Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma

Abstract

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Figure 1.. Outcomes following CD19-CAR-T in LBCL.

(A) A study flow diagram describing the population. Three hundred five patients were included; 165 patients were treated at MSKCC and 140 at Sheba Medical Center. One hundred thirty-five patients received subsequent anti-cancer treatment for relapsed or progressive or stable disease post-CAR-T therapy. (B) Post-CAR-overall survival (OS) and post-CAR-event-free survival (EFS) from the day of CAR-T infusion across the entire cohort. (C) Cumulative incidence of relapse or progression after CD19-CAR-T therapy. MSKCC – Memorial Sloan Kettering Cancer Center; r/r – relapsed/refractory; LBCL – large B-cell lymphoma; PR – partial response; CR – complete response.

Figure 2.. Characteristics at time of CAR-T treatment failure

(A) CD19 expression was assessed by flow cytometry in 52 tumor biopsies that were performed after CD19-CAR-T therapy. The color intensity represent CD19 expression intensity as measured by the MFI ratio (see methods). Expression was categorized into dim and normal based on the MFI ratio level. Absent (B) A divergent bar plot representing differences between pre- and post-CAR-T features of LBCL refractory to CAR-T vs. LBCL that initially responded to CAR-T and then relapsed (Table S2). P-values represent Pearson’s Chi-squared test or Fisher’s exact test. COO– Cell of origin; LDH – lactate dehydrogenase; LBCL – large B-cell lymphoma; auto-HCT – autologous hematopoietic stem cell transplantation; PR – partial response; CR – complete response; CRS–Cytokine release syndrome (CRS); ICANS– Central Nervous System (CNS); GCB– Germinal center B cells; ULN–Upper Limit of Normal; PR– Partial response; CR– Complete response; PD– Progressive disease; SD– Stable disease.

Figure 3.. Outcomes among patients receiving first treatment after CD19-CAR-T.

(A) Post-treatment-overall survival (OS) and post-treatment-event-free survival (EFS) from initiation of first-line treatment post-CD19-CAR-T. (B) Treatment components among the most common treatments groups. Treatment strategies of the remaining treatment groups are listed in Table S3. (C) First-line treatment strategies, by disease stage at time of relapse or progression, after CD19-CAR-T treatment failure. (D) Response rates by treatment group. (E) Post-treatment-OS by leading treatment strategies. (F) Overall survival by prognostic strata. AutoSCT – autologous stem cell transplantation; GCB – germinal center B-cell; CRS – cytokine release storm; ICANS – immune effector cell-associated neurotoxicity syndrome; LDH – lactate dehydrogenase; ICI – immune checkpoint inhibitor; BTKi – Bruton’s tyrosine kinase inhibitor; ISRT – involved site radiation therapy; alloHCT – allogeneic hematopoietic stem cell transplantation; Ibr - Ibrutinib; Tafa – tafasitimab; Benda - bendamustine; CR – complete response; PR – partial response; SD/PD – stable disease/progressive disease