open access

Vol 52, No 4 (2021)
Review article
Published online: 2021-08-31
Submitted: 2021-07-16
Accepted: 2021-07-23
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Improving first-line treatment in diffuse large B-cell lymphoma

Monika Palka1, Wojciech Jurczak1
DOI: 10.5603/AHP.2021.0061
·
Acta Haematol Pol 2021;52(4):320-324.
Affiliations
  1. Maria Skłodowska-Curie National Research Institute of Oncology, Krakow, Poland

open access

Vol 52, No 4 (2021)
REVIEW ARTICLE
Published online: 2021-08-31
Submitted: 2021-07-16
Accepted: 2021-07-23

Abstract

R-CHOP remains the standard of care in first-line treatment of diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype. Patients who fail this therapy have a poor outcome, with relapse or refractory disease resulting in fatality in the majority.

In this short paper, we summarize recent clinical studies exploring alternative regimens and efficacy of autologous stem cell transplantation (ASCT) consolidations. In ABC DLBCL, adequately identifying patients with poor prognosis but failed to recognize the patient for molecular target of therapy. Immunotherapy, which may potentially be used in less well genetically characterized patients, is most potent if used relative to chemotherapy protocols, therefore its optional combination remains to be determined. The hope is ultimately to move away from a universal chemotherapeutic mentality towards an individualized approach, be it through the use of a targeted small molecule or a biological drug.

We discuss the role of new monoclonal antibodies such as obinutuzumab, brentuximab vedotin, polatuzumab vedotin and bispecific antibodies (BIABs) in first-line treatment regimens. BIABs which can bind to two different antigens at the same time are under investigation. After neurotoxic blinatumomab, anti-CD20/anti-CD3 BIABs take the lead, and due to their favorable toxicity profile they can be used in elderly patients with comorbidities, causing durable responses in patients with B-cell non-Hodgkin lymphoma who otherwise have limited options, even in those relapsing or refractory to chimeric antigen receptor (CAR) T-cell therapy.

Abstract

R-CHOP remains the standard of care in first-line treatment of diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype. Patients who fail this therapy have a poor outcome, with relapse or refractory disease resulting in fatality in the majority.

In this short paper, we summarize recent clinical studies exploring alternative regimens and efficacy of autologous stem cell transplantation (ASCT) consolidations. In ABC DLBCL, adequately identifying patients with poor prognosis but failed to recognize the patient for molecular target of therapy. Immunotherapy, which may potentially be used in less well genetically characterized patients, is most potent if used relative to chemotherapy protocols, therefore its optional combination remains to be determined. The hope is ultimately to move away from a universal chemotherapeutic mentality towards an individualized approach, be it through the use of a targeted small molecule or a biological drug.

We discuss the role of new monoclonal antibodies such as obinutuzumab, brentuximab vedotin, polatuzumab vedotin and bispecific antibodies (BIABs) in first-line treatment regimens. BIABs which can bind to two different antigens at the same time are under investigation. After neurotoxic blinatumomab, anti-CD20/anti-CD3 BIABs take the lead, and due to their favorable toxicity profile they can be used in elderly patients with comorbidities, causing durable responses in patients with B-cell non-Hodgkin lymphoma who otherwise have limited options, even in those relapsing or refractory to chimeric antigen receptor (CAR) T-cell therapy.

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Keywords

DLBCL, targeted molecular therapies, immunotherapy

About this article
Title

Improving first-line treatment in diffuse large B-cell lymphoma

Journal

Acta Haematologica Polonica

Issue

Vol 52, No 4 (2021)

Article type

Review article

Pages

320-324

Published online

2021-08-31

DOI

10.5603/AHP.2021.0061

Bibliographic record

Acta Haematol Pol 2021;52(4):320-324.

Keywords

DLBCL
targeted molecular therapies
immunotherapy

Authors

Monika Palka
Wojciech Jurczak

References (40)
  1. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993; 328(14): 1002–1006.
  2. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010; 116(12): 2040–2045.
  3. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013; 381(9880): 1817–1826.
  4. Li X, Huang He, Xu B, et al. Dose-Dense rituximab-CHOP versus standard rituximab-CHOP in newly diagnosed Chinese patients with diffuse large B-cell lymphoma: a randomized, multicenter, open-label phase 3 trial. Cancer Res Treat. 2019; 51(3): 919–932.
  5. Schmitz N, Nickelsen M, Ziepert M, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012; 13(12): 1250–1259.
  6. Chiappella A, Martelli M, Angelucci E, et al. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017; 18(8): 1076–1088.
  7. Vitolo U, Chiappella A, Brusamolino E, et al. Rituximab dose-dense chemotherapy followed by intensified high-dose chemotherapy and autologous stem cell transplantation (HDC+ASCT) significantly reduces the risk of progression compared to standard rituximab dose-dense chemotherapy as first line treatment in young patients with high-risk (aa-ipi 2–3) diffuse large b-cell lymphoma (DLBCL): final results of phase III randomized trial DLCL04 of the Fondazione Italiana Linfomi (FIL). Blood. 2012; 120(21): 688.
  8. 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.
  9. Wilson W, sin-Ho J, Pitcher B, et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large b-cell lymphoma: CALGB/Alliance 50303. Blood. 2016; 128(22): 469.
  10. 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.
  11. 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.
  12. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015; 125(1): 22–32.
  13. Nogai H, Dörken B, Lenz G. Pathogenesis of non-Hodgkin's lymphoma. J Clin Oncol. 2011; 29(14): 1803–1811.
  14. Nowakowski GS, Czuczman MS. ABC, GCB, and double-hit diffuse large B-cell lymphoma: does subtype make a difference in therapy selection? Am Soc Clin Oncol Educ Book. 2015: e449–e457.
  15. Hong JY, Hong ME, Choi MK, et al. The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases. Ann Oncol. 2014; 25(1): 182–188.
  16. Béguelin W, Teater M, Gearhart MD, et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell. 2016; 30(2): 197–213.
  17. Staudt LM. Molecular diagnosis of the hematologic cancers. N Engl J Med. 2003; 348(18): 1777–1785.
  18. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's lymphoma classification project. J Clin Oncol. 1998; 16(8): 2780–2795.
  19. Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure-what to do? Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 366–378.
  20. 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.
  21. Younes A, Sehn LH, Johnson P, et al. PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019; 37(15): 1285–1295.
  22. Schaffer M, Chaturvedi S, Davis C, et al. Activity of ibrutinib plus R-CHOP in diffuse large B-cell lymphoma: response, pharmacodynamic, and biomarker analyses of a phase Ib study. Cancer Treat Res Commun. 2020; 25: 100235.
  23. Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017; 31(6): 833–843.e5.
  24. Vitolo U, Witzig TE, Gascoyne RD, et al. ROBUST: First report of phase III randomized study of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Hematological Oncology. 2019; 37(52): 36–37.
  25. Celgene Corporation. Efficacy and safety study of lenalidomide plus R-CHOP chemotherapy versus placebo plus R-CHOP chemotherapy in untreated ABC type diffuse large B-cell lymphoma (ROBUST). https://www.clinicaltrials.gov/ct2/show/NCT02285062 (20.04.2021).
  26. Nowakowski GS, Hong F, Scott DW, et al. Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large b-cell lymphoma in a randomized phase II US intergroup study ECOG-ACRIN E1412. J Clin Oncol. 2021; 39(12): 1329–1338.
  27. Belada D, Nowakowski G, Burgues JB, et al. A phase Ib, open-label, randomized study to assess safety and preliminary efficacy of tafasitamab (MOR208) or tafasitamab + lenalidomide in addition to R-CHOP in patients with newly diagnosed diffuse large b-cell lymphoma: analysis of the safety run-in phase. Blood. 2020; 136(Suppl 1): 27–28.
  28. Burke J, André M, Cheson B, et al. A phase Ib, open-label, randomized study to assess safety and preliminary efficacy of tafasitamab (MOR208) or tafasitamab + lenalidomide in addition to R-CHOP in patients with newly diagnosed diffuse large b-cell lymphoma: the first-mind trial. Blood. 2019; 134(Suppl 1): 2877.
  29. Salles G, Duell J, Barca EG, et al. Primary analysis results of the single-arm phase ii study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (l-mind). Hematol Oncol. 2019; 37(52): 173–174.
  30. Vitolo U, Trněný M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017; 35(31): 3529–3537.
  31. Yasenchak C, Farber C, Budde L, et al. Brentuximab vedotin in combination with RCHOP as front-line therapy in patients with DLBCL: interim results from a phase 2 study. Blood. 2014; 124(21): 1745.
  32. Yasenchak C, Halwani A, Advani R, et al. Brentuximab vedotin with RCHOP as frontline therapy in patients with high-intermediate/high-risk diffuse large b cell lymphoma (DLBCL): results from an ongoing phase 2 study. Blood. 2015; 126(23): 814.
  33. Sehn LH, Herrera AF, Matasar MJ, et al. Addition of polatuzumab vedotin to bendamustine and rituximab (BR) improves outcomes in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) versus BR alone: results from a randomized phase 2 study. Blood. 2017; 130(Suppl 1): 2821.
  34. 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.
  35. Bartlett N, Chen A, Kolibaba K, et al. Polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated diffuse large B-cell lymphoma (DLBCL): preliminary results of a phase Ib dose-escalation. Blood. 2015; 126(23): 2726.
  36. Tilly H, Flowers C, Friedberg JW, et al. Polarix: a phase 3 study of polatuzumab vedotin (POLA) plus R-CHP versus R-CHOP in patients (Pts) with untreated DLBCL. Hematol Oncol. 2019; 37(S2): 68–70.
  37. A randomized, multicenter, phase III trial comparing treatment with R-mini-CHOP with R-mini-CHP + polatuzumab vedotin in patients with diffuse large cell B cell lymphoma (POLAR BEAR). https://clinicaltrials.gov/ct2/show/NCT04332822/ (10.04.2021).
  38. Goebeler ME, Knop S, Viardot A, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016; 34(10): 1104–1111.
  39. Schuster S, Bartlett N, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor t-cell (CAR-T) therapies, and is active in treatment through multiple lines. Blood. 2019; 134(Suppl 1): 6.
  40. Olszewski A, Avigdor A, Babu S, et al. Single-agent mosunetuzumab is a promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B-cell lymphoma. Blood. 2020; 136(Suppl 1): 43–45.

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