Novel monoclonal antibodies for diffuse large B-cell lymphoma
Abstract
Novel immunotherapeutic approaches to the treatment of diffuse large B-cell lymphoma (DLBCL), including recent approvals of chimeric antigen receptor T-cell therapy, the antibody-drug conjugates polatuzumab vedotin (PV) and loncastuximab tesirine-lpyl, and the anti-CD19 antibody tafasitamab, provide efficacious new treatment options for patients with relapsed and refractory disease.
PV was the first novel therapy approved in combination with bendamustine/rituximab (BR) for relapsed/refractory (r/r) DLBCL patients after two or more lines of treatment who are ineligible for high-dose chemotherapy and autologous hematopoietic cell transplantation. This approval was based on a randomized phase II study comparing PV-BR versus BR arms, resulting in significantly improved rates of complete metabolic response, progression-free survival, and overall response (OS). Remarkably, this was the first randomized study in DLBCL demonstrating OS benefit to an experimental arm to have been conducted in several years. The promising activity of PV-BR in rrDLBCL may be a result of the use of innovative target CD79b that enables the bypassing of resistance mechanisms related to the CD20 molecule.
Two other recently approved antibodies are directed to CD19 antigen, the other attractive alternative target in lymphoma. Although these agents are generally approved for use as third- or second-line therapy, studies are in progress exploring their value in earlier treatment lines including induction treatment.
While we still await the successful incorporation of other targeted agents into the treatment of DLBCL, R-CHOP prevails as the standard of care for DLBCL, regardless of immunohistochemical or molecular subtype at diagnosis.
Keywords: diffuse large B-cell lymphomamonoclonal antibodiesclinical trials
References
- Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021; 384(9): 842–858.
- Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014; 123(6): 837–842.
- 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.
- van Imhoff GW, McMillan A, Matasar MJ, et al. Ofatumumab versus rtuximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017; 35(5): 544–551.
- 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.
- Nowakowski GS, Chiappella A, Gascoyne RD, et al. ROBUST: lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Future Oncol. 2016; 12(13): 1553–1563.
- Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019; 20(1): 31–42.
- Schuster SJ, Bishop MR, Tam CS, et al. JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019; 380(1): 45–56.
- Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020; 396(10254): 839–852.
- Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020; 38(27): 3119–3128.
- Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017; 130(16): 1800–1808.
- Jurczak W, Zinzani PL, Gaidano G, et al. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Ann Oncol. 2018; 29(5): 1266–1272.
- Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020; 21(7): 978–988.
- lles G, Duell J, Gonzalez Barca E et al.: Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. 25th EHA Congress 2020: abstract EP1201.
- NCT02763319. https://clinicaltrials.gov/ct2/show/NCT02763319 (July 26, 2021).
- NCT04134936. https://clinicaltrials.gov/ct2/show/NCT04134936 (July 26, 2021).
- Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021; 137(19): 2634–2645.
- NCT03589469. https://clinicaltrials.gov/ct2/show/NCT03589469 (July 26, 2021).
- 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.
- Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory diffuse large B-cell lymphoma: updated results of a phase Ib/II randomized study and preliminary results of a single-arm extension. Blood. 2020; 136(Suppl 1): 17–19.
- Advani R, Flinn I, Popplewell L, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin's lymphoma. N Engl J Med. 2018; 379(18): 1711–1721.
- Viardot A, Goebeler ME, Hess G, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016; 127(11): 1410–1416.
- Schuster SJ, Bartlett NL, 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): 6–6.
- Shah H, Stephens D, Seymour J, et al. Incorporating novel targeted and immunotherapeutic agents in treatment of B-cell lymphomas. Am Soc Clin Oncol Educ Book. 2021; 41: 1–18.