Abstract

Chemotherapy with R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, prednisolone) is the standard of care for patients with diffuse large B-cell lymphoma as the first-line therapy. The recent approval of polatuzumab as the first-line therapy after demonstration of its efficacy in the Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma (POLARIX) trial is the first significant change in this treatment regimen over two decades. This concise appraisal of trial evidence and clinical context highlights the limited potential for a clinically significant benefit with the addition of polatuzumab to the first-line therapy for this common hematologic malignancy.

Introduction

Approval of rituximab as a part of the first-line combination therapy for diffuse large B-cell lymphoma (DLBCL) in 2006 was an important milestone. It was the first monoclonal antibody approved for cancer that substantially improved the overall response rates and progression-free survival (PFS) compared with conventional chemotherapy alone.[1] [2] Since then, the R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, prednisolone) drugs have continued to be a part of the first-line therapy for CD20-positive lymphomas. Additionally, no newer agents have shown a similar magnitude of benefit in addition to this chemotherapy backbone.[3] This paradigm was challenged in 2022 when polatuzumab vedotin (antibody–drug conjugate targeting CD79b) was proven effective in newly diagnosed patients with DLBCL in the randomized phase 3 POLARIX trial. This trial randomized 879 newly diagnosed patients to R-CHOP or Polatuzumab- Rituximab - Cyclophosphamide - Adriamycin- Prednisolone (Pola-R-CHP). After a median follow-up period of 28.2 months, PFS was higher in the polatuzumab group (76.7 vs. 70.2%), with no difference in response rates or overall survival (OS) at 2 years.[4] Based on these findings, polatuzumab received Food and Drug Administration (FDA) approval as the first-line therapy for DLBCL in 2023—a major change in upfront therapy for DLBCL for the first time in 20 years. However, the finer details of this clinical trial must be carefully reviewed in the context of real-world practice before effecting a change in a regimen that already has extensive and durable data on its safety and efficacy.

The magnitude of benefit noted with polatuzumab is much lower than that noted with the addition of rituximab to conventional chemotherapy. The addition of rituximab to CHOP was associated with added overall response rates of approximately 10 to 15%, with a notable augmentation of PFS and OS, which is not seen with polatuzumab vedotin.[2] The potential impact of polatuzumab vedotin on an OS benefit may be blunted by an already high efficacy of R-CHOP as the first-line therapy for most patients with DLBCL. In the POLARIX trial, overall response rates of 83.8%-were noted in the control arm compared with 85.5%-in the intervention arm, With this efficacy, the effect size of the addition of any new drug to the control arm required to detect a statistically significant difference between the two options may be substantial, and may not be detected in a trial setting.[5] The OS benefit may be further masked by the availability of effective second-line therapies including salvage chemotherapy, autologous stem cell transplant, and chimeric antigen receptor (CAR) T-cell therapy.

Moreover, achieving a complete response (CR) is important for an aggressive disease like DLBCL, where a majority of patients (>80%) achieving CR are functionally “cured” with less than 20%-risk of relapse after 5 years.[6] Similar rates of CR in both arms may further diminish any observable OS benefit in this trial.

Powering this study for OS would considerably prolong the trial duration to greater than 5 years and delay the approval of potentially effective therapy. Several drugs for hematological cancers have recently been approved after assessing surrogate endpoints to reduce the time to regulatory approval.[7] PFS has been espoused as a valid surrogate endpoint by industry-sponsored reviews, lending credence to selecting this as a primary endpoint.[8] Older trials leading to rituximab approval also considered PFS as the primary endpoint. However, the quantitative effect of adding rituximab to chemotherapy on PFS and OS made it a viable first-line therapeutic option.[9] Using endpoints other than OS may enable the achievement of favorable but clinically less relevant endpoints for regulatory approval in the trial setting.

From a policy perspective, the absolute risk reduction for progression from the POLARIX trial is 0.06, indicating a number needed to treat (NNT) of 16.7. At present, the addition of a second drug likely to be priced higher than rituximab may not be viable in India due to the small PFS benefit and high NNT as noted earlier.

R-CHOP therapy's efficacy appears to have plateaued for a subset of patients; hence, introducing a second drug may not enhance treatment outcomes for standard-risk patients. However, specific subgroups of high-risk diseases including double-/triple-hit lymphomas still present an unmet need, and may benefit from a second drug.[10] [11] There is a mismatch between double-/triple-hit lymphomas, implying that most “high-risk lymphomas” in this trial are ABC: Activated B Cell Lymphoma (ABC) lymphomas and not true double-/triple-hit lymphomas (highlighted by Dr. Advani, Lymphoma CME on May 5, 2023). A preferential benefit on ABC lymphoma subtypes has been recently highlighted, making it possible that this drug may show greater efficacy when evaluated on this specific patient subset.[12] Similar findings were noted in the POLARIX trial, with no clear benefit in patients younger than 60 years or those with low international prognostic index scores or germinal center subtypes, further limiting the target population for this new drug.

A substantial proportion of patients with high-risk DLBCL subtypes are of advanced age. The development of newer non-chemotherapy-based treatment options is necessary in this subset. Until then, R-CHOP appears to be the best option for most patients with DLBCL. Furthermore, polatuzumab is likely a better option as the second-line therapy till better efficacy than R-CHOP can be documented. The allure of innovation may entice, but older and dependable ways may hold greater value in certain scenarios.

Conflict of Interest

None declared.

Patient Consent

None declared.

References

1. Feugier P, Van Hoof A, Sebban C. et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005; 23 (18) 4117-4126
   CrossrefPubMedSearch in Google Scholar
2. Pfreundschuh M, Trümper L, Osterborg A. et al; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7 (05) 379-391
   CrossrefPubMedSearch in Google Scholar
3. Susanibar-Adaniya S, Barta SK. 2021 update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol 2021; 96 (05) 617-629
   CrossrefPubMedSearch in Google Scholar
4. Tilly H, Morschhauser F, Sehn LH. et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 2022; 386 (04) 351-363
   CrossrefPubMedSearch in Google Scholar
5. Faraone SV. Interpreting estimates of treatment effects: implications for managed care. P&T 2008; 33 (12) 700-711
   Search in Google Scholar
6. Jakobsen LH, Bøgsted M, Brown PN. et al. Minimal loss of lifetime for patients with diffuse large B-cell lymphoma in remission and event free 24 months after treatment: a Danish population-based study. J Clin Oncol 2017; 35 (07) 778-784
   CrossrefPubMedSearch in Google Scholar
7. Beaver JA, Howie LJ, Pelosof L. et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol 2018; 4 (06) 849-856
   CrossrefPubMedSearch in Google Scholar
8. Shi Q, Schmitz N, Ou FS. et al. Progression-free survival as a surrogate end point for overall survival in first-line diffuse large B-cell lymphoma: an individual patient-level analysis of multiple randomized trials (SEAL). J Clin Oncol 2018; 36 (25) 2593-2602
   CrossrefPubMedSearch in Google Scholar
9. 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 (04) 235-242
   CrossrefPubMedSearch in Google Scholar
10. Oki Y, Noorani M, Lin P. et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol 2014; 166 (06) 891-901
    CrossrefPubMedSearch in Google Scholar
11. Laude MC, Lebras L, Sesques P. et al. First-line treatment of double-hit and triple-hit lymphomas: survival and tolerance data from a retrospective multicenter French study. Am J Hematol 2021; 96 (03) 302-311
    CrossrefPubMedSearch in Google Scholar
12. Palmer AC, Kurtz DM, Alizadeh AA. Cell-of-origin subtypes and therapeutic benefit from polatuzumab vedotin. N Engl J Med 2023; 389 (08) 764-766
    CrossrefPubMedSearch in Google Scholar

    
    

    Address for correspondence

    Suvir Singh, MD, DM

    Department of Clinical Haematology, & Bone Marrow Transplantation, Dayanand Medical College and Hospital

    Ludhiana, Punjab 141001

    India   

    Email: suvirs@gmail.com

    
    

    Publication History

    Article published online:
    21 October 2024
    

    © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

    Thieme Medical and Scientific Publishers Pvt. Ltd.
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References

1. Feugier P, Van Hoof A, Sebban C. et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005; 23 (18) 4117-4126
   CrossrefPubMedSearch in Google Scholar
2. Pfreundschuh M, Trümper L, Osterborg A. et al; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7 (05) 379-391
   CrossrefPubMedSearch in Google Scholar
3. Susanibar-Adaniya S, Barta SK. 2021 update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol 2021; 96 (05) 617-629
   CrossrefPubMedSearch in Google Scholar
4. Tilly H, Morschhauser F, Sehn LH. et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 2022; 386 (04) 351-363
   CrossrefPubMedSearch in Google Scholar
5. Faraone SV. Interpreting estimates of treatment effects: implications for managed care. P&T 2008; 33 (12) 700-711
   Search in Google Scholar
6. Jakobsen LH, Bøgsted M, Brown PN. et al. Minimal loss of lifetime for patients with diffuse large B-cell lymphoma in remission and event free 24 months after treatment: a Danish population-based study. J Clin Oncol 2017; 35 (07) 778-784
   CrossrefPubMedSearch in Google Scholar
7. Beaver JA, Howie LJ, Pelosof L. et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol 2018; 4 (06) 849-856
   CrossrefPubMedSearch in Google Scholar
8. Shi Q, Schmitz N, Ou FS. et al. Progression-free survival as a surrogate end point for overall survival in first-line diffuse large B-cell lymphoma: an individual patient-level analysis of multiple randomized trials (SEAL). J Clin Oncol 2018; 36 (25) 2593-2602
   CrossrefPubMedSearch in Google Scholar
9. 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 (04) 235-242
   CrossrefPubMedSearch in Google Scholar
10. Oki Y, Noorani M, Lin P. et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol 2014; 166 (06) 891-901
    CrossrefPubMedSearch in Google Scholar
11. Laude MC, Lebras L, Sesques P. et al. First-line treatment of double-hit and triple-hit lymphomas: survival and tolerance data from a retrospective multicenter French study. Am J Hematol 2021; 96 (03) 302-311
    CrossrefPubMedSearch in Google Scholar
12. Palmer AC, Kurtz DM, Alizadeh AA. Cell-of-origin subtypes and therapeutic benefit from polatuzumab vedotin. N Engl J Med 2023; 389 (08) 764-766
    CrossrefPubMedSearch in Google Scholar