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 characterised. Current practice is guided by physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult LBCL patients in relation to outcomes following axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel). The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity/mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death following 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/partial response to BT may be more important for Tisa-cel than Axi-cel, as all Tisa-cel patients 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 towards optimal response and disease debulking, to improve CD19CAR-T patient outcomes. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete/partial response to BT pre-Tisa-cel may prompt consideration of further lines of BT where possible.

Diagnosis and management of mantle cell lymphoma: A British Society for Haematology Guideline

“…118,119 With the goal of achieving disease control and maintaining ECOG PS prior to cell infusion, UK practice favours BT, administered to 87% of patients with high-grade B-NHL after T-cell harvest, where a CR/PR to BT conferred a 42% reduction in PD and death following infusion. 120 Likewise, markers of high-grade B-NHL activity, 3+ extra-nodal sites and inferior ECOG PS correlate with inferior survival and immediate CAR T-related toxicity post-infusion. [120][121][122][123][124] Extrapolating this experience to MCL, adequate disease control may be critical to improve the drop-out rate but also to optimise the chances of durable remission and improve tolerability of brexu-cel.…”

“…120 Likewise, markers of high-grade B-NHL activity, 3+ extra-nodal sites and inferior ECOG PS correlate with inferior survival and immediate CAR T-related toxicity post-infusion. [120][121][122][123][124] Extrapolating this experience to MCL, adequate disease control may be critical to improve the drop-out rate but also to optimise the chances of durable remission and improve tolerability of brexu-cel. In real-world practice, the vast majority of MCL patients are receiving BT with poor ORRs of 22%-33%, 113,125,126 highlighting the need for more effective bridging strategies.…”

“…Some retrospective analyses suggest inferior CAR‐T outcomes in high‐grade B‐NHL patients receiving BT but also demonstrate an association between the use of BT and high‐risk disease features 118,119 . With the goal of achieving disease control and maintaining ECOG PS prior to cell infusion, UK practice favours BT, administered to 87% of patients with high‐grade B‐NHL after T‐cell harvest, where a CR/PR to BT conferred a 42% reduction in PD and death following infusion 120 . Likewise, markers of high‐grade B‐NHL activity, 3+ extra‐nodal sites and inferior ECOG PS correlate with inferior survival and immediate CAR T‐related toxicity post‐infusion 120–124 …”

Supportive care for chimeric antigen receptor T-cell patients

“…Bridging therapy (BT) should be actively considered for all patients to prevent uncontrolled disease progression in the interval between leukapheresis and CAR-T administration, as disease progression can negatively impact intention-to-treat (ITT) and confer a higher risk of CAR-T toxicity [19]. Individualised decisions on BT modality should be made in the context of an MDT review and popular choices include rituximab-bendamustine-polatuzumab (RBP) for widespread disease, and radiotherapy for localised disease, albeit practice varies widely [20,21]. Novel approaches to BT are required.…”

Pixantrone as bridging therapy to allogeneic transplantation or in chimeric antigen receptor T‐cell pathway in patients with diffuse large B‐cell lymphoma

“…There is also the chemotherapy (CHT) option, and particularly low dose CHT, with an ORR of 18%, which is comparable to our data regarding pixantrone. 9 The choice is tailored to each patient and based on Center drug availability.…”