CAR T-cell therapy in large B cell lymphoma

Abstract

CD19-targeted chimeric antigen receptor (CAR) T-cells have revolutionized the treatment of lymphoid malignancies, including large B cell lymphoma (LBCL). Following seminal early phase multicenter clinical trials published between 2017 and 2020, three CD19-CAR T-cell products received FDA and EMA approval designations in lymphoma in the third-line setting, paving the way for follow-up studies in the second-line. Meanwhile, investigations into the applications of CAR T-cell therapy have further broadened to treating high-risk patients even prior to completion of first-line conventional chemo-immunotherapy. Furthermore, as early trials excluded patients with central nervous system involvement with lymphoma, several studies have recently shown promising efficacy of CD19-CAR T-cells in primary and secondary CNS lymphoma. Here we provide a detailed overview on clinical data supporting the use of CAR T-cells in patients with LBCL.

Keywords: B-cell lymphoma; CD19; autologous stem cell transplantation (ASCT); chimeric antigen receptor (CAR) T cell; diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL); primary CNS lymphoma (PCNSL); secondary CNS lymphoma (SCNSL).

Figure 1.. Diagnostic and therapeutic algorithm for large B cell lymphoma (LBCL) in first and second or later relapse.

When relapse is suspected clinically, routine laboratory evaluation should include at minimum an assessment of creatinine clearance (CrCl), liver function (LFT’s), blood counts (CBC), and lactate dehydrogenase (LDH) levels. Bone marrow evaluation is typically reserved for patients with cytopenia not explained by other clinical factors. Peripheral blood flow cytometry should be performed if circulating lymphoma cells are suspected. Staging evaluation should be performed with 18F-fluorodeoxyglucose positron-emission tomography and computed tomography (18F-FDG PET-CT). Diagnostic confirmation is based on careful pathological review of biopsy material, preferably from an excisional biopsy. Patients with confirmed first relapse of LBCL at 12 months or less from the time of completion of first-line chemoimmunotherapy should be considered for second-line CAR T-cell therapy. Candidacy is based on Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2, CrCl greater than or equal to 30 mL/min, adequate left ventricular function with ejection fraction (EF) greater than or equal to 40%, and adequate liver function with alanine transaminase (ALT) levels less than or equal to 5 times the upper limit of normal (ULN) and total bilirubin (T_bili) less than 2–3 mg/dL. Age might not be a limitation by itself. In the second-line setting, we suggest favoring liso-cel in patients 70 years and older, those with ECOG 2, and those with baseline renal (CrCl 30–60) and/or cardiac (EF 40–50%) dysfunction. Both axi-cel and liso-cel are appropriate for younger and fitter CAR T-cell candidates without organ dysfunction. Transplant-eligible patients with confirmed first relapse greater than 12 months from first-line therapy should undergo platinum-based salvage chemotherapy. Those who respond should proceed to consolidation with high dose chemotherapy and autologous stem cell transplant (auto-HCT). If disease does not respond to salvage therapy, CAR T should be considered. Transplant-ineligible patients should be considered for liso-cel if CAR T-eligible. Patients with suspected second or later relapse of LBCL should undergo similar diagnostic evaluation as above with an additional focus on CD19 immunohistochemistry (IHC) or flow cytometry in those who received CD19-targeted agents. CAR T-cell-naïve patients with CD19⁺ disease should be considered for axi-cel or liso-cel. We suggest considering liso-cel, or eventually tisa-cel, in patients based on the above criteria regarding age and organ function. Clinical trials incorporating investigational agents should be strongly considered at all phases of therapy, including those evaluating new immune effector cells (IEC).