Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy

Abstract

Over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (<2 months [1.9 months], 2-6 months [5.2 months], and >6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab-bendamustine-rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12-month progression-free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty-two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow-up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T-cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T-cell therapy failure.

Figure 1

Overall survival (OS) for patients who progressed after chimeric antigen receptor (CAR) T‐cell therapy. (A) Global OS for the full patient population (N = 387). (B) OS depending on the time from CAR T‐cell infusion to disease progression, including patients who progressed within 2 months (N = 175), between 2 and 6 months (N = 169), and beyond 6 months of infusion (N = 43). (C) OS curves for patients who received treatment (N = 237) and for patients who only received palliative treatment or best supportive care (N = 150). (D) OS curves according to CAR T‐cell construct, including axicabtagene ciloleucel (N = 127), tisagenlecleucel (N = 96), and lisocabtagene maraleucel (N = 13); this latter analysis was restricted to patients who received subsequent treatment after progression to CAR T‐cell therapy. CAR‐T‐PD, time interval between CAR T‐cell infusion and disease progression.

Figure 2

Response rate for the different regimens administered as a first‐line treatment after progression from CAR T‐cell therapy. BsAbs, bispecific antibodies; CR, complete response; CT, chemotherapy; ICI, immune checkpoint inhibitors; LENA, lenalidomide; PD, progressive disease; POLA, polatuzumab–bendamustine–rituximab; PR, partial response; RT, radiotherapy; SD, stable disease.

Figure 3

Survival outcomes for patients who received treatment after chimeric antigen receptor T‐cell therapy progression. (A) Progression‐free survival (PFS) for all patients who received treatment (N = 237). (B) PFS according to the type of first subsequent therapy. (C) Overall survival according to the type of first subsequent therapy. BsAbs, bispecific antibodies; CI, confidence interval; CT, chemotherapy; HR, hazard ratio; ICI, immune checkpoint inhibitors; LENA, lenalidomide; POLA, polatuzumab–bendamustine–rituximab; RT, radiotherapy.

Figure 4

Multivariate analysis (MVA) for patients receiving treatment after CAR T‐cell therapy progression. (A) MVA for progression‐free survival. (B) MVA for overall survival. Footnote shows values of ECOG, LDH, and IPI at the time of CAR T‐cell therapy. BsAbs, bispecific antibodies; CI, confidence interval; CR, complete response; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitors; IPI, International Prognostic Index; LDH, lactate dehydrogenase; LENA, lenalidomide; PD, progressive disease; POLA, polatuzumab–bendamustine–rituximab; PR, partial response; RT, radiotherapy; SD, stable disease; ULN, upper limit of normal.