma.

The Role of R-CHOP as Standard of Care

One of the main struggles in treating DLBCL is the heterogeneity of treatment outcomes for patients receiving the same standard-of-care therapies, Hill, the director of the Lymphoid Malignancies Program at the Cleveland Clinic Taussig Cancer Institute, said.¹

Various factors can indicate the level of risk for patients. International Prognostic Index (IPI) status considers risk based on age greater than 60, poor performance status, advanced stage, serum lactate dehydrogenase above normal limits, and at least 1 extranodal site. Higher IPI is predictive of worse overall survival (OS).²

The standard of care for frontline therapy is R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone), which is given once a day every 3 weeks for 6 cycles. A viable alternative is dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen given as continuous infusions over 4 to 5 days every 3 weeks for 6 cycles, with dose escalation every cycle. For double-hit lymphoma, which is especially high-risk, data suggest that intensive induction regimens such as R-EPOCH are more effective than R-CHOP. Only 10% of patients who have double-hit lymphoma will receive R-EPOCH as opposed to R-CHOP in most cancer centers.³

R-CHOP and R-EPOCH were directly compared in the A50303 trial (NCT00118209), but the results were negative.4 No difference was found in terms of OS, with a 2-year OS rate of 86.5% for R-EPOCH and 85.7% for R-CHOP with a hazard ratio of 1.09 (95% CI, 0.75-1.59; P = .64). Hill noted that this trial may have been influenced by factors such as having a longer period of time before patients started receiving treatment, which may have led to enrolling patients with more favorable risk.

Germinal Subtypes Indicate Risk, But Trials Fail to Improve Outcomes

There are 2 major subtypes of DLBCL based on the cell of origin: germinal center (GC) and activated B-cell (ABC) types.5 In general, patients with ABC DLBCL have worse outcomes. To determine if patients could be targeted based on subtype, a phase 2 trial (NCT00151320) of the proteasome inhibitor bortezomib (Velcade) plus R-CHOP was run from 2004 to 2007 and suggested better responses in patients with the ABC subtype.⁶

Other trials over the past 10 years have been unsuccessful in utilizing germinal subtypes. Following these findings, the phase 2 PYRAMID trial (NCT00931918) investigated bortezomib plus R-CHOP versus R-CHOP exclusively in patients with non-GC subtype DLBCL, but did not find benefit from bortezomib.⁷ The phase 3 REMoDL-B trial (NCT01324596) enrolled patients of both subtypes but also did not find differences in outcomes in general or for those with non-GC subtypes.⁸ Hill noted that other trials comparing new agents plus R-CHOP versus R-CHOP alone were also negative: the GOYA trial (NCT01287741) of obinutuzumab (Gazyva), the ROBUST (NCT02285062) and E1412 trials (NCT01856192) of lenalidomide (Revlimid), and the PHOENIX trial (NCT01855750) of ibrutinib (Imbruvica).

“Perhaps one of the reasons that these trials have failed is that, in many cases, we’re treating this as one disease, but it really is a constellation of multiple subtypes that may have differing sensitivities to individual pathway inhibitors,” Hill said.¹

Polatuzumab PFS Improvement Challenges Standard of Care

One of the most important changes to standard of care in upfront therapy has been the introduction of polatuzumab vedotin (Polivy), an antibody-drug conjugate that targets CD79B, a component of the B-cell receptor signaling apparatus.

In the relapsed/refractory setting, a phase 2 trial (NCT02257567) compared polatuzumab with bendamustine and rituximab versus bendamustine and rituximab alone. Though it was a small study, Hill points out a higher number of complete responses (CR) with polatuzumab/bendamustine/rituximab in the patients with ABC versus GC DLBCL. There were no differences in subgroups in the non-polatuzumab group.⁹

Based on the positive outcomes with polatuzumab in the relapsed setting, vincristine was substituted from the R-CHOP regimen to create the pola-R-CHP regimen, and the 2 regimens were compared directly in previously-untreated patients in the phase 3 POLARIX trial (NCT03274492). The 2-year progression-free survival (PFS) rate was 76.7% with pola-R-CHP versus 70.2% with R-CHOP, favoring polatuzumab with a stratified hazard ratio of 0.73 (95% CI, 0.57-0.95; P = .02).¹⁰ Subgroup analysis showed that patients with high IPI had better outcomes with pola-R-CHP, and those in the ABC group fared better with polatuzumab despite their expected higher risk. However, there was no OS advantage in this trial.

Based on the subsequent treatments received by the patients in each arm of POLARIX, Hill suggested that in approximate terms, several times as much money was spent to prevent relapse in those who received R-CHOP versus those receiving pola-R-CHP, which could warrant more investigation of costs and benefits of treatment.¹

Advanced Molecular Testing for DLBCL Finds New Subgroups

The work of Sandeep Dave, MD, MS, of Duke University has led to advanced molecular analysis of DLBCL and its subtypes through the sequencing of 1001 patients.¹¹ Certain genes were associated with GC or ABC subtypes. Bjoern Chapuy, MD, PhD, and Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute, also identified 5 gene clusters common among patients with DLBCL.¹²

Work at the National Cancer Institute showed that patients with the GC subtype had worse outcomes with EZH2 mutations and BCL-2 translocations, identifying this as the EZB group.13 In ABC DLBCL, the MCD and N1 groups included genetic markers that were associated with higher risk than the BN2 group, which included most other patients with ABC disease.

“Both schemas came up with very highly similar results, which was that there were low risk and high-risk GC patients with recurring genetic abnormalities that are mirrored in both studies, and in the ABC patients, again, particularly for cluster 5 in the MCD patients, these patients had poorer outcomes, and there is a group of cluster 2 of which have p53 mutations,” Hill said.¹

Hill predicts that in the future, genetic testing of biopsies will be able to identify these groups, which will aid in the development of rationally targeted therapies.

A recent retrospective analysis of the PHOENIX trial of ibrutinib found that in the patients with the MCD and N1 subtypes, 3-year event-free survival was 100% and was far superior to R-CHOP alone, suggesting that ibrutinib and other targeted agents can be used effectively once these genetic subgroups are identified.¹⁴

Going Forward Using Targeted Therapies

In his presentation, Hill proposed the development of 5 new comparison trials for patients with each of 5 molecular subtypes that would compare pola-R-CHP plus a targeted inhibitor versus pola-R-CHP alone. If these trials show differences in outcomes due to the targeted therapy, patients could be treated more effectively upfront based on the results of genetic testing.

“DLBCL is not a single entity but largely approached this way clinically in 2022. While in general GC-derived tumors have better outcomes than those derived from ABCs, there is a heterogeneity which can be explained in the subgroup analysis,” Hill concluded. “Future clinical trials should be based on integration of multiomic biomarkers to test precision medicine with specific pathway inhibitors for individual subtypes of DLBCL.”¹

_References:

_{1. Hill, BT. Upfront therapy in DLBCL: R-CHOP and beyond. Oral Presentation at: 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma; February 23-25, 2022; Miami, FL.}

_{2. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(14):2373-2380. doi:10.1200/JCO.2009.26.2493}

_{3. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354-2361. doi:10.1182/blood-2014-05-578963}

_{4. 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}

_{5. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937-1947. doi:10.1056/NEJMoa012914}

_{6. Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(6):690-697. doi:10.1200/JCO.2010.31.1142}

_{7. Leonard JP, Kolibaba KS, Reeves JA, et al. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3538-3546. doi:10.1200/JCO.2017.73.2784}

_{8. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(5):649-662. doi:10.1016/S1470-2045(18)30935-5}

_{9. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172}

_{10. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304}

_{11. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481-494.e15. doi:10.1016/j.cell.2017.09.027}

_{12. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes Nat Med. 2018;24(5):679-690. doi:10.1038/s41591-018-0016-8}

_{13. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-1407. doi:10.1056/NEJMoa1801445}

_{14. Wilson WH, Wright GW, Huang DW, et al. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell. 2021;39(12):1643-1653.e3. doi:10.1016/j.ccell.2021.10.006}