Cancer Res Treat.  2023 Jan;55(1):325-333. 10.4143/crt.2022.008.

Outcomes in Refractory Diffuse Large B-Cell Lymphoma: Results from Two Prospective Korean Cohorts

• Yi JH
• Jeong SH
• Kim SJ
• Yoon DH
• Kang HJ
• Koh Y
• Kim JS
• Lee WS
• Yang DH
• Do YR
• Kim MK
• Yoo KH
• Choi YS
• Yun WJ
• Park Y
• Jo JC
• Eom HS
• Kwak JY
• Shin HJ
• Park BB
• Yi SY
• Kwon JH
• Oh SY
• Kim HJ
• Sohn BS
• Won JH
• Hong DS
• Lee HS
• Lee GW
• Suh C
• Kim WS

• KMID: 2538015
• DOI: http://doi.org/10.4143/crt.2022.008

Abstract

Purpose
Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%-50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal.
Materials and Methods
We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation.
Results
Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529).
Conclusion
In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.

Keyword

Diffuse large B-cell lymphoma; Refractory; Clinical outcomes

Figure

• 

  Fig. 1 Patient inclusion and flow diagram. ASCT, autologous stem cell transplantation; CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

• 

  Fig. 2 Overall survival from commencement of salvage therapy: overall population (A); by refractory category (B); by tumor response (C); by cell-of-origin subtype (D). ASCT, autologous stem cell transplantation; CR, complete response; GCB, germinal center B-cell; PD, progressive disease; PR, partial response; SD, stable disease.

Reference

References

1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002; 346:235–42.

2. Vitolo U, Trneny M, Belada D, Burke JM, Carella AM, Chua N, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017; 35:3529–37.

3. Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, 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; 37:1790–9.

4. Nowakowski GS, Chiappella A, Gascoyne RD, Scott DW, Zhang Q, Jurczak W, et al. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021; 39:1317–28.

5. International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993; 329:987–94.

6. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018; 378:1396–407.

7. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010; 28:4184–90.

8. Hamadani M, Hari PN, Zhang Y, Carreras J, Akpek G, Aljurf MD, et al. Early failure of frontline rituximab-containing chemo-immunotherapy in diffuse large B cell lymphoma does not predict futility of autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014; 20:1729–36.

9. Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017; 130:1800–8.

10. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017; 377:2531–44.

11. Salles G, Duell J, Gonzalez Barca E, Tournilhac O, Jurczak W, Liberati AM, 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; 21:978–88.

12. Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020; 38:155–65.

13. Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner FC, Sureda A, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J Clin Oncol. 2021; 39:1959–70.

14. Kim SJ, Hong JS, Chang MH, Kim JA, Kwak JY, Kim JS, et al. Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: results of a multicenter prospective cohort study. Oncotarget. 2016; 7:72033–43.

15. Hyun JS, Kim SJ, Hong JY, Koh Y, Kang HJ, Park Y, et al. A prospective registry study of Peg-G-CSF prophylaxis for pati-ents with diffuse large B-cell lymphoma (CISL 1403). Blood. 2017; 130(Suppl 1):2840.

16. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H. WHO classification of tumours of the haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press;2008.

17. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004; 103:275–82.

18. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 32:3059–68.

19. Vannata B, Conconi A, Winkler J, Cascione L, Margiotta Casaluci G, Nassi L, et al. Late relapse in patients with diffuse large B-cell lymphoma: impact of rituximab on their incidence and outcome. Br J Haematol. 2019; 187:478–87.

20. Epperla N, Badar T, Szabo A, Vaughn J, Borson S, Saini NY, et al. Postrelapse survival in diffuse large B-cell lymphoma after therapy failure following autologous transplantation. Blood Adv. 2019; 3:1661–9.

21. Wang S, Wang L, Hu J, Qian W, Zhang X, Hu Y, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from a multicenter real-world study in China. Cancer Commun (Lond). 2021; 41:229–39.