Response rates of extra-nodal diffuse large B cell lymphoma to anti-CD19-CAR T cells: A real word retrospective multicenter study.

Chimeric antigen receptor T-cells (CAR-T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR-T cell therapy in patients with extra-nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR-T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)-only and 12 of 126 (10%) showed no disease assessed by PET-CT. There were no significant differences in CAR-T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8-13.6] vs. 14.1 [95% CI: 10-18.1] months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5-18.2] vs. 18.4 [95% CI 14.8-22.1] months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9-15.5] vs. 4.28 months [95% CI 0.6-7.9], p = .010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4-19.6] vs. 8.7 months [95% CI 4.6-12.8], p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.

Toxicity and efficacy of chimeric antigen receptor T-cell therapy in patients with diffuse large B-cell lymphoma above the age of 70 years compared to younger patients - a matched control multicenter cohort study.

Data regarding efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in the elderly, geriatric population are insufficient. In 2019, tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory diffuse large B-cell lymphoma. From May 2019 onwards, 47 relapsed/refractory diffuse large Bcell lymphoma patients, ≥70 years underwent lymphopharesis in three Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG performance status and lactose dehydrogenase levels. There were no differences in CD4/CD8 ratio (P=0.94), %CD4 naive (P=0.92), %CD8 naive (P=0.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T cell products in both cohorts. Forty-one elderly patients (87%) received CAR-T cell infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (P=0.29), grade≥3 neurotoxicity (P=0.54), and duration of hospitalization (P=0.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (P=0.145). Response rates were similar between the two groups (complete response 46% and partial response 17% in the elderly group, P=0.337). Non-relapse mortality at 1 and 3 months was 0 in both groups. With a median follow-up of 7 months (range, 1.3-17.2 months), 6- and 12-months progression-free and overall survival in elderly patients were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly versus younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between elderly, geriatric and younger patients, indicating that age as per se should not preclude CAR-T cell administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.

[18F]FDG PET-CT in patients with DLBCL treated with CAR-T cell therapy: a practical approach of reporting pre- and post-treatment studies.

PURPOSE: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy. METHODS: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4-16.0) months from CAR-T infusion. RESULTS: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv < 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv < 0.01), LDH > 450 U/l (HR 7.7; Pv < 0.01), and ECOG score > 1 (HR 5.5; Pv = 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv < 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (Pv = 0.02) but not to TT-SUVmax (Pv = 0.38). CONCLUSION: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.

Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience.

Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.

Polatuzumab-based regimen or CAR T cell for patients with refractory/relapsed DLBCL-a matched cohort analysis.

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL.

Characteristics and recognition of early infections in patients treated with commercial anti-CD19 CAR-T cells.

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion-A Phase 2, Prospective Interventional Study.

Patients with large B-cell lymphoma (LBCL) in stable or progressive disease (SD/PD) at lymphodepletion prior to chimeric antigen receptor T cell (CAR-T) therapy have an inferior outcome. we hypothesized that enhancing in-vivo expansion of CAR-T cells could overcome this grim prognosis leading to improved outcomes. We conducted a phase 2 prospective trial (NCT05385263) investigating the addition of nivolumab to enhance CAR-T cell expansion and response in patients with SD/PD-LBCL. Eligible patients received 1 dose of nivolumab between day +5 and +9 post CAR-T infusion. An additional dose of nivolumab was administered on day +19 only to patients whose CAR-T cell levels in peripheral blood were below 100 cells/µL at day +7. Twenty patients were enrolled and received anti-CD19 CAR-T (Axicabtagene ciloleucel, n = 12; tisagenlecleucel, n = 8). Eight were ineligible to receive nivolumab due to active CAR-T-associated toxicities. Overall, the protocol was safe. One-month PET-CT showed an 84% overall response rate (complete response, 53%). The cumulative incidence of progression-free survival at 6 and 12 months were 50% (95% CI 36%-64%) and 42% (95% CI 26%-58%), respectively. The cumulative incidence of overall survival at 6 and 12 months were 85% (95% CI 72%-98%) and 51% (95% CI 31%-71%), respectively. Nivolumab administration significantly reduced PD-1 expression on all immune cells. CAR-T cell expansion was similar between nivolumab-eligible and noneligible patients. Notably, there was a significant enrichment of CD45RO-CD27+ CD8+ cells and CD45RO-CD27+ CD8+ CAR-T cells in the nivolumab-eligible group compared to those ineligible, suggesting that specific cell enrichment could potentially contribute to an enhanced response rate. We conclude that the addition of nivolumab based on CAR-T cell expansion in patients with SD/PD-LBCL is safe and yields promising early response rates.

Immunogenicity of a Third Dose of the BNT162b2 mRNA Covid-19 Vaccine in Patients with Impaired B Cell Reconstitution After Cellular Therapy-A Single Center Prospective Cohort Study.

Patients with delayed B-cell reconstitution/B-cell aplasia after cellular therapy show decreased immunogenicity to the BNT162b2 mRNA COVID-19 vaccine. We prospectively evaluated both humoral and cellular immune response to a third vaccine dose in patients after allogeneic HCT (n = 10) or CD19-based chimeric antigen receptor T cells (CAR-T) therapy (n = 6) with low absolute B cell numbers and who failed to mount a humeral response after 2 vaccine doses. Humoral response was documented in 40% and 17% after allogeneic HCT and CAR-T therapy, respectively. None of the patients with complete B-cell aplasia developed anti-vaccine antibodies. Cellular response was documented in all patients after allogeneic HCT and in 83% of the patients after CAR-T. T-cell subclasses levels were not predictive for response, while a longer duration from infusion of cells was associated with a better cellular response. We conclude that cellular response develops with repeated vaccine doses even in patients with B-cell aplasia or delayed B-cell reconstitution, and these patients should therefore be vaccinated. These results should be considered in future studies analyzing immunogenicity in this population. Larger and longer follow-up studies are required to confirm whether cellular immunogenicity translates into vaccine efficacy.

Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.