For DLBCL patients awaiting CAR-T cell therapy, particularly those with aggressive disease, bispecific antibodies are the preferred bridging strategy. This approach effectively controls disease and reduces tumor burden for better CAR-T outcomes, while avoiding the T-cell depleting effects of traditional chemotherapy.
Recent data indicates high-dose methotrexate is ineffective for preventing CNS relapse in ultra-high-risk DLBCL patients. The focus is shifting to better upfront identification of occult CNS disease with MRI, lumbar puncture, and potentially CSF ctDNA, rather than relying on an inadequate prophylactic strategy.
A key hesitation in adopting the tafasitamab-lenalidomide-R-CHOP regimen is the theoretical risk of CD19 antigen loss. If a patient becomes refractory, their eligibility and the efficacy of subsequent CD19-targeted CAR T-cell therapy could be compromised, influencing upfront treatment decisions.
To mitigate the risk of severe Cytokine Release Syndrome (CRS) from bispecific antibodies in patients with high tumor burden, a debulking strategy is effective. Administering two initial cycles of chemotherapy dramatically reduces disease volume, leading to almost zero CRS when the bispecific is introduced, making the treatment much safer.
For older or frail DLBCL patients who are not candidates for CAR-T cell therapy, the combination of mosunetuzumab and polatuzumab offers a potent and significantly more tolerable alternative to other bispecifics. This regimen is logistically simpler for community practice and can be used successfully even in very elderly patients.
Despite the Polarix trial showing no benefit for Pola-R-CHP in the germinal center (GCB) subtype, many centers use it for all patients with an IPI score ≥2. This is because current IHC-based subtyping may miss aggressive GCB subtypes that could benefit. Practice follows the study's primary inclusion criteria over retrospective subgroup analysis.
Administering IT chemotherapy during a lumbar puncture is an outdated practice for CNS prophylaxis in DLBCL. Its penetration into the brain parenchyma is minimal (~3mm), rendering it useless against parenchymal recurrences, the most common type of CNS relapse. The focus should be on systemic agents with better CNS penetration.
Indefinite treatment with bispecific antibodies is likely unnecessary and exposes DLBCL patients to risks like hypogammaglobulinemia and recurrent infections. A fixed duration of no more than one year is a reasonable approach, with a readiness to stop earlier for patients in a deep, sustained complete response, potentially guided by ctDNA.