Raising the Standard Beyond Frontline R-CHOP in DLBCL

Rituximab (Rituxan) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is not a suitable frontline treatment regimen for all patients with diffuse large B-cell lymphoma (DLBCL), explained Andre H. Goy, MD, who specified that patients with a high-risk International Prognostic Index (IPI), elderly patients, and patients with high-risk molecular subtypes require alternative treatment.

“The old standard of R-CHOP, which was a great accomplishment and progress in large cell lymphoma, is no longer valid in over half of patients,” said Goy, Physician in Chief Hackensack Meridian Health Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, in a presentation during the 25th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma, a program hosted by the Physicians Education Resource^®, LCC.

Approximately 50% of patients with DLBCL are cured with R-CHOP induction therapy. However, 20% to 30% of patients will relapse and 10% to 15% represent primary failures.^1,2

Patients with a high-risk IPI have particularly poor overall survival (OS) with R-CHOP compared with low- and intermediate-risk patients. In a real-world analysis, patients with a high IPI of 4 or 5 who received R-CHOP had a median OS of 4.5 years vs a median OS that had not been reached in patients with a low IPI of 0 or 1 at a median follow-up of 6 years.²

Patients with double-hit lymphoma (DHL) also do poorly with R-CHOP, said Goy. Typically, these patients are recommended for allogeneic stem cell transplant. However, findings from the phase 2 ZUMA-12 trial, which were presented at the 2020 ASH Annual Meeting and Exposition, demonstrated encouraging results with the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) as consolidation in patients with DHL or DLBCL with a high IPI of 3 or greater.

In the study, patients received 2 cycles of rituximab and chemotherapy, and if they were PET positive, they received axi-cel as consolidation. The objective response rate (ORR) with this approach was 85%, comprising a complete response (CR) rate of 74% (n = 20) and a partial response rate of 11% (n = 3).³

Other potential strategies for patients with DHL include the addition of venetoclax (Venclexta) to R-CHOP, particularly in patients with BCL-2 positivity or overexpression, said Goy. Such a strategy is based on a matched analysis of patients who received R-CHOP vs R-CHOP plus venetoclax in the phase 3 GOYA trial and phase 1/2 CAVALLI trial, respectively.^4,5

According the analysis, 65% and 70% of patients with BCL-2 positivity and BCL-2 overexpression experienced a CR with R-CHOP/venetoclax, respectively, in the CAVALLI trial vs 60% and 48% of patients who received R-CHOP alone, respectively, in the GOYA trial.

These data served as the rationale for an ongoing phase 1 trial (NCT03036904), which is evaluating dose-adjusted R-EPOCH (R-CHOP plus etoposide) plus venetoclax or dose-adjusted R-EPOCH alone in patients with DHL.⁶ The study will also compare R-CHOP plus venetoclax with R-CHOP alone in patients with double expression.

Mutated TP53 is another high-risk feature that confers early resistance to frontline treatment, explained Goy. In a large cohort of patients with DLBCL who received R-CHOP, those with TP53 mutations had worse overall and progression-free survival compared with those without. The median OS of 395 patients with wild-type TP53 was 94.49 months vs 52.90 months in the 111 patients with TP53 mutations (HR, 0.5320; 95% CI, 0.37-0.76).⁷

To that end, another regimen that has been put forth as an alternative for patients with poor-risk features is that of rituximab plus lenalidomide (Revlimid; R²) and ibrutinib (Imbruvica). In the relapsed/refractory setting, the regimen led to an ORR of 44% and a CR rate of 28%.⁸ In the activated B-cell subtype, the ORR was 65%, and the CR rate was 41%. These findings led to a phase 2 trial (NCT02636322) in the frontline setting, which evaluated the same regimen plus chemotherapy in patients with the adverse prognostic variables of non-germinal center B-cell subtype, Ki-67 of greater than 80%, and double expression. The results demonstrated comparable outcomes with other patients, with an ORR of 86% and a CR rate of 36%.⁹

“This is interesting because you can potentially kill the clones that are P53 positive and then can use chemotherapy afterwards,” said Goy.

Other approaches that are under study as a way to build upon R-CHOP include combinations with targeted therapies, such as with copanlisib (Aliqopa) and selinexor (Xpovio), monoclonal antibodies, such as tafasitamab-cxic (Monjuvi), antibody drug-conjugates, such as polatuzumab vedotin-piiq (Polivy), as well as with checkpoint inhibitors and bispecific T-cell engagers, concluded Goy.

References

1. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med. 2002;346(4):235-242. doi:10.1056/NEJMoa011795
2. Dlugosz-Danecka M, Szmit S, Ogorka T, et al. The average relative dose intensity of R-CHOP is an independent factor determining favorable overall survival in diffuse large B-cell lymphoma patients. Cancer Med. 2019;8(3):1103-1109. doi:10.1002/cam4.2008
3. Neelapu SS, Dickinson M, Ulrickson ML, et al. Interim analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients (pts) with high-risk large B cell lymphoma (LBCL). Blood. 2020;136(suppl 1):49. doi:10.1182/blood-2020-134449
4. Zelenetz AD, Salles G, Mason KD, et al. Venetoclax plus R– or G–CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial. Blood. 2019;133(18):1964-1976. doi:10.1182/blood-2018-11-880526
5. Morschhauser F, Feugier P, Flinn IW, et al. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021;137(5):600-609. doi:10.1182/blood.2020006578
6. Study of venetoclax plus DA-EPOCH-R for the treatment of aggressive B-cell lymphomas (V+DA-EPOCH-R). Clinicaltrials.gov. Posted January 30, 2017. Updated September 25, 2020. Accessed February 26, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03036904.
7. Xu-Monette ZY, Wu L, Visco C, et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL rituximab-CHOP consortium program study. Blood. 2012;120(19):3986-3996. doi:10.1182/blood-2012-05-433334
8. Goy A, Ramchandren R, Ghosh N, et al. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non–germinal center B–cell–like DLBCL. Blood. 2019;134(13):1024-1036. doi:10.1182/blood.2018891598
9. Westin JR, Nastoupil LJ, Fayad L, et al. Smart start: rituximab, lenalidomide, and ibrutinib alone and in combination with standard chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma: final phase II results. Blood. 2019;134(suppl 1):1581. doi:10.1182/blood-2019-128475