Effective bridging therapy can improve CD19 CAR-T outcomes while maintaining safety in patients with large B-cell lymphoma

Abstract

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterized. Current practice is guided through physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve both CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult patients with LBCL in relation to outcomes after axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel) administration. The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity or mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death after CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of polatuzumab-containing chemotherapy regimens. Our data suggested that complete or partial response to BT may be more important for Tisa-cel than for Axi-cel, because all patients receiving Tisa-cel with less than partial response to BT experienced frank relapse within 12 months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned toward optimal response and disease debulking, to improve patient outcomes associated with CD19CAR-T. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete or partial response to BT before Tisa-cel administration may prompt consideration of further lines of BT where possible.

Summary of BT modality, BT response and PFS post-CAR-T in all apheresed LBCL patients.

Figure 1.

Consort diagram of all approved patients.

Figure 2.

PFS and OS post-CAR-T according to BT modality and response. (A) PFS: comparing BT groups 1-year rates; no BT 46.0% (29.7-60.9), steroids 23.7% (10.2-40.2), RT 59.1% (44.8-70.9), CT 31.3% (23.9-38.9), CMT 45.5% (16.7-70.7). (B) OS: comparing BT groups 1-year rates; no BT 69.7% (51.4-82.2), steroids 37.4% (20.2-54.5), RT 70.3% (55.4-81.0), CT 46.9% (38.1-55.2), CMT 62.3% (27.8-84.0). (C) PFS: comparing BT responder vs nonresponder: HR 0.55 (0.39-0.79), P = .001. 1-year rates: Responder: 50.1% (39.6-59.7); Nonresponder: 29.7% (21.3-38.6). (D) OS: comparing BT responder vs nonresponder: HR 0.51 (0.33-0.77), P = .001. 1-year rates: Responder: 63.2% (51.5-72.8); Nonresponder: 45.9% (35.9-55.3).

Figure 3.

PFS following Axi-cel and Tisa-cel according to BT response. (A) PFS after Axi-Cel administration: comparing BT responders vs nonresponders: HR (response vs no response): 0.68 (0.45-1.03), P = .071. (B) PFS after Tisa-Cel administration: comparing BT responders vs nonresponders: HR (response vs no response): 0.22 (0.11-0.44), P = <.001.