Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).

Summary: CD4⁺ and CD8⁺ chimeric antigen receptor T cells (CAR‐T) play different roles in the in vivo anti‐tumour response, but the role of the CD4⁺/CD8⁺ ratio among infused CAR‐T has not been clearly defined yet. We analysed leftovers from infused anti‐CD19 CAR‐T bags of 31 patients with aggressive B‐cell lymphomas. The median ratio was 1.44, lower for brexu‐cel compared to tisa‐cel and axi‐cel. The CAR+CD4⁺/CD8⁺ ratio was influenced by lactate dehydrogenase levels at apheresis, not by age, previous treatments or the CD4⁺/CD8⁺ ratio in peripheral blood. Patients with a response at 3 months after CAR‐T (M3) had a lower CAR+CD4⁺/CD8⁺ ratio in the infused products compared to non‐responders (ratio 0.74 vs. 2.47, p = 0.011). A CAR+CD4⁺/CD8⁺ ratio higher than the cut point of 1.12 was associated with an increased risk of treatment failure at M3 (OR 23.3, p = 0.012) and M6 (OR 10, p = 0.028). The median 6‐month PFS was 76% for patients with a ratio lower than 1.12% vs. 31% for the others. The prognostic role of the CAR+CD4⁺/CD8⁺ ratio was independent of the costimulatory domain (CD28 vs. 4‐1BB) of the product (OR 16.41, p = 0.041). Our data indicate a crucial role for CD8⁺ CAR‐T and the CAR+CD4⁺/CD8⁺ ratio in predicting CAR‐T efficacy.

Summary: Cytokine release syndrome (CRS) and consumptive coagulopathy can complicate the treatment with chimeric antigen receptor T (CAR‐T) cells. The modified version of the Endothelial Activation and Stress Index (mEASIX), a score derived from haematopoietic stem cell transplantation, combines platelets, C‐reactive protein (CRP), and lactate dehydrogenase (LDH) and has been correlated with CRS and endothelial biomarkers. In 38 consecutive patients with aggressive lymphoproliferative disease we measured a coagulative laboratory panel at baseline and early after infusion of anti‐CD19 CAR‐T. The panel was investigated also in the presence of CRS graded 2 or higher, or immune effector cell‐associated neurotoxicity syndrome (ICANS). Moreover, we examined the relationship between mEASIX, coagulation biomarkers, and toxicities of CAR‐T cells. During CRS grade 2 or higher, we found increased prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen, D‐dimer, factor VIII (FVIII), and von Willebrand factor (vWF) antigen levels, and decreased platelet count and antithrombin levels. The occurrence of immune effector cell‐associated neurotoxicity syndrome was associated with higher PT values, D‐dimer, FVIII, and vWF levels, and decreased fibrinogen levels and platelet count. A higher mEASIX score correlated with increased aPTT values, fibrinogen, D‐dimer, FVIII and vWF levels, and decreased antithrombin levels. Baseline mEASIX was predictive for consumptive coagulopathy and CRS graded 2 or higher, and for progression‐free survival and overall survival.

Early response evaluation with [¹⁸F]fluordeoxyglucose (FDG) positron emission tomography after 2 cycles of chemotherapy (interim PET) has been indicated as the strongest predictor for outcome in classical Hodgkin lymphoma (HL). We studied the prognostic role of the number of tumor‐infiltrating CD68+ cells and of the plasma levels of TARC (thymus and activation‐regulated chemokine) in the context of interim PET in 102 patients with classical HL treated with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD). After 2 ABVD cycles, interim PET according to Deauville criteria was negative (score 0–3) in 85 patients and positive (score 4–5) in 15 patients (2 patients technically not evaluable). TARC levels were elevated in 89% of patients at diagnosis, and decreased after 2 cycles in 82% of patients. Persistently elevated TARC levels in 18% of patients were significantly associated with a positive PET result (P = 0.007). Strong predictors for progression‐free survival (PFS) were a negative interim PET (85% vs. 28%, P < 0.0001) and CD68+ cell counts <5% (89% vs. 67%, P = 0.006), while TARC levels at diagnosis and at interim evaluation had no prognostic role. In multivariate analysis, interim PET, CD68+ cell counts and presence of B‐symptoms were independently associated with PFS. We conclude that although TARC levels are a biomarker for early response evaluation, they cannot substitute for interim PET as outcome predictor in HL. The evaluation of CD68 counts and B‐symptoms at diagnosis may help to identify low‐risk patients regardless positive interim PET.

Interleukin-31 and thymic stromal lymphopoietin expression in plasma and lymph node from Hodgkin lymphoma patients Interleukin-31 and thymic stromal lymphopoietin expression in plasma and lymph node from Hodgkin lymphoma patients